On the Formation and Transformation of α

On the Formation and Transformation of α-Iminonitriles, the Desymmetrization of Bicyclic Bislactones and Total Synthesis of (-)-Leucomidine B and (-)-Rhazinilam. Presented on the 12th of November 2014 at the Laboratory of Synthesis and Natural Products ÉCOLE POLYTECHNIQUE FÉDÉRALE DE LAUSANNE

By Jean-Baptiste Gualtierotti

Jury members Prof. Cramer Nicolai, jury president Prof. Zhu Jieping, thesis advisor Prof. Rueping Magnus, external expert Prof. Lacour Jérôme, external expert Prof. Waser Jérôme, internal expert

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“Victory is but a prelude to the next battle” Space Marine Mantra, Warhammer 40 000

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Table of Contents Table of Contents ..................................................................................................5 i.

Résumé, Mots Clés ..........................................................................................8

ii. Abstract, Key words ........................................................................................9 iii. Acknowledgements ........................................................................................ 11 iv. List of Abbreviations ..................................................................................... 15 General Introduction .......................................................................................... 19 Chapter 1: The Synthesis of α-Iminonitriles and their Subsequent Transformations ............................................................................ 21 1.1. α-Iminonitriles, A Brief Background .............................................................. 22 1.1.1.

Known Methods for the Synthesis of α-Iminonitriles............................. 22

1.1.2.

Known Functionalizations of α-Iminonitriles ........................................ 32

1.1.3. Synthesis of α-Iminonitriles through the IBX Mediated Three Component Oxidative Strecker Reaction. ............................................................................. 38 1.2. Amidation of Aldehydes Through Hydrolysis of α-Iminonitriles .................. 41 1.2.1.

Project Overview .................................................................................. 41

1.2.2.

Optimization......................................................................................... 42

1.1.1.

Scope ................................................................................................... 43

1.3. Thio-Michael Reaction of α-Iminonitriles ...................................................... 45 1.3.1.

Project Overview .................................................................................. 45

1.3.2.

Optimization......................................................................................... 46

1.4. One pot Thio-Michael-Hydrolysis of α-Iminonitriles. .................................... 49 1.4.1.

Project Overview .................................................................................. 49

1.4.2.

Optimisation ......................................................................................... 49

1.4.3.

Scope ................................................................................................... 52

1.4.4.

One Pot oxidative Strecker Thio-Michael Amidation MCR. .................. 55

1.5. Synthesis of α-Iminonitriles through Oxone Mediated Three Component Oxidative Strecker Reaction ........................................................................... 57 1.5.1.

Project Overview .................................................................................. 57

1.5.2.

Optimization......................................................................................... 58

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1.5.3.

Scope ................................................................................................... 61

1.6. Studies Towards the Metal Catalyzed C-CN Insertion .................................. 65 1.6.1.

Background .......................................................................................... 65

1.6.2.

Results.................................................................................................. 71

1.7. Conclusion ....................................................................................................... 73

Chapter 2: Phosphoric Acid-catalyzed Desymmetrization of Bicyclic Bislactones Bearing an All Carbon Quaternary Stereogenic Center ............................................................................................. 75 2.1. Desymmetrization of Anhydrides ................................................................... 76 2.1.1.

Desymmetrization of anhydrides via Organocatalysis............................ 76

2.1.2.

Desymmetrization of anhydrides via Enzymes ...................................... 81

2.1.3.

Results.................................................................................................. 83

2.2. Desymmetrization of Bislactones .................................................................... 88 2.2.1.

Project Origin and Rational ................................................................... 88

2.2.2.

Optimization......................................................................................... 94

2.2.3.

Scope ................................................................................................... 97

2.2.4.

Catalyst synthesis ............................................................................... 105

2.3. Conclusion ..................................................................................................... 110

Chapter 3: Catalytic Enantioselective Syntheses of (-)-Rhazinilam, (-)Leucomidine B and Rhazinicine.................................................. 111 3.1. (-)-Rhazinilam, (-)-Leucomidine B ................................................................ 111 3.1.1.

(-)-Leucomidine B: Isolation and Biosynthesis .................................... 111

3.1.2.

(-)-Rhazinilam: Isolation, Biosynthesis and Previous Syntheses .......... 113

3.1.3.

Retrosynthesis .................................................................................... 120

3.1.4.

Racemic Forward Pathway for Leucomidine B ................................... 121

3.1.5.

Enantioselective forward pathway for Leucomidine B......................... 129

3.1.6.

Enantioselective Forward Pathway for Rhazinilam.............................. 138

3.2. Rhazinicine .................................................................................................... 140 3.2.1.

Isolation and Retrosynthesis................................................................ 140

3.2.2.

Synthesis ............................................................................................ 142

3.3. Conclusion ..................................................................................................... 145

General Conclusion ........................................................................................... 147 6

Bibliography ...................................................................................................... 149 Experimental data ............................................................................................. 157 Curriculum Vitae .............................................................................................. 319

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i. Résumé, Mots Clés Deux sujets principaux sont traités dans cette thèse. Le premier concerne le développement de nouvelles réactions multi-composantes. Trois réactions principales sont explorées. La première concerne la synthèse d’amide à partir d’amines et d’aldéhydes par l’intermédiaire d’α-iminonitriles en conditions douces. La deuxième décrit la formation d’amides β-fonctionnalisé via l’intermédiaire d’α-iminonitriles en partant d’amines, d’aldéhydes et de thiols. La troisième décrit la synthèse d’α-iminonitriles en conditions douces à partir d’amines, d’aldéhydes et de TMSCN en utilisant de l’Oxone comme oxydant en présence d’un agent der de transfert de phase. Le deuxième sujet traité concerne la desymmetrization de structure du type pimelate dimethyl-4,4-disubstitué par l’intermédiaire de bislactones bi-cyclique pour fixer la conformation absolue du centre quaternaire présent au sein de ces fragments. Ces fragments sont ensuit utilisé pour la synthèse de trois produits naturels qui sont la Leucomidine B, le Rhazinilam et le Rhazinicine. Mots Clés: α-Iminonitrile, rections multi-composantes, acide phosphorique chiraux, organo-catalyse, desymmetrisation, synthèse totale, Leucomidine B, Rhazinilam, Rhazinicine, alcaloïdes.

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ii. Abstract, Key words Two principle topics are covered in this thesis. The first section deals with the development of novel synthetically useful multicomponent reactions. The development of three multicomponent reactions, based on α-iminonitriles, is presented. The first describes a process for the easy and straightforward synthesis of amides from amines, aldehydes and TMSCN via α-iminonitriles intermediates. The second describes the formation of β-functionalized amides from aldehydes, amines and thiols with again α-iminonitriles as key intermediate structure. The third reaction described covers the formation of α-iminonitriles via a selective oxidative multicomponent process using Oxone and a phase transfer agent. The second section covers the desymmetrization of dimethyl 4,4-disubstituted pimelate fragments via the ring opening of bicyclic bislactones for the formation of optically active ten carbon synthons containing an all carbon quaternary center. These fragments are subsequently used in the total synthesis of three diverse indole alkaloid Leucomidine B. Rhazinilam, Rhazinicine. Key words: α-Iminonitrile, multicomponent reactions, chiral phosphoric acids, organocatalysis, desymmetrization, total synthesis, Leucomidine B, Rhazinilam, Rhazinicine, alkaloids.

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iii. Acknowledgements No research can be truly done in isolation, which is why when someone talks about science he or she will use the pronoun we instead of I. This thesis does not escape that rule; many people have contributed to its success knowingly or not. Here I would like to take the time and space to mention and thank all those people. There is no particular order in which I am going to do so. This is written more or less as names and faces come to my mind. I would, first of all, like to thank Professors Rueping, Lacour, Waser and Cramer, the members of my jury, for accepting to serve on my thesis committee, and for having taken the time to review the work I did during my PhD, via this manuscript, and for being present at my thesis defense. I would then like to thank Jieping for having welcomed me to his lab, and for the projects he had me work on. Through these, and his continued support, I have learned more about chemistry, and even science in general, than I had ever thought possible. I would also like to thank him for his patience with me, for his advice, for always being ready to discuss chemistry, and for having trusted me with many responsibilities in the organization and upkeep of his lab. Through that I gained experience, in both organizational and technical domains, which I, today, realize is essential to the pursuit of research in good conditions, a facet of which which so many people are blatantly unaware. I would like to thank Qian for all her help during those four years. Her advice on both theoretical and practical matters was invaluable, and nothing would have worked as well as it did without her input. I would also like to thank her for always being there to discuss many topics and for her rigor in the attention to detail which greatly helped in numerous occasions. I cannot write these lines without acknowledging Thomas who started his PhD work at the same time as I did. Over those four years we went through a lot together, sharing the ups and downs of day to day chemistry, be it laughing at our own mistakes, knocking our heads together to try and figure out the structure of an unexpected compound, or sharing emergency chocolate when things were crashing down around us. We also built this lab together, and spent so much time trying to keep it afloat despite The Horde actively trying to destroy everything they could get their hands on. We reach the end of our PhD’s with many shared memories and well-honed “ancestral techniques” which allow survival in a laboratory. Next up in the thank you list is Olivier. We first met when we sat side by side during our first class, during our first year of the bachelor program, listening with one ear to whichever professor taught us that day and now we finish our PhD’s in the same lab. It’s been a fun 10 years together, from farming the Scarlet Dungeon all the way to Davide’s wedding via all the four o’clock coffee breaks during which we bemoaned our lack of results for the next research update (no link at all between the two I am sure...), and wondering why we didn’t take the soft option to go into the humanities or art. I know the good times will go on even after we have both graduated and that your wordplays will keep everyone smiling.

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Then I have to mention Hugo, aka the crazy Dutch guy, who came to our lab for a master internship. It was really fun to have a guy in the lab with a shared appreciation of twisted humor. Finally someone who would answer my jokes with even darker ones instead of simply returning horrified looks... I will remember all the ski trips, especially the first one, where we (I) put him on skies, took him to the top of a mountain during a blizzard and pushed… He not only survived but kept coming back to Switzerland for more each year. I am sure that after all of that he will survive the trails of a PhD brilliantly. This section would not be complete without my citing a few persons who, each in its own way, taught me many things. Firstly, Ioulia, a PhD who had the courage to move over from France to the new laboratory (and lab-mates), she was always ready to laugh, and the first to be ready when it was time for lunch. It is also she who taught me maybe the most useful of those “ancestral techniques” I have already cited, aka the emergency chocolate in the top desk drawer. I will remember her lessons. Then Yann, a postdoc, for a year in our lab, who occupied the desk behind mine, he not only taught me many things about optimizing efficiency in the lab, but was also a great companion for coffee breaks and discussion of many things outside of chemistry. Finally, Zhengren, a postdoc for three years in our lab; his example on how to pursue the noble art of total synthesis, and how to remain calm and clear headed in the face of the setbacks of chemistry, will long remain with me. He also taught me that a good post-doc devours impressive quantities of IBX… A word of thanks also goes to those who were lost along the way, but are missed, as they were always fun to work alongside: Nick, who brought some British humor to the lab which was much appreciated; Giulia whose Italian mannerisms brought a lot of fun to our daily lives; Tiffany, whose strength of character will remain in many memories; Stephan, whose views on life were so different from what we had become accustomed to that it proved distracting, as well as Claire, whose eternal optimism and high spirits provided a welcome change to what is normally found in a laboratory; to the master students we coached, Samuel, Mathias, and Raphael who will surely succeed in their own PhD’s later on. I have also to thank the lab apprentices I had the occasion to work with: firstly, Xavier, who was my first brush with having to manage someone else than just myself. His boundless motivation and efficiency proved great in our common endeavours and provided many solutions to the problems we encountered. Then Delphine, I owe it to her that I learned patience, and how to think outside the box. The energy and motivation she constantly showed greatly helped my own efficiency during the year and a half we worked together. She also was a great cook, her mais j’ai pas fait exprès (“but I didn’t do it on purpose”) cakes greatly helped smooth over the days when she made me want to rip my hair out. I have to mention and thank the new guys in the group who provided a dose of fresh air to a laboratry who was becoming too mired in its habits. It is also now their job to take over the daily upkeep of the laboratory. To Dylan and Antonin, who have already taken over much of the work, I can only wish good luck, though I am not too worried, they will manage to keep the machines alive. To Cyril, who has taken over most of the remaining duties I will not wish good luck, but instead much patience, as the chores you have inherited require much calm and self-control to prevent bloodshed. To Nicholas, the latest among the newcomers, I also wish the best of luck. 12

I would also like to mention a few more fellow PhD’s. Ala, who‘s fumehood was next to mine for two years: her singular opinions and methods, which sparked so many discussions, have left a lasting mark in all our memories. And Tu, who was always smiling and ready to help whenever help was needed. I also have to mention Victoria, who helped me keep things in perspective, and realize we tend to quickly blow things out of proportion when we feel pressured. No matter how stressed one feels there always will be someone far more stressed than you. I also have to thank the remaining members of our post-doc team whoes dedication to their research proved inspirational: Weiwu and Yang, our lab’s cute couple; Shuo, quiet and efficient; Bo, who, through example, also taught me many things, though he may never have realized it; as also the three new additions to the team, Xu, Wangqing and Guanyinsheng We have also had a few visiting professors who proved most memorable. Firstly, Jian, who had a very unique and original take on many standard lab techniques, then Yoshiyuki, who stayed on only a week with us, but may have discovered more of this country than many others. I have to thank Sandrine for many things. For having accepted me as part of her team for my master’s degree, for her sponsorship in my favor for the PhD position, and the post-doc fellowship, as well as for always having been available to talk about science and other things, even after my master was completed. I have to thank the team of 5409, the group of Sandrine, within which I did my master, for the good times during these past five years. Solene, who was also a master student at the time, who valiantly fought to keep a real life alongside her thesis, and who actually succeeded. Davide, the biologist lost among the chemists: he took all the jokes, long coffee breaks, and absurd demands on his time, with good humor and seriousness, which was much to his credit. Francoise, who kept everyone going strong through her energy and songs, though she did have the nasty habit of rearranging my flasks according to size whenever they were mixed up... Pascal, who trusted me enough to show me in detail how the NMR works which proved to be extremely useful over the years. Horacio, a post-doc in the group at the time, who had the patience during my master internship to show me the basics with a smile. And finally Slavo, whose French progressed maybe a bit too fast due to us. I have to thank the diverse technical teams of ISIC for all their efforts over the years, to provide efficient services which greatly facilitated our work. The NMR department composed, of Pascal, Martial and Anto, who kept the machines on which we are so dependent alive. The mass spectrometry department with Laure, Francisco and Daniel who made sure our analyses was always done as fast as possible. The shop, with Giovanni, Annelise, Gladys and Benjamin, who always did their best to ensure we had all we needed to work in terms of supplies. The whole team of the mechanical workshop, who were always there when we needed some homemade equipment, or some apparatus tinkered with; especially Vladan, who always managed to fix the pumps that mishandling had destroyed. I have to thank Monique, the person who dealt with all our administrative needs, for keeping things fluid and under control.

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I have to thank all of the LCSA and LCSO for the good working atmosphere, the group outings, the molecule of the month, challenges and the follow up barbecues. I would like to thank the companies who made our equipment for motivating me, through the costefficiency of their support teams, to learn how these machines work and to fix them by myself when they broke, as well as the UNIBAT team for being so unbelievably cooperative when we tried to organize events. I would like to thank the persons with whom I did most of my studies and kept in contact with after. The paper RPG/Twilight Imperium team, Sahra, Clement, and Vincent, with whom I sunk a lot of time in unproductive games. And Mathieu, who, much to my horror, transitioned to physics and, as expected managed to get a PhD out of it. It is with him that I survived though these ten years, with him that we transmogrified all the dull and tedious courses, and practical modules, into fun memories. It was great to have someone as prone to complaining, arguing, and criticizing as I was to help vent frustration and be able to make a mile out of an inch. I know these habits will perdure. I would also like to say have a work of thanks for the team of the riding ring of Pampigny, who provided a welcome diversion to the routine of the lab, and helped keep my spirits up. To Caroline, who trusted me with the two horses, (Ralf and Lutteur) who (literally) carried me over the years, and who tried to teach me how to handle them. To Tanja, who kept trying to convince me that not only one can survive one’s PhD, but that one could even find a job thereafter as she had. To Marie, and her very youthful view on life. Here again, I have to mention, and thank, Sandrine. Having her horses also in Pampigny, she proved an invaluable companion when leaving the ring and strolling with them through the surrounding woods (horses tend to prefer to be in groups, especially Lutteur). The discussions we had during these outings were most enjoyable. To Aurelle, with whom I also explored much of the forest when I was still riding at Apples, and also shared many a discussion. I would like to thank the friends who know nothing about chemistry, or the way of life of a scientist but who stayed true along the way nonetheless, despite my being very absorbed in my work and not very available. I would like to thank a few of them directly as they were the most present. Andrea, with whom I shared many a Warhammer battle and many totally crazy discussions on science, economy and more. Ben, one of my oldest friends, with whom I managed to keep contact despite the distance which separates us. And finally Maxime, with whom I also wasted of lot of time blasting through the diverse levels of many games be it the Halo’s, the Gears of war on Xbox, or the AoE’s on PC. I do hope all there friendships will continue in the upcoming years. Last but not least, in any sense, as the most important is often kept for the very end, I would like to thank my family. Were I to enumerate all the reasons for that this section would be longer than the rest of the thesis combined, and very soppy, so I will stick to the essentials. I would like to thank all of them, and most especially my parents, for their constant support over the years and for their help in all things. I would also like to thank them for always being understanding, and for sticking with me, even if my patience was short, or if I was not very talkative on how things were going. I would like, in short, to thank them for just being my family, and being there, no matter what. 14

iv. List of Abbreviations (DHQ)2AQN

Hydroquinine anthraquinone-1,4-diyl diether

(DHQD)2AQN °C Ac AcOEt Act. AH AIDS PTSA Ar BHT Bn Boc BRSM Bu Cat. d.r. dba DBU DCE DCM DEAD DFT DIBAL-H DMAP DME DMF DMPU DMSO DNPH

Hydroquinidine anthraquinone-1,4-diyl diether Degree Celsius Acetyl Ethyl acetate Activity Acid Acquired immunodeficiency syndrome p-Toluenesulfonic acid Aryl Butylated hydroxytoluene Benzyl tert-Butyl carbamates By recovered starting material Butyl Catalyst Diastereomeric ratio Dibenzylideneacetone 1,8-Diazabicycloundec-7-ene Dichloroethane Dichloromethane Diethylazodicarboxylate Density functional theory Diisobutylaluminium hydride 4-Dimethylaminopyridine Dimethoxyethane, Dimethylformamide 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone Dimethyl sulfoxide 2,4-Dinitrophenylhydrazine 2-(2,3-Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-ylimino)-2-(4nitrophenyl) acetonitrile Entgegen 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Enantiomeric excess Equivalent Enantiomeric ratio Ethyl

DOPNA E EDC e.e equiv e.r. Et

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g h HATU HPLC hv IBA IBX i Pr IUPAC LA LDA M M mmbar mCPBA MCR Me min mmol MOM Ms MTBD MW N n.a NBS NCS NHC NIS NMR Nu opPCC Ph PIDA pin PLE Pr Rr.t

Gram Hour (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) High-performance liquid chromatography Light Idosobenzoic acid Iodoxybenzoic acid iso-Propyl International Union of Pure and Applied Chemistry Lewis acid Lithium diisopropylamide, Molar Metal Meta Milibar meta-Chloroperoxybenzoic acid Multicomponent reaction Methyl Minutes Milimole Methoxymethyl ether Mesyl 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene Microwave Normal Not available N-Bromosuccinimide, N-Chlorosuccinimide, N-Heterocyclic carbene N-Iodosuccinimide, Nuclear magnetic resonance Nucleophile Ortho Para Pyridinium chlorochromate Phenyl Phenyliodine diacetate Pinacol Pig liver esterase Propyl Rectus Room temperature 16

rpm SSAR SFC T° TBAB TBAH TBAI TBAX TBDMS TBDPS TBME t Bu Tf TFA TFAA THF TMEDA TMS TOP TRIP Ts TSE UV Z

Rotations per minute Sinister Structure activity relationship Supercritical fluid chromatography Temperature (in Celsius) Tetra-n-butylammonium bromide Tetrabutylammonium hydroxide Tetrabutylammonium iodide Tetrabutylammonium halide tert-Butyldimethylsilyl ether tert-Butyldiphenylsilyl ether Methyl tert-butyl ether tert-Buthyl Trifluoromethanesulfonate Trifluoroacetic acid Trifluoroacetic anhydride Tetrahydrofuran Tetramethylethylenediamine Trimethylsilyl Tandem oxydative process 3,3′-Bis(2,4,6-triisopropylphenyl)-1,1′-bi-2-naphthol cyclic monophosphate Tosyl Trimethylsilyethyl Ultraviolet light Zusammen

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General Introduction Multicomponent reactions have become an important tool among those available to the synthetic community due to their capacity to furnish highly functionalized and complex structures from relatively simple starting materials in an inexpensive, short and straightforward manner. This allows for the bypassing of numerous issues which are inherent to multistep processes such as functional group compatibility, purification or resource monopolization. It was the high potential of this type of transformation that drew our interest and fueled our efforts towards expanding the synthetic methods available to the synthetic community. The first part of this thesis will therefore deal with the development of the multicomponent synthesis of α-iminonitriles and their subsequent elaboration into synthetically relevant building blocks

The control of the absolute configuration of the chiral centers in new compounds has become a critical requirement in many processes. This came from a growing understanding of the potential impact on the properties of a compound a simple inversion of a single center can bring. Therefore the development of new methods for the formation and control of these centers has become an important area of interest in the synthetic community over the years. Full carbon quaternary centers are a prime target as their configuration is often harder to control during their installation in a skeleton due to the lack of nearby handholds to use as directing groups for catalysts. Many strategies have been pursued over the years and desymmetrization of existing all carbon quaternary enters has proven a successful one as it can take advantage of functional groups even far from that very center. The second part of this thesis will therefore be dedicated to the development of the desymmetrization of dimethyl 4,4disubstituted pimelate fragments in the optic of furnishing optically pure moieties bearing all carbon quaternary centers to be used as flexible building blocks in the construction of useful compounds. This evolved into the development of novel strategic routes using these building blocks to access the biologically and pharmaceutically relevant compounds which are indole alkaloids. The third part of this thesis will therefore be dedicated to the work done towards the total synthesis of (-)-rhazinilam, and (-)leucomidine B.

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Chapter 1: The Synthesis of α-Iminonitriles and their Subsequent Transformations α-Iminonitriles, or imidoyl cyanides by their IUPAC name, are a class of densely functionalized compounds that can serve as precursors for various key functional groups or structures such as ketoacids, amides, nitrogen containing heterocycles and so forth. While they have been known for well over a century they have been little studied or used. It was this unexploited potential that drew our interest and fuelled our efforts towards developing new methodologies involving α-iminonitriles. This chapter will first focus on setting the background within which this work was pursued by describing the known methods for the synthesis of α-iminonitriles, attempting to highlight the strengths and weaknesses of these, before presenting what transformations based on α-iminonitriles are known. It will then present the work that has been performed during this thesis on the topic of α-iminonitriles as shown in Scheme 1.

Section 1.2

R1

R NH2 2

+

O

a) TMSCN then IBX/TBAB

1.1

O N H

R1

b) Al2O3

1.2

R2

1.3

Section 1.3 CN N

R1

R3

HSEt AlCl3 60°

R2

S

CN

R1

N

1.4

R2

1.5

Section 1.4 CN R1

N

R2

R3

HSR3 Yb(OTf)3

N

R3

Al2O3

CN

R1

0° DCM

1.4

S

R2

S

O

R1

N H

1.5

R2

1.6

Section 1.5

TMSCN 1.7

+

Ph

O 1.8

+

R NH2 2 1.2

TBAB Oxone

CN R1

N

R2

1.4

Scheme 1: Summary of developed transformation for Chapter 1

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1.1. α-Iminonitriles, A Brief Background 1.1.1. Known Methods for the Synthesis of α-Iminonitriles

Synthetic approaches to α-iminonitriles can be regrouped in four major strategic routes. The earliest of which is through condensation type reactions such as the strategy employed by Ehrlich and Sachs in 18991. The reaction involves the condensation of a nitrosoarene with phenylacetonitrile (Scheme 2).

Scheme 2: The Ehrlich Sachs Reaction

This major drawback of this method, as in many cases, is that it is limited to simple diaryl αiminonitriles; other types of substitution patterns are liable to cause the reaction to undergo subsequent transformations (Scheme 3)2, though some have taken advantage of this3 to efficiently access more complex products. Some studies have been performed to limit these side reactions by using microwave irradiation or phase transfer agents in biphasic systems.4

Scheme 3: Common Ehrlich Sachs Reaction byproducts

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P. Ehrlich, F. Sachs, Ber 1899, 32, 2341-2346. F. Barrow, F. J. Thorneycroft, J. Chem. Soc 1939, 769-773; D. M. W. Anderson, F. Bell, J. Chem. Soc 1959, 37083713; D. M. W. Anderson, J. L. Duncan, J. Chem. Soc 1961, 1631-1635; R. W. Layer, Chem. Rev. 1963, 63, 489-510. 3 M. J. Haddadin, M. El-Khatib, T. A. Shoker, C. M. Beavers, M. M. Olmstead, J. C. Fettinger, K. M. Farber, M. J. Kurth, J. Org. Chem 2011, 76, 8421-8427. 4 K. Takahashi, S. Kimura, Y. Ogawa, K. Yamada, H. Iida, Synthesis 1978, 1978, 892-893; D. D. Laskar, D. Prajapati, J. S. Sandhu, Synth. Commun. 2001, 31, 1427-1432. 2

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These condensation reactions can also be performed between sodium nitrite and beta cyano esters or malonitrile to yield hyroxyimidoyl cyanides which can be then trapped with tosyl chloride without suffering from further side reactions as demonstrated by Kinast (Scheme 4)5.

Scheme 4: Sodium nitrate Ehrlich-Sach reaction

In a similar fasion, aza-Wittig reactions on acyl cyanides can also be performed to obtain αiminonitriles (Scheme 5) as first demonstrated by Zbiral and Stroh6 though the yield of the reaction is heavily dependent on the nucleophilicity of the amine partner.7

Scheme 5: Aza-Wittig reaction of acyl cyanides

The second strategy often employed is through the induction of an elimination reaction on αaminonitriles. It is also through this process that many serendipitous methods for the synthesis of αiminonitriles were reported. Early records dating back to the 1960’s by Kröhnke et al. showed that the action of sodium cyanide on the condensation adduct of nitrosoarenes and 2-phenoxy-1phenylethanones yielded α-iminonitriles (Scheme 6) after the elimination of sodium hydroxide8.

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G. Kinast, Liebigs Ann. Chem. 1981, 1981, 1561-1567. E. Zbiral, J. Stroh, Justus Liebigs Ann. Chem. 1969, 725, 29-36. 7 C. Trione, L. M. Toledo, S. D. Kuduk, F. W. Fowler, D. S. Grierson, J. Org. Chem 1993, 58, 2075-2080; F. Palacios, I. Perez de Heredia, G. Rubiales, J. Org. Chem 1995, 60, 2384-2390; F. Palacios, A. M. O. de Retana, E. M. de Marigorta, M. Rodriguez, J. Pagalday, Tetrahedron 2003, 59, 2617-2623. 8 F. Kröhnke, G. Kröhnke, G. M. Ahrenholz, J. Prakt. Chem. 1960, 11, 239-248; M. Masui, M. Yamauchi, C. Yijima, K. Suda, K. Yoshida, J. Chem. Soc. D 1971, 312-312. 6

23

Scheme 6: Kröhnke at al. synthesis

This strategy was then used in the following years with diverse leaving groups instead of the phenol, such as fluoroamine9, and using diverse amines instead of the hydroxylamine such as fluoroamines9, phthalimides10 or simple amines via their magnesium iodine salt11. However not only do these methods require very specific starting materials but also yields and chemo selectivities were often very poor and the generated byproducts highly toxic which is why in parallel new methods emerged utilizing milder and more efficient leaving groups. Fujimori at al. used thionyl chloride on beta cyano amides to generate α-iminonitrile 1.27 (Scheme 7) in moderate yield12. Similar procedures with tert-butyl hypochlorite and a base were reported with better yields and the possibility to synthetize two N-H αiminonitriles.13 No scope is presented with these methods.

Scheme 7: Fujimori and Echenmoser α-iminonitrile synthesis

Tsuge described a Strecker reaction on N-oxide aldimines which generates in situ the leaving group on the amine of the intermediate (1.33, Scheme 8). From this intermediate two reaction pathways are possible. If the aromatic ring bears electron-withdrawing substituents (1.34-1.35), this intermediate will thermally decompose to give the corresponding α-iminonitriles through elimination. If the aromatic ring bears electron donating substituents it will undergo homolytical cleavage of the C-N bond (1.38) and

9

T. E. Stevens, J. Org. Chem 1968, 33, 2660-2663. H. Person, A. Foucaud, K. Luanglath, C. Fayat, J. Org. Chem 1976, 41, 2141-2143. 11 N. De Kimpe, R. Verhe, L. De Buyck, J. Chys, N. Schamp, J. Org. Chem 1978, 43, 2670-2672. 12 M. Fujimori, E. Haruki, E. Imoto, Bull. Chem. Soc. Jpn. 1968, 41, 1372-1375. 13 G. Ksander, G. Bold, R. Lattmann, C. Lehmann, T. Früh, Y.-B. Xiang, K. Inomata, H.-P. Buser, J. Schreiber, E. Zass, A. Eschenmoser, Helv. Chim. Acta 1987, 70, 1115-1172; J. H. Boyer, H. Dabek, J. Chem. Soc. D 1970, 1204-1205. 10

24

only recombination products are observed (1.39-1.40), Scheme 8)14. Subsequently, Baruah and then Koehler reported a modified procedure changing the solvent from toluene to DMF and adding a base to directly obtain the α-iminonitriles in good yields without needing to heat though the scope remains limited to aromatic substrates15.

Scheme 8: Tsuge synthesis of α-iminonitriles

More recently Iovel showed that the Strecker intermediate of pyridine aldimine 1.36 in the presence aluminum bromide gives α-iminonitrile 1.3716. They hypothesize that the chelating group on the aromatic ring coordinates to the Lewis acid which catalysts the cleavage of the C-H and C-Si bond to eliminate trimethylsilyl hydride (Scheme 9) but no evidence is provided.

Scheme 9: Iovel synthesis

14

O. Tsuge, S. Urano, T. Iwasaki, Bull. Chem. Soc. Jpn. 1980, 53, 485-489. D. K. Ducta, D. Prajapati, J. S. Sandhu, J. N. Baruah, Synth. Commun. 1985, 15, 335-339; A. Padwa, K. F. Koehler, J. Chem. Soc., Chem. Commun. 1986, 789-790. 16 I. Iovel, L. Golomba, J. Popelis, A. Gaukhman, E. Lukevics, Chem. Heterocycl. Compd. 2003, 39, 721-725. 15

25

The best yields and product scope with this elimination type strategy were obtained by Fowler who used a Lewis acid catalyzed Strecker reaction on silylated N-oxide aldimines in presence of an acyl chloride to generate in situ Diels-Alder precursor 1.47 in reasonable yields.17 If desired these precursors could also be isolated in good yields (Scheme 10).

Scheme 10: Fowler synthesis

De Kimpe used NCS to generate β-chlorinated aldimines which, when treated with potassium cyanide furnished α-iminonitriles though these often equilibrated to the enamine tautomer, the equilibrium could be shifted back to the imidoyl cyanide upon treatment of 1.51 with another equivalent of NCS18 in good overall yields (Scheme 11).

Scheme 11: De Kimpe β-chloro-α-iminonitrile synthesis

2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile, one of the rare commercially available αiminonitriles, is also made through the elimination of methanol from 2(hydroxy(methoxy)amino)propanenitrile and subsequent trapping of the oxime (Scheme 12).19

Scheme 12: Preparation of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile 17

M. Teng, F. W. Fowler, J. Org. Chem 1990, 55, 5646-5653. N. De Kimpe, R. Verhé, L. D. Buyck, J. Chys, N. Schamp, Synth. Commun. 1979, 9, 901-913; R. Verhé, N. De Kimpe, L. De Buyck, M. Tilley, N. Schamp, Tetrahedron 1980, 36, 131-142; B. De Corte, J. M. Denis, N. De Kimpe, J. Org. Chem 1987, 52, 1147-1149. 19 M. Itoh, D. Hagiwara, T. Kamiya, Org. Synth. 1979, 59, 95. 18

26

Two methods were used by Boyer in 1975 (Scheme 13). The first is based upon dehydrochlorination of N-chloro-N-alkylaminoacetonitriles previously prepared from Nalkylaminoacetonitriles in the presence of calcium hypochlorite20. This method has the advantage of being relatively substrate tolerant; its disadvantage is that the N-chloro-α-aminonitriles are highly unstable. The second method proposed is through the photolysis of azidoacetonitrile21. Both of these methods were used as intermediates in their study of the formation of adenine.

Scheme 13: Boyer synthesis

Danheiser developed a method in 2003 through the base mediated elimination of trifluoromethansulfinate22. These are obtained from the corresponding alcohols through Mitsunobu coupling in good yields (Scheme 14). Both aliphatic and aromatic substituents on the alcohol were tolerated though only non-substituted α-iminonitriles were reported.

Scheme 14: Danheiser synthesis

In 1999, Konwar developed a one-step synthesis of α-iminonitriles by reaction of nitrones with Amberlite ira 400 [CN-]23 based on an ion exchange mechanism. Yields and reaction times are improved verses the non-supported methods though again only aromatic substituents are used (Scheme 15).

20

J. H. Boyer, J. Dunn, J. Kooi, J. Chem. Soc., Perkin Trans 1 1975, 1743-1747. J. H. Boyer, J. Kooi, J. Am. Chem. Soc. 1976, 98, 1099-1103. 22 D. T. Amos, A. R. Renslo, R. L. Danheiser, J. Am. Chem. Soc. 2003, 125, 4970-4971; K. M. Maloney, R. L. Danheiser, Org. Lett. 2005, 7, 3115-3118. 23 D. Konwar, B. Nath Goswami, N. Borthakur, J. Chem. Res., Synop . 1999, 242-243. 21

27

Scheme 15: Konwar synthesis

Addition of cyanide to aromatic imidoyl chlorides, triflates or imidoyl pyridinium salts have also been used to give α-iminonitriles in moderate to good yields (Scheme 16)24.

X

X

R N

KCN 50-90%

CN N

TfO

R N

LiCN

NC

R N

Crown ether 25-60%

R = Cl, pyridine.HCl 1.67

1.68

1.69

1.70

Scheme 16: α-Iminonitrile synthesis via substitution

A method from aromatic aldehydes and aliphatic amines was developed by Pochat in 1981 as an attempt at a larger reaction scope but it is hindered by the need for toxic reagents and is a four step procedure25. The reaction proceeds through bromination of the 2-aryl-2-(ethylthio)acetonitrile intermediate 1.72, substitution with an amine and finally elimination of ethanethiol to yield the desired α-iminonitrile in moderate to good yields (Scheme 17).

Scheme 17: Pochat synthesis

24

J. W. Ledbetter, D. N. Kramer, F. M. Miller, J. Org. Chem 1967, 32, 1165-1168; J. G. Smith, D. C. Irwin, Synthesis 1978, 1978, 894-895; N. J. Sisti, E. Zeller, D. S. Grierson, F. W. Fowler, J. Org. Chem 1997, 62, 2093-2097; I. A. Motorina, D. S. Grierson, Tetrahedron Lett. 1999, 40, 7215-7218; J. E. Tarver Jr, K. M. Terranova, M. M. Joullié, Tetrahedron 2004, 60, 10277-10284. 25 F. Pochat, Tetrahedron Lett. 1981, 22, 955-956.

28

Krespan reported the addition of hydrogen cyanide to perfluoronitrile in 1968 but this method is limited to trifluoroacetonitrile and by its toxicity (Scheme 18)26.

Scheme 18: Krespan synthesis

First reported by Saegusa, the formation of imidoyl cyanides is possible as a byproduct of the oligomerisation of isocyanides (Scheme 19) resulting of the scission and recombination of its fragments under Lewis acid catalysis27.

Scheme 19: Saegusa polymerisation

The third major strategic route is composed of rearrangement reactions. Early reports by Yamamoto in 1983 involving a Beckmann rearrangement of oxime mesylates allowed for one of the rare synthesis of both dialkyl and diaryl α-iminonitriles in good yields28. Migratory selectivity was good in the case of alkyl verses aryl (R1 = Ph) substituents (Scheme 20).

Scheme 20: Beckmann synthesis

26

W. J. Middleton, C. G. Krepsan, J. Org. Chem 1968, 33, 3625-3627. T. Saegusa, N. Takaishi, Y. Ito, J. Org. Chem 1969, 34, 4040-4046; H. Pellissier, G. Gil, Tetrahedron Lett. 1988, 29, 6773-6774. 28 K. Maruoka, T. Miyazaki, M. Ando, Y. Matsumura, S. Sakane, K. Hattori, H. Yamamoto, J. Am. Chem. Soc. 1983, 105, 2831-2843. 27

29

De Kimpe reported the use of a Grob type fragmentation from 2-cyano-5-bromopiperidines.29 In this reaction, de-protonation of the acidic proton of the α-aminonitrile with NaH triggers the fragmentation cascade to unfold the piperidine system and afford the γ-δ-unsaturated-α-iminonitrile in varying yields. The major byproduct is the simple elimination of the bromide to yield tetrahydropyridines (Scheme 21). This can be attributed to conformational issues as the yield of this side reaction is heavily dependent on the substituent on the amine.

Scheme 21: De Kimpe Grob fragmentation synthesis of α-iminonitriles

An unexpected fragmentation of pyrazolidinone was reported in 2008 to yield α-iminonitriles in moderate to good yields (Scheme 22)30.

Scheme 22: Svete pyrazolidinone fragmentation

The most general strategy to reach iminonitriles until now has been through the oxidation of Strecker adducts. While first observed in the 1970s with the oxidation of biary α-aminonitriles with magnesium dioxide it was not explored further31. This strategy was then reused a few years later through ruthenium and NBS mediated oxidation of similar substrates32 though this reactivity was only truly

29

E. Rosas Alonso, K. Abbaspour Tehrani, M. Boelens, D. W. Knight, V. Yu, N. De Kimpe, Tetrahedron Lett. 2001, 42, 3921-3923. 30 L. Pezdirc, U. Grošelj, A. Meden, B. Stanovnik, J. Svete, Tetrahedron Lett. 2007, 48, 5205-5208. 31 J. S. Sandhu, S. Mohan, A. L. Kapoor, Chem. Ind. (London, U. K.) 1971, 5, 152-153; J. S. Sandhu, S. Mohan, P. S. Sethi, A. L. Kapoor, Indian J. Chem. 1971, 9, 504-505. 32 S.-I. Murahashi, T. Naota, H. Taki, J. Chem. Soc., Chem. Commun. 1985, 613-614; H. Härle, J. C. Jochims, Chem. Ber. 1986, 119, 1400-1412.

30

exploited later with the air induced oxidation of heteroaromatic compounds (Scheme 23) by Jursic in 2002 but it also remains limited to basic diaryles33.

Scheme 23: Jursic synthesis

Recently Jiao reported the synthesis of α-iminonitriles from methylamines using hypervalent iodine PIDA as oxidant and an azide as nitrogen source (Scheme 24)34. The scope however remains again limited to bi-aromatic systems and an excess of reagents is needed to obtain moderate yields.

Scheme 24: Jiao synthesis

The first viable methodology allowing the synthesis of a wide range of α-iminonitriles was developed by our lab through an IBX mediated Strecker reaction (Scheme 25)35. This method permits the use of a wide range of aldehyde and amine substrates and also gives the possibility to start from the corresponding alcohols with a second in-situ oxidation to give, in a one pot process, a wide range of both aromatic and aliphatic α-iminonitriles.

Scheme 25: Zhu synthesis

33

B. S. Jursic, F. Douelle, K. Bowdy, E. D. Stevens, Tetrahedron Lett. 2002, 43, 5361-5365. F. Chen, X. Huang, Y. Cui, N. Jiao, Chem. Eur. J 2013, 19, 11199-11202. 35 P. Fontaine, A. Chiaroni, G. Masson, J. Zhu, Org. Lett. 2008, 10, 1509-1512; P. Fontaine, G. Masson, J. Zhu, Org. Lett. 2009, 11, 1555-1558. 34

31

As this previous experience in the field of α-iminonitriles was the starting point to all the projects in this field that were undergone during this thesis it will be presented in-depths in the third section of this subchapter. 1.1.2. Known Functionalizations of α-Iminonitriles

As a direct result of the difficulty to obtain α-iminonitriles and the restricted scope of structures available prior to 2008, reports describing the use of these structures are rare. Existing reports show that α-iminonitriles can serve as electrophiles as firstly demonstrated by Fujimori et al in 1968 where they reacted electron poor α-iminonitrile 2.27 with diverse nucleophiles to yield quaternary centers bearing diverse functionalities in good yields (Scheme 26)12.

Scheme 26: Fujimori synthesis

When the nucleophile is a hydroxyl equivalent the final compound eliminates cyanide to regenerate the imide which then equilibrates to the amide as shown by De Kimpe in 197836 and reused by other groups in a one pot method from α-aminonitriles37. In 2006 Roychowdhury developed several transformations of diarylimidoylcyanides based on the substitution or hydrolysis of the nitrile. As shown in Scheme 27, under the proper conditions, αiminonitriles can be transformed in moderate yields into amides under strong basic conditions (1.105), glyoxalic acid derivates under strong acidic conditions (1.103), benzimidines in the presence of an amine and a base (1.102) and finally β-nitroenamines with DBU and nitromethane (1.104)38

36

N. D. Kimpe, R. Verhé, L. D. Buyck, J. Chys, N. Schamp, Org. Prep. Proced. Int. 1978, 10, 149-156. G. Boche, F. Bosold, M. NieBner, Tetrahedron Lett. 1982, 23, 3255-3256; D. Enders, A. S. Amaya, F. Pierre, New J. Chem. 1999, 23, 261-262; Z. Zhang, Z. Yin, J. F. Kadow, N. A. Meanwell, T. Wang, J. Org. Chem 2004, 69, 1360-1363. 38 A. Roychowdhury, V. V. Kumar, A. P. Bhaduri, Synth. Commun. 2006, 36, 715-727. 37

32

. Scheme 27: Roychowdhury reactions

Later Dias studied the reactivity of 5-amino-4-cyanoformimidoyl imidazoles in the presence of various nucleophiles (Scheme 28) and showed that α-iminonitriles could be selectively hydrolyzed to the acyl cyanide in presence of water and TFA (1.109) and to the imidate in presence of TFA and alcohol (1.108). More interestingly transimination occurred in the presence of one equivalent of TFA and amine in acetonitrile (1.107) while substitution of the nitrile to yield amidine occurred in the presence of a catalytic amount of acetic acid and amine in ethanol (1.110)39. A variety of substrates were used and yields were moderate to excellent.

39

A. M. Dias, A. S. Vila-Chã, A. L. Costa, D. P. Cunha, N. Senhorães, M. F. Proença, Synlett 2011, 2011, 2675-2680.

33

Scheme 28: Dias Synthesis

α-Iminonitriles were also used by Ye as an electrophilic partner in a NHC coupling reaction (Scheme 29)40. While a single example was reported it gave good yields and enantioselectivities to form a quaternary carbon center.

Scheme 29: Ye synthesis

Recently Kisch reported the chemoselective photocatalysed addition of unsaturated systems on α-iminonitriles with zinc sulfide supported cadmium sulfide (Scheme 30)41.

40 41

L.-H. Sun, Z.-Q. Liang, W.-Q. Jia, S. Ye, Angew. Chem. Int. Ed. 2013, 52, 5803-5806. M. Gartner, J. Ballmann, C. Damm, F. W. Heinemann, H. Kisch, Photochem. Photobiol. Sci. 2007, 6, 159-164.

34

Scheme 30: Kirsh synthesis

Dias also showed that N-H α-iminonitriles could act as nucleophiles when reacted with anhydrides, ethyl chloroformate and ketenes with good yields (Scheme 31)42.

Scheme 31: Dias nucleophilic iminonitrile

When treated with carbon nucleophiles the more reactive position appears to be the nitrile as shown by De Kimpe with the addition of lithium species on α-chloroimidoyl cyanides to yield α-chloro1,2-diimines which can be hydrolyzed during work up to give diketones in excellent yields (1.116, Scheme 32)43. One exception was with n-buthyl lithium which yielded ketenimine 1.118 through a chlorine–metal exchange and expulsion of cyanide (1.117).

Scheme 32: Kimpe lithium species addition

The formation of keteneimine from α-iminonitriles had already been reported by De Kimpe in 1987 using a strong base, elevated temperature and high vacuum to induce the elimination of cyanide18.

42

B. L. Booth, I. M. Cabral, A. M. Dias, A. P. Freitas, A. M. Matos Beja, M. F. Proenca, M. R. Silva, J. Chem. Soc., Perkin Trans. 1 2001, 1241-1251; A. M. Dias, I. Cabral, A. S. Vila-Chã, D. S. Costa, M. F. Proença, Eur. J. Org. Chem. 2007, 2007, 1925-1934; N. Senhorães, A. M. Dias, L. M. Conde, M. F. Proença, Synlett 2011, 2011, 181-186. 43 R. Surmont, B. De Corte, N. De Kimpe, Tetrahedron Lett. 2009, 50, 3877-3880.

35

One of the most well-known applications of α-iminonitriles is the hetero Dies-Alder reaction. Building on preliminary studies in the previous decade,44 Fowler reported in 1997 the synthesis of indolizidines by an intramolecular Dies-Alder reaction of α-iminonitriles (Scheme 33)24. The advantage of having a cyano group on the diene is that it can block any unwanted imine type reactivity of the starting substrate and lowers the eneamine character of the product to minimize side reactions. It can also be potentially used as a functional group in subsequent steps. Cyano substitution also makes for more reactive azadienes, who are known to be poor dienes in normal electronic demand Dies-Alder reactions, by reinforcing the inverse electron demand nature of the system. Attempts at an enantioselective diesalder reaction by Grierson with pybox type ligands proved unsuccessful as the catalyst apparently did not coordinate as desired to the nitrile which allowed for a loose transition state and therefore low ee’s (about 8%)24. The racemic Lewis acid catalyzed reaction on the other hand allowed for lower reaction temperatures. This method was then perfected to accept more varied dienes and dienophiles45

Scheme 33: Fowler synthesis

Danheiser in 2003 reported the use of α-iminonitriles as dienophiles for a Dies-Alder reaction22. The cyano group is responsible for the relative configuration of the final product. Studies suggested that the epimeric cycloadduct formed equilibrates to afford the axial cyano isomer favored due to an αaminonitrile anomeric effect similar to what was described by Husson46. BHT is necessary as radical inhibitor to avoid degradation in this reaction. The cyano group can then be modulated to fit synthetic requirements as illustrated by the total synthesis of quinolizidine alkaloid (−)-217A (Scheme 34)22.

Scheme 34: Synthesis of (-)-217A

44

M. Teng, F. W. Fowler, Tetrahedron Lett. 1989, 30, 2481-2484; N. J. Sisti, F. W. Fowler, D. S. Grierson, Synlett 1991, 1991, 816-818. 45 N. J. Sisti, I. A. Motorina, M.-E. Tran Huu Dau, C. Riche, F. W. Fowler, D. S. Grierson, J. Org. Chem 1996, 61, 37153728; J.-C. M. Monbaliu, K. G. R. Masschelein, C. V. Stevens, Chem. Soc. Rev. 2011, 40, 4708-4739. 46 M. Bonin, J. R. Romero, D. S. Grierson, H. P. Husson, J. Org. Chem 1984, 49, 2392-2400.

36

In 2009 our group developed a synthesis of fully substituted pyrroles through lewis acid catalyzed 4 + 1 cyclo-addition of isocyanides with α-iminonitriles in good yields (Scheme 35)35. As with the Dies-Alder reaction the nitrile serves in a stabilization role on both starting material and product.

Scheme 35: pyrrole synthesis

Beyond synthetic chemistry α-iminonitrile structures have found a couple of applications in both bio- and physico-chemistry. In 2006 Sączewski tested triazine bearing α-iminonitriles as anti-tumor agents, one derivate was found to have interesting activities against melanoma MALME-3 M cell line while the corresponding amide resulting from its hydrolysis proved totally inactive (Scheme 36)47.

Scheme 36: Hit vs MALME-3 M cell line

In 2008 Zeyada used 3-pyrazolone bearing an α-iminonitrile as an organic dye for a hybrid solar cell with interesting results (Scheme 37)48.

Scheme 37: DOPNA solar dye

47 48

F. Sączewski, A. Bułakowska, P. Bednarski, R. Grunert, Eur. J. Med. Chem. 2006, 41, 219-225. H. M. Zeyada, M. M. El-Nahass, E. M. El-Menyawy, Sol. Energy Mater. Sol. Cells 2008, 92, 1586-1592.

37

1.1.3. Synthesis of α-Iminonitriles through the IBX Mediated Three Component Oxidative Strecker Reaction.

The quality of a synthesis in terms of length and cost is often directly dependent on the amount of useful molecular complexity generated during each step. This in turn is linked to the number of bonds formed or rearranged per operation. Therefore developing processes wherein multiple bonds are formed as schematized in Figure 1 are highly interesting by modern day standards that require synthetic routes to fulfil certain efficiency criteria. These include atom economy, operational simplicity, resource availability and cost from an environmental and economic point of view. As Multicomponent reactions are sequences where at least three reagents are combined, they fulfill many of the stated criteria and have become the center of much attention from the synthetic community49. In addition MCR’s are ideal for the development of compound libraries for medicinal and material chemistry when used in combination with diversity oriented synthesis or bio-oriented synthesis. But while these multicomponent reactions hold great interest they also hold great challenge from a synthetic point of view as they are intrinsically more complex than bimolecular processes due to the number of added parameters to take into account during their development, as is beautifully summarize by Aristotle “The whole is greater than the sum of its parts”.

Figure 1: Multicomponent reactions

A sub category of MCR’s are those containing a tandem oxidation process (TOP). This step brings an additional layer of complexity to a MCR by adding the possibility of generating controlled domino processes to generate new functional groups which can, in turn, lead to further reaction to an additional component therefore exponentially increasing the structural complexity generated in a single step via an MCR. Over the years diverse methodologies have been reported where well known MCR’s, such the Passerini or Ugi reactions50, have been combined with great effect with oxidative steps to access interesting synthetic scaffolds.

49

J. Zhu, H. Bienayme. Multicomponent Reactions, Wiley, 2005, ; D. J. Ramón, M. Yus, Angew. Chem. Int. Ed. 2005, 44, 1602-1634; B. B. Touré, D. G. Hall, Chem. Rev. 2009, 109, 4439-4486; A. Dömling, W. Wang, K. Wang, Chem. Rev. 2012, 112, 3083-3135; S. Brauch, S. S. van Berkel, B. Westermann, Chem. Soc. Rev. 2013, 42, 4948-4962; G. van der Heijden, E. Ruijter, R. V. A. Orru, Synlett 2013, 24, 666-685; M. Vishe, R. Hrdina, L. Guénée, C. Besnard, J. Lacour, Adv. Synth. Catal. 2013, 355, 3161-3169. 50 For recent examples of TOP/MCR’s see: T. Ngouansavanh, J. Zhu, Angew. Chem. Int. Ed. 2006, 45, 3495-3497; T. Ngouansavanh, J. Zhu, Angew. Chem. Int. Ed. 2007, 46, 5775-5778; J. Brioche, G. r. Masson, J. Zhu, Org. Lett. 2010, 12, 1432-1435; M. Rueping, C. Vila, Org. Lett. 2013, 15, 2092-2095; C. Vila, M. Rueping, Green Chem. 2013, 15, 2056-2059; M. Bekkaye, G. Masson, Org. Lett. 2014, 16, 1510-1513; F. D. Moliner, M. Bigatti, L. Banfi, R. Riva, A. Basso, Org. Lett. 2014, 16, 2280-2283.

38

Among the earliest of the commonly known MCR’s is the Strecker reaction51 in which an aldehyde, an amine and a cyanide source combine to form α-aminonitriles (Scheme 38). Even after one and a half century it remains highly used for the preparation of amino acids, imine acyl anions and iminium ion precursors. Enantioselective versions have been developed and applied, among others, to natural and non-natural amino acid synthesis.

Scheme 38: Strecker alanine synthesis

It is based on this well documented reaction that our lab first entered the field of α-iminonitriles with the objective to develop methodologies addressing the issues stated in the previous section and further developing the field. This resulted in the development of an IBX mediated three component oxidative Strecker reaction who gave access to a wide variety of α-iminonitriles in good yields (Scheme 39).

Scheme 39: Oxidative Strecker reaction

During the development of this reaction several points had to be taken into account. The chosen oxidant had to be capable of selectively oxidizing the correct intermediate and leave untouched the potentially oxidizable starting materials and product. Among the wide variety of commercial oxidants available, IBX was a favored candidate as it’s slightly acidic character could help catalyze the Strecker reaction and was known to be able to oxidize amines with an α-acidic proton

52

into imines while not

53

interacting with aldehydes, nitriles or other amines . Of the many available procedures the Ramon-Yus 54

method seemed ideal as acetonitrile works well with IBX and as the reaction goes at room temperature without catalyst minimizing the risk of side reactions. Preliminary trials were promising though the 51

A. Strecker, Justus Liebigs Ann. Chem. 1850, 75, 27-45; A. Strecker, Justus Liebigs Ann. Chem. 1854, 91, 349-351; J. Wang, X. Liu, X. Feng, Chem. Rev. 2011, 111, 6947-6983. 52 K. C. Nicolaou, C. J. N. Mathison, T. Montagnon, Angew. Chem. Int. Ed. 2003, 42, 4077-4082. 53 M. Frigerio, M. Santagostino, S. Sputore, G. Palmisano, J. Org. Chem 1995, 60, 7272-7276; T. Wirth, Angew. Chem. Int. Ed. 2001, 40, 2812-2814; K. C. Nicolaou, C. J. N. Mathison, T. Montagnon, J. Am. Chem. Soc. 2004, 126, 5192-5201; J. N. Moorthy, N. Singhal, K. Senapati, Tetrahedron Lett. 2008, 49, 80-84. 54 R. Martínez, D. J. Ramón, M. Yus, Tetrahedron Lett. 2005, 46, 8471-8474.

39

55

method required non stabilized IBX , but the reaction rate of the oxidation was relatively slow which entailed degradation of the final product over time. To accelerate this step, diverse TBAX (tetrabutylammonium halide) were added to the reaction as quaternary ammonium salts were known to 56

accelerate IBX mediated reactions . Of the different counter anions tested bromide proved to be the most efficient to afford the product in up to 90% yield.

Scheme 40: Effect of TBAX on the reaction

The scope of the reaction extended to both aliphatic and aromatic aldehydes and amines, which was a significant improvement on previously described methods, though limitations remained when using acid sensitive substrates. The mechanism of this transformation was hypothesized based on literature precedence (Scheme 41) with firstly IBX being activated by the counteranion of the phase transfer agent to form a penta-coordinated species. This activated oxidant is more prone to nucleophilic attack by the amine to displace the activating agent followed by syn-elimination of water. The ionic character of the mechanism was supported by the possibility to use cyclopropane bearing derivates without ring opening.

Scheme 41: Oxydative strecker hypothesized mechanism 55

The major stabilizers found in commercial sources, benzoic acid and isophthalic acid, cause degradation of αiminonitriles. IBX was prepared following M. Frigerio, M. Santagostino, S. Sputore, J. Org. Chem 1999, 64, 45374538. Aldehydes and amines were redistilled prior to use. 56 H. Tohma, S. Takizawa, H. Watanabe, Y. Fukuoka, T. Maegawa, Y. Kita, J. Org. Chem 1999, 64, 3519-3523; V. G. Shukla, P. D. Salgaonkar, K. G. Akamanchi, J. Org. Chem 2003, 68, 5422-5425.

40

While our methodology for the synthesis of α-iminonitriles provided access to a far broader range of substrates than previously accessible, it still possessed some limitations in terms of functional group tolerance. For example the only aliphatic α-β-unsaturated α-iminonitrile available in good yield was the crotonaldehyde equivalent, the terminal or disubstituted olefin equivalent led to significant amounts of degradation. The major reason for this appeared to be the acidity of the reagents used; IBX and its reduced derivates are in essence carboxylic acids, and are always in excess within the reaction media. Indeed the relative stability of diverse α-iminonitres varies substantially towards thermal and acidic conditions. For example substrate 1.140 could be purified on standard silica gel with only 20% loss of yield compared to when using silanised silica gel and is fridge stable for several months while α-iminonitrile 1.141 requires careful monitoring of reaction times and purification only on silanised silica gel to obtain moderate yields.

Scheme 42: Examples of substrate relative stability.

1.2. Amidation of Aldehydes Through Hydrolysis of α-Iminonitriles 1.2.1. Project Overview During the development of our studies on α-iminonitriles it was observed that whenever alumina was used as a means of purification a side product identified as the corresponding amide was formed. Such a reaction had already been described as cited previously though the hydrolysis of αiminonitriles to amides required very harsh conditions such as strong alkaline bases or oxidants and worked on a very limited scope of substrates. To the best of our knowledge no mild and substrate tolerant methods existed. Therefore if this alumina based hydrolysis could be developed further it would offer an interesting alternative especially if combined with the oxidative MCR to give a very general, mild and cost effective amidation of amines and aldehydes. Therefore the goal of this first project was to develop the two reactions shown in Scheme 43

Scheme 43: Hydrolysis of α-iminonitriles

41

Amidation of aldehydes and alcohols has drawn significant interest from the synthetic community recently as they are a cost and atom economical attractive alternative to more classical methods such as the coupling of acids and amines via acyl chlorides or in the presence of coupling reagents57. Conceptually the alumina could activate the α-iminonitrile and catalyze the nucleophilic addition on the imine by the hydroxyl groups present on the alumina’s surface. The resulting amino-cyano-alcohol intermediate would then undergo elimination of the cyano group to form the amide while trapping the potentially dangerous leaving group on the alumina to avoid any toxicity problems.

1.2.2. Optimization

We began our investigation by using purified α-iminonitrile 1.134 as test substrate for our reaction (Scheme 44). We first used basic Brockmann 1 alumina58 as absorbent for the reaction (Table 1).

Scheme 44: Model reaction for the amidation reaction

Entry

Solvent

T°

Loading [mmol/g]

time [h]

Recovered 1.134 [%]

yield [%]

1 2 3 4

DCM toluene toluene toluene

r.t r.t 130 130 (MW)

0.5 0.5 0.5 0.5

24 24 24 1

100 41 42 0

0 59 39 100

Table 1: Screening of conditions for the hydrolysis of α-iminonitriles

No reaction was observed in DCM after a prolonged period of time at room temperature, the starting material could be fully recovered after filtration. Some conversion was observed when toluene was used as solvent as the α-iminonitrile could probably absorb more easily on the alumina in a more apolar solvent. In these conditions a 60% conversion could be obtained with 40 % of recovered starting material. Increasing the temperature up to 130°C led to a lower yield of the amide, most probably owing 57

For recent reviews see: C. L. Allen, J. M. J. Williams, Chem. Soc. Rev. 2011, 40, 3405-3415; V. R. Pattabiraman, J. W. Bode, Nature 2011, 480, 471-479. 58 The activity grade is proportional to the water content of the alumina. Act I = 0%, Act II = 20%, Act III = 40% and so forth. H. Brockmann, H. Schodder, Ber. Dtsch. Chem. Ges 1941, 74, 73-78.

42

to degradation of the α-iminonitrile. By switching to microwave irradiation the reaction times could be shortened significantly which negated most of the degradation and furnished a quantitative yield after filtration. 1.1.1. Scope

Having established optimal reaction conditions we investigated the scope of this reaction (Figure 2).

Figure 2: Scope for the microwave assisted hydrolysis of α-iminonitriles

α-Iminonitriles derived from aromatic, aliphatic, and α,β-unsaturated aldehydes were hydrolyzed efficiently to their corresponding amides. Hydrolysis of both aniline and aliphatic amine derived iminonitriles worked equally well. Only compound 1.3c was obtained with a lower yield (63%). Another advantage of the alumina is that it can trap cyanide anions therefore minimizing the risk hazard59. We then studied the reaction starting from aldehydes and amines (Figure 3). We started by performing the oxidative Strecker reaction as per our standard protocol before adding the alumina and heating under microwave irradiation. Surprisingly reaction using aromatic aldehydes did not furnish the 59

K. S. Kirollos, G. M. Mihaylov, B. I. Truex (MicroTeq LLC, USA), US-A 20080176317, 2008

43

desired amide, only the α-iminonitrile could be isolated in lower yield than that of the simple oxidative Strecker reaction. On the other hand reactions using aliphatic aldehydes gave good yields of the amide. The explanation for the failed hydrolysis in the case of aromatic aldehydes was presumably that the absorption of these compounds was quite poor. Therefore we proceeded to remove all solvent after the alumina had been added and leaving the resulting powder to stand for several hours before purification. With this modified procedure the corresponding amides were obtained in good yields though the amount of alumina needed for full conversion remained very variable, up to six grams per milimole of compound in certain cases. This second procedure was very general in its scope and it was also applicable to α-iminonitriles that were derived from aliphatic aldehydes.

Figure 3: Scope for the amidation of aldehydes and amines

44

1.3. Thio-Michael Reaction of α-Iminonitriles 1.3.1. Project Overview

Our second study on the reactivity of α-iminonitriles focused on exploring the behavior of α-βunsaturated-α-iminonitriles towards conjugate addition reactions using thiols as nucleophiles as to the best of our knowledge no use of α-β-unsaturated α-iminonitriles as Michael acceptors had ever been described (Scheme 45).

Scheme 45: Thio-Michael reaction of α-iminonitriles

Thio-ethers are important motifs in biological chemistry60 with structures such as angina relieving diltiazem, antihypertensive clentiazem or anti-AIDS Nelfinavir (Figure 4), and materials science61 for surface coating, biomaterials or photolitography as well as organic chemistry which has therefore generated a need for efficient C-S bond forming methods62.

Figure 4: Thio-ether bearing drugs 60

J. M. Vierfond, L. Legendre, C. Martin, P. Rinjard, M. Miocque, Eur. J. Med. Chem. 1990, 25, 251-255; H. Inoue, M. Konda, T. Hashiyama, H. Otsuka, K. Takahashi, M. Gaino, T. Date, K. Aoe, M. Takeda, J. Med. Chem. 1991, 34, 675687; V. Ambrogi, A. Giampietri, G. Grandolini, L. Perioli, M. Ricci, L. Tuttobello, Arch. Pharm. (Weinheim, Ger.) 1992, 325, 569-577; Z.-Y. Sun, E. Botros, A.-D. Su, Y. Kim, E. Wang, N. Z. Baturay, C.-H. Kwon, J. Med. Chem. 2000, 43, 4160-4168; M. A. Raggi, R. Mandrioli, C. Sabbioni, V. Pucci, Curr. Med. Chem. 2004, 11, 279-296; J. B. Bariwal, K. D. Upadhyay, A. T. Manvar, J. C. Trivedi, J. S. Singh, K. S. Jain, A. K. Shah, Eur. J. Med. Chem. 2008, 43, 2279-2290; C. B. W. Phippen, C. S. P. McErlean, Tetrahedron Lett. 2011, 52, 1490-1492; H. S. Jung, X. Chen, J. S. Kim, J. Yoon, Chem. Soc. Rev. 2013, 42, 6019-6031. 61 A. Dondoni, Angew. Chem. Int. Ed. 2008, 47, 8995-8997; A. B. Lowe, Polymer Chemistry 2010, 1, 17-36; D. P. Nair, M. Podgórski, S. Chatani, T. Gong, W. Xi, C. R. Fenoli, C. N. Bowman, Chem. Mater. 2013, 26, 724-744. 62 T. Kondo, T.-a. Mitsudo, Chem. Rev. 2000, 100, 3205-3220; C.-F. Lee, Y.-C. Liu, S. S. Badsara, Chem. Asian. J. 2014, 9, 706-722.

45

One of the major strategies for the formation of C-S bonds is the 1,4-conjugate addition of thiols on activated double bonds, also commonly called the thio-Michael reaction. While the seminal report of Komnenos63 in 1883 and the systematic studies by Michael from 1887 onwards64 covered the attack of carbon nucleophiles on double or triple bonds the concept became so popular and was generalized to so many other nucleophiles that nowadays virtually any nucleophile to activated pi-system reaction is referred to as a Michael addition65. The Thio-Michael reaction was first developed by Posner in 1902 with the attack of thiols on dibenzylideneacetone (Scheme 46)66.

Scheme 46: Original Thio-Michael reaction

This strategy has been applied to a huge variety of systems with great success and the subject has been extensively reviewed67 and the 1,4-addition of thiols to α,β-unsaturated substrates is regarded as an efficient, atom-economical, and powerful reaction for the preparation of the corresponding thioether compounds

1.3.2. Optimization The feasibility of the reaction was first probed with compound 1.134 as a model substrate in the presence of ethanethiol and AlCl3 as Lewis acid in dichloroethane at 60°C.

63

T. Komnenos, Justus Liebigs Ann. Chem. 1883, 218, 145-167. A. Michael, J. Prakt. Chem. 1887, 35, 349-356; A. Michael, J. Prakt. Chem. 1894, 49, 20-25. 65 L. Kurti, B. Czako. Strategic Applications of Named Reactions in Organic Synthesis, Wiley, 2005, 286-287 66 T. Posner, Berichte der deutschen chemischen Gesellschaft 1902, 35, 799-816. 67 For reviews see J. Christoffers, Eur. J. Org. Chem. 1998, 1998, 1259-1266; J. Comelles, M. Moreno-Mañas, A. Vallribera, ARKIVOC (Gainesville, FL, U. S.) 2005, ix, 207-238; S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 2007, 17011716; D. Enders, K. Lüttgen, A. A. Narine, Synthesis 2007, 2007, 959-980; J. L. Vicario, D. Badía, L. Carrillo, Synthesis 2007, 2007, 2065-2092; Y. Zhang, W. Wang, Catal. Sci. Technol. 2012, 2, 42-53; M. Kawatsura, T. Itoh, in Comprehensive Chirality (Eds.: E. M. Carreira and H. Yamamoto), Elsevier, Amsterdam, 2012, pp. 436-469 and references cited within all aforementioned. 64

46

Scheme 47: Preliminary Thio-Michael trials

The reaction mixture obtained was relatively complex but a trace amount of the target compound was detected by NMR as a mixture of imine/enamine, similar results were obtained in toluene. After several trials it became apparent that the resulting β-thio-α-iminonitrile was unstable and both polymerized readily over time and degraded on silica which made isolation difficult. Despite this, and after some optimization, sufficient material was isolated to confirm that the desired compound was indeed formed. With these preliminary results in hand we screened Lewis acids chosen depending on their azaphilic character in an attempt to obtain a clean reaction to avoid purification (Table 2).

Entry

Catalyst

Solvent

C Loading

T°

1

Cu(OTf)2

DCE

10%

r.t

.

2

BF3 Et2OxH2O

DCE

10%

r.t

3

Bi(OTf)3

MeCN

10%

r.t

4

InBr3

DCE

10%

r.t

5

Sc(OTf)3

DCE

10%

r.t

6

Yb(OTf)3

DCE

10%

r.t

7

Al(OTf)3

MeCN

10%

r.t

8

AlCl3

MeCN

40%

r.t

9

Al2O3 (I)

DMF

0.55g/mmol

r.t

Table 2 Catalyst optimization for thio-michael reaction.

All except entry 9 gave the desired compound with short reaction times compared to previous attempts, about an hour at room temperature. Based on crude NMR spectra analysis as isolation was problematic due to degradation, each potential catalyst was evaluated, BF3 etherate gave the cleanest reaction with InBr3 and Yb(OTf)3 being nearly as clean. Cu(OTf)2, Bi(OTf)3 and Sc(OTf)3 gave a larger percentage of degradation while the aluminum based catalysts gave about as much side products as the desired one. Based on this Yb(OTf)3 in DCM was first selected as catalyst for the reaction as it is more practical of use than both BF3.Et2O and InBr3 due to its stability towards moisture, (InBr3 lost considerable activity over time). The follow up attempts saw reaction temperature lowered to 5° which gave an even cleaner reaction, inhibiting the formation of several byproducts. Reaction at -40° showed no further improvement thought it apparently inversed the imine/enamine ratio in favor of the enamine.

47

Isolated yields at this point were around 82% after filtration through a short pad of silica gel though this poorly represented of how clean the reaction proceeded. Note that only the imine (not the enamine) was isolated under these conditions.

48

1.4. One pot Thio-Michael-Hydrolysis of α-Iminonitriles. 1.4.1. Project Overview

In view of the poor stability of the Michael adducts of the previous project it was decided to combine this step with the previous methodology to develop a one pot process which would yield more stable substrates as shown in Scheme 48.

Scheme 48: one-pot Thio-Michael hydrolysis reaction

1.4.2. Optimisation

We first attempted to apply the diverse conditions which had proven effective for the hydrolysis on our model reaction. The thio-Michael was complete but in most cases no hydrolysis to the amide was noted (Scheme 49). After diverse attempts varying the amount of alumina, reaction time or temperature it became clear that the compound did not interact with the alumina. The solvent was changed to toluene in hopes that it’s lower polarity would allow the compound to adsorb onto the alumina and react but no conversion was observed and only the α-iminonitrile was obtained. Heating caused only degradation of the intermediate over time.

Scheme 49: Model reaction for the one-pot Thio-Michael hydrolysis reaction

In the follow up attempts the reaction was progressively concentrated but only when the intermediate was fully absorbed on the alumina under vacuum that hydrolysis occurred. The model reaction gave 1.6a in 70% yield over two steps yet we remained dissatisfied with this result as the crude NMR showed that a much higher yield could be expected. We reasoned that the intermediate could 49

polymerize during the hydrolysis step and the missing mass balance remained absorbed on the alumina, a similar result was obtained when starting from a purified α-iminonitriles. After extensive washing (10% MeOH, AcOEt) it was confirmed that a polymer about equivalent in mass to the missing 30% could be obtained from the alumina. This prompted us to screen the available types of alumina. The three parameters that were studied were the Brockmann activity I-IV, acidity (acid, neutral, basic) and quantity/time adsorbed. We first screened the activity of the alumina (Table 3) reasoning that the amount of hydroxy groups available might play an important role in the reaction, the results obtained appeared incoherent; the activity did not seem to affect the yield which was always in the same range.

Loading [mmol/g] 1 1 1

estimated conversion imine/enamine to amide 36% 26% 35%

Time on Al2O3 20 min 20 min 20 min

estimated conversion imine/enamine to amide

Time on Al2O3

r.t 40°

45% 70%

20 min 20 min

Loading [mmol/g]

T°

estimated conversion imine/enamine to amide

Time on Al2O3

0.25 0.1 0.1

r.t r.t 40°

89% 66% 86%

overnight 20 min 20 min

Entry

Al2O3 act

1 2 3

neutral II neutral III neutral IV

Entry

Al2O3 act

4 6

neutral II neutral II

0.25 0.25

Entry

Al2O3 act

7 8 9

neutral II neutral II neutral II

Loading [mmol/g]

T° r.t r.t r.t

T°

Table 3: Screenings of activity, acidity and time/temperature of the hydrolysis reaction

We then turned our attention to the amount of alumina necessary as it appeared to be the parameter which had the most impact on the conversion if not the yield, full conversion could be obtained overnight with a loading of approximately 0.1 mmol of compound per gram of alumina.

50

Entry 1 2 3 4

Loading [mmol/g] 0.75 0.2 0.15 0.1

Time on Al2O3 30 min 30 min overnight overnight

Conversion [%] 36 45 90 100

Table 4: Screening of alumina to compound ratio

It was then understood that polymerization occurred while the solvent was being removed. Evaporation was done in a water bath at 40°C, this and the growing concentration was favoring polymerization of the substrate. A brief screening was redone with evaporation at room temperature, the differences between alumina types became more apparent but hydrolysis times lengthened considerably (Table 5).

Entry

Al2O3 act

1 2 3 4

neutral I neutral II neutral III neutral IV

Entry

Al2O3 act

5 6 7

Basic III Neutral III Acid III

Loading [mmol/g] 0.1 0.1 0.1 0.1 Loading [mmol/g] 0.1 0.1 0.1

T° Overnight 24 h 36 h 36 h

T° 36 h stopped 36 h 36 h

estimated conversion imine/enamine to amide 95 84 66 67 estimated conversion imine/enamine to amide / 67 84

Table 5: Screening of alumina activity.

Counterintuitively the higher the water content the lower conversion was observed but this could be attributed to the fact that compounds are less well absorbed at the alumina’s surface at higher activities. The acidity of the alumina also played a crucial role as probably some form of acid based activation of the substrate was necessary as basic alumina give very low conversions. We then reasoned that once the substrate was absorbed onto the alumina it could no longer polymerize and that the media could then be heated to accelerate the reaction. Indeed once the substrate was fully absorbed at room temperature heating the media to 40°C reduced the reaction time considerably to around 4 hours. Under these conditions the difference between acid and neutral alumina 51

was no longer noticeable so for further reaction activity I neutral alumina was used as it is more common. 1.4.3. Scope

With reaction conditions well in hand the methodology was applied to our other substrates to probe its scope. With regards to the nature of the nucleophiles (Scheme 50), benzenethiol, as well as aliphatic thiols, including ethanethiol, benzylthiol, and sterically hindered tert-butylthiol, were well tolerated as reactants. When N-Boc-L-cystein methyl ester was used as a thiol donor, the desired compound was obtained in 70% yield as a mixture of two diastereomers. The same experiment was performed with NBoc-D-cysteine methyl ester to afford another pair of diastereomers. Supercritical fluid chromatography analysis with a chiral stationary phase∗ allowed us to conclude that no racemization occurred during this reaction sequence.

Scheme 50: Thio-Michael hydrolysis reaction scope part 1

∗

4 mL/min, 15% MeOH, chiralpak IA. 52

Pleasingly, we also found that the amine moiety could also be varied because both aliphatic amines and anilines were tolerated. Also both β-aryl- and β-alkyl-substituted α,β-unsaturated-α-iminonitriles with different electronic properties were appropriate substrates for this reaction though some required heating (Scheme 51).

Scheme 51: Thio-Michael hydrolysis reaction scope part 2

Indeed the formation of 1.6l and 1.6n required longer reaction times or heating which led to degradation. If we take the synthesis of 1.6l as example Table 6 shows the temperature screening that was needed to obtain reactivity. Entry

Reaction T° (C)

Reaction time for step 1

Isolated compound 1.6l

Recovered starting material 1.146

Hydrolyzed starting material

1 2 3 4

0 r.t 35 50

66 h stopped 66 h stopped 24 h stopped 18h

0 20% 45% 61%

n/a 23% 45% 0

n/a 25% 5% 0

Table 6: Optimising yield of less reactive α-iminonitriles

53

Reactions corresponding to entries 1-3 were stopped before full conversion as degradation became too important; entry 4 reached full conversion after 18 hours. With these less reactive unsaturated α-iminonitriles degradation of the intermediate becomes a problem and causes a net loss in overall yield. This is particularly notable between entries 3 and 4 as pushing the reaction from 45% conversion to 100% resulted only in an increase of yield of 16%. The reaction for the formation of compound 1.6m gave only degradation. Finally, we noted that different functional groups, such as carboxylic esters and N-Boc amines were also well tolerated with the exception of lighter silyl ethers which deprotected under our hydrolysis conditions. Indeed when using 2-((tertbutyldimethylsilyl)oxy)ethanethiol as nucleophile, reaction yielded a mixture of protected and deprotected β-mercaptoamides. (Scheme 52)

Scheme 52: De-protection issues.

This can be rationalized though the work of Guerrero in 1994 who showed that alumina could be used as a mild and selective de-protective media for diverse primary and secondary silyl ethers68. Based on their report the reaction was reattempted with a larger amount of alumina to fully deprotect the alcohol which gave deprotected β-mercaptoamide in 64% yield. Based on the same report switching the protecting group to a tert-butyldidiphenylsilyl and closely monitoring reaction time gave the protected β-mercaptoamide in an 83% yield with little or no trace of de-protected compound (Scheme 53).

68

J. Feixas, A. Capdevila, A. Guerrero, Tetrahedron 1994, 50, 8539-8550.

54

Scheme 53: Resilient silyl ether

. 1.4.4. One Pot oxidative Strecker Thio-Michael Amidation MCR.

Always in the optic of developing more efficient and environmentally friendly chemistry it was sought to combine all the aforementioned reactions into a single one. Results after hydrolysis of the preliminary trials are summarized in Table 7. These were encouraging and allowed us to synthesize βfunctionalized amides from aldehydes and amines through the sequential addition of reactants (Scheme 54).

Scheme 54: β-functionalized amides from aldehydes

Entry

Solvent

1 2 3

CH2Cl2 MeCN Toluene

Estimated proportion of iminonitrile (Crude NMR) 100% 66% 20%

Estimated proportion of Michael adduct (Crude NMR) trace trace 20%

Estimated proportion of amide (Crude NMR) 0% 33% 50%

Yield on isolated amide/γ-thioamide 0%/0% 20%/5% 0%/46%

Table 7: One pot preliminary trails

What was surprising was the lower efficiency of the third and fourth steps compared to when done independently. For the hydrolysis it could be reasoned that the TBAB and IBX/IBA remaining in the mixture saturated the alumina which was corrected with a higher alumina loading.

55

As for the thio-Michael, why it occurred slower than expected or not at all in DCM, solvent in which the independent reaction had a near quantitative yield, is harder to explain. One hypothesis would be that the residual oxidant interferes with the Lewis acid. This might explain why the reaction still proceeds in toluene as from experimental observations IBX is far less soluble in toluene than in DCM or acetonitrile and in this solvent IBA precipitates during the reaction. Therefore in an attempt to quench all the excess IBX which was visibly posing problem sodium sulfite and metabissulfite was added to the reaction but this gave no improvements. In the end adding an excess of thiol before the catalyst to quench the remaining IBX and cause all the IBA to precipitate out of the media helped avoid the destruction of the catalyst and pushed the yield to 75% on our model reaction with matched the stepwise process. The scope was than expanded to give reasonable yields though they remain lower than in two steps (Scheme 55).

Scheme 55: one pot scope

56

1.5. Synthesis of α-Iminonitriles through Oxone Mediated Three Component Oxidative Strecker Reaction 1.5.1. Project Overview

We then considered modifying our method for the synthesis of α-iminonitriles to use IBX catalytically, regenerating it in situ, thereby diminishing the acidity of the media and providing milder conditions potentially compatible with a new range of functional groups. A secondary achievement would be to enhance the overall atom/ waste economy of the method whose environmental cost remained high, especially for the formation of IBX. Precedence existed in literature, the growing popularity of IBX as an oxidant has led several groups to work on methods that addressed this reagents common issues, meaning its low solubility, preparative waste and potential safety hazard. In early 2005 Vinod proposed the first catalytic use of IBX for the oxidation of primary and secondary alcohols69. They developed a methodology for the oxidation of primary and secondary alcohols into the corresponding ketones and carboxylic acids using a catalytic amount of iodobenzoic acid and Oxone as a co-oxidant in a water/acetonitrile mix (Scheme 56).

Scheme 56: Vinod catalytic IBX based oxydation

Later in 2006 Giannis reported a water/ethyl acetate biphasic system bridged by a phase transfer catalyst to oxidize primary benzylic alcohols to aldehydes (Scheme 57). 70

Scheme 57: Giannis catalytic IBX based oxydation 69 70

A. P. Thottumkara, M. S. Bowsher, T. K. Vinod, Org. Lett. 2005, 7, 2933-2936. A. Schulze, A. Giannis, Synthesis 2006, 2006, 257,260.

57

In parallel, several analogs of IBX were synthetized by diverse groups with similar aims, and while used as oxidants in stoichiometric amounts, each has its own advantages in comparison to traditional IBX53,71. In 2008 Ishihara combined these advances with the concept of Oxone regenerated IBX to propose a new oxidative system. Using 2-Iodoxybenzenesulfonic acid in catalytic amounts with Oxone in acetonitrile at 70°, he demonstrated the smooth oxidation of many complex alcohols to the corresponding ketones72 (Scheme 58).

Scheme 58: Ishihara optimized catalytic oxidative system

The use of Oxone has many advantages, it is considered safe in comparison with IBX, easily removable as water soluble, cheap and bench-top stable. The use of Oxone in organic synthesis has recently been reviewed very nicely73 1.5.2. Optimization

Based on these results we were convinced that our objective was achievable and therefore began on our first trials on the following model reaction (Scheme 59).

Scheme 59: Model reaction for the Oxone mediated synthesis of α-iminonitriles 71

A. P. Thottumkara, T. K. Vinod, Tetrahedron Lett. 2002, 43, 569-572; A. Ozanne, L. Pouységu, D. Depernet, B. François, S. Quideau, Org. Lett. 2003, 5, 2903-2906; J. T. Su, W. A. Goddard, J. Am. Chem. Soc. 2005, 127, 1414614147; A. Ozanne-Beaudenon, S. Quideau, Tetrahedron Lett. 2006, 47, 5869-5873; R. D. Richardson, J. M. Zayed, S. Altermann, D. Smith, T. Wirth, Angew. Chem. Int. Ed. 2007, 46, 6529-6532. 72 M. Uyanik, M. Akakura, K. Ishihara, J. Am. Chem. Soc. 2008, 131, 251-262. 73 H. Hussain, I. R. Green, I. Ahmed, Chem. Rev. 2013, 113, 3329-3371.

58

Primary results were disappointing (Table 8). Only trace amounts of desired compound were observed at room temperature (entry 2-6) and no regenerative activity from the Oxone was observed. This is understandable when compared to literature results as procedures published up to this point all required elevated temperatures (about 70°C). While this is a common requirement when using IBX to oxidize alcohols it is on the other hand an obligatory step when generating IBX from iodobenzoic acid. While the oxidation of iodine I to III is possible at room temperature with Oxone, oxidation to an iodine V state requires heating.

Entry

Solvent

1 2 3 4 5 6 7 8 9 10

Toluene Toluene MeCN Toluene/H2O Toluene/H2O EtOAc/H2O MeCN/H2O Toluene/H2O EtOAc/H2O MeCN/H2O

T [°C] r.t r.t r.t r.t r.t r.t r.t 70 70 70

IBX [equiv] 0 0.1 0.1 0 0.1 0.1 0.1 0.1 0.1 0.1

TBAB [equiv] 0 1 1 0 1 1 1 1 1 1

Oxone [equiv] 1 1 1 1 1 1 1 1 1 1

Reaction time 4h 4h 4h overnight overnight overnight overnight overnight overnight overnight

Product none trace trace trace trace trace none none none none

Table 8: primary trials Oxone medaited synthesis of α-iminonitriles

This posed a problem as some α-iminonitriles, as our model compound, do not survive at higher temperatures (entry 8-10). Conversion was total overnight but no desired compound could be isolated. What on the other hand was most interesting was the trace amount of compound detected in the blank reaction (entry 4) and the slight increase in yield noted when using a biphasic system. From this observation rose our next hypothesis, that under the proper conditions Oxone could oxidize α-aminonitriles into α-iminonitriles. We therefore tried to modify our reaction conditions to augment the proportion of oxidative species being solubilized in our organic phase with a phase transfer reagent (Scheme 60).

Scheme 60: phase transfer oxidation

59

Toluene, having given the best primary results, was chosen as solvent, Oxone and TBAB equivalents were arbitrarily fixed to 1 for the initial optimization phase. The organic to aqueous solvent ratio was first studied. A ratio between 10 and 20 percent was found to be optimal, dissolving the all salts fully. The next parameter studied was the concentration as this had proven to have its importance in the previous method for synthetizing α-iminonitriles. It indeed proved key raising yields by 25% when the concentration was augmented from 0.5 to 0.75 M. Above this concentration the solubility of both the reagents and the intermediate aminonitrile become too poor and the reagents precipitated. This concentration effect can be attributed to a shortening of the reaction time which diminishes the possibility of side reactions. A notable smoothing of the baseline on the crude mixture NMR spectra was noticed at higher concentrations (Table 9).

Entry

Solvent

Co-Solvent [water %]

Oxidant

Additive [equiv]

Concentration vs Toluene [M]

Reaction time

Yield [%]

1 2 3 4 5 6 7

Toluene Toluene Toluene Toluene Toluene Toluene Toluene

10 5 10 20 10 10

Oxone Oxone Oxone Oxone Oxone Oxone Oxone

TBAB (1) TBAB (1) TBAB (1) TBAB (1) TBAB (1)

0.25 0.25 0.25 0.25 0.25 0.5 0.75

4h 4h 45 min 3.5h 1.5h 1h 30 min

0 14 42 57 52 65 75

Table 9: co-solvent and concentration effects

The quantity and ratio of Oxone and TBAB were then studied. Ideality these could be reduced to 0.5 equivalents of Oxone (each equivalent of Oxone representing 2 equivalents of oxidative species) and catalytic amounts of TBAB. Sadly TBAB degrades over time in the presence of Oxone and the reaction stops before full conversion when less than one equivalent is used. An unequal ratio of Oxone to TBAB also gave poorer results as the reaction media precipitated in these cases. Increasing the amount of TBAB and Oxone did not improve the yield any further and therefore the equivalence was left at 1 for both Oxone and TBAB (Table 10).

60

Entry

Solvent

1 2 3 4 5 6 7

Toluene (10% H2O) Toluene (10% H2O) Toluene (10% H2O) Toluene (10% H2O) Toluene (10% H2O) Toluene (10% H2O) Toluene (10% H2O)

Oxone [equiv] 1 2 2 1 0.55 0.55 1

TBAB [equiv] 2 1 2 0.5 1 0.5 1

Concentration [M] 0.75 0.75 0.75 0.75 0.75 0.75 0.75

Yield [%] 68 61 79 25 29 10 75

Table 10: Oxone/TBAB ratio optimization

In an effort to further improve the yield we turned our attention to the overall acidity of our media. One observation was that the reaction media was far more acidic than when IBX was used. This was very possibly one of the major reasons for the loss of yield. The pH was therefore corrected with an inorganic base to avoid potential interference within the organic phase (Table 11). Adding 1.5 equivalents of sodium bicarbonate at 5°C to avoid overheating due to exothermicity corrected the pH to about 6, two units higher than with IBX. This saw the yield raise a further 17% for an overall yield of 92%. The addition of 3 equivalents of base pushed pH to 8 and required 20% of water for correct solubility but this would prove useful in certain examples.

Entry

Solvent

Oxone/TBAB

NaHCO3

Concentration

Yield

1

Toluene (10% H2O)

1:1

1

0.75

83%

2

Toluene (10% H2O)

1:1

2

0.75

86%

3

Toluene (10% H2O)

1:1

1.5

0.75

88%

4

Toluene (10% H2O)

1:1

1.5

0.75/5°C

92%

Table 11: pH screening

1.5.3. Scope

The scope of the reaction was then probed. A large panel of functional groups with diverse steric and electronic properties was studied (Scheme 61 and Scheme 62).

61

Scheme 61: Scope of Oxone iminonitrile synthesis

All the examples above worked well giving the desired iminonitriles in good yield. Functional group tolerance in regards to the aldehyde is broad, the method allows for both electron rich and poor groups, aromatic or aliphatic, and has a high tolerance for steric hindrance. One point to note is that for electron-richer aromatic aldehydes, i.e. anisaldehyde a slight modification of procedure is needed as a side reaction yielding the cyanohydrin takes place. Increasing the reaction time for the condensation 62

step is key to avoid this side reaction. With regards to amines, electron neutral and rich substituents function well including highly oxydizable p-methoxyaniline and cyclopropylamine though with limited allowance for steric hindrance. Interestingly amino-alcohols can be used directly without the competitive oxidation of the alcohol which is in-situ protected to the trimethylsilylether. Due to the milder acidity of the reaction media, acid sensitive groups are also well tolerated such as silyl ethers and acetals. It is noteworthy to note that no side oxidation of double bonds or of the imines are observed despite the excess of oxidant in the mixture which gives this reaction a remarkable chemoselectivity. Limitations of scope were encountered; a representative list of these is detailed below (Scheme 62).

Scheme 62: Oxone based method, failed cases.

Steric hindrance on the amine was shown to be important, quaternary neighboring centers block reactivity and only trace amounts of the desired compound was observed, this might be an indication that the reaction mechanism is similar to the one described for IBX (Scheme 41). The oxidant needs to be able to react with the amine to initiate the reaction and form an N-hydroxy amine, making it highly dependent on the hindrance of any group present on the amine. The second step would then be the elimination of the neighboring proton to form water and the desired product; this step would be weakly influenced by the spacial nature of any substituent on the aldehyde. Cyclopropylamine functions well as reagent which can indicate that the reaction does not pass through a radical pathway. A reaction replacing TBAB with tetrabutylammonium hydrogen sulfate gave a similar yield which confirmed its role as phase transfer agent and another reaction using tetrabutylammonium Oxone74 demonstrated that 74

B. M. Trost, R. Braslau, J. Org. Chem 1988, 53, 532-537.

63

this was indeed the active species. Finally electron withdrawing groups on the amine hindered the oxidative process and only the Strecker adduct could be isolated while reactions to form Nitro-derivates 1.138t and 1.138u yielded only degradation. Starting material for the 1,3 acetal protected example (1.138d) was made with the following sequence (Scheme 63). OH I

Ac2O

O

Ac

allyl alcohol Pd(OAc)2

88% 1.157

1.156 1) ethyleneglycol, 2) MeOH, K2CO3 3) PCC

Ac O

I quantitative

1.155

O

O O O 55% 1.158

Scheme 63: Noncommercial aldehyde preparation

64

1.6. Studies Towards the Metal Catalyzed C-CN Insertion 1.6.1. Background To continue our exploration of the synthetic potential of α-iminonitriles we decided to investigate their behavior towards C-CN bond insertion. The whole topic of C-C bond insertions will only be briefly overviewed as too broad; focus will be centered on the specific section of interest to this project. Carbon-carbon single bonds are among the most poorly reactive functions available in organic chemistry to the point they are barely considered as such. While examples of their reactivity exist in some named reaction such the Bayer-Williger or Wagner–Meerwein rearrangements they are relatively rare. Even so, with the aid of transition metals, the chemistry of their activation and cleavage has been studied over the years to yield some interesting synthetic methods; several reviews exist on the subject.75 The methods that exist to cleave C-C bonds can be regrouped in four major families as briefly described below. Decarbonylation, first described by Nilsson76 in 1966, involves breaking at least one C-C bond neighboring a carbonyl to remove from the core skeleton a CO or CO2 moiety (Scheme 64). The principle of migratory carbonyl extrusion has been reused over the years and studied in depths by several groups.

Scheme 64: Migratory carbonyl extrusion

Retro-allylation (Scheme 65), which was extensively studied by Oshima from 2006 onwards77 but which had been known though understudied long prior to his work and considered as a potential side reaction to diverse alkylmetal additions as Grignard reactions for example78

75

Y. J. Park, J.-W. Park, C.-H. Jun, Acc. Chem. Res. 2008, 41, 222-234; C. Nájera, J. M. Sansano, Angew. Chem. Int. Ed. 2009, 48, 2452-2456; M. Murakami, T. Matsuda, Chem. Commun. (Cambridge, U. K.) 2011, 47, 1100-1105; K. Ruhland, Eur. J. Org. Chem. 2012, 2012, 2683-2706. 76 M. Nilsson, Acta. Chem. Scand. 1966, 423-426. See previous reviews for more details. 77 For representative publications see: S. Hayashi, K. Hirano, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2006, 128, 2210-2211; H. Yorimitsu, K. Oshima, Bull. Chem. Soc. Jpn. 2009, 82, 778-792. 78 R. A. Benkeser, W. E. Broxterman, J. Am. Chem. Soc. 1969, 91, 5162-5163; V. Peruzzo, G. Tagliavini, J. Organomet. Chem. 1978, 162, 37-44; T. Kondo, K. Kodoi, E. Nishinaga, T. Okada, Y. Morisaki, Y. Watanabe, T.-a. Mitsudo, J. Am. Chem. Soc. 1998, 120, 5587-5588.

65

Scheme 65: Retro-allylation

β-carbon elimination, an intramolecular process, where early transition metals break C-C bonds through an sp3-carbon linking moiety and late transition metals break the same bonds through a heteroatom linking moiety though it requires the aid of an additional driving force such as strain release from ring opening for example with the exception of β-aryl/alkynyl eliminations as summarized in Scheme 66.79

Scheme 66: β-carbon elimination

The final family is oxidative additions which is the most studied and well documented transformation (Scheme 67).

Scheme 67: Oxidative insertion

Diverse strategies have been employed for metal insertion; early methods relied on an auxiliary driving force such as the release of ring strain or re-aromatization. Then were developed methods relying on the kinetic and thermodynamic aid of neighboring groups through chelation or activation.80 The metal centers responsible for the diverse reported reactions have the common feature of being able to back donate electrons to the anti-bonding orbital of the bond to cleave while varying its oxidation level by +/2. This mostly means the use of electron rich late transition metals with low oxidation states is necessary with some exceptions. Mechanistically the few results that exits indicate that agnostic interactions

79

For representative papers on the diverse aspects see: P. L. Watson, D. C. Roe, J. Am. Chem. Soc. 1982, 104, 64716473; T. Nishimura, K. Ohe, S. Uemura, J. Am. Chem. Soc. 1999, 121, 2645-2646; M. Murakami, T. Tsuruta, Y. Ito, Angew. Chem. Int. Ed. 2000, 39, 2484-2486; T. Nishimura, H. Araki, Y. Maeda, S. Uemura, Org. Lett. 2003, 5, 29972999; H. Kusama, H. Yamabe, Y. Onizawa, T. Hoshino, N. Iwasawa, Angew. Chem. Int. Ed. 2005, 44, 468-470; H. Li, Y. Li, X.-S. Zhang, K. Chen, X. Wang, Z.-J. Shi, J. Am. Chem. Soc. 2011, 133, 15244-15247. 80 J. J. Garcia, W. D. Jones, Organometallics 2000, 19, 5544-5545; T. l. A. Ateşin, T. Li, S. b. Lachaize, J. J. García, W. D. Jones, Organometallics 2008, 27, 3811-3817.

66

between the desired bond and the metal center precedes cleavage of the C-C bond as shown below in one of the rare characterized intermediates (Figure 5).81

Figure 5: Agostic complex

The specific oxidative addition family which is of interest to us is the cleavage of C-CN bonds. Several metals have been used for this reaction though nickel and palladium are the most common. This proved to be a challenging transformation as the C-CN bond strength is >100kcal/mole and kinetically inert75. The use of nickel was first described by Turco in 198382 using a nickel 0 complex for the insertion in NC-Ar bonds, this type of insertion has been studied in detail since then. Mechanistic studies and DFT based calculations were performed by Jones on such reaction types from 200080 bringing into light the diverse η2 type of interactions between metal and nitrile or neighboring directing group before insertion to the desired C-C bond (Scheme 68).

Scheme 68: Example of systems studied by Jones.

A similar study was performed by Bergman and Brookhart later on.83 They study the capacity of a rhodium silyl complex to insert in a NC-R bond (Scheme 69).

81

A. B. Chaplin, J. C. Green, A. S. Weller, J. Am. Chem. Soc. 2011, 133, 13162-13168. G. Favero, A. Morvillo, A. Turco, J. Organomet. Chem. 1983, 241, 251-257. 83 F. L. Taw, A. H. Mueller, R. G. Bergman, M. Brookhart, J. Am. Chem. Soc. 2003, 125, 9808-9813. 82

67

Scheme 69: Brookhart/Bergman system.

Miller published a coupling reaction using a similar C-CN insertion intermediate (Scheme 70).84

Scheme 70: Miller oxidative insertion

From 2006 and onwards Nakao and Hiyama published a series of reaction involving the oxidative insertion within the C-CN bond for the formation of various structures demonstrating the versatility of the reaction and the importance of the use of a chelating Lewis acid to facilitate the transition from the η2 system to the inserted complex in the case of less activated C-CN bonds (Scheme 71).85

84

J. M. Penney, J. A. Miller, Tetrahedron Lett. 2004, 45, 4989-4992. Y. Nakao, Y. Hirata, T. Hiyama, J. Am. Chem. Soc. 2006, 128, 7420-7421; Y. Nakao, S. Ebata, A. Yada, T. Hiyama, M. Ikawa, S. Ogoshi, J. Am. Chem. Soc. 2008, 130, 12874-12875; Y. Hirata, T. Yukawa, N. Kashihara, Y. Nakao, T. Hiyama, J. Am. Chem. Soc. 2009, 131, 10964-10973; Y. Hirata, T. Inui, Y. Nakao, T. Hiyama, J. Am. Chem. Soc. 2009, 131, 6624-6631; Y. Nakao, A. Yada, T. Hiyama, J. Am. Chem. Soc. 2010, 132, 10024-10026; Y. Hirata, A. Yada, E. Morita, Y. Nakao, T. Hiyama, M. Ohashi, S. Ogoshi, J. Am. Chem. Soc. 2010, 132, 10070-10077; A. Yada, S. Ebata, H. Idei, D. Zhang, Y. Nakao, T. Hiyama, Bull. Chem. Soc. Jpn. 2010, 83, 1170-1184; A. Yada, T. Yukawa, H. Idei, Y. Nakao, T. Hiyama, Bull. Chem. Soc. Jpn. 2010, 83, 619-634; J.-C. Hsieh, S. Ebata, Y. Nakao, T. Hiyama, Synlett 2010, 2010, 1709,1711; Y. Minami, H. Yoshiyasu, Y. Nakao, T. Hiyama, Angew. Chem. Int. Ed. 2012, asap; Y. Minami, H. Yoshiyasu, Y. Nakao, T. Hiyama, Angew. Chem. Int. Ed. 2013, 52, 883-887. 85

68

Scheme 71: Examples of Hiyama’s reactions

In 2007 Radius performed a study showing that N-heterocyclic carbenes are also highly active ligands for the oxidative insertion of a metal within a C-CN bond.86 In 2008 Jacobsen demonstrated that an asymmetric version of the previously described synthesis was possible using diverse bidentate phosphine ligands in similar conditions to Hiyama (Scheme 72).87

Scheme 72: Asymmetric version of C-CN insertion

The palladium based oxidative insertion reaction was first described in 1985 by Murahashi on acyl cyanides as a decarbonylation reaction to form aryl cyanides (Scheme 73).88

86

T. Schaub, C. Doring, U. Radius, Dalton Trans. 2007, 1993-2002. M. P. Watson, E. N. Jacobsen, J. Am. Chem. Soc. 2008, 130, 12594-12595. 88 S. Murahashi, T. Naota, N. Nakajima, J. Org. Chem 1986, 51, 898-901. 87

69

Scheme 73: Decarbonylation of aryl cyanides

From 2003 both the Nishihara and Takemoto group published papers on diverse transformations involving C-CN insertion. Nishihara reported the addition of cyanoesters onto diverse norbornene derivates with palladium89 before publishing an in depths study on the mechanism of the transformation (Scheme 74).90

Scheme 74: Proposed mechanism for Nishihara’s transformation

Takemoto in 2006 and 2007 reported the cyclisation reaction of cyanoamides with palladium to form lactams of diverse ring sizes proposing a similar reaction mechanism.91 In 2008 he reported an asymmetric version by replacing the ligand from triphenylphosphine to chiral phosphoramidite and N,Ndimethylpropylene (Scheme 75).92

Scheme 75: Takemoto transformation.

89

Y. Nishihara, Y. Inoue, M. Itazaki, K. Takagi, Org. Lett. 2005, 7, 2639-2641. Y. Nishihara, M. Miyasaka, Y. Inoue, T. Yamaguchi, M. Kojima, K. Takagi, Organometallics 2007, 26, 4054-4060. 91 Y. Kobayashi, H. Kamisaki, R. Yanada, Y. Takemoto, Org. Lett. 2006, 8, 2711-2713; Y. Kobayashi, H. Kamisaki, H. Takeda, Y. Yasui, R. Yanada, Y. Takemoto, Tetrahedron 2007, 63, 2978-2989. 92 Y. Yasui, H. Kamisaki, Y. Takemoto, Org. Lett. 2008, 10, 3303-3306; Y. Yasui, H. Kamisaki, T. Ishida, Y. Takemoto, Tetrahedron 2010, 66, 1980-1989. 90

70

Later in 2011 Douglas reported a similar cyclisation reaction on cyanoesters (Scheme 76).93

Scheme 76: Douglas transformation

1.6.2. Results

The first transformation attempted was the insertion of a metal in the C-CN bond before addition to a triple bond as shown in Scheme 77.

Scheme 77: General insertion scheme.

The first model reaction based on this scheme used readily available α-iminonitrile 1.138j that was judged as best substrate for primary trials (Scheme 78).

Scheme 78: Primary model reaction 93

N. R. Rondla, S. M. Levi, J. M. Ryss, R. A. Vanden Berg, C. J. Douglas, Org. Lett. 2011, 13, 1940-1943.

71

A screening of conditions was performed during which various sources of both nickel and palladium were tested in the presence of both ligands and additives chosen in function of the literature precedence mentioned previously but sadly no desired product was detected. In most cases only starting material was recovered or only degradation of the reagents was observed due to prolonged periods at reflux in the presence of Lewis acids. A second model reaction was studied with a more electron neutral α-iminonitrile in case the too rich substrate was the cause for the poor reactivity (Scheme 79).

Scheme 79: Second model reaction

A similar screening of conditions was performed but the same reactivity pattern was noted with no desired product detected. Test reactions on cyanoesters were performed and confirmed that the catalysts were of good quality and not the cause of this poor reactivity. A third model reaction was studied to see if the reaction was possible intramolecularly.

Scheme 80: Third model reaction.

Screening of conditions yielded no reaction or degradation as with previous model reactions though a side reaction consisting of the migration of the double bond from terminal to benzylic position was observed when palladium was used as catalyst which suggested that some form of palladium allyl complex might be formed preferentially to the C-CN insertion which might block reactivity. Another point of interest is the color shift of the reaction before and after addition of the nickel catalyst. Jones describes this same color shift as due to the η2 coordination of nickel to the nitrile. This could indicate that the preliminary interaction is present but as the color doesn’t fade as described even after

72

prolonged periods of heating. This suggests that that the oxidative insertion doesn’t take place and the intermediate ends up decomposing. Following these primary observation the project was placed on hold as positive results were being obtained in another project. A recent publication by Douglas94 reported a very similar transformation with palladium (Scheme 81), validating therefore our initial working hypothesis.

Scheme 81: Douglas nitrile insertion

1.7. Conclusion In summary, we have developed the first mild and general conditions for the hydrolysis of α-iminonitriles to amides. This method was applicable to a wide range of substrates bearing both aromatic and aliphatic substituents. We than extended the concept by developing an efficient one pot amidation of aldehydes and amines which was also applicable to a broad scope of substrates in good to excellent yields (Scheme 82).

Scheme 82: Amidation of aldehydes via α-iminonitriles

94

N. R. Rondla, J. M. Ogilvie, Z. Pan, C. J. Douglas, Chem. Comm. 2014, 8974-8977.

73

We then developed the first Lewis acid catalyzed thio-Michael addition of thiols to α-iminonitriles in good yields and applied this method to a wide variety of substrates. We then proceeded to combine it with our first methodology in an integrated process with positive results (Scheme 83).

Scheme 83: One pot thio-Michael-hydrolysis of α-Iminonitriles.

As a follow up, an alternative one pot oxidative Strecker reaction was developed using environmentally friendly Oxone as oxidant which further expanded the scope of available α-iminonitriles (Scheme 84).

Scheme 84: Oxone mediated oxidative Strecker reaction.

Building on these projects we tackled the topic of metal-catalyzed oxidative insertion within the C-CN bond of α-iminonitriles. While preliminary results were negative in this case, recent reports shed new light on the concept which might provide ideas as to a solution to the problems encountered. The results obtained thus far on this project were gathered and published95.

95

J.-B. Gualtierotti, X. Schumacher, P. Fontaine, G. Masson, Q. Wang, J. Zhu, Chem. Eur. J 2012, 18, 14812-14819; J.B. Gualtierotti, X. Schumacher, Q. Wang, J. Zhu, Synthesis 2013, 45, 1380-1386.

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Chapter 2: Phosphoric Acid-catalyzed Desymmetrization of Bicyclic Bislactones Bearing an All Carbon Quaternary Stereogenic Center This second chapter will cover the work that has been done on the desymmetrization of eight membered anhydrides and bislactones in view of their use in the total synthesis of natural compounds (Scheme 85). Catalytic desymmetrization of prochiral compounds has become over the years one of the major strategies to reach enantiomerically pure compounds. This method is based on the breaking of a symmetry element through the selective reaction on one enantiotopic element verses the other via the aid of a chiral catalyst. Its key feature over other asymmetric methods is that the established chiral center can be far away from the reaction site96. Classification of the families of desymmetrizable compounds have been made and tend to grossly regroup anhydrides and epoxides as well as their heteroatom analogues96,97,100,100, diols, diesters, diethers and other meso type compounds98, enes, dienes, imines and ketones96,98 and finally asymmetric deprotonation99. As these topics have been extensively reviewed this chapter will only elaborate on what background is needed to put in perspective the project presented hereafter.

Scheme 85: Target desymmetrization reactions.

96

For reviews on the subject see: M. C. Willis, J. Chem. Soc., Perkin Trans. 1 1999, 1765-1784; H. Fernandez-Perez, P. Etayo, J. R. Lao, J. L. Nunez-Rico, A. Vidal-Ferran, Chem. Comm. 2013, 49, 10666-10675. 97 See P.-A. Wang, Beilstein J. Org. Chem. 2013, 9, 1677-1695. 98 K. Mikami, M. Lautens. New Frontiers in Asymmetric Catalysis, Wiley, 2007, ; A. Enriquez-Garcia, E. P. Kundig, Chem. Soc. Rev. 2012, 41, 7803-7831; M. D. Díaz-de-Villegas, J. A. Gálvez, R. Badorrey, M. P. López-Ram-de-Víu, Chem. Eur. J 2012, 18, 13920-13935. 99 P. O'Brien, J. Chem. Soc., Perkin Trans. 1 1998, 1439-1458; J. Eames, Eur. J. Org. Chem. 2002, 2002, 393-401.

75

2.1. Desymmetrization of Anhydrides 2.1.1. Desymmetrization of anhydrides via Organocatalysis

As previously mentioned, the desymmetrization of cyclic anhydrides is relatively well known in organic chemistry.100 This method is based on the breaking of molecular symmetry through functional group differentiation. A variety of catalysts have been used to do so including enzymes101, chiral metal complexes102 and organocatalysts. This last category of catalysts has recently drawn a lot of interest, mostly due to the fact that their precursors are often inexpensive and easily available. Most are also nontoxic, bench-top stable and compatible with many diverse functional groups and conditions. Of these, cinchona alkaloid derivatives have often proven their efficiency for this type of transformation. Seminal reports date back to the end of the 1980s by the Oda103 and Aitken104 groups who reported the methanolysis of bi and tri-cyclic anhydrides with quinine and quinidine as catalysts. The enantioselectivity remained moderated, the reaction affording the product with ee’s ranging from 25% to 65% (Scheme 86).

Scheme 86: First anhydride desymmetrizations

100

For reviews on the subject see : I. Atodiresei, I. Schiffers, C. Bolm, Chem. Rev. 2007, 107, 5683-5712; M. D. Diaz de Villegas, J. A. Galvez, P. Etayo, R. Badorrey, P. Lopez-Ram-de-Viu, Chem. Soc. Rev. 2011, 40, 5564-5587. 101 E. García-Urdiales, I. Alfonso, V. Gotor, Chem. Rev. 2004, 105, 313-354. 102 J. B. Johnson, T. Rovis, Acc. Chem. Res. 2008, 41, 327-338. 103 J. Hiratake, Y. Yamamoto, J. i. Oda, J. Chem. Soc., Chem. Commun. 1985, 1717-1719. 104 R. A. Aitken, J. Gopal, J. A. Hirst, J. Chem. Soc., Chem. Commun. 1988, 632-634.

76

In 1999 Bolm proposed a new protocol based on the principle established some 15 years previously. By changing the polarity of the solvent used and the reaction temperature, he pushed yields and enantioselectivities up to 90% and 90% ee.105 More in depths studies on the influence of the solvent’s polarity on the reaction were done some years later by Carloni106. He also studied what effect an auxiliary base would have on the reaction and the possibility of using a solid supported catalyst. The two major conclusions were that while amine bases allowed for lower catalyst loadings they are detrimental to enantioselectivity and that aprotic polar solvents like THF are optimal for the reaction.

Scheme 87: Bolm improvements

In order to enhance further scope and enantioselectivity of this type of transformations, many derivatives of the naturally occurring cinchona alkaloids were both made and tested. Deng used (DHQD)2AQN and (DHQ)2AQN107 to obtain higher ee’s (>90%) and yields (>70%) at higher temperatures (20°C) and lower catalyst loadings (Scheme 88).

Scheme 88: Deng synthesis

105

C. Bolm, A. Gerlach, C. L. Dinter, Synlett 1999, 1999, 195-196; C. Bolm, I. Schiffers, C. L. Dinter, A. Gerlach, J. Org. Chem 2000, 65, 6984-6991. 106 F. Bigi, S. Carloni, R. Maggi, A. Mazzacani, G. Sartori, G. Tanzi, J. Mol. Catal. A: Chem. 2002, 182–183, 533-539. 107 Y. Chen, S.-K. Tian, L. Deng, J. Am. Chem. Soc. 2000, 122, 9542-9543.

77

Deng furthered his studies on the effect of derivatization of the benzylic position of quinine and quinidine towards the desymmetrization of cyclic anhydrides, -O-naphtalene and -O-CH2-CO2-adamentyl derivates showed the best results especially in trifluoroethanol108. Other functionalizations of that particular position that proved particularly effective were through the urea and thiourea moieties. As shown by Connon109 in 2008 their enhanced H bond donor character makes a remarkable difference as they obtain at room temperature and extremely low loadings superior results to what had been previously reported (Scheme 89). It was clearly shown that the concentration and solvent effects were critically important in this process; ee’s were above 90% only in TBME at 0.025 M. In the same year Song published similar results with an extended study on the solvent and concentration effect as well as computation supported mechanistic investigations.110

Scheme 89: Connon thioura based method

After these reports this family of catalyst continued to evolve until it lost nearly entirely the cinchona backbone to conserve only the essential thiourea and tertiary amine moieties as reported by Chen111, Pedrosa112 and Bolm113 giving in mild conditions high enantioselectivities for the desymmetrization of many anhydrides (Scheme 90).

108

S.-K. Tian, Y. Chen, J. Hang, L. Tang, P. McDaid, L. Deng, Acc. Chem. Res. 2004, 37, 621-631. A. Peschiulli, Y. Gun'k, S. J. Connon, J. Org. Chem 2008, 73, 2454-2457. 110 H. S. Rho, S. H. Oh, J. W. Lee, J. Y. Lee, J. Chin, C. E. Song, Chem. Commun. (Cambridge, U. K.) 2008, 1208-1210. 111 S.-X. Wang, F.-E. Chen, Adv. Synth. Catal. 2009, 351, 547-552. 112 R. n. Manzano, J. M. Andrés, M. a.-D. Muruzábal, R. Pedrosa, J. Org. Chem 2010, 75, 5417-5420. 113 E. Schmitt, I. Schiffers, C. Bolm, Tetrahedron 2010, 66, 6349-6357. 109

78

Scheme 90: Chen catalytic system

In a similar optic of catalyst optimization, binol based phosphoramide and sulfonamide derivates of quinidine at the benzylic position were also studied. Song reported a highly efficient desymmetrization at room temperature with a quinine sulfonamide catalyst114 (Scheme 91). He then made a library of sulfonamide bearing catalysts by changing substitution patterns on the sulfonamide, quinoline and vinyl positions115, all of which gave ee’s above 90% and yields in a similar range. Structural studies showed that in opposition to the other bifunctional catalysts mentioned above these did not form selfaggregates through H bonding and therefore avoided self-deactivation issues. This was felt in terms of reactivity by a significant shortening of the reaction times.

Scheme 91: Song’s sulfonamide catalyst

Later they developed a polymer supported version through the tethering of the catalyst by the aryl moiety of the sulfonamide116 which proved just as efficient and resilient; no loss of ee or yield was observed even after 10 cycles. As with the thiourea catalyst, it was also edited to yield an efficient lightweight version as described by Nagao in 2005117 with thiols as nucleophile and in 2009118 with alcohols.

114

S. H. Oh, H. S. Rho, J. W. Lee, J. E. Lee, S. H. Youk, J. Chin, C. E. Song, Angew. Chem. Int. Ed. 2008, 47, 7872-7875. S. E. Park, E. H. Nam, H. B. Jang, J. S. Oh, S. Some, Y. S. Lee, C. E. Song, Adv. Synth. Catal. 2010, 352, 2211-2217. 116 S. H. Youk, S. H. Oh, H. S. Rho, J. E. Lee, J. W. Lee, C. E. Song, Chem. Commun. (Cambridge, U. K.) 2009, 22202222. 117 T. Honjo, S. Sano, M. Shiro, Y. Nagao, Angew. Chem. Int. Ed. 2005, 44, 5838-5841. 118 T. Honjo, T. Tsumura, S. Sano, Y. Nagao, K. Yamaguchi, Y. Sei, Synlett 2009, 2009, 3279-3282. 115

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In 2010 List challenged the traditional Lewis base catalyzed model by proposing a Brønsted acid/base bifunctional phosphoramide catalytic system119 with both high yields and ee’s (Scheme 92).

Scheme 92: List’s phosphoramide catalyst

The mechanism of action of the diverse catalysts presented has been well studied and always follows a similar pattern. The nucleophile is activated and guided in its attack to the anhydride through H bonding with the tertiary amine moiety of the catalyst, the anhydride itself is activated through the H bond donor moiety of the catalyst; this interaction also defines the facial selectivity of the reaction, as is illustrated below (Figure 6).

Figure 6: Catalyst mode of action

119

V. N. Wakchaure, B. List, Angew. Chem. Int. Ed. 2010, 49, 4136-4139.

80

2.1.2. Desymmetrization of anhydrides via Enzymes

A second, less employed, strategy for the desymmetrization of anhydrides is through the use of enzymes. Enzymes have found numerous uses within synthetic chemistry as they provide an easy access towards highly enantioenriched substrates at far lower cost than with many catalysts that require multistep syntheses for their formation. They also offer other significant advantages as they are often easily removable, stable and even reusable. Their high activity also allows them to be used at very low loadings. Despite these advantages several drawbacks limit their overall use in the field. They are often used in water which can prove impractical and are very “hit or miss” making both their scope and efficiency hard to predict. Within the topic of desymmetrization enzymes have been applied with varying degrees of success to multiple functional groups including esters and anhydrides. The most commonly used enzymes are so-called hydrolases. The term hydrolases is applicable the very wide range of enzymes which are typically classified as EC 3 following the standards of the Enzyme Commission, a biochemical equivalent to the IUPAC, who categorize enzymes by the type of reaction they catalyze. These can be further divided into subclasses such as esterase and lipases. Hydrolyses have given the best results among the diverse classes of enzymes for the transformation of esters and anhydrides as they often do not need cofactors and have flexible active sites which accept a high range of compounds. Their mode of action is relatively well understood as most possess at least one amino acid within their chiral pocket capable of nucleophilic attack to form a covalent substrate-enzyme bond and another capable of water activation for subsequent hydrolysis. Their tolerance to organic co-solvents also tends to also be higher. A full recount of the field would be impossible as this method is firmly integrated into the synthetic panorama; many reviews efficiently cover the subject101. Only some more pertinent examples will be discussed here. Reports on the enantioselective opening of anhydrides by enzymes are scarce due to inherent incompatibility between the required aqueous media for the enzymes and the nucleophilicity of the water which would compete for the opening of the anhydride with the nucleophile. What exists consists mostly of the work of Ozegowski120 (Scheme 93) and Ostaszewski121 (Scheme 94) who showed that certain hydrolases were compatible with ethereal solvents and gave high reactivity and enantioinduction. Through careful screening of the substituents present on the substrates such as protecting groups, of the ethereal solvent used and which enzyme family they used, they showed that both enantiomers of a desired substrate could be obtained. This is an important point as it is often difficult to obtain both enantiomers with enzymes as, unlike chiral catalysts, obtaining the inverse configuration of the active site is challenging. One point of interest is that most active enzymes are polymer supported; possibly because of the aggregation of the hydrophilic domains of free enzymes in ethereal solvents negate reactivity.

120 121

R. Ozegowski, A. Kunath, H. Schick, Liebigs Ann. Chem. 1993, 805-808. R. Ostaszewski, D. E. Portlock, A. Fryszkowska, K. Jeziorska, Pure Appl. Chem. 2003, 75, 413-419.

81

Scheme 93: Ozegowski anhydride opening

Scheme 94: Ostaszewski anhydride opening

As with anhydrides, long chain desymmetrizations of diesters are rare, most examples deal with alpha, beta or gamma diesters. Desymmetrization of longer chain diesters is apparently far more difficult as shown by Tamm122 in 1983 where he obtains 10% ee with PLE on a longer chain diester while having enantiomeric excesses up to 90% with shorter chains (Scheme 95).

Scheme 95: Tamm diester desymmetrization

One rare example of an efficient longer chain desymmetrization lies in the work of Gutman123 in 1989 who uses an internal nucleophile to desymmetrize a long chain diester to obtain an enantioenriched lactone (Scheme 96).

Scheme 96: Gutman lactone synthesis 122 123

P. Mohr, N. Waespe-Šarčević, C. Tamm, K. Gawronska, J. K. Gawronski, Helv. Chim. Acta 1983, 66, 2501-2511. A. L. Gutman, K. Zuobi, T. Bravdo, J. Org. Chem 1990, 55, 3546-3552.

82

2.1.3. Results

While five and six membered cyclic anhydrides are readily desymmetrized. The desymmetrization of eight membered anhydrides remains to the best of our knowledge unknown. Yet being able to desymmetrize eight membered cyclic anhydrides (accessed as shown in Scheme 97, full synthetic details in section 3.1.4)124 would yield dimethyl 4,4-disubstituted pimelate fragments which could be very useful in the total synthesis of indole alkaloids125. We therefore chose to explore the feasibility of this reaction based on the model reaction shown in Scheme 98. A control reaction showed that the catalyst free opening of the anhydride with methanol is slow at room temperature (10% overnight, 10 equivalents of methanol) and nearly nonexistent below 0°C. We then started screening catalysts, starting with simple quinidine at room temperature and two equivalents of methanol. While yields were good (approx. 80%), no enantiomeric induction was observed, lowering the temperature to 0 °C gave 50% conversion overnight and showed no improvement in terms of ee. Hydrogenated quinine gave no better results either. Benzylated quinine showed no longer any catalytic activity. The catalysts described by Song and Connon (2.19 and 2.23 respectively) gave, at 0 °C, 90% yield but no enantioinduction. Lowering the reaction temperature to 50°C caused the reaction to slow down consequentially (about 50% conversion over three days, one equivalent of catalyst), but still no enantioselectivity could be observed.

Scheme 97: Anhydride preparation

124

M. E. Kuehne, J. Am. Chem. Soc. 1964, 86, 2946-2946. L. Castedo, J. Harley-Mason, M. Kaplan, J. Chem. Soc. D 1969, 1444-1444; p. J.-Y. Laronze, J. Laronze-Fontaine, J. Lévy, J. Le Men, Tetrahedron Lett. 1974, 15, 491-494; J. W. Blowers, J. Edwin Saxton, A. G. Swanson, Tetrahedron 1986, 42, 6071-6095; G. Costello, J. Edwin Saxton, Tetrahedron 1986, 42, 6047-6069; C. CaritÉ, J. P. Alazard, K. Ogino, C. Thal, Tetrahedron Lett. 1990, 31, 7011-7014; J.-P. Alazard, C. Terrier, A. Mary, C. Thal, Tetrahedron 1994, 50, 6287-6298; A. Nemes, C. Szántay jr, L. Czibula, I. Greiner, ARKIVOC (Gainesville, FL, U. S.) 2008, 154-166. 125

83

Scheme 98: desymmetrization reaction

The poor UV activity of the monoacid rendered SFC determination of the enantiomeric ratio impossible so all enantiomeric excesses were measured on the benzylated derivate (Scheme 99).

Scheme 99: Derivation of the monoacid intermediate

As no enantioinduction was observed with any of the catalysts that had been described for six membered anhydrides, we decided to widen our catalyst screening to other bifunctional organocatalysts which we considered might show some activity. Chiral phosphoric acids gave good yields but no induction (Figure 7).

Figure 7: Attempted phosphoric acids

Other cinchona derivatives gave the desired product in low yields (20%) without observable ee (Figure 8). 84

Figure 8: Cinchona variants tested.

Faced with these disappointing results, we concluded that this type of transformation was apparently not feasible with the classical systems described for six membered cyclic anhydrides and decided to alter our strategy and investigate the possibility of desymmetrizing eight membered cyclic anhydrides by using enzymes. Another option we considered was to study the desymmetrization of its precursors as they could also be potential targets for enzymes and would yield the same final substrate (Scheme 100).

Scheme 100: Potential desymmetrization intermediates.

85

We reasoned that this would be a valid alternative as the chiral pocket of an enzyme might well be the ideal solution to the issues we suspected were the reasons for this lack of results, meaning, most probably, the higher flexibility of our substrate in respect to six membered anhydrides. We based our screening of conditions on a library of enzymes that had proven activity towards desymmetrization of diesters or anhydrides. Our first attempts focused on opening of anhydride 2.39, results are summarized below (Table 12). Our first observation was that the typical incubation temperature of 40°C caused a too important background reaction so further tests were run at 25°C where the background reaction was lowered to a reasonable rate. Reactions were then run with the selected enzymes though no significant activity was noted, conversions always matching that of the control reaction within experimental error. No enantioselective induction was ever noted. Diesters 2.48 (Table 13) and 2.37 (Table 14) were then tested to see if any enantioselective induction could be achieved. Control reactions first showed that 10% of a water miscible co-solvent was necessary for the solubility of the substrate. Then both the protected and non-protected diester were submitted to our selection of enzymes. The diverse enzymes tested showed a reduced activity towards the protected diester (2.48) with yields in the 10-20% range vs 30-50% for the free aldehyde (2.37). The unprotected diester showed a far better conversion than the yield might suggest but a significant amount of over-hydrolysis was present. Sadly in all the tested conditions, on both substrates, no significant enantioselective induction was noted to the exception of the resin immobilized esterase on the unprotected diester which gave a 58:42 e.r. (Table 14, entry 7) which while interesting remained insufficient to make this method viable.

Control

Solvent [0.1M] toluene

Incubation conditions 40°C, 72h, 1k rpm

MeOH [Equiv] 2

Yield [%] quant.

2

Control

toluene

25°C, 72h, 1k rpm

2

80

n.a

3

Lipase (aspergillus niger I)

TBME

25°C, 72h, 1k rpm

2

80

50:50

4

Novozyme 435

toluene

25°C, 72h, 1k rpm

2

82

50:50

5

Lipase (aspergillus niger II)

toluene

25°C, 72h, 1k rpm

2

75

50:50

6

Esterase (porcine liver)

toluene

25°C, 72h, 1k rpm

2

80

50:50

7

esterase (immobilized)

toluene

25°C, 72h, 1k rpm

2

82

50:50

8

lipase amano PS

toluene

25°C, 72h, 1k rpm

2

78

50:50

Entry

Enzyme

1

e.r. n.a

86

Table 12: Enzymatic anhydride ring opening

Control

Solvent [0.1M], (pH = 7) Buffer, 10% acetone

Incubation conditions 40°C, 72h, 1k rpm

Yield [%] 0

3

Lipase (aspergillus niger I)

Buffer, 10% acetone

40°C, 72h, 1k rpm

0

50:50

4

Novozyme 435

Buffer, 10% acetone

40°C, 72h, 1k rpm

20

50:50

5

Lipase (aspergillus niger II)

Buffer, 10% acetone

40°C, 72h, 1k rpm

34

50:50

6

Esterase (porcine liver)

Buffer, 10% acetone

40°C, 72h, 1k rpm

15

50:50

7

esterase (immobilized)

Buffer, 10% acetone

40°C, 72h, 1k rpm

26

50:50

8

lipase amano PS

Buffer, 10% acetone

40°C, 72h, 1k rpm

16

50:50

Entry

Enzyme

2

e.r. n.a

Table 13: desymmetrization of protected diester.

Control

Solvent [0.1M], (pH = 7) Buffer

Incubation conditions 40°C, 72h, 1k rpm

Yield [%] 0

2

Control

Buffer, 10% acetone

40°C, 72h, 1k rpm

0

n.a

3

Lipase (aspergillus niger I)

Buffer, 10% acetone

25°C, 72h, 1k rpm

18

50:50

3

Lipase (aspergillus niger I)

Buffer, 10% acetone

40°C, 72h, 1k rpm

20

50:50

4

Novozyme 435

Buffer, 10% acetone

40°C, 72h, 1k rpm

50

52.5:47.5

5

Lipase (aspergillus niger II)

Buffer, 10% acetone

40°C, 72h, 1k rpm

62

50:50

6

Esterase (porcine liver)

Buffer, 10% acetone

40°C, 72h, 1k rpm

26

50:50

7

esterase (immobilized)

Buffer, 10% acetone

40°C, 72h, 1k rpm

29

58:42

8

lipase amano PS

Buffer, 10% acetone

40°C, 72h, 1k rpm

6

50:50

9

Chemotrypsin

Buffer, 10% acetone

40°C, 72h, 1k rpm

trace

50:50

Entry

Enzyme

1

e.r. n.a

Table 14: Desymmetrization of diester.

87

2.2. Desymmetrization of Bislactones 2.2.1. Project Origin and Rational

Confronted with these dead ends we next considered modifying our model substrate. We reasoned that all the potential issues (flexibility of substrate, poor facial differentiation …) might be circumvented by adapting our starting material. We hoped that by modifying the aldehyde present on the anhydride by either leaving it unprotected, reducing it to the alcohol or transferring it to a bulkier protecting group (Scheme 101) we might get either some two point interaction with the catalyst or a better facial discrimination between the catalyst and the substrate which would help induce a better selectivity.

Scheme 101: Alternative anhydrides

Various attempts at reducing the aldehyde in views of protection gave the lactone (Scheme 102).

Scheme 102: Reduction of the aldehyde

When attempted to form the unprotected anhydride a side product was isolated (Scheme 103). This was identified as bicyclic bislactone 2.58 resulting from the cyclisation of the both acid moieties onto the aldehyde. This type of transformation was moderately known though never described to form six membered bicycles. X-ray analysis showed this type of structure possessed a cis fused configuration presumably due to an anomeric affect between both lactone moieties (Figure 9).

88

Scheme 103: Formation of Bislactone.

This compound caught our attention as we believed it a structural equivalent to an eight membered anhydride but with a more rigid and compact structure. We believed that we could take advantage of this especially as they appeared to reopen under acidic conditions in the presence of a nucleophile. If the acid used were to be chiral, we hypothesized that this opening could be performed enantioselectivly. Though, as there is no longer any obvious plane of symmetry on this bislactone, its opening can no longer be called a desymmetrization process. Despite this, as from a conceptual point of view this compound was considered as pseudo-symmetric and the project was devised based on that hypothesis, we will continue to use the term desymmetrization hereafter.

Figure 9: X-ray structure of the Bislactone

The closest literature equivalents, five membered bislactones, have been mostly used in polymer chemistry, and are formed through the cyclisation of tricarballylic acid in the presence of a base and the corresponding anhydride. They are then often opened by an oxygen based nucleophilic initiator to give branched polymers (Scheme 104)126.

126

R. Fittig, Justus Liebigs Ann. Chem. 1901, 314, 1-16; R. M. Wilson, A. C. Hengge, A. Ataei, D. M. Ho, J. Am. Chem. Soc. 1991, 113, 7240-7249; S. Ohsawa, K. Morino, A. Sudo, T. Endo, Macromolecules 2011, 44, 1814-1820; S. Ohsawa, B. Barkakaty, A. Sudo, T. Endo, J. Polym. Sci. A Polym. Chem. 2012, 50, 1281-1289.

89

Scheme 104: Ring closing and reopening of five membered bislactones

Other reactions involve the exchange of one of the lactones to a lactam with a primary amine or the opening of one of the rings under reductive conditions (Scheme 105)127.

Scheme 105: Further five membered bislactone reactions

Six membered bislactones are even rarer and to the best of our knowledge only two examples of such structures exits from Basavaiah in 2001128 and Kim in 2007129. As with the 5 membered ring bislactones no enantioselective opening exists.

Scheme 106: Basavaiah synthesis

127

T. Takata, A. Tadokoro, T. Endo, Macromolecules 1992, 25, 2782-2783; A. Tadokoro, T. Takata, T. Endo, Macromolecules 1993, 26, 4400-4406; K. Chung, T. Takata, T. Endo, Macromolecules 1995, 28, 3048-3054; M. Arasa, X. Ramis, J. M. Salla, A. Serra, A. Mantecón, Polymer 2009, 50, 1838-1845; S. Ohsawa, K. Morino, A. Sudo, T. Endo, Macromolecules 2010, 43, 3585-3588. 128 D. Basavaiah, T. Satyanarayana, Org. Lett. 2001, 3, 3619-3622. 129 S. J. Kim, H. S. Lee, J. N. Kim, Tetrahedron Lett. 2007, 48, 1069-1072.

90

Scheme 107: Kim’s bicyclic bislactone

To perform the opening we believed that chiral phosphoric acids would be the best choice. These have drawn significant attention since their first uses in asymmetric organocatalysis in 2004 by Akiyama130 and Terada131 and their history has been nicely summarized in diverse reviews132. They have been used in many a process including desymmetrization of anhydrides as mentioned before. The major reason they are so used is that they are highly versatile. The chiral information is provided through the axially chiral backbone. Each alternative backbone class provides a different bite angle while the R substituents on the backbone provide the steric bulk needed to shield the active site and control the stereochemical outcome of a reaction (Figure 10)132.133. As the chemistry needed to create these backbones is well known the scope of available moieties is expansive (for synthetic details see section 2.2.4).

130

T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. Int. Ed. 2004, 43, 1566-1568. D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356-5357. 132 T. Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 2006, 348, 999-1010; T. Akiyama, Chem. Rev. 2007, 107, 57445758; M. Terada, Chem. Comm. 2008, 4097-4112; D. Kampen, C. Reisinger, B. List, in Asymmetric Organocatalysis, Vol. 291 (Ed.: B. List), Springer Berlin Heidelberg, 2009, pp. 1-37; A. Zamfir, S. Schenker, M. Freund, S. B. Tsogoeva, Org. Biomol. Chem. 2010, 8, 5262-5276; M. Terada, Synthesis 2010, 2010, 1929-1982; M. Rueping, A. Kuenkel, I. Atodiresei, Chem. Soc. Rev. 2011, 40, 4539-4549; T. Akiyama, J. Synth. Org. Chem. Jpn. 2011, 69, 913-925; M. Rueping, B. J. Nachtsheim, W. Ieawsuwan, I. Atodiresei, Angew. Chem. Int. Ed. 2011, 50, 6706-6720; J. Lv, S. Luo, Chem. Comm. 2013, 49, 847-858; D. Parmar, E. Sugiono, S. Raja, M. Rueping, Chem. Rev. 2014, DOI: 10.1021/cr5001496. 133 I. Coric, B. List, Nature 2012, 483, 315-319. 131

91

Figure 10: Samples of available phosphoric acid backbones and substituents

The overall acidity of a phosphoric acid is tunable by modifying either the H-bond acceptor heteroatom, the most common being Y = O but some catalysts with Y = S have shown interesting effects or the H-bond donor with X = OH, SH or NHTf being the most commonly utilized moieties (Figure 11). The fine-tuning of the catalyst acidity is controlled by the electronic properties of the R moieties. This, combined with the fact that their acidity is also heavily dependent on the solvent used, from 6 to 14 in acetonitrile and around 10 units lower in DMSO134, means they can activate a wide range of substrates selectively depending on the conditions and catalyst family used.

Figure 11: Phosphoric acid activity parameters

Their mode of action has been studied and this has shed some light between the catalyst’s four potential ways to activate substrates (Figure 12). These could hypothetically be either by H-bonding in a bidentate (2.78) or double interaction pattern (2.79), or by contact ion pairing (2.80 & 2.81) with ionic intermediates as exemplified in Figure 12. Mechanical investigations have led to evidence supporting the

134

K. Kaupmees, N. Tolstoluzhsky, S. Raja, M. Rueping, I. Leito, Angew. Chem. Int. Ed. 2013, 52, 11569-11572. For DMSO values see corresponding supporting information

92

double interaction activation mode (2.79) and showed reaction pathways begin with H-bonding before passing through an ion pair intermediate (2.79 to 2.81)135.

Figure 12: Four alternate modes of bonding

135

M. Yamanaka, J. Itoh, K. Fuchibe, T. Akiyama, J. Am. Chem. Soc. 2007, 129, 6756-6764; M. Fleischmann, D. Drettwan, E. Sugiono, M. Rueping, R. M. Gschwind, Angew. Chem. Int. Ed. 2011, 50, 6364-6369.

93

2.2.2. Optimization

We first subjected our bislactone to methanol in the presence of diphenylhydrogenophosphate in toluene to test its reactivity (Scheme 108). We were pleased to discover that it indeed yielded the desired ring-opened substrate (2.43) with an 80% yield in two hours at room temperature, the remaining 20% were isolated as the diacid equivalent (2.57) resulting from the ring opening by residual water. Rerunning the reaction under thoroughly anhydrous conditions eliminated this byproduct and gave 95% yield.

Scheme 108: Diphenylhydrogenophosphate catalyzed ring opening reaction

We then switched to a chiral phosphoric acid to see if any enantioinduction could be observed (Figure 13). We were delighted when we obtained a 55:45 e.r. with catalyst 2.43. Further catalyst screening using diverse phosphoric acids raised the observed e.r. to 84:16 through the use of the TRIP derivate (2.44) (Table 15).

Figure 13: Available chiral phosphoric catalysts

94

Entry 1 2 3 4

Catalyst (10mol %) Diphenylhydrogenophosphate 2.43 2.82 2.42

Temperature (°C) r.t r.t r.t r.t

Solvent Toluene Toluene Toluene Toluene

e.r. n.a 55:45 65:35 65:35

5

2.44 (Trip)

r.t

Toluene

84:16

6 7 8

2.93 2.83 2.91

r.t r.t r.t

Toluene Toluene Toluene

85:15 68:33 76.24

Table 15: Catalyst screening for the ring opening reaction

The temperature effect was then studied. Surprisingly lowering the temperature returned negative results, optimal e.r.’s being obtained at room temperature (Table 16). This result is surprising as normally a lowering of the temperature results in either no change or an improvement of enantioselectivity. It is hard to track down examples of such occurrences in literature; such cases are rarely underlined or discussed as this phenomenon is limited to very specific cases136. One of the better known exceptions is with CBS reductions where cooling often leads to worse results, this effect was attributed to the dimerization of the catalyst which leads to a decreased activity and selectivity137. In our case the catalyst is presumably not the problem as phosphoric acids are known to function better at lower temperatures. This leaves the substrate but as very little is known about these structures it is hard to corroborate any hypothesis. One explanation might be a conformational difference in solution between room temperature and at 0°C that might cause a less favorable catalyst-substrate interaction at certain temperatures.

Entry 1

Catalyst (10 mol %) 2.44

Temperature (°C) 60

Solvent Toluene

e.r. 82:18

2

2.44

r.t

Toluene

84:16

3 4

2.44 2.44

-10 -60

Toluene Toluene

75:25 56:45

Table 16: Temperature screening for the ring opening reaction

136

For examples see the optimization tables of M. Terada, T. Komuro, Y. Toda, T. Korenaga, J. Am. Chem. Soc. 2014, 136, 7044-7057; S. Zhong, M. Nieger, A. Bihlmeier, M. Shi, S. Brase, Org. Biomol. Chem. 2014, 12, 3265-3270; D. R. Williams, A. A. Shah, J. Am. Chem. Soc. 2014, 136, 8829-8836. 137 J. M. Brunel, M. Maffei, G. Buono, Tet. Asym. 1993, 4, 2255-2260.

95

The optimal solvent for the reaction was then studied. While most solvents showed minor variance in e.r. when compared to toluene, cyclic ethers such as THF or dioxane showed a positive effect on the enantioselective outcome of the reaction pushing e.r.’s to 89:11 (Table 17).

Entry 1 2

Catalyst (10 mol %) 2.44 2.44

Temperature (°C) r.t r.t

Solvent DCM ACN

e.r. 85:15 86:14

3

2.44

r.t

Dioxane

89:11

4 5 6 7 8

2.44 2.44 2.44 2.44 2.44

r.t r.t r.t r.t r.t

THF AcOEt TBME diglyme

88:12 86:14 85:15 87:13 85:15

Anisole

Table 17: Solvent screening for the ring opening reaction

As we were not yet satisfied with the result we expanded our catalyst screening in the hopes of finding a more suitable one. The calcium salt of TRIP (2.90) gave an inverse and poor selectivity while the H8-equivalents (2.85-2.86) gave no change compared to their non-hydrogenated forms. Spinol138 based catalysts gave better selectivities with anthracyl (2.87) and naphtyl (2.88) substituents, the same for List’s phosphoimidates139 (2.92-2.93) who showed a notable dependence on the solvent. The latter (2.93) was chosen as optimal catalyst verses the spinol anthracene (2.87) as it is recyclable at about 95% yield from the reaction media (Table 18).

Entry 1 2 3 4

Catalyst (10 mol %) 2.44 2.90 2.83 2.84

Temperature (°C) r.t r.t r.t r.t

Solvent Dioxane Dioxane Dioxane Dioxane

e.r. 89:11 43:57 80:20 80:20

5

2.93(phosphoimidate)

r.t

Dioxane

92:8

6 7 8 9

2.92 2.85 2.86 2.89

r.t r.t r.t r.t

Dioxane Dioxane Dioxane Dioxane

80:20 82:18 87:13 65:35

10

2.87 (Spinol-anthracene)

r.t

Dioxane

92:8

11

2.88

r.t

Dioxane

90:10

Table 18: Further catalyst screening for the ring opening reaction

138 139

F. Xu, D. Huang, C. Han, W. Shen, X. Lin, Y. Wang, J. Org. Chem 2010, 75, 8677-8680. J. H. Kim, I. Čorić, S. Vellalath, B. List, Angew. Chem. Int. Ed. 2013, 52, 4474-4477.

96

The determination of the absolute configuration of the monoacid proved difficult. Monoacid 2.49 is an oil at room temperature so we were forced to derive it. Several groups were added to the acid via coupling but only the biphenylbromide derivate (2.97) proved to be solid, the same when the aldehyde was functionalized, only the DNPH derivate (2.95) proved to be a solid (Figure 14). On these two, many attempts at crystal growth were made but with moderate success. The DNPH derivate was not at all crystalline. Diphenylbromide 2.97 was slightly better and gave some low quality crystals which were nonetheless sufficient to determine the absolute configuration. S-Binol derived phosphoimidate 2.93 gives an S-configuration for 2.49 (Figure 15).

Figure 14: Non crystalline derivates

Figure 15: X-ray for the determination of the absolute configuration of 2.49.

2.2.3. Scope

We then investigated the scope of the reaction. Firstly a range of alcohol nucleophiles were tested. In addition to methanol both isopropanol and benzyl alcohol worked well, the later showing a slightly better e.r. The reaction of 2.3a with tert-butanol gave mostly the diacid compound (2.55) even under rigorously anhydrous conditions. By NMR, peaks that were attributed to the desired compound could be observed but never isolated which might indicate that the reaction worked but that the tertbutyl ester deprotected under the reaction conditions. Reaction with phenol as nucleophile to give 2.98d only leads to recovered starting material even when it was heated (Scheme 109).

97

Scheme 109: Scope of alcohol nucleophiles for asymmetric bislactone opening

We then turned our attention to the substitution tolerance on the C4 position of our bislactone. As no synthesis of these bicyclic bislactones had ever been reported we first had to develop a route for the synthesis of our starting materials. A series of 4-derivates (Scheme 110) could be synthetized in moderate yields similarly to what had been done for our model substrate by using a modified procedure to the one proposed by Kuehne and Saxton124,125. These were then transferred to the bislactones as developed previously by first hydrolysis of the esters and cyclisation in the presence of acetic anhydride. Yields were overall good especially when a base was added to the cyclisation step.

98

Scheme 110: General pathway and scope for the synthesis of 4a substituted bislactones

For C5 substituted bislactones this method did not work, only mono-alkylation substrates could be observed even under harsh conditions and long reaction times. Attempts at alkylation through via Michael addition of enolate to acrylate with a variety of bases also proved ineffective. Grignard addition to the aldehyde of 2.31 gave only degradation (Scheme 111).

99

Scheme 111: Attempts towards the formation of 4,5-disubstituted bislactones

A solution was found by replacing methyl acrylate with acrylonitrile and using TBAH (tetrabutylammonium hydroxide) as base (Scheme 112)140, this method actually proved more efficient in terms of yield than the previous one and could potentially be adapted to additional derivates if needed.

Scheme 112: Formation of 4,5 disubstituted bislactones

Two other substrates, including a C4 unsubstituted bislactone, were prepared in parallel by reacting tert-butyl acrylate with a malonate type nucleophile (Scheme 113)141.

140

H. A. Bruson, T. W. Riener, J. Am. Chem. Soc. 1942, 64, 2850-2858. Y. Hirayama, T. Nakamura, S. Uehara, Y. Sakamoto, K. Yamaguchi, Y. Sei, M. Iwamura, Org. Lett. 2005, 7, 525528. 141

100

Scheme 113: Formation of C5 monosubstituted bislactone.

With these nine new substrates in hand, we submitted them to our reaction conditions (Scheme 114). The presence of diverse substituents at the C4 position was well tolerated and gave good yields and enantioselectivities. The 4-methyl-5-phenyl bisubstituted bislactone (2.101h to 2.111g, R1 = Me, R2 = Ph) also worked well. Sadly the 4-H-5-methyl monosubstituted bislactone (2.101j to 2.111h, R1 = H, R2 = Me) gave a poor result which tends to indicate that a quaternary center at that position is needed. More probably to help shield one face during the transition state rather than to block racemization as resubmitting the final product to acidic conditions did not give any loss of e.r. The 4-ester-5-methyl bislactone (2.101i to 2.111l, R1 = COOBn, R2 = Me) also gave slightly lower selectivities results.

101

Scheme 114: Scope of 4,5-substitution for the asymmetric bislactone opening

We next investigated if five membered rings were appropriate substrates for the reaction. Several methods for the synthesis of the starting materials were pursued as briefly summarized in Scheme 115142. Enolate addition of aldehydes to methyl bromo-acetate gave predominantly the aldol byproduct. Stork enamine type reactions resulted in exclusively monoalkyated substrates, the intermediate degraded before any significant amount of dialkylation could be observed. Enamine salt chemistry with magnesium bromides were unreactive at lower temperatures and degraded when at higher temperatures. Formation of a silyl enolate was possible on monoalkylated substrate (2.116) through the action of zinc chloride and trimethylsily chloride in the presence of a base to give observed intermediate 2.117. However this intermediate also proved resistant to a second alkylation as no reaction was observed at lower temperatures and the silyl enol ether degraded rapidly when heated.

142

M. B. Smith, J. March, in March's Advanced Organic Chemistry Reactions, Mechanisms and Structure, Wiley, 2007, pp. 626-637

102

Scheme 115: Attempts towards the formation of five membered bislactones

A solution was found with the use of propane-1,2,3-tricarboxylic acid which was described to undergo acylative decarboxylation to form bislactones in the presence of anhydrides. With this method two sample substrates could be synthetized. Disappointingly these gave poor results with e.rs being in the range of 75:25, also reaction rates were very sluggish in dioxane with about 50-60% yields after 7 days (85-90% BRSM). This probably indicated that the catalyst was not optimal for substrates without a quaternary center at the C5 position such as 2.120 and 2.121. We decided not to optimize the method for these substrates in view of the poor availability of starting materials (Scheme 116).

103

Scheme 116: Formation and asymmetric ring opening of five membered bislactones

104

2.2.4. Catalyst synthesis

Of the catalysts presented in Figure 13, 2.43, 2.82, 2.42 and 2.44 were previously synthetized in the laboratory and were readily available. The remaining were synthetized according to known literature procedures. In general these were all made following a similar pathway. First protection of the backbone’s hydroxyl groups under the form of a methyl ether or MOM followed by directed orthometalation to install an iodine or boronic acid. Then the aryl substituents are installed through a coupling reaction with palladium or nickel. The diol is then deprotected and phosphorylated with POCl3, the resulting chloride is then hydrolyzed to the phosphoric acid. Following purification by FCC the phosphoric acid is washed with HCl to fully reprotonate the catalyst. Catalyst 2.83 was synthetized as shown in Scheme 117143 from commercial S-Binol. The iodination of 2.123 to obtain 2.124 has a poor yield compared to literature procedure as TBME was used instead of Et2O and it was observed that iodine solubilized very badly in TBME which caused for a lot of monoiodinated product to be obtained. Catalysts 2.90 and 2.91 were made in-situ prior to use from TRIP catalyst 2.44144. In the case of 2.90, calcium isopropoxide was replaced by calcium methoxide for equivalent results due to the recent commercial unavailability of calcium iso-propoxide.

n

Reaction conditions: (a) NaH, THF then MOMCl r.t 90%. (b) BuLi, TMEDA, TBME, then I2 r.t 35%, (c) ArB(OH)2, Cs2O3, Pd(PPh3)4, DME-H2O, reflux. (e) HCl, dioxane, reflux. 71% two steps. (e) POCl3, NEt3, DCM, r.t. then H2O r.t, then 6N HCl reflux 73%. Scheme 117: Formation of catalyst 2.83

143

M. Rueping, B. J. Nachtsheim, R. M. Koenigs, W. Ieawsuwan, Chem. Eur. J 2010, 16, 13116-13126; G. Lu, V. B. Birman, Org. Lett. 2011, 13, 356-358; F. Romanov-Michailidis, L. Guénée, A. Alexakis, Org. Lett. 2013, 15, 58905893. 144 T. Yue, M.-X. Wang, D.-X. Wang, G. Masson, J. Zhu, J. Org. Chem 2009, 74, 8396-8399; F. Drouet, C. Lalli, H. Liu, G. r. Masson, J. Zhu, Org. Lett. 2010, 13, 94-97.

105

Catalysts 2.85 and 2.86 were made following Scheme 118145. Overall, all H8-binol substrates proved to be less reactive than their binol counterparts.

n

Reaction conditions: (a) PtO2, H2, AcOH 88%, (b) NaH, THF then MOMCl r.t 95%. (c) BuLi, TMEDA, Et2O, then I2 r.t. 52% (d) ArB(OH)2, Cs2O3, Pd(PPh3)4, DME-H2O, reflux. (e) HCl, dioxane, reflux. 11% two steps. (f) POCl3, NEt3 , DCM, r.t. then H2O r.t, then 6N HCl reflux 48%. (g) ArMgBr, NiCl2(PPh3)2, THF, 80 °C (h) HCl, dioxane, reflux. 16% two steps. (i) POCl3, NEt3, DCM, r.t. then H2O r.t, then 6N HCl reflux 52%. Scheme 118: Formation of 2.85 and 2.86

The spinol backbone is not easily accessible commercially and was therefore synthetized in six steps from m-anisaldehyde according to the procedure reported by Birman with minor modifications (Scheme 119)146. The racemic spinol thus obtained was resolved through inclusion crystallization with NBenzylcinchonidinium chloride to give enantiopure (R)- and (S)- spinol in good yields following a modified procedure reported by Deng and Ye147.

145

R. R. Schrock, J. Y. Jamieson, S. J. Dolman, S. A. Miller, P. J. Bonitatebus, A. H. Hoveyda, Organometallics 2002, 21, 409-417; M. Bartoszek, M. Beller, J. Deutsch, M. Klawonn, A. Köckritz, N. Nemati, A. Pews-Davtyan, Tetrahedron 2008, 64, 1316-1322; G. Pousse, A. Devineau, V. Dalla, L. Humphreys, M.-C. Lasne, J. Rouden, J. Blanchet, Tetrahedron 2009, 65, 10617-10622. 146 V. B. Birman, A. L. Rheingold, K.-C. Lam, Tet. Asym. 1999, 10, 125-131. 147 J.-H. Zhang, J. Liao, X. Cui, K.-B. Yu, J. Zhu, J.-G. Deng, S.-F. Zhu, L.-X. Wang, Q.-L. Zhou, L. W. Chung, T. Ye, Tet. Asym. 2002, 13, 1363-1366.

106

Reaction Conditions: (a) Me2CO, NaOH, 50% EtOH-H2O, r.t, 60%. (b) Raney Ni, H2, Me2CO, r.t (c) Br2, pyridine, DCM, 0°C. (d) n Polyphosphoric acid, 105°C, 60% 3 steps. (e) BuLi, THF, -78°C, 95%. (f) BBr3, DCM, -78°C, 85%. g) N-Benzylcinchonidinium chloride, toluene, reflux. h) HCl, (R)-spinol 90%, >99% ee, (S)-spinol 80%, >99% ee. Scheme 119: Synthesis of spinol

Starting from (S)-spinol catalysts 2.87, 2.88 and 2.89 were synthetized as shown in Scheme 148

120

148

F. Xu, D. Huang, C. Han, W. Shen, X. Lin, Y. Wang, J. Org. Chem 2010, 75, 8677-8680; I. Čorić, S. Müller, B. List, J. Am. Chem. Soc. 2010, 132, 17370-17373; S. Müller, M. J. Webber, B. List, J. Am. Chem. Soc. 2011, 133, 1853418537.

107

s

Reaction Conditions: (a) NaH, THF then MOMCl r.t 83%. (b) BuLi, TMEDA, TBME, then I2 r.t 75%, (c) ArB(OH)2, K3PO4, Pd(PPh3)4, DME, reflux. (d) HCl, dioxane, reflux. 50% two steps. (e) POCl3, pyridine, reflux then dioxane, H2O reflux 82%. (f) HCl, dioxane, reflux (g) ArB(OH)2, K2CO3,Pd/C, Dioxane-H2O 80 °C (h) POCl3, pyridine, reflux then dioxane, H2O reflux 25% three steps. (i) ArMgBr, NiCl2(PPh3)2, Et2O, reflux. (j) HCl, dioxane, reflux, 48% two steps. (k) POCl3, pyridine, reflux then dioxane, H2O reflux 63%. Scheme 120: Synthesis of 2.87, 2.88 and 2.89

Catalysts 2.94 and 2.95 were synthetized as shown in Scheme 121133,139. For these confined C2 symmetric catalysts the procedures are identical at the beginning and only differ for the last steps. After installation of the aryl substituents and deprotection of the diols the phosphorylation is done as normal. However, at this point, instead of hydrolyzing the chloride, one half of the batch is kept as such and used in the final step while the second half is dissolved in liquid ammonia to form the phosphoramide. The latter is then recombined with the first in the presence of NaH to form the final imidodiphosphoric acid.

108

n

Reaction Conditions: (a) MeI, K2CO3, acetone, reflux, quant. (b) BuLi, TMEDA, Et2O, r,t then B(OEt)3, then HCl 67% (c) 2.126, . Ba(OH)2 H2O , Pd(PPh3)4, reflux, Dioxane-H2O. (d) BBr3, r.t, 79% two steps. (e) Tf2O, pyridine, DCM, r.t, 92%. (f) POCl3, pyridine, 60 °C.97%. (g) POCl3, pyridine, 60 °C then NH3, -78 °C to r.t, 92%. (h) NaH, THF, r.t, 74%. Scheme 121: Synthesis of 2.93

Reaction Conditions: (a) 2.125, POCl3, pyridine, 60 °C.80%. (b) 2.125, POCl3, pyridine, 60 °C then NH3, -78 °C to r.t, 85%. (h) NaH, THF, r.t, 25%. Scheme 122: synthesis of 2.92

109

2.3. Conclusion In summary during this project we have investigated the possibility of desymmetrizing both eight membered cyclic anhydrides and dimethyl 4,4-disubstituted pimelates via either cinchona alkaloid catalysis or through enzymatic processes and shown after extensive screening that was poorly feasible. We then developed an alternative method using a structural equivalent to the said anhydrides, 6 membered bicyclic bislactones, with a phosphoric acid as catalyst (Scheme 123). This method was applied to a wide range of substrates and gave overall good yields and enantioselectivities. This methodology can be applied in principle to the total synthesis of many natural compounds as the asymmetric 4,4-disubstituted pimelates generated is a moiety which can be found in many natural product skeletons.

Scheme 123: Enantioselective desymmetrization of bislactones

110

Chapter 3: Catalytic Enantioselective Syntheses of (-)Rhazinilam, (-)-Leucomidine B and Rhazinicine With our enantioenriched fragment well in hand we sought to use it in the total synthesis of a number of natural products. This chapter will cover therefore the total synthesis of Leucomidine and Rhazinilam and our progress towards the total synthesis of Rhazinicine.

3.1. (-)-Rhazinilam, (-)-Leucomidine B 3.1.1. (-)-Leucomidine B: Isolation and Biosynthesis

The Apocynaceae family is a group of plants mostly found in warmer climates with many members present in Madagascar, Mexico, most of the US, south America, especially Brazil and Indonesia.149 Coming in diverse varieties of trees and shrubs with mostly latex style sap, simple opposite pinnately veined leaves, it typically flowers twice a year to give a variety fruit. They are known to be rich in poisonous substances and many types of alkaloids and glycosides. The nature of these is apparently highly dependent on its geographical location. The genus Leuconotis comprises a subfamily of about 10 species widely found in the Malaysia and Indonesia regions, among these figures Leuconotis griffithii. Several alkaloids were already isolated from this particular plant over the years such as leucolusine, leucophyllidine, leuconolam, bisleuconothine A, rhazinilam and 5,21-dihydrorhazinilam (Scheme 138).150

149

Data from zipcodezoo at http://zipcodezoo.com/Plants/L/Leuconotis_griffithii/ and Tropicos® http://www.tropicos.org/Name/1804499 150 S. H. Goh, A. R. Mohd Ali, W. H. Wong, Tetrahedron 1989, 45, 7899-7920; C.-Y. Gan, T.-S. Kam, Tetrahedron Lett. 2009, 50, 1059-1061; C.-Y. Gan, W. T. Robinson, T. Etoh, M. Hayashi, K. Komiyama, T.-S. Kam, Org. Lett. 2009, 11,

111

Scheme 124: Previously isolated unique structures from L. Griffithii

In their search for new structurally and biogenetically interesting alkaloids, mostly focusing on those found in tropical plants, the group of Morita first reported in early 2012 the isolation and structure determination of three other members of the same family from L. Griffithii, Leucomidines A-C.(Scheme 125)151

Scheme 125: Leucomidine A-C

From a biosynthetic point of view these three compounds are hypothesized to originate from leuconolam (3.6, Scheme 126). The oxidative cleavage of the double bond could give an intermediate (3.12) from which the three compounds could derive. Consecutive ring closures could give leucomidine A (3.10) while hydrolysis and then ring closures could give leucomidine B (3.1). Leucomidine C (3.11) would 3962-3965; Y. Hirasawa, S. Miyama, T. Hosoya, K. Koyama, A. Rahman, I. Kusumawati, N. C. Zaini, H. Morita, Org. Lett. 2009, 11, 5718-5721; A. E. Nugroho, Y. Hirasawa, N. Kawahara, Y. Goda, K. Awang, A. H. A. Hadi, H. Morita, J. Nat. Prod. 2009, 72, 1502-1506; Y. Hirasawa, T. Shoji, T. Arai, A. E. Nugroho, J. Deguchi, T. Hosoya, N. Uchiyama, Y. Goda, K. Awang, A. H. A. Hadi, M. Shiro, H. Morita, Bioorg. Med. Chem. Lett. 2010, 20, 2021-2024. 151 M. Motegi, A. E. Nugroho, Y. Hirasawa, T. Arai, A. H. A. Hadi, H. Morita, Tetrahedron Lett. 2012, 53, 1227-1230.

112

arise from further oxidations and then once more ring closures. Leuconolam itself is the result of a long biosynthetic pathway which can be traced back to simpler structures such as tryptamine152.

Scheme 126: Biosynthesis of Leucomidine A-C

3.1.2. (-)-Rhazinilam: Isolation, Biosynthesis and Previous Syntheses (-)-Rhazinilam was first isolated in 1965 by Linde153 from a member of the Apocynaceae family called Melodinus australis. It was then found in other Apocynaceae family members such as Rhazya stricta154 or Aspidosperma quebrachoblanco155 and several other South-East Asian representatives156

152

S. B. Jones, B. Simmons, A. Mastracchio, D. W. C. MacMillan, Nature 2011, 475, 183-188. B. David, T. Sévenet, O. Thoison, K. Awang, M. Païs, M. Wright, D. Guénard, Bioorg. Med. Chem. Lett. 1997, 7, 2155-2158. 153 H. H. A. Linde, Helv. Chim. Acta 1965, 48, 1822-1842. 154 A. Banerji, P. L. Majumder, A. Chatterjee, Phytochemistry 1970, 9, 1491-1493; K. T. De Silva, A. H. Ratcliffe, G. F. Smith, G. N. Smith, Tetrahedron Lett. 1972, 13, 913-916. 155 D. J. Abraham, R. D. Rosenstein, R. L. Lyon, H. H. S. Fong, Tetrahedron Lett. 1972, 13, 909-912.

113

including, as mentioned above, leuconotis giffithii157. The structure of this indole alkaloid was established in the isolation papers of 1972. The history of rhazinilam has been reviewed on 2004 by Baudoin158 and in 2011 by Neier159. The structure elucidation studies suggested that rhazinilam itself may not be directly found in the Apocynaceae family plants but is the oxidized form of unstable natural 5,21-dihydrorhazinilam (3.9) resulting from exposure to air during extraction and isolation160. From a biosynthetic point of view rhazinilam (or more precisely the 5,21-dihydroRhazinilam precursor) is believed to arise from the oxidation of vincadifformine (3.17) though this has never been proven as only circumstantial evidence exists in the form of SAR studies or semi-syntheses (Scheme 127) from suspected precursors161. In this postulate, hydrolysis and decarboxylation of vincadifformine leads to 1,2-didehydroaspidospermidine (3.18) which then undergoes a two-step oxidative-reductive sequence to yield 5,21-dihydrorhazinilam which then undergoes air oxidation to rhazinilam.

Scheme 127: Biomimetic semi-synthesis of Rhazinilam 156

S. H. Goh, A. R. Mohd Ali, W. H. Wong, Tetrahedron 1989, 45, 7899-7920; G. M. T. Robert, A. Ahond, C. Poupat, P. Potier, C. Jollès, A. Jousselin, H. Jacquemin, J. Nat. Prod. 1983, 46, 694-707; T. Varea, C. Kan, F. Remy, T. Sevenet, J. C. Quirion, H. P. Husson, H. A. Hadi, J. Nat. Prod. 1993, 56, 2166-2169; M. Zèches, K. Mesbah, B. Richard, C. Moretti, J. M. Nuzillard, L. L. Men-Olivier, Planta Med. 1995, 61, 89-91; Y. Wu, M. Suehiro, M. Kitajima, T. Matsuzaki, S. Hashimoto, M. Nagaoka, R. Zhang, H. Takayama, J. Nat. Prod. 2009, 72, 204-209. 157 C.-Y. Gan, Y.-Y. Low, N. F. Thomas, T.-S. Kam, J. Nat. Prod. 2013, 76, 957-964. 158 F. Guéritte, D. Guénard, O. Baudoin, Mini-Rev. Org. Chem. 2004, 1, 333-341. 159 Inga Kholod, Olivier Vallat, Ana-Maria Buciumas, R. Neier, Heterocycles 2011, 82, 917-948. 160 S. H. Goh, A. R. Mohd Ali, Tetrahedron Lett. 1986, 27, 2501-2504. 161 B. David, T. Sévenet, O. Thoison, K. Awang, M. Païs, M. Wright, D. Guénard, Bioorg. Med. Chem. Lett. 1997, 7, 2155-2158. A. H. Ratcliffe, G. F. Smith, G. N. Smith, Tetrahedron Lett. 1973, 14, 5179-5184; C. Dupont, D. Guénard, L. Tchertanov, S. Thoret, F. Guéritte, Bioorg. Med. Chem. 1999, 7, 2961-2969.

114

A number of syntheses of rhazinilam (and its analogues) have been reported over the years, it is a privileged target because of its unusual structure. The first was reported by Smith in 1973 (Scheme 128)161, the skeleton was constructed via N-alkylation of the sodium salt of a 3-orthonitrophenyl-pyrrole (3.22) with lactone 3.21. Friedel-Crafts cyclisation of the pyrrole onto the lactam followed by hydrogenation and peptide coupling furnished rhazinilam in ten steps and 3.6% overall yield along the pyrrole pathway.

NO2 O TsO

O

NaH

+

NH

O O2N

O N

COOMe 3.21

MeOOC

3.22

3.23 HO O

AlCl3

O2N

Rhazinilam N

MeOOC 3.24

Scheme 128: Smith synthesis of Rhazinilam

Trauner in 2005 (Scheme 129)162 combined the same lactone (3.21) with methyl 1H-pyrrole-2carboxylate, this was followed by Friedel-Crafts cyclisation to give 3.25 and peptide coupling with iodoaniline to create his key intermediate (3.26). Pd-catalyzed cyclisation, via presumably a C-H functionalization process, gave 3.27 which yielded upon decarboxylation rhazinilam in thirteen steps and 1.7% overall yield.

Scheme 129: Trauner synthesis of Rhazinilam

162

A. L. Bowie, C. C. Hughes, D. Trauner, Org. Lett. 2005, 7, 5207-5209.

115

In 2000 Sames used rhazinilam as a target for an elegant C-H bond activation methodology (Scheme 130)163. They prepared their key precursor (3.29) via a silver carbonate promoted [3+2] cyclisation between piperideine 3.28 and nitrophenyl bearing allyl bromide 3.27 and then reduction of the nitro to an amine. On this they used the amine to generate a Shiff base (3.30) that would serve as guide for a platinum complex (3.31) to transform one of two ethyl groups into an ethylene (3.31) which could then converted to the fragment needed to close the final nine membered ring.

Scheme 130: 2000 Sames synthesis of Rhazinilam

The year after Magnus164 used a similar [3+2] cyclisation strategy with a piperideine bearing an already differentiated quaternary center (3.33) which shortened the synthesis and gave rhazinilam in only nine steps from δ-valerolactam and 7.6% overall yield (Scheme 131).

Scheme 131: Magnus synthesis of Rhazinilam

163 164

J. A. Johnson, D. Sames, J. Am. Chem. Soc. 2000, 122, 6321-6322. P. Magnus, T. Rainey, Tetrahedron 2001, 57, 8647-8651.

116

In 2012 Gaunt reported a synthesis of rhazinilam based on the C-H activation of the pyrrole (Scheme 132)165, strategy which they had already applied to the synthesis of rhazinicine166. A first iridium catalyzed C-H activation followed by one-pot palladium coupling furnished the same nitro-pyrrole (3.22) used by Smith with better yields. N-alkylation of pyrrole (3.35) set up key intermediate 3.37 for a second palladium catalyzed C-H activation that closes the final six membered ring (3.38). He finishes the synthesis in 11 steps and 15% overall yield.

Scheme 132: Gaunt synthesis of Rhazinilam

The most recent synthesis of rhazinilam, to the best of our knowledge, was reported in 2014 by Yao167. He applies his methodology for the C-H alkenylation of 4-aryl-1H-pyrrole-3-carboxylates via a Pd(OAc)2 catalyzed oxidative Heck reaction on a fragment similar to 3.37 to close the piperideine ring of rhazinilam. Several syntheses of enantiopure Rhazinilam were also reported. In 2002 Sames adapted his method to use enantiopure aldehyde 3.39 to generate a chiral Shiff base and obtain 3.40 with 66% d.e. After HPLC separation of the diastereoisomers and release of the chiral auxiliary, a 96% ee could be obtained on the precursor for rhazinilam (Scheme 133)168.

165

L. McMurray, E. M. Beck, M. J. Gaunt, Angew. Chem. Int. Ed. 2012, 51, 9288-9291. E. M. Beck, R. Hatley, M. J. Gaunt, Angew. Chem. Int. Ed. 2008, 47, 3004-3007. 167 Y. Su, H. Zhou, J. Chen, J. Xu, X. Wu, A. Lin, H. Yao, Org. Lett. 2014, 16, 4884-4887. 168 J. A. Johnson, N. Li, D. Sames, J. Am. Chem. Soc. 2002, 124, 6900-6903. 166

117

Scheme 133: 2002 Sames synthesis of (-)-Rhazinilam

In 2006 Banwell adapted their synthesis of racemic rhazinal to achieve an eighteen step synthesis of (-)-rhazinilam in 4.4% overall yield (Scheme 134)169. The configuration of the quaternary center is set through a Michael reaction catalyzed by MacMillan’s chiral organocatalyst. O N N Ph H2 CF3COO

O

O O

N

O

I N

N 3.42

3.43

3.44

O O NH2

Rhazinilam 74% ee

N 3.45

Scheme 134: Banwell synthesis of (-)-Rhazinilam

Also in 2006 Nelson reported a synthesis of (-)-rhazinilam which begins with the cyclocondensation of pentynal and propionyl chloride, catalyzed by a quinine derivative, to give 3.47. This installs, with excellent e.e, the chiral center which will control the selectivity of his key step and set the configuration of the quaternary center of (-)-rhazinilam. He then performs a ring opening reaction via the copper catalyzed addition of a Grignard on the triple bond to prepare pyrrole bearing allene 3.48. He then uses the gold catalyzed intramolecular addition of the pyrrole onto the allene to construct the six membered ring of 3.49. From that intermediate, he finishes the synthesis for an overall total of eleven steps and 19.8% yield (Scheme 135)170

169 170

D. A. S. Beck, A. C. Willis, M. G. Banwell, ARKIVOC (Gainesville, FL, U. S.) 2006, 163-174. Z. Liu, A. S. Wasmuth, S. G. Nelson, J. Am. Chem. Soc. 2006, 128, 10352-10353.

118

Scheme 135: Nelson synthesis of (-)-Rhazinilam

In 2010 Zakarian applied an intramolecular pyrrole Heck reaction to close the six membered ring of rhazinilam last (Scheme 136)171. After having built his core structure in a series of elemental steps employing a strategy similar to Gaunt’s166, he takes advantage of the axial chirality of macrocycle 3.54, which is caused by the iodine, to perform a chiral HPLC separation of the atropoisomers. Each isomer can then undergo an enantiospecific palladium catalyzed transannular cyclisation to obtain (+) and (-) rhazinilam.

Scheme 136: Zakarian synthesis of Rhazinilam

In 2013 Tokuyama reported a synthesis of (-)-rhazinilam via a gold catalyzed cascade cyclisation (Scheme 137)172. After having set the quaternary center early on via chiral enamine chemistry (3.57), 171

Z. Gu, A. Zakarian, Org. Lett. 2010, 12, 4224-4227. K. Sugimoto, K. Toyoshima, S. Nonaka, K. Kotaki, H. Ueda, H. Tokuyama, Angew. Chem. Int. Ed. 2013, 52, 71687171.

172

119

they build their key precursor (3.58) in eight steps from the chiral cyclohexanone. On it they then apply their methodology to close both the six membered ring and the pyrrole in one step. The quaternary center alpha to the triple bond slowed the reaction down consequently and therefore imposed the choice of the bulky substituents on the acetal to stop the gold catalyzed methanolysis of the triple bond.

Scheme 137: Tokuyama synthesis of Rhazinilam

3.1.3. Retrosynthesis

In the diverse syntheses of rhazinilam, a lot of attention was dedicated to the construction of the six membered ring bearing the all carbon quaternary center of the molecule which is potentially the most challenging component to install. Many of these syntheses involved methodologies developed specifically with the construction of this very center as main objective. We believed that the construction of this ring could be obtained easily via our methodology. This same ring could also be identified in leucomidine B and in this case again the quaternary center was also potentially the most challenging fragment to put into place. This similarity should allow for the conception of a divergent strategy to reach both targets from a common intermediate. With this in mind we envisioned our first disconnections to reveal this six membered ring. For rhazinilam breaking the amide bond followed by opening of the pyrrole gives key piperideine 3.46. For leucomidine B the deconstruction of the most functional group rich zone of the molecule, the lactam ring, seems the most logical approach. Once split it leads to an indole equivalent and to the same piperideine. We envisioned that the piperideine could be constructed through the condensation of an aldehyde and amine equivalent which could come directly from a fragment resulting from the differentiation of both esters from Kuehne’s aldehyde 2.37. 120

Briefly the retrosynthetic scheme can be summarized as such (Scheme 138).

Scheme 138: Retrosynthesis of leucomidine B

3.1.4. Racemic Forward Pathway for Leucomidine B

This synthetic pathway was first attempted in a racemic fashion in parallel to the desymmetrization studies presented in section 2.1 and therefore goes through the cyclic anhydride derivate and not the bislactone. This pathway started off with the formation of Kuehne’s aldehyde as described in literature as previously mentioned for the methodology. The procedure requires some attention as not as straightforward as it seems. The first intermediate (3.47) is highly unstable spontaneously hydrolyzing when left open to air and quickly degrades over the course of minutes into a viscous yellowish oil. This requires the intermediate to be prepared, distilled and immediately used in the next step as a too important amount if degradation visibly inhibits the reaction (Scheme 139).

Scheme 139: Synthesis of Kuehne’s aldehyde

121

We then proceeded to protect the aldehyde as it could potentially prove problematic in certain future steps; a simple cyclic acetal was chosen as protecting group (2.48). First trials, on a small scale, were done with sodium sulfate as dehydration agent and gave the desired compound in a 76% yield. An issue was encountered on larger scales when a Dean-Stark was used in the place of sodium sulfate as neither any starting material or desired compound could be recovered (Scheme 140).

Scheme 140: Protection with ethylene glycol.

During the reaction utilizing a Dean-Stark as water remover, it was noticed that a highly viscous oil separated from the toluene and congealed around the magnetic stirrer. Upon inspection of this poorly soluble oil we came to believe that transesterification between the esters and the excess of ethylene glycol had occurred and that the oil was therefore a mixture of oligomers of our compound. Upon treatment of this oil with sodium hydroxide in a 1:1 mixture of methanol-water we obtained protected diacid 2.38 in an 80% yield which confirmed our previous hypothesis (Scheme 141).

Scheme 141: Protected Kuehne’s diacid

From the diacid formation of the cyclic anhydride was attempted. Literature precedence suggested the most convenient method was refluxing it with acetic anhydride173. The transformation worked smoothly though some degradation was noted, lowering the temperature to 50°C gave a clean and quantitative reaction. One issue was that anhydride 2.39 was highly viscous and trapped some of the remaining acetic anhydride and acetic acid. Removal of this excess acetic anhydride was achieved through iterative co-evaporation with xylene with a Kugelrohr at 80°C under high vacuum (1*10-3 mbar). This was then followed by co-evaporation in toluene to remove water accumulated from the xylene 173

E. M. Beck, R. Hatley, M. J. Gaunt, Angew. Chem. Int. Ed. 2008, 47, 3004-3007; N. L. Allinger, J. Am. Chem. Soc. 1959, 81, 232-236.

122

which also remained trapped, with these conditions we could obtain our cyclic anhydride sufficiently clean with only a small amount of toluene remaining and we could attempt the next step (Scheme 142).

Scheme 142: formation of the anhydride

The opening of the cyclic anhydride with methanol did not prove efficient. Yields never exceeded 50% with about 32% recovered diacid. Even using extra dry methanol did not affect the ratio. It seemed that despite our best efforts the amount of water trapped in the starting material was still too high (Scheme 143).

Scheme 143: Racemic ring opening.

Selective reduction of the acid was then performed with a borane complex in THF which went smoothly and gave alcohol 3.48 in 73% yield. The alcohol was then transformed to the azide via the mesylate in 75% yield (Scheme 144).

Scheme 144: Formation of the azide.

123

At this point the synthesis totaled seven steps from Kuehne’s aldehyde with an intermediate yield of 22%. We first decided to tackle the synthesis of Leucomidine B. Several pathways to construct the piperideine ring were open to us. Our first pathway studied (Scheme 145) was via the coupling of reduced 3.49 with indol-2-carboxilic acid to yield an amide bearing intermediate followed by deprotection of the aldehyde for the intramolecular formation of the piperideine which would then undergo a Picktet-Spengler type reaction to furnish the natural product.

Scheme 145: Picktet-Spengler pathway

Staudinger reduction afforded the desired amine though it is important to note that it proved unstable over time (Scheme 146). Coupling to the indole moiety was achieved through EDC mediated reaction with commercially available indol-2-carboxylic acid (75% yield).

Scheme 146: Staudinger and coupling reaction.

Deprotection of the aldehyde was not as clean as hoped for. Diverse acidic cleavage such as PTSA, HCl aq/DCM only yielded degradation of the starting material, no desired compound or PicktetSpengler adduct could be observed. Citric acid cleavage with silica in DCM showed no reaction even at 50°C just as PPTS. Finally PdCl2 in acetone174 provided the desired compound in 60% yield (Scheme 147).

174

B. H. Lipshutz, D. Pollart, J. Monforte, H. Kotsuki, Tetrahedron Lett. 1985, 26, 705-708.

124

Scheme 147: deprotection of the acetal.

The final cyclisation was then attempted with diverse Brønsted acids (PTSA, TFA, diphenylphosphate) but all these trials were all met with no reaction at lower temperatures and total degradation of starting materials when the reactions were heated with no a trace of the desired compound. Lewis acids were then attempted as an alternative, SnCl2, BF3-Et2O, Yb(OTf)3, TiCl4 and AlCl3 were tried but no reactivity was observed (Scheme 148).

Scheme 148: Cyclisation via iminium formation

This lack of reactivity might originate from α-quaternary center that generates a too high steric hindrance and blocks the attack of the amide on the aldehyde. It might also be explained by a too poor nucleophilicity of the amide due to conjugation with the indole π-system175. Not wishing to be set back by these issues we decided to inverse the order in which we formed the final bonds. If the bond between the indole C3 carbon and piperideine 3.46 could be formed the second closure of the amine onto the ester might be easier (Scheme 149). The piperideine was obtained by treatment of 3.49 with HCl after the Staudinger reaction.

175

E. E. van Tamelen, G. G. Knapp, J. Am. Chem. Soc. 1955, 77, 1860-1862.

125

Scheme 149: Cyclisation with the indole C3 bond formed first.

This was first attempted with indol-2-carboxylic acid (X = OH). Phosphoric acids, TFA and PTSA were used as catalysts but no reactivity was obtained, some Lewis acids were also attempted to promote the reaction but these (BF3-Et2O, Yb(OTf)3, AlCl3) also proved to be inefficient. Reaction with the acyl chloride equivalent of the indole was also tried ( X = Cl). The starting material was rapidly consumed at room temperature in under an hour but it did not give any trace of the desired compound, only coupling product 3.54 could be obtained in a relatively good yield. Reaction with the aldehyde (X = H) also proved unreactive under the same conditions as the acid. This lack of reactivity was attributed to the deactivation of the indole due to the presence of electron withdrawing groups at the C2 position. We therefore attempted the reaction on simple indole as shown in Scheme 150.

Scheme 150: Friedel-Crafts reaction with indole

When the reaction was treated with an excess of acetic acid and refluxed overnight in toluene some conversion was noted. After 16 hours 50% conversion to what was confirmed to be the desired compound had occurred. We then sought to bypass this poor reactivity by activation of the imine through acyliminium formation (Scheme 151).

126

Scheme 151: methyl chloroformate activated cyclisation

Preliminary trials gave a compound that was identified as intermediate 3.63 as a mixture of diastereoisomers and rotamers in about 50% yield. It is interesting to note that this required acidic conditions to work, if an organic base such as triethylamine was used the reactivity was quenched and desired product was not obtained. The final bond formation was then attempted but did not yield the desired product. Thermal cyclisation did not show any conversion while both Brønsted and Lewis acid catalysis resulted in degradation of the reaction mixture. As the methyl carbamate appeared not sufficiently electrophilic to be able to react with the indole C2 position we sought to change the methylchloroformate to a doubly activated CO equivalent. We therefore attempted the final cyclisation by employing triphosgene as shown in Scheme 152.

Scheme 152: Alternative cyclisation strategy.

Sadly only degradation was observed at this stage, it is possible that the activated imine was too reactive degrading or polymerizing before it could be trapped by the indole as no more piperideine could be detected within an hour at 0° C and most of the indole could be recovered. A two-step sequence was then attempted in the hopes that the intermediate acyl chloride could be trapped intramolecularly (Scheme 153). The formation of precursor 3.60 was first optimized. By stirring indole with piperideine 3.46 in refluxing toluene with a catalytic amount of phosphoric acid full conversion could be obtained giving 3.60 in 50 % yield as a roughly 1:1 mixture of diastereoisomers, the yield was pushed to 70% by switching to 10 equivalents of acetic acid in refluxing toluene overnight. 3.60 was then mixed with triphosgene which reacted rapidly in DCM at room temperature to give a partially stable compound identified as 3.61 as a complex mixture of rotamers and diastereoisomers. Trace quantities of the fully cyclized compound were found by mass spectroscopy probably through 127

cyclisation within the ionizer rather than in the reaction flask. Heartened by this discovery we proceeded to heat 3.61 in toluene and were pleased to see it convert relatively cleanly to racemic leucomidine B in 40% yield from 3.60,

Scheme 153: Two step final cyclisation.

Further investigations showed that performing the first addition at 0°C and waiting until full conversion of 3.60 to 3.61 before heating to reflux in toluene to form 3.1 could push to yield of the final step to 68%. In summary we were able to form piperideine 3.46 from Kuehne’s aldehyde in seven steps with a reasonable yield (18%). From this intermediate we were able to form 3.60 by attack of the C3 position of indole to the imine in 70% yield. The final ring of leucomidine B was closed by the action of triphosgene on 3.60 in 68% yield.

Scheme 154: Summery of the racemic pathway

128

3.1.5. Enantioselective forward pathway for Leucomidine B

At this point it had become clear that the desymmetrization of Kuehne’s aldehyde would pass through the bislactone pathway rather than the anhydride pathway. Therefore to rejoin the developed pathway unprotected intermediate 2.49 would have to be protected to obtain 2.40. Firstly, racemic 2.49 was obtained via trimethyltin hydroxide mediated hydrolysis in 83% yield (Scheme 155)176, while enantioenriched 2.49 was obtained via our methodology.

Scheme 155: Hydrolysis with tin hydroxide.

The protection of the aldehyde to the acetal did not give the desired compound, again transesterification with ethylene glycol occurred even under mild conditions. While this had been a minor issue beforehand it was now very problematic, the best conditions available gave maximum yield of 33% which varied strongly in-between attempts (Scheme 156).

Scheme 156: Protection of mono-hydrolysis product

The first option considered to bypass this issue was simply by avoiding the protection step, this was a risky choice as several of the functional groups present were very similar in reactivity. The reduction conditions chosen would need to be highly selective as if the aldehyde was reduced at any point during the reaction the intermediate would cyclize. Several methods for the selective reduction of esters in the presence of aldehydes exist. These methods mostly base themselves on the in-situ masking of the aldehyde though no report could be found where a both a carboxylic acid and ester function were present on the same molecule. Of these methods three appeared compatible with our substitution pattern (Scheme 157): a first method 176

K. C. Nicolaou, A. A. Estrada, M. Zak, S. H. Lee, B. S. Safina, Angew. Chem. Int. Ed. 2005, 44, 1378-1382.

129

reported in 2010 by Colby177 who used DIBAl-H to form an N,O-dimethylhydroxylamine complex in order to mask the aldehyde and selectively reduce an ester or add a Grignard onto it. A second in 2011 in which Fujioka178 formed phosphonium salts with triphenylphosphine and trimethylsilyltriflate to in situ protect aldehydes from addition. A third method considered was based on a report from 2012 by Marko179 who used diethylaluminium benzenethiolate to mask aldehydes with good results.

Scheme 157: Selective masking of aldehydes.

A test reaction was run on Kuehne’s aldehyde to probe the methods behavior towards our type of substrate. All three conditions gave a mixture of the mono and bi-ester reduced. The encouraging point was that the aldehyde appeared mostly untouched. Our monoester 2.40 was then submitted to these conditions but they all gave very messy reaction with a multitude of compounds in all cases. One point was nonetheless clear, no trace of an aldehyde moiety remained.

Scheme 158: Selective reduction in the presence of aldehydes

177

F. J. Barrios, X. Zhang, D. A. Colby, Org. Lett. 2010, 12, 5588-5591; F. J. Barrios, B. C. Springer, D. A. Colby, Org. Lett. 2013, 15, 3082-3085. 178 H. Fujioka, K. Yahata, O. Kubo, Y. Sawama, T. Hamada, T. Maegawa, Angew. Chem. Int. Ed. 2011, 50, 1223212235. 179 G. Bastug, S. Dierick, F. Lebreux, I. E. Markó, Org. Lett. 2012, 14, 1306-1309.

130

NMR experiments showed that it was masking of the aldehyde through complexation which posed problem. This step was never clean nor reached full conversion unlike the reaction run in the same conditions on Kuehne’s aldehyde. This was potentially due to the presence of the acid which could interfere with the reagents. In-situ protection of the acid with a silyl before complexation of the aldehyde did not give any improvement. These issues pushed us to abandon the protecting group free pathway and look for another protecting group. When considering potential protecting groups to replace the acetal the use of dithianes appealed to us as a highly selective protection method had been previous developed by our group180. Hafnium triflate has such a high affinity difference between oxygen and sulfur that protection of an aldehyde with ethanethiol or ethanedithiol can be run without the need for a water removal method to push the equilibrium towards the desired compound. While no example of an aldehyde alpha to a quaternary center was reported we were confident that this would not be an issue. Indeed the reaction proceeded smoothly giving the desired dithiane protected intermediate (3.71) in near quantitative yield, though it required a higher catalyst loading than usual, around 5% instead of 0.1mol%.

Scheme 159: Dithiane protection of the aldehyde

Reduction of the acid now proceeded smoothly to give alcohol (3.72a) with a slightly better yield than with the acetal protecting group as the reaction could be treated with acid when complete. At this point in the synthesis we managed to determine the absolute configuration of the products obtained via our methodology (2.111) with the S-Binol based catalyst. It was determined to give the S- absolute configuration which was in opposition to our natural product targets. Instead of changing catalysts we took advantage of the functional flexibility of our substrate and reduced the ester selectively instead of the acid. This, in essence, inverses the configuration of our stereocenter to give an R- absolute configuration after methylation of the acid (3.72b) (Scheme 160).

180

Y.-C. Wu, J. Zhu, J. Org. Chem 2008, 73, 9522-9524.

131

Scheme 160: Stereocontrol via selective reduction.

The next step also needed to be re-optimized. When alcohol 3.72 was transferred to azide 3.73 the reaction was not clean, only 45% of 3.73 could be isolated (Scheme 161). Step by step investigation showed that the mesylation in DMF was very dirty. This difference in reactivity was attributed to the potential nucleophilic character of the sulfur atoms of our protecting group. While to the best of our knowledge never reported, some partial deprotection of the dithiane by the mesyl chloride may occur which could, in turn, could lead to side products and a messy reaction. This deprotection would operate in a similar manner to the way methyl iodine works for the cleavage of this family of protecting groups181.

Scheme 161: Azide formation

Changing the reaction solvent to DCM gave a very clean reaction for the mesylation (observed via an NMR sample) without trace of the degradation that had taken place beforehand. Therefore in an attempt to keep this reaction one pot an equal volume of DMF was added to the reaction along with sodium azide and the mixture warmed to 50°C which gave then desired compound in a better yield (70%). Addition of a soluble azide source such as TMSN3 instead of the DMF/NaN3 mix gave similar results. The remaining 30% represented a side product which co-eluted with the desired one during purification. This was identified as the product resulting of the substitution of the mesylate by a chloride anion, though this side-reaction only occurred when the reaction was heated to 50°C not at room temperature. It was also observed that this compound only underwent substitution by sodium azide at a higher temperature than the mesylate (80°C vs 50°C), but this temperature also caused significant degradation of our desired compound. Therefore we decided to use a two-step process with first 181

M. Fetizon, M. Jurion, J. Chem. Soc., Chem. Commun. 1972, 382-383; T.-L. Ho, C. M. Wong, Synthesis 1972, 1972, 561-561.

132

mesylation and removal of the chlorine salts by aqueous treatment to stop any chance of formation of the chlorinated product followed by substitution of the mesylate via sodium azide in DMF. This minimized the formation of the side product and pushed yields to 83% (two steps, Scheme 162).

Scheme 162: Two step formation of the azide

The sequence to form the piperideine needed also to be reconsidered as the deprotection of the aldehyde after the Staudinger reaction by simple acidic treatment was no longer possible. Reduction of the azide then deprotection was considered a bad choice as most reported dithiane deprotection conditions involve either methylation or oxidative agents which would react with the amine. Therefore we chose to first deprotect the aldehyde (Scheme 163).

Scheme 163: Deprotection of the dithiane

A series of classical conditions182 were tried as summarized below (Table 19) but disappointingly yields were always very poor. The best yields obtained were when using N-chlorosuccinimide in aqueous acetone which gave 45% yield. One reason for these poor yields was the instability of the aldehyde when purified by silica. Interestingly under certain conditions the piperideine could be isolated from the reaction media especially when methyl iodine was used. This might be caused by the diverse sulfur containing by-products which result of the deprotection of the dithiane as sulfur containing compounds can be used as a reducing agent, especially of azides183. Bypassing the purification and directly proceeding with the Staudinger reaction gave only degradation products. Hydrogenation to reduce the azide also gave poor results.

182 183

P. G. M. Wuts, T. W. Greene. Greene's Protective Groups in Organic Synthesis, 2007, H. Bayley, D. N. Standring, J. R. Knowles, Tetrahedron Lett. 1978, 19, 3633-3634.

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Entry

Conditions

Solvent/T°

NMR Ratio 3.73 [%]

3.74 [%]

3.75 [%]

Isolated Yield

1 2 3 4 5 6

NBS (1 equiv) NBS (2.2 equiv) CuCl2/CuO AgNO3 NBS/AgClO4 MeI (10 equiv) MeI (10 equiv) /NaHCO3

aq acetone r.t aq acetone 50°C aq acetone r.t EtOH reflux aq acetone r.t aq acetone reflux

41 0 40 41 0

33 100 40 33 20

26 0 20 26 80

40% (3.74) 30% (3.74) degradation n.a n.a 33% (3.75)

aq acetone reflux

-

-

-

degradation

7 8

MeI (10 equiv)

aq acetone 35°C

10

20

70

46% (3.75)

9 10

NCS (2.2 equiv) NCS (2.2 equiv) NCS (2.2 equiv)/NaHCO3

aq acetone 0°C aq acetone r.t

0 0

100 100

0 0

42% (3.74) 45% (3.74)

aq acetone r.t

0

100

0

43% (3.74)

10

Table 19: deprotection of dithiane

We then attempted the deprotection using Nicolaou’s conditions with IBX (Table 20)52. While no reaction was noted under the described conditions the addition of TBAB to activate the IBX gave clean deprotection of the aldehyde in good yields by NMR.

Entry 1 2 3 4 5 6 7 8

DMSO/H2O (V/V) 1/0 90/10 90/10 90/10 90/10 90/10 90/10 90/10, 0°C

AcOH (%V) 0 10% 10% 10% 10% 10% 0% 10%

IBX (equiv) 2 2 2 2 2 3 3 3

TBAB (equiv) 0 0 Cat. 1 2 3 3 3

Conv (%) 0 0 trace 20 50 100 100 100

NMR yield 3.74 (%) 90 60 90

Table 20: Dithiane deprotection with IBX

134

Attempts to do the Staudinger reduction directly on the reaction mixture gave as before only degradation. Optimization of the extraction conditions (Et2O:NaHCO3) gave the desired aldehyde in about a 1:1 mix with TBAB, it did not however interfere with the Staudinger reaction who gave the desired imine in a 60% yield over two steps. With this enantioenriched piperideine in hand we were able to finish the synthesis of Leucomidine B as described in Scheme 150 and Scheme 153. However as the Friedel-Crafts reaction gave a 1:1 mixture of diastereoisomers we decided to attempt to develop a method to obtain diastereocontrol of that center. We first attempted to do so by switching to a chiral phosphoric acid as catalyst. Sadly the reactivity was poor with very low conversions and no apparent diastereomeric induction. We then decided to hydrolyze the ester reasoning that the resulting acid might intramolecularly shield one face via H-bonding and guide the attack towards the opposite face to give the trans configuration we required (Scheme 164).

Scheme 164: Facial selectivity via internal H-bonding

Hydrolysis with potassium hydroxide of the piperideine gave the desired compound cleanly. We then attempted to quench the potassium salt and isolate piperideine 3.76 but visibly when the acid is reprotonated piperideine 3.76 is in zwitterionic form and could not therefore be separated from the salts formed during the reaction. Despite this we could obtain a reasonably clean crude which we believed we could use in the next step after adding one equivalent of acid and co-evaporating the mixture with toluene several times. One issue was that the amount of water trapped within the product remained high and we feared it would interfere with the intramolecular H-bonding we were looking for. The Friedel-Crafts reaction proceeded nonetheless reasonably cleanly with 10% acetic acid and when intermediate 3.75 was trapped with TMS-diazomethane we could obtain the desired compound in a reasonable yield (about 50%,Scheme 165).

135

Scheme 165: Face directed Friedel-Craft reaction

The diastereomeric ratio was also interesting as we obtained a 2:1 mix between the diastereoisomers. Additives were screened to try and push the selectivity higher, while various Lewis acids gave only degradation, TRIP pushed the d.r. to, at its highest, a 12 to 1 ratio but this proved irreproducible. We did not further investigate this as we realized that we were obtaining the wrong facial selectivity and that the acid was directing the indole towards the wrong face of the piperideine instead of shielding it as is presented later. This might hypothetically be due to some further H-bonding effect between the indole NH and the carboxylate moiety which would guide the attack towards the same face as the acid.

Figure 16: Rational for facial selectivity

Under our previous conditions starting from a 2:1 diastereomeric mix we obtained Leucomidine B in a 1:1 ratio presumably due to the ring opening and reclosing of the intermediate (Scheme 166).

Scheme 166: Loss of diastereoselectivity for the final ring closing step.

136

We bypassed this problem by employing a modified procedure for the formation of the carbamate. By bubbling CO2 through a mixture of 3.60 and MTBD in DCM at low temperature and then adding an equivalent of thionyl chloride it was possible to form intermediate 3.78 which upon stirring with silica cyclized without apparent loss of diastereoselectivity to give Leucomidine B, in 70% yield (Scheme 167).184

Scheme 167: MTBD mediated carbonylation

We next turned our attention to an alternative pathway. We hoped that by performing a Mannich type reaction between our piperideine 3.46 and methyl 3-(2-nitrophenyl)-2-oxopropanoate we might be able to control the formation of the second asymmetric center as well as streamlining the final steps of the synthesis.

After heating at 90°C for several hours in toluene we obtained the Mannich adduct in good yield (80%, Scheme 168) and a 1:1 mixture of diastereoisomers in the form of atropoisomers.

184

W. D. McGhee, Y. Pan, J. J. Talley, Tetrahedron Lett. 1994, 35, 839-842; J. Zhu, A. E. Graham, in Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons, Ltd, 2001

137

Scheme 168: Mannich reaction of Piperideine 3.46

Reduction of the nitro group with palladium on charcoal gave a mixture of cyclized and noncyclized Leucomidine B. The mixture had to be heated to 110°C in toluene over several hours to overcome the rotational barrier around the CAr-C bond to fully convert the mixture to the natural product (Scheme 169).

Scheme 169: Final reduction and cyclisation for Leucomidine B

We then attempted to induce diastereoselectivity via chiral acid catalysis of the Mannich reaction but no induction was observed, we then attempted using chiral proline derivates but the condensation of the ketone onto the amine did not even occur as in solution. Methyl 3-(2-nitrophenyl)2-oxopropanoate is predominantly in enol form and therefore unreactive towards amines. A slight enantio-enrichment of the final product compared to its monoacid precursor was noticed with this alternative sequence. In total this pathway allowed us to synthetize both epimers of Leucomidine B in 12 steps from Kuehne’s aldehyde with an overall yield of 13% and an enantiomeric ratio of 92:8.

3.1.6. Enantioselective Forward Pathway for Rhazinilam

Starting for piperideine 3.46 we then tackled the synthesis of Rhazinilam (3.2). Reaction with 1-(3bromoprop-1-en-1-yl)-2-nitrobenzene in DMF at 100°C gave salt 3.81 which was then suspended in toluene and heated in the presence of silver carbonate to form pyrrole 3.82 in 20-30% yield (Scheme 170). 138

Degasing of the reaction media helped clean up the reaction pushing the yield to about 50%, it also became clear that reaction times were very important as the pyrrole was not stable at higher temperatures. This step also proved to be quite sensitive to the quality of reagents. Silver carbonate, often used for Fetizon type oxidations185, is unstable to light degrading into inactive silver oxide. It had to be prepared prior to use, dried by co-evaporation with toluene and kept shielded from light to obtain the best results. To avoid any problems it was also added to the reaction media after the latter had already been degased. These precautions helped clean the reaction further and pushed the yield up to 70%. 3.82 was therefore obtained from piperideine 3.46 in 60% yield over two steps.

Scheme 170: Formation of the pyrrole with silver carbonate

This pyrrole was then transformed into (-)-Rhazinilam in three steps and 80% yield via the reduction of the nitro group with palladium on charcoal, hydrolysis of the ester with potassium hydroxide and finally peptide coupling with EDC to close the nine membered ring . Overall this pathway provided (-)-Rhazinilam in 15 steps and 20% yield from Kuehne’s aldehyde.

Scheme 171: Final ring closing for (-)-Rhazinilam

185

H. Rapoport, H. N. Reist, J. Am. Chem. Soc. 1955, 77, 490-491; W. King, W. Penprase, M. Kloetzel, J. Org. Chem 1961, 26, 3558-3558; M. Fetizon, V. Balogh, M. Golfier, J. Org. Chem 1971, 36, 1339-1341.

139

3.2. Rhazinicine 3.2.1. Isolation and Retrosynthesis

With these two natural products in hand we turned our attention to other members of the rhazinilam family, 2-oxo-rhazinilam or rhazinicine (Figure 17). Isolated from Rauvolfia serpentina Benth. ex Kurz and Rhazyastricta Decaisne (Apocynaceae) hybrids 186and Kopsia dasyrachis187 this metabolic derivate has only been synthetized once by Tokuyama in 2013172. The synthetic interest of this structure is the N-acyl-pyrrole moiety which is highly reactive as exemplified by the difficulties encountered in Tokuyama’s work and whose synthesis proved more challenging than expected.

Figure 17: Rhazinicine

While less well developed and slightly more difficult than for simple pyrroles, the synthesis of these N-acyl-pyrroles are in principle well known, starting from either the acyl chloride or the amide188, however these methods require often harsh conditions which makes the formation of more complex Nacyl-pyrrole moieties challenging, strategies therefore tend to form the N-acyl-pyrrole first and then functionalize it as needed. We were therefore interested to see if we could develop conditions to construct the complex core of rhazinicine from our intermediate (Scheme 172).

Scheme 172: Retrosynthetic analysis of Rhazinicine

186

I. Gerasimenko, Y. Sheludko, J. Stöckigt, J. Nat. Prod. 2000, 64, 114-116. T.-S. Kam, G. Subramaniam, W. Chen, Phytochemistry 1999, 51, 159-169. 188 S. D. Lee, M. A. Brook, T. H. Chan, Tetrahedron Lett. 1983, 24, 1569-1572; D. A. Evans, G. Borg, K. A. Scheidt, Angew. Chem. Int. Ed. 2002, 41, 3188-3191; N. Yamagiwa, H. Qin, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2005, 127, 13419-13427; X. Yuan, X. Xu, X. Zhou, J. Yuan, L. Mai, Y. Li, J. Org. Chem 2007, 72, 1510-1513; D. Zhu, J. Zhao, Y. Wei, H. Zhou, Synlett 2011, 2011, 2185-2186; T. Maehara, R. Kanno, S. Yokoshima, T. Fukuyama, Org. Lett. 2012, 14, 1946-1948; T. Kinoshita, S. Okada, S.-R. Park, S. Matsunaga, M. Shibasaki, Angew. Chem. Int. Ed. 2003, 42, 4680-4684. 187

140

We were also curious to see if, in a second stage, we could develop a divergent strategy for the whole family of products via a common intermediate by carefully controlling reduction conditions. (Scheme 173)

Scheme 173: Retrosynthetic analysis for the Rhazinilam family

141

3.2.2. Synthesis

Coupling between monoacid 2.98c obtained via our methodology and amine 3.98 synthetized in three steps according to literature (Scheme 174)189 gave the precursor for the formation of the pyrrole (Scheme 175).

Scheme 174: Synthesis of starting amine 3.97

O HO

O

BnOOC

NO2

O O

Ph

+

NH3Cl

HATU

HN

O

O

62% NO2

2.98c

3.98

3.84

Scheme 175: Synthesis of pyrrole precursor 3.84

We first screened a variety of coupling agents as the yields for the formation of the amide were poor, despite this only a maximum yield of 62% could be obtained with HATU. The reason for this quickly became clear when we understood that the amine spontaneously cyclized under neutral conditions to the hemi-aminal which proved to be stable as it could even be isolated by column chromatography as a mixture of two distinct diastereoisomers. Out of the possible two pairs of diastereoisomers obtainable, we believe we obtained the pair which possesses the hydroxyl group in pseudo-axial position. This conformation is probably favored due to an anomeric effect between the hydroxyl and the amine. Apparently, what we believed was the cis stereoisomer, could continue to cyclize to bicyclic compound 3.100 (Scheme 176) under mild acidic conditions, such as trace HCl in chloroform, or mild basic conditions such as trace base remaining from work-up.

189

The amine was used as the HCl salt as the free amine is unstable at room temperature. C. J. Moody, K. F. Rahimtoola, B. Porter, B. C. Ross, J. Org. Chem 1992, 57, 2105-2114.

142

Scheme 176: Spontaneous cyclisation of compound 3.99

We then attempted to induce the formation of the acyl iminium (3.101) which we hoped would spontaneously cyclize to the dihydropyrrole (3.102). We first tried basic conditions as was we hoped that a small amount of iminium 3.101 would spontaneously form and that we could trap if by base triggered deprotonation/cyclisation (Scheme 177). Inorganic bases such Ca(OMe)2 or K2CO3 simply pushed the equilibrium between 3.84 and 3.99 fully to the hemiaminal with partial cyclisation of one of the diastereoisomers to 3.100 presumably through attack of the hydroxy onto the ester. Organic bases such as DBU or NEt3 gave a 1:1 mixture between the trans-diastereoisomer and cyclized product. This was our first indication that no iminium 3.101 was formed as even when heating the reaction over a prolonged period the trans-diastereoisomer did not significantly epimerize.

Scheme 177: Base catalyzed cyclisation

We next attempted acid catalyzed cyclisation in the hope of promoting the iminium formation. Mild acidic conditions such as catalytic amounts of PTSA, acetic acid or diphenyl phosphate gave a mixture of fully cyclized (3.100) and non-fully cyclized compounds (3.84 and 3.99(a&b)). Lewis acids such as ZnCl2 or YbCl2 gave mostly the hemi-aminal while stronger acidic conditions such as TFA, HCl or an excess of acetic acid gave the fully cyclized compound cleanly. This indicated that under acidic conditions the iminium could presumably form both the isomers but that the cyclisation on the ester was also facilitated under acidic conditions and therefore the predominant product of the reaction (80%). Attempts to trap the hemi-aminal in the hopes of forming a good leaving group and promoting the cyclisation with MsCl, AcCl or TMSCl proved unsuccessful. We then attempted to trap the iminium with

143

methanol in acidic conditions, this worked partially and gave a mixture which was apparently composed of the hemiaminal, methoxy trapped hemiaminal and cyclized product (Scheme 178).

Scheme 178: methanol trapping of the iminium

We then attempted to trap the intermediate with a cyano group which might allow to then then treat the compound with base and force the cyclisation. Treatment of 3.84 with TMSCN in the presence of BF3-Et2O yielded a new pair of compounds which are being identified.

144

3.3. Conclusion In summary we have fully developed a pathway which allows access to two natural products190. The first was (-)-Rhazinilam which we obtained in 15 steps and 20% yield from Kuehne’s aldehyde with as key steps the desymmetrization of our key bislactone and the formation of the pyrrole. The second was Leucomidine B, which represented the first total synthesis of that natural product, in 12 steps and 8% overall yield. Continued studies are ongoing on the synthetic use of our intermediate via the synthesis of Rhazinicine.

Scheme 179: Summary of the total synthesis of (-)-Leucomidine B and (-)-Rhazinilam

190

J.-B. Gualtierotti, D. Pasche, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2014, 53, 9926-9930; Highlighted, Synfacts 2014, 10, 1096.

145

146

General Conclusion In summary we have developed several synthetically useful methodologies which can be split in two categories. The first concerns multicomponent reactions based on the unique structures of αiminonitriles95. By combining a method for the formation of α-iminonitriles via an oxidative three component Strecker reaction and the subsequent hydrolysis of these adducts on alumina we developed a multicomponent reaction allowing for the easy and straightforward amidation of amines and aldehydes. We then studied the behavior of α,β-unsaturated-α-iminonitriles towards Michael addition by thiols and based on our findings developed a second methodology for the formation of β-functionalized amides from aldehydes, amines and thiols with again α-iminonitriles as key intermediate structure.

A third study was then performed towards the development of an alternative oxidative multicomponent reaction for the formation of α-iminonitriles using mild and highly selective conditions. Based on the synergetic combination of Oxone® and a phase transfer catalysis in a biphasic system this method proved to be highly selective and a large scope of substrates was shown to be tolerated. This method proved to be also compatible with the previously described methodologies.

A second type of reaction was then developed which concerned the desymmetrization of all carbon quaternary center bearing moieties derived from dimethyl 4,4-disubstituted pimelate. We first attempted to desymmetrize eight-membered cyclic anhydrides but were unsuccessful. We then turned our attention to developing a method utilizing bicyclic bislactones. In the presence of a chiral phosphoric acid and an alcohol these give optically ten carbon synthons with up to four differentiated functional groups around the chiral center190. The scope of this method was then studied in depth with regards to both the starting substrates and the methodology proved to be applicable to a large range of substrates.

147

These fragments were then used in the total synthesis of biologically and pharmaceutically relevant natural compounds. Firstly the total synthesis of indole alkaloid leucomidine B was performed in ten steps from our key fragment and twelve steps from a well-known literature compound in a relatively good yield. This involved the transformation of our moiety in seven elemental steps to an optically active piperideine which was then used in either a Friedel-craft or a Mannish reaction to construct the tetracyclic skeleton of the target natural product. This key piperideine was also applied in the total synthesis of another indole alkaloid, rhazinilam, in fifteen steps.

Studies towards a third natural product using our key moieties are underway and the first results towards the second key step, the formation of the acyl pyrrole moiety have been presented.

O N N H

O

HO

O O

O

Ph

O

(-)-Rhazinicine

148

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Experimental data General Considerations ........................................................................................................ 163 Amides ........................................................................................................................................... 164 1.3a) N-phenethylbenzamide ........................................................................................................... 165 1.3b) N-benzylbenzamide................................................................................................................. 166 1.3c) N-(4-methoxyphenyl)benzamide ............................................................................................. 166 1.3d) 4-methoxy-N-phenethylbenzamide ......................................................................................... 167 1.3e) N-phenethylcinnamamide ....................................................................................................... 168 1.3f) N-cyclopropylcinnamamide...................................................................................................... 168 1.3g) N-phenethyl-3-phenylpropanamide......................................................................................... 169 1.3h) (E)-2-methyl-N-phenethylbut-2-enamide ................................................................................ 169 1.3i) N-phenethylisobutyramide....................................................................................................... 170 1.3j) N-phenethylcyclohexanecarboxamide ...................................................................................... 171 1.3k) N-cyclopropylbenzamide ......................................................................................................... 171 1.3l) 2-iodo-N-phenethylbenzamide ................................................................................................. 172 1.3m) 2-ethyl-N-phenethylhexanamide ............................................................................................ 172 1.3n) 3-methyl-N-phenethylbutanamide .......................................................................................... 173 1.3o) N-phenethylcyclopropanecarboxamide ................................................................................... 174

Mercapto Amides ..................................................................................................................... 174 1.6a) 3-(ethylthio)-N-phenethyl-3-phenylpropanamide .................................................................... 175 1.6b) 3-(benzylthio)-N-phenethyl-3-phenylpropanamide.................................................................. 175 1.6c) N-phenethyl-3-phenyl-3-(phenylthio)propanamide ................................................................. 176 1.6d) 3-(tert-butylthio)-N-phenethyl-3-phenylpropanamide............................................................. 177 1.6e-f) methyl 2-((tert-butoxycarbonyl)amino)-3-((3-oxo-3-(phenethylamino)-1phenylpropyl)thio)propanoate ......................................................................................................... 178 1.6g) 3-(benzylthio)-N-phenethylbutanamide................................................................................... 181 1.6h) 3-(benzylthio)-N-phenethylbutanamide .................................................................................. 181 1.6i) 3-(ethylthio)-N-phenethylbutanamide ...................................................................................... 182 1.6j) 3-(benzylthio)-3-(4-bromophenyl)-N-phenethylpropanamide ................................................... 183 157

1.6k) 3-(ethylthio)-N-(4-methoxyphenyl)-3-(4-nitrophenyl)propanamide ......................................... 183 1.6l) N-cyclopropyl-3-(4-methoxyphenyl)-3-(phenylthio)propanamide ............................................. 184 1.6n) 3-(tert-butylthio)-N-(4-methoxyphenyl)-3-phenylpropanamide ............................................... 185 1.6o) 3-((2-hydroxyethyl)thio)-N-phenethyl-3-phenylpropanamide .................................................. 185 1.6p) 3-((2-((tert-butyldiphenylsilyl)oxy)ethyl)thio)-N-phenethyl-3-phenylpropanamide .................. 186

Iminonitriles............................................................................................................................... 187 1.36) N-phenylbenzimidoyl cyanide.................................................................................................. 187 1.140) N-phenethylcinnamimidoyl cyanide....................................................................................... 187 1.97a) N-phenethyl-3-phenylpropanimidoyl cyanide ........................................................................ 188 1. 97b) (2E)-N-benzyl-3-(4-methoxyphenyl)acrylimidoyl cyanide ...................................................... 188 1. 97c) N-cyclopropylbenzimidoyl ..................................................................................................... 189 1. 97d) 2-(2-(1,3-dioxolan-2-yl)ethyl)-N-phenethylbenzimidoyl cyanide............................................ 189 1. 97e) N-(2-((trimethylsilyl)oxy)propyl)benzimidoyl cyanide ............................................................ 190 1. 97f) (2E)-2-methyl-N-phenethylbut-2-enimidoyl cyanide .............................................................. 191 1. 97g) 3-methyl-N-phenethylbut-2-enimidoyl cyanide..................................................................... 191 1. 97h) N-benzylpentanimidoyl cyanide............................................................................................ 192 1. 97i) N-benzylpivalimidoyl cyanide ................................................................................................ 192 1. 97j) (Z)-4-methoxy-N-phenethylbenzimidoyl cyanide ................................................................... 193 1. 97k) N-cyclopropylcinnamimidoyl cyanide.................................................................................... 193 1. 97l) 4-((tert-butyldimethylsilyl)oxy)-3-methoxy-N-phenethylbenzimidoyl cyanide ........................ 194 1. 97m) 2,6-dichloro-N-phenethylbenzimidoyl cyanide..................................................................... 194 1. 97n) N-(4-methoxyphenyl)-3-(4-nitrophenyl)acrylimidoyl cyanide ................................................ 195 1. 97o) 3-(4-bromophenyl)-N-phenethylacrylimidoyl cyanide ........................................................... 196 1. 97y) 2-allyl-N-phenethylbenzimidoyl cyanide ............................................................................... 197 1.141) (2E)-N-phenethylbut-2-enimidoyl cyanide ............................................................................. 197 1.156) 2-iodobenzyl acetate ............................................................................................................. 198 1.157) 2-(3-oxopropyl)benzyl acetate ............................................................................................... 198 1.158) 2-(2-(1,3-dioxolan-2-yl)ethyl)benzaldehyde ........................................................................... 199 1.204a) N-cyclopropyl-3-(4-methoxyphenyl)acrylimidoyl cyanide..................................................... 200 1.204b) N-(4-methoxyphenyl)cinnamimidoyl cyanide....................................................................... 201 1.204c) (Z)-N-(4-methoxyphenyl)benzimidoyl cyanide ...................................................................... 201

158

1.204d) N-benzylbenzimidoyl cyanide .............................................................................................. 202 1.204e) (Z)-N-phenethylbenzimidoyl cyanide ................................................................................... 202 1.204f) (Z)-N-phenethylisobutyrimidoyl cyanide............................................................................... 203 1.204g) 4-methoxy-N-phenethylbenzimidoyl cyanide ....................................................................... 203

Desymmetrization General Procedures: .................................................................... 205 General procedure for the synthesis of bislactones: ......................................................................... 205 General procedure desymmetrization of bislactones: ....................................................................... 206 General procedure for the determination of the enantiomeric ratio of monoacids: .......................... 206 Enzymatic Desymmetrisation General Procedure and Screening ...................................................... 207

Desymetrization: Spectroscopic Data .......................................................................... 208 2.37) Dimethyl 4-ethyl-4-formylheptanedioate (Kuehne’s aldehyde) ................................................ 208 2.38) 4-(1,3-dioxolan-2-yl)-4-ethylheptanedioic acid ........................................................................ 208 2.39) 5-(1,3-dioxolan-2-yl)-5-ethyloxocane-2,8-dione ....................................................................... 209 2.48) Dimethyl 4-(1,3-dioxolan-2-yl)-4-ethylheptanedioate .............................................................. 210 2.40) 4-(1,3-dioxolan-2-yl)-4-ethyl-7-methoxy-7-oxoheptanoic acid ................................................. 210 2.53) 4-ethyl-4-formylheptanedioic acid........................................................................................... 211 2.55) 3-(3-ethyl-6-oxotetrahydro-2H-pyran-3-yl)propanoic acid ....................................................... 212 2.94) methyl 7-((2-bromophenyl)amino)-4-(1,3-dithiolan-2-yl)-4-ethyl-7-oxoheptanoate ................. 212 2.95) 4-((2-(2,4-dinitrophenyl)hydrazono)methyl)-4-ethyl-7-methoxy-7-oxoheptanoic acid ............. 213 2.96) methyl 4-(1,3-dithiolan-2-yl)-4-ethyl-7-((4-nitrophenyl)amino)-7-oxoheptanoate .................... 214 2.97) 1-(4'-bromo-[1,1'-biphenyl]-4-yl) 7-methyl 4-ethyl-4-formylheptanedioate ............................. 214 2.98a) (S)-4-ethyl-4-formyl-7-methoxy-7-oxoheptanoic acid ............................................................. 215 2.98b) (S)-4-ethyl-4-formyl-7-isopropoxy-7-oxoheptanoic acid ......................................................... 216 2.98c) (S)-7-(benzyloxy)-4-ethyl-4-formyl-7-oxoheptanoic acid......................................................... 216 2.100e) Dimethyl 4-formyl-4-phenylheptanedioate .......................................................................... 218 2.100f) Dimethyl 4-formyl-4-isopropylheptanedioate....................................................................... 218 2.100g) dimethyl 4-(3-(benzyloxy)propyl)-4-formylheptanedioate.................................................... 219 2.101a) Cis-4a-ethyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione ............................................. 219 2.101b) 4a-(2-(phenylthio)ethyl)tetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione .......................... 220 2.101c) 4a-allyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione .................................................... 221 2.101d) 4a-vinyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione ................................................... 221 159

2.101e) 4a-phenyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione................................................ 222 2.101f) 4a-isopropyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione ............................................ 223 2.101g) 4a-(3-(benzyloxy)propyl)tetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione ......................... 223 2.101h) 4a-methyl-8a-phenyltetrahydropyrano [2,3-b]pyran-2,7(3H,8aH)-dione.............................. 224 2.101j) 8a-methyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione ................................................ 225 2.101l) (4as,8ar)-benzyl 8a-methyl-2,7-dioxooctahydropyrano[2,3-b]pyran-4a-carboxylate ............. 226 2.111a) (R)-4-formyl-4-isopropyl-7-methoxy-7-oxoheptanoic acid (2f) ............................................. 226 2.111b) (R)-4-formyl-7-methoxy-7-oxo-4-vinylheptanoic acid........................................................... 227 2.111c) (R)-4-formyl-4-(3-methoxy-3-oxopropyl)hept-6-enoic acid ................................................... 228 2.111d) (R)-4-formyl-7-methoxy-7-oxo-4-(2-(phenylthio)ethyl)heptanoic acid.................................. 228 2.111e) (R)-4-formyl-7-methoxy-7-oxo-4-phenylheptanoic acid ....................................................... 230 2.111f) (S)-4-(3-(benzyloxy)propyl)-4-formyl-7-methoxy-7-oxoheptanoic acid .................................. 232 2.111g) (S)-4-benzoyl-7-methoxy-4-methyl-7-oxoheptanoic acid...................................................... 233 2.111h) 4-acetyl-7-methoxy-7-oxoheptanoic acid............................................................................. 234 2.111l) 4-acetyl-4-((benzyloxy)carbonyl)-7-methoxy-7-oxoheptanoic acid ........................................ 234 2.41) (R)-1-benzyl 7-methyl 4-ethyl-4-formylheptanedioate and (S)-1-benzyl 7-methyl 4-ethyl-4formylheptanedioate ....................................................................................................................... 235 2.41b) (S)-1-benzyl 7-isopropyl 4-ethyl-4-formylheptanedioate........................................................ 237 2.41c) (S)-1-benzyl 7-methyl 4-formyl-4-vinylheptanedioate ............................................................ 239 2.41d) (S)-1-benzyl 7-methyl 4-allyl-4-formylheptanedioate ............................................................. 241 2.41e) (S)-1-benzyl 7-methyl 4-formyl-4-isopropylheptanedioate ..................................................... 243 2.41f) (R)-1-(4'-bromo-[1,1'-biphenyl]-4-yl) 7-methyl 4-(3-(benzyloxy)propyl)-4-formylheptanedioate ........................................................................................................................................................ 245 2.41g) (R)-1-(4'-bromo-[1,1'-biphenyl]-4-yl) 7-methyl 4-benzoyl-4-methylheptanedioate ................. 247 2.41h) 1-benzyl 7-methyl 4-acetylheptanedioate ............................................................................. 249 2.41i) 3-benzyl 1-(4'-bromo-[1,1'-biphenyl]-4-yl) 5-methyl 3-acetylpentane-1,3,5-tricarboxylate ..... 251 2.41j) 1-benzyl 7-methyl 4-(1,3-dioxolan-2-yl)-4-ethylheptanedioate ............................................... 253 2.120) 3-benzoyl-5-(benzyloxy)-5-oxopentanoic acid........................................................................ 254 2.121) 3-acetyl-5-(benzyloxy)-5-oxopentanoic acid .......................................................................... 256

Procedures and Spectroscopic Data: Total Synthesis ......................................... 258 3.48) methyl 4-(1,3-dioxolan-2-yl)-4-ethyl-7-hydroxyheptanoate ..................................................... 258 3.49) methyl 7-azido-4-(1,3-dioxolan-2-yl)-4-ethylheptanoate ......................................................... 258 160

3.52) methyl 7-amino-4-(1,3-dioxolan-2-yl)-4-ethylheptanoate ........................................................ 259 3.53) methyl 4-(1,3-dioxolan-2-yl)-4-ethyl-7-(1H-indole-2-carboxamido)heptanoate ........................ 260 3.60) methyl 3-(3-ethyl-2-(1H-indol-3-yl)piperidin-3-yl)propanoate .................................................. 261 3.71) (S)-4-(1,3-dithiolan-2-yl)-4-ethyl-7-methoxy-7-oxoheptanoic acid ........................................... 262 3.72) (R)-methyl 4-(1,3-dithiolan-2-yl)-4-ethyl-7-hydroxyheptanoate ............................................... 263 3.73) (R)-methyl 7-azido-4-(1,3-dithiolan-2-yl)-4-ethylheptanoate ................................................... 264 3.46) (R)-methyl 3-(3-ethyl-3,4,5,6-tetrahydropyridin-3-yl)propanoate ............................................ 265 3.82) (R)-methyl 3-(8-ethyl-1-(2-nitrophenyl)-5,6,7,8-tetrahydroindolizin-8-yl)propanoate .............. 266 3.45) (R)-methyl 3-(1-(2-aminophenyl)-8-ethyl-5,6,7,8-tetrahydroindolizin-8-yl)propanoate ............ 267 3.2) (-)-Rhazinilam ............................................................................................................................ 267 3.79) methyl 3-((8R)-8-ethyl-2-hydroxy-1-(2-nitrophenyl)-3-oxo-3,5,6,7,8,8a-hexahydroindolizin-8yl)propanoate .................................................................................................................................. 270 3.1) (-)-Leucomidine B ...................................................................................................................... 272 (+)-Leucomidine B (ent-8)................................................................................................................. 276 (11R, 11aR) Diastereoisomer of Leucomidine B ................................................................................ 277 (11S, 11aS) Diastereoisomer of Leucomidine B ................................................................................. 279

X-ray Data for 2.97 and 2.101a ........................................................................................ 280 2.97) 1-(4'-bromo-[1,1'-biphenyl]-4-yl) 7-methyl 4-ethyl-4-formylheptanedioate ............................. 280 2.101a) Cis-4a-ethyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione ............................................. 281

Rhazinicine .................................................................................................................................. 289 3.84) (E)-benzyl 4-ethyl-4-formyl-7-((3-(2-nitrophenyl)allyl)amino)-7-oxoheptanoate ...................... 289 3.99) benzyl 3-((2S,3R)-3-ethyl-2-hydroxy-1-((E)-3-(2-nitrophenyl)allyl)-6-oxopiperidin-3-yl)propanoate ........................................................................................................................................................ 290 3.100) (4aS,8aR)-4a-ethyl-8-((E)-3-(2-nitrophenyl)allyl)hexahydro-2H-pyrano[2,3-b]pyridine-2,7(3H)dione................................................................................................................................................ 291

Catalysts ........................................................................................................................................ 292 Strip derived ............................................................................................................................. 292 2.150) 1,5-bis(3-methoxyphenyl)penta-1,4-dien-3-one .................................................................... 292 2.132) 1,5-bis(3-methoxyphenyl)pentan-3-one ................................................................................ 292 2.133) 1,5-bis(2-bromo-5-methoxyphenyl)pentan-3-one.................................................................. 293 2.134) 4,4'-dibromo-7,7'-dimethoxy-2,2',3,3'-tetrahydro-1,1'-spirobi[indene] .................................. 294 2.135) 7,7'-dimethoxy-2,2',3,3'-tetrahydro-1,1'-spirobi[indene] ....................................................... 294 161

2.136) Spinol .................................................................................................................................... 295 2.136) (S/R)-Spinol ........................................................................................................................... 296 2.138) 7,7'-bis(methoxymethoxy)-2,2',3,3'-tetrahydro-1,1'-spirobi[indene] ...................................... 298 2.139) (S)-6,6'-diiodo-7,7'-bis(methoxymethoxy)-2,2',3,3'-tetrahydro-1,1'-spirobi[indene] ............... 298 2.140) (S)-6,6'-di(anthracen-9-yl)-2,2',3,3'-tetrahydro-1,1'-spirobi[indene]-7,7'-diol ......................... 299 2.89) (S)-6,6'-bis(2,4,6-triisopropylphenyl)-2,2',3,3'-tetrahydro-1,1'-spirobi[indene]-7,7'-diol........... 300 2.88) 1,10-di(naphthalen-1-yl) spinol phosphoric acid ...................................................................... 301 2.89) STRIP ....................................................................................................................................... 302 2.87) 1,10-di(naphthalen-1-yl) spinol phosphoric acid ...................................................................... 303

Binol derived ............................................................................................................................ 303 2.142) (S)-2,2'-dimethoxy-1,1'-binaphthalene .................................................................................. 303 2.123) (S)-2,2'-bis(methoxymethoxy)-1,1'-binaphthalene ................................................................. 304 2.124) (S)-3,3'-diiodo-2,2'-bis(methoxymethoxy)-1,1'-binaphthalene ............................................... 305 2.143) (S)-(2,2'-dimethoxy-[1,1'-binaphthalene]-3,3'-diyl)diboronic acid .......................................... 305 2.125) (S)-3,3'-di(anthracen-9-yl)-[1,1'-binaphthalene]-2,2'-diol ....................................................... 306 2.83) (11bS)-2,6-di(anthracen-9-yl)-binol phosphoric acid ................................................................ 307 2.144) (S)-3,3'-bis(2-isopropyl-5-methylphenyl)-[1,1'-binaphthalene]-2,2'-diol ................................. 308 2.84) 2,6-bis(2-isopropyl-5-methylphenyl)-binol phosphoric acid ..................................................... 309 General Procedure for the Preparation of the Imidodiphosphoric Acids ........................................... 310 2.92) (11bS)-2,6-di(anthracen-9-yl)-binol imidodiphosphoric acid .................................................... 310 2.93) 2,6-bis(2-isopropyl-5-methylphenyl)-binol imidodiphosphoric acid.......................................... 311

H8-binol derived ..................................................................................................................... 312 2.126) (S)-5,5',6,6',7,7',8,8'-octahydro-[1,1'-binaphthalene]-2,2'-diol ............................................... 312 2.127) (S)-2,2'-bis(methoxymethoxy)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene ..................... 312 2.128) (S)-3,3'-diiodo-2,2'-bis(methoxymethoxy)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthalene... 313 2.129) (1S,3's)-3,3'-di(anthracen-9-yl)-5,5',6,6',7,7',8,8'-octahydro-[1,1'-binaphthalene]-2,2'-diol .... 314 2.85) (1S,3's)-3,3'-di(anthracen-9-yl)-H8-binol phosphoric acid ........................................................ 314 2.130) (S)-3,3'-bis(2,4,6-triisopropylphenyl)-5,5',6,6',7,7',8,8'-octahydro-[1,1'-binaphthalene]-2,2'-diol ........................................................................................................................................................ 315 2.86) H8-TRIP ................................................................................................................................... 316

Bibliography Concerning the Experimental Data ................................................ 317 162

General Considerations Reagents and solvents were purchased from commercial sources (Aldrich, Acros, Merck, Fluka and VWR international) and preserved under argon. More sensitive compounds were stored in a desiccator or in a glove-box if required. Reagents were used without further purification unless otherwise noted. All reactions were performed under argon (or nitrogen) and stirring unless otherwise noted. When needed, glassware was dried overnight in an oven (T > 100°C) or under vacuum with a heat gun (T > 200°C). Flash column chromatography was performed using Silicycle P60 silica: 230-400 mesh (40-63 μm) silica. Reactions were monitored using Merck Kieselgel 60F 254 aluminium plates. TLC were visualized by UV fluorescence (254 nm) then one of the following: KMnO4 , phosphomolybdic acid, ninhydrin, panisaldehyde, vanillin. NMR spectra were recorded on a Brüker AvanceIII-400, Brüker Avance-400 or Brüker DPX-400 spectrometer at room temperature, 1H frequency is at 400.13 MHz, 13C frequency is at 100.62 MHz. Chemical shifts (δ) were reported in parts per million (ppm) relative to residual solvent peaks rounded to the nearest 0.01 for proton and 0.1 for carbon (ref: CHCl3 [1H: 7.26, 13C: 77.2]). Coupling constants (J) were reported in Hz to the nearest 0.1 Hz. Peak multiplicity was indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad). Attribution of peaks was done using the multiplicities and integrals of the peaks. When needed, a COSY and/or HSQC experiments were carried out to confirm the attribution. IR spectra were recorded in a Jasco FT/IR-4100 spectrometer outfitted with a PIKE technology MIRacleTM ATR accessory as neat films compressed onto a Zinc Selenide window. The spectra were reported in cm−1. Mass spectra were determined with a Waters ACQUITY H-class UPLC/MS ACQ-SQD by electron ionisation (EI positive and negative) or a Finnigan TSQ7000 by electrospray ionization (ESI+). The accurate masses were measured by the mass spectrometry service of the EPFL by ESI-TOF using a QTOF Ultima from Waters or APPI-FT-ICR using a linear ion trap Fourier transform ion cyclotron resonance mass spectrometer from Thermo Scientific. Optical rotations αD were obtained with a Jasco P-2000 polarimeter (589 nm). Enantiomeric excesses were determined with a Thar SFC Investigator system using chiral stationary phase columns by comparing the samples with the appropriate racemic samples, column and elution details specified in each entry. Melting points were measured using a Stuart SMP30. For all general procedures the order of addition of reagents has to be respected. 163

Amides Procedure A: Hydrolysis of α-Iminonitrile (Microwave assisted). To a solution of α-iminonitrile (0.2 mmol) in toluene (2 mL, c = 0.1 M) was added alumina (Neutral Brockmann activity I, 1 g), the suspension was irradiated with microwave (300 W, 130 °C) for 1 h. The mixture was then filtered through a sintered-glass funnel (porosity 3), and the solid was repeatedly rinsed with EtOAc (3 x 10 mL). Solvent was removed from the filtrate under reduced pressure to afford analytically pure amide. Procedure B: Hydrolysis of α-Iminonitriles. To a solution of α-iminonitrile (0.2 mmol) in toluene (10 mL, c = 0.02 M) was added alumina (6 g), the solvent was removed under reduced pressure. The resulting powder was left to stand overnight before being repeatedly rinsed with ethyl acetate using a sintered-glass funnel. Solvent was removed from the filtrate under reduced pressure to afford analytically pure amide. Procedure C: One-pot Synthesis of Amides from Aldehydes and Amines via α-Iminonitrile Intermediates. To a stirred solution of aldehyde (1.0 mmol), amine (1.1 mmol, 1.1 equiv) and TMSCN (1.1 mmol, 1.1 equiv) in acetonitrile (1.0 mL, c = 1.0 M) were added IBX (1.1 mmol, 1.1 equiv) and tetrabutylammonium bromide (1.1 mmol, 1.1 equiv) at room temperature. The stirring was maintained at room temperature (water bath) until starting materials have disappeared (TLC), then the mixture was diluted with toluene (2.0 mL) and alumina (Neutral Brockmann activity I, 1.0 g) was added. The suspension was irradiated with microwave (300 W, 130 °C) for 1 h and solvent was removed under reduced pressure. The resulting powder was dropped on a silica gel column for flash chromatography purification (solid deposit) (Hept/EtOAc = 7/3) to afford pure amide.

Procedure D: Tandem Oxidative Amidation of Alcohols via α-Iminonitrile Intermediates. To a solution of alcohol (1.0 mmol) in acetonitrile (4.0 mL, c = 0.25 M) was added IBX (3.0 mmol, 3.0 equiv). The suspension was heated at reflux for 25 min and cooled to room temperature. The amine (1.0 mmol, 1.0 equiv), TMSCN (1.1 mmol, 1.1 equiv) and TBAB (1.1 mmol, 1.1 equiv) were added. The stirring was maintained until starting materials were consumed (TLC) and the mixture was filtered. The filtrate was diluted with toluene (20.0 mL) and alumina (Neutral Brockmann activity I, 1.0g) was added. Solvent was removed under reduced pressure. The resulting powder was left to stand overnight before dropped on a silica gel column for flash chromatography purification (solid deposit) (Hept/EtOAc = 7/3) to afford analytically pure amide.

164

Procedure E: One Pot Synthesis of α-Iminonitriles (IBX) To a stirred solution of aldehyde (0.3 mmol), amine (0.3 mmol, 1.0 equiv) and TMSCN (0.33 mmol, 1.1 equiv) in acetonitrile (0.3 mL, c = 1.0 M) was added IBX (0.33 mmol, 1.1 equiv, 95% pure) and TBAB (0.33 mmol, 1.1 equiv) at room temperature (water bath). The mixture was left to stir at room temperature until disappearance of starting materials (TLC), the mixture was then filtered over Celite® and the filtrate was concentrated under reduced pressure. The crude product was purified by FCC on silanised silica gel (PE/AcOEt = 99/1) to afford pure α-iminonitrile.

Procedure F: One Pot Synthesis of α-Iminonitriles (Oxone) To a solution of aldehyde (0.1 mmol, 1 equiv) in toluene (0.13 mL, C = 0.75 M) was added amine (0.1 mmol, 1 equiv) at r.t. The mixture was stirred till disappearance of the starting material ( 1 minute for most aldehydes, up to 4 hours for electron-rich aromatic aldehydes) before TMSCN (0.1 mmol, 1equiv) was added. The mixture was stirred for 5 minutes before addition of water, NaHCO3, Oxone and TBAB at 0 °C portion-wise. The biphasic solution was then stirred vigorously at room temperature until disappearance of the intermediate; the biphasic mixture was then partitioned between satd. NaHCO3 and AcOEt. The aqueous phase was extracted twice more with AcOEt and the combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified by FCC on silanised silica gel (pure pentane to 95:5 PE:AcOEt) to yield pure α-iminonitriles.

1.3a) N-phenethylbenzamide

Yield: quant. (procedure A), 81% (procedure D) Aspect: white crystals Molecular Formula: C15H15NO MP: 108-109 °C HRMS calcd for C15H15NONa+ [M+Na]+: 248.1051; Found: 248.1051 1

H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.5 Hz, 2H, CHAr 4,8), 7.52 -7.21 (m, 8H, CHAr 1-3,13-17), 6.58 (br s, 1H, NH), 3.67-3.75 (m, 2H, CH2 10), 2.93 (t, J = 7.0 Hz, 2H, CH2 11) 165

13

C NMR (100 MHz, CDCl3) δ 167.5 (C7), 138.9 (C5), 134.7 (C12), 131.4 (C2), 128.8, 128.7, 128.5, 126.9 (C 1, 3, 4, 6, 13, 14, 16, 17), 126.6 (C18), 41.2 (C10), 35.7 (C11) IR: υ (cm-1) 3340, 3060, 3026, 2861, 1636, 1536, 1485, 1453, 1293, 1192, 1005

1.3b) N-benzylbenzamide

Yield: quant. (procedure A) Aspect: white solid Molecular Formula: C14H13NO MP: 103-105 °C HRMS calcd for C14H13NONa + [M+Na]+: 234.0895; Found: 234.0901 1

H NMR (400 MHz, CDCl3) δ 7.81-7.30 (m, 10H, CHAr), 5.83 (br s, 1H, NH), 4.68 (d, J = 6.0 Hz , 2H CH2 10)

13

C NMR (100 MHz, CDCl3) δ 167.2 (C7), 138.2 (C2), 134.4 (C11), 131.7 (C2), 128.9, 128.7, 128.0, 127.7 (C 1, 3, 4, 6, 12, 13, 15, 16), (C14), 127.1 (C 1, 3, 4, 6, 12, 13, 15, 16), 44.2 (C 10) IR: υ (cm-1) 3279, 3061, 2926, 1634, 1600, 1547, 1487, 1451, 1416, 1314, 1260

1.3c) N-(4-methoxyphenyl)benzamide

Yield: 63% (procedure A), 77% (procedure D) 166

Aspect: white crystals Molecular Formula: C14H13NO2 MP: 152-154 °C HRMS calcd for C14H13NO2Na + [M+Na]+: 250.0844; Found: 250.0840 1

H NMR (400 MHz, CDCl3) δ 7.86-7.84 (m, 2H CHAr 11), 7.81 (br s, 1H, NH 8), 7.58-7.44 (m, 5H CHAr 1-6), 6.92-6.88 (m, 2H, CHAr 12), 3.81 (s, 3H, CH3 17) 13

C NMR (100 MHz, CDCl3) δ 165.6 (C7), 156.6 (C13), 135.1 (C5), 131.7 (C2), 131.0 (C10), 128.7, 127.0 (1, 3, 4, 6), 122.1 (C11, 15), 114.2 (C12, 14), 55.5 (C17) IR: υ (cm-1) 3327, 3049, 2962, 2837, 1644, 1614, 1602, 1511, 1408, 1246, 1027

1.3d) 4-methoxy-N-phenethylbenzamide

Yield: quant. (procedure A), 76% (procedure D) Aspect: white crystals Molecular Formula: C16H17NO2 MP: 115-116 °C HRMS calcd for C16H17NO2Na + [M+Na]+: 278.1157; Found: 278.1158 1

H NMR (400 MHz, CDCl3) δ 7.72-7.66 (m, 2H CHAr17, 13), 7.34-7.19 (m, 5H CHAr 13-17), 6.92-6.84 (m, 2H CHAr 14, 16), 6.41 (br s, 1H, NH), 3.81 (s, 3H CH319), 3.69 (m, 2H CH210), 2.92 (m, 2H CH211)

13

C NMR (100 MHz, CDCl3) δ 167.1 (C7), 162.1 (C2), 139.1 (C5), 128.9, 128.7 (C 4, 6, 13, 14, 16, 17), 127.0 (C12), 126.5 (C15), 113.7 (C1, 3), 55.4 (C19), 41.2 (C10), 35.8 (C11), IR: υ (cm-1) 3344, 3011, 2961, 2839, 1633, 1605, 1539, 1503, 1454, 1297, 1250, 1180

167

1.3e) N-phenethylcinnamamide

Yield: quant. (procedure A) Aspect: white crystals Molecular Formula: C17H17NO MP: 114-116°C HRMS calcd for C17H17NONa+ [M+Na]+: 274.1208; Found: 274.1209 1

H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 15.5 Hz, 1H CH 7), 7.53-7.22 (m, 10H, CHAr 1-5, 6, 15-19), 6.34 (d, J = 15.5 Hz, 1H, CH 8), 5.61 (br s, 1H, NH), 3.69 (q, J = 7.0 Hz, 2H CH 12), 2.92 (t, J = 7.0 Hz, 2H C 13) 13

C NMR (100 MHz, CDCl3) δ 167.2 (C9), 141.1 (C7), 138.9 (C5), 134.8 (C14), 129.7 (C2), 128.8, 128.6, 127.8, 127.6 (C1, 3, 4, 6, 15, 16, 18, 19), 126.6 (C17), 120.6 (C8), 40.8 (C12), 35.7 (C13). IR: υ (cm-1) 3280, 3060, 3028, 2925, 2856, 1650, 1605, 1542, 1494, 1450, 1332, 1219

1.3f) N-cyclopropylcinnamamide

Yield: quant. (procedure A) Aspect: white solid Molecular Formula: C12H13NO HRMS calcd for C12H13NO + [M+Na]+: 210.0895; Found: 210.0901

168

1

H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 15.5 Hz, 1H CH 7), 7.42-7.19 (m, 5H, CHAr 1-4, 6), 6.30 (d, J = 15.5 Hz, 1H CH 8), 5.98 (br s, 1H, NH), 2.85-2.71 (m, 1H, CH 12), 0.81-0.70 (m, 2H, CH2 13, 14), 0.54-0.48 (m, 2H CH2 13, 14) 13

C NMR (100 MHz, CDCl3) δ 167.3 (C9), 140.9 (C7), 134.8 (C5), 129.6 (C2), 128.8, 127.8 (C1, 3, 4, 6), 120.5 (C8), 22.9 (C12), 6.8 (C 13, 14)

1.3g) N-phenethyl-3-phenylpropanamide

Yield: quant. (procedure A), 73% (procedure C), 80% (procedure D) Aspect: white crystals Molecular Formula: C17H19NO MP: 94-95 °C HRMS calcd for C17H19NONa + [M+Na]+: 276.1364; Found: 276.1364 1

H NMR (400 MHz, CDCl3) δ 7.35-7.09 (m, 10H CHAr 1-6, 15-19), 5.51 (br s, 1H NH), 3.50 (m, 2H CH2 12), 2.97 (t, J = 7.5 Hz, 2H CH2 7), 2.76 (t, J = 6.5 Hz, 2H CH2 13), 2.45 (t, J = 7.5 Hz, 2H CH2 8)

13

C NMR (100 MHz, CDCl3) δ 172.0 (C9), 140.9 (C14), 138.9 (C5), 128.7, 128.6, 128.4 (C1, 3, 4, 6, 15, 16, 18, 19), 126.5, 126.3 (C2, 17), 40.6 (C12), 38.5 (C8), 35.7 (C13), 31.7 (C7). IR: υ (cm-1) 3296, 3029, 2928, 1633, 1541, 1495, 1453, 1234, 1191, 1029

1.3h) (E)-2-methyl-N-phenethylbut-2-enamide

Yield: quant. (procedure A), 74% (procedure C) Aspect: colorless oil Molecular Formula: C13H17NO 169

HRMS calcd for C13H17NONa + [M+Na]+: 226.1208; Found: 226.1201 1

H NMR (400 MHz, CDCl3) δ 7.34-7.22 (m, 5H CHAr 11-15), 6.38 (q, J = 7.0 Hz, 1H (CH 2)), 5.73 (br s, 1H NH), 3.59 (q, J = 7.0 Hz, 2H CH2 8), 2.87 (t, J = 7.0 Hz, 2H CH2 9), 1.80 (s, 3H CH3 5), 1.72 (d, J = 7.0 Hz, 3H CH3 1)

13

C NMR (100 MHz, CDCl3) δ 169.3 (C4), 139.1 (C2), 131.8 (C3), 130.5 (C10), 128.8, 128.6 (C11, 12, 14, 15), 126.5 (C13), 40.8, 35.7, 13.9, 12.3 IR: υ (cm-1) 3316, 3026, 2924, 2857, 1660, 1614, 1524, 1453, 1385, 1301, 1173, 1029

1.3i) N-phenethylisobutyramide

Yield: quant. (procedure C) Aspect: white crystals Molecular Formula: C12H17NO MP: 89-90 °C 1

H NMR (400 MHz, CDCl3) δ 7.37-7.18 (m, 5H CHAr 10-14), 5.49 (br s, 1H NH), 3.57-3.49 (m, 2H CH2 7), 2.84 (t, J = 7.0 Hz, 2H CH2 8), 2.30 (sep, J = 7.0 Hz, 1H CH 2), 1.12 (d, J = 7.0 Hz, 6H CH3 1, 4)

13

C NMR (100 MHz, CDCl3) δ 176.9 (C3), 138.9 (C9), 128.8, 128.6 (C 10, 11, 13, 14), 126.5 (C12), 40.4 (C12), 35.7, 35.6 (C2, 8), 19.6 (C1, 4) IR: υ (cm-1) 3290, 3029, 2967, 2870, 1638, 1545, 1454, 1240, 1194, 1100

170

1.3j) N-phenethylcyclohexanecarboxamide

Yield: 97% (procedure C) Aspect: white crystals Molecular Formula: C15H21NO MP: 90-92 °C HRMS calcd for C15H21NONa + [M+Na]+: 254.1521; Found: 254.1517 1

H NMR (400 MHz, CDCl3) δ 7.37-7.17 (m, 5H CHAr 13-17), 5.52 (br s, 1H NH), 3.53 (q, J = 7.0 Hz, 2H CH2 10), 2.83 (t, J = 7.0 H, 2H CH2 11), 2.08-1.97 (m, 1H CH 5), 1.87-1.14 (m, 10H CH2 1-4, 6) 13

C NMR (100 MHz, CDCl3) δ 176.1 (C7), 139.1 (C12), 128.9, 128.6 (C 13, 14, 16, 17), 126.5 (C15), 45.5 (C5), 40.4 (C10), 35.7 (C11), 29.7, 25.7 (C1-4, 6) IR: υ (cm-1) 3296, 3028, 2928, 2852, 1636, 1538, 1446, 1255, 1215, 1029

1.3k) N-cyclopropylbenzamide

Yield: 83% (procedure D) Aspect: white crystals Molecular Formula: C10H11NO MP: 92-94 °C HRMS calcd for C10H11NONa + [M+Na]+: 184.0738; Found: 184.0739 171

1

H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.0 Hz, 2H CHAr 4,6), 7.46-7.28 (m, 3H CHAr 1-3), 6.95 (br s, 1H NH), 2.87-2.80 (m, 1H Ch 10), 0.79-0.59 (m, 4H CH2 11, 12)

13

C NMR (100 MHz, CDCl3) δ 169.1 (C7), 134.4 (C5), 131.3 (C2), 128.4 (C1, 3), 127.0 (C4, 6), 23.2 (C10), 6.6 (C11, 12) IR: υ (cm-1) 3228, 3064, 2863, 1622, 1555, 1487, 1361, 1311, 1179, 1026

1.3l) 2-iodo-N-phenethylbenzamide

Yield: 81% (procedure D) Aspect: white solid Molecular Formula: C15H14INO MP: 114-115 °C HRMS calcd for C15H14INONa + [M+Na]+: 374.0018; Found: 374.0023 1

H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 1H CHAr 1), 7.40-7.07 (m, 8H CHAr 2-4, 14-18), 5.79 (br s, 1H NH), 3.76 (q, J = 7.0 Hz, 2H CH2 10), 2.99 (t, J = 7.0 Hz, 2H CH2 11)

13

C NMR (100 MHz, CDCl3) δ 169.5 (C7), 142.4 (C1), 140.0 (C5), 138.8 (C13), 131.2, 129.0, 128.9, 128.3, 128.3 (2-4, 14-18), 126.8 (C16), 92.9 (C6), 41.6 (C10), 36.0 (C11) IR: υ (cm-1) 3280, 3066, 3027, 2923, 2853, 1637, 1537, 1495, 1454, 1309, 1283, 1256, 1193, 1163

1.3m) 2-ethyl-N-phenethylhexanamide

172

Yield: 77% (procedure D) Aspect: colorless oil Molecular Formula: C16H25NO 1

H NMR (400 MHz, CDCl3) δ 7.38-7.17 (m, 5H CHAr 14-18), 5.49 (br s, 1H NH), 3.56 (m, 2H CH2 11), 2.84 (t, J = 7.0 Hz, 2H CH2 12), 1.91-1.78 (m, 1H CH 5), 1.67-1.10 (m, 8H CH2 2-4. 6), 0.94-0.80 (m, 6H CH3 1, 9)

13

C NMR (100 MHz, CDCl3) δ 175.8 (C7), 139.0 (13C), 128.8, 128.6 (C14, 15, 17, 18), 126.5 (C16), 49.9 (C5), 40.3 (C11), 35.9 (C12), 32.5 (C4), 29.9 (C3), 26.1 (C6), 22.8 (C2), 14.0 (C1), 12.1 (C9). IR: υ (cm-1) 3290, 3064, 3028, 2925, 2853, 1636, 1546, 1453, 1378, 1244, 1232, 1118

1.3n) 3-methyl-N-phenethylbutanamide

Yield: 74% (procedure D) Aspect: clear oil Molecular Formula: C13H19NO MP: 73 °C 1

H NMR (400 MHz, CDCl3) δ 7.39-7.19 (m, 5H CHAr 11-15), 6.55 (br s, 1H NH), 4.31 (d, J = 4.5 Hz, 2H CH2 1), 3.63-3.52 (m, 2H CH2 8), 2.86 (t, J = 7 Hz, 2H CH2 9), 2.45-2.33 (m, 1H CH 5), 1.04 (d, J = 6.5 Hz , 3H CH3 7), 0.93 (d, J = 6.5 Hz, 3H, CH3 6) 13

C NMR (100 MHz, CDCl3) δ 168.1 (C2), 138.5 (C10), 128.9, 128.7 (C11, 12, 14, 15), 126.7 (C13), 62.0 (C1), 41.1 (C8), 35.5 (C9), 32.2 (C5), 20.9 (C7), 18.1 (C6) IR: υ (cm-1) 3297, 3085, 3027, 2955, 2924, 2869, 1650, 1551, 1495, 1452, 1365, 1231, 1190, 1041, 1029

173

1.3o) N-phenethylcyclopropanecarboxamide

Yield: 84% (procedure D) Aspect: white crystals Molecular Formula: C12H15NO MP: 101-103 °C HRMS calcd for C12H15NONa + [M+Na]+: 212.1051; Found: 212.1048 1

H NMR (400 MHz, CDCl3) δ 7.35-7.19 (m, 5H CHAr 8-12), 5.80 (br s, 1H NH), 3.55 (q, J = 7.0 Hz, 2H CH2 5), 2.84 (t, J = 7.0 Hz, 2H CH2 6), 1.30 (m, 1H C1), 1.01-0.93 (m, 2H CH2 13, 14), 0.76-0.69 (m, 2H CH2 13, 14)

13

C NMR (100 MHz, CDCl3) δ 174.0 (C2), 139.4 (C), 129.2, 129.0 (C8, 9, 11, 12), 126.9 (C10), 41.2 (C5), 36.2 (C6), 15.1 (C1), 7.5 (C13, 14). IR: υ (cm-1) 3295, 3087, 3009, 2927, 2876, 1633, 1547, 1402, 1239, 1191, 1032

Mercapto Amides Procedure E: Thio-Michael Addition of α,β-Unsaturated-α-iminonitriles and Subsequent Hydrolysis to αMercaptoamides To a stirred solution of α-iminonitrile (0.1 mmol) and thiol (0.5 mmol, 5 equiv) in CH2Cl2 (0.25 mL, c = 0.4 M) cooled to 0° (ice bath) was added Yb(OTf)3 (0.1 equiv). The mixture was left to stir at 0 °C until disappearance of starting materials (TLC). The mixture was then diluted with CH2Cl2 (2.0 mL) and alumina was added (neutral, Brockmann activity I, 1.0 g/0.1 mmol iminonitrile) and stirred for one minute before the solvent was removed under vacuum (water bath at 20 °C). The deposit was left to stand at 40°C for 4 h before being filtered over Celite® and washed with AcOEt. The filtrate was evaporated under reduced pressure to give β-thioamide. If necessary the crude compound was purified by FCC (PE/AcOEt = 7/3) to afford the pure γ-thioamide.

174

Procedure F: One-pot Synthesis of β-Mercaptoamides from Aldehydes and Amines To a stirred solution of aldehyde (0.10 mmol, 1.0 equiv), amine (0.11 mmol, 1.1 equiv) and TMSCN (0.11 mmol, 1.1 equiv) in toluene (0.25 ml, c = 0.4 M) was added IBX (0.10 mmol, 1.0 equiv) and tetrabutylammonium bromide (0.1 mmol, 1.0 equiv) at room temperature. The stirring was maintained at room temperature until starting materials were consumed (TLC). Thiol (0.5 mmol, 5 equiv) was then added to the cooled solution (0 °C, ice bath) followed by Yb(OTf)3 (0.1 equiv) after 5 min. The mixture was left to stir at 0° until disappearance of starting materials (TLC). The mixture was then diluted with CH2Cl2 (2 mL) and alumina was added (neutral, Brockmann activity I, 1.5 g/0.1 mmol iminonitrile) and stirred for one minute before the solvent was removed under vacuum (water bath at 20 °C). The deposit was left to stand at 40 °C for 4 h before being filtered over Celite® and washed with AcOEt. The filtrate was evaporated under reduced pressure to give β-thioamide. If necessary the crude compound was purified by FCC (PE/AcOEt = 7/3) to afford the pure β-thioamide.

1.6a) 3-(ethylthio)-N-phenethyl-3-phenylpropanamide

Yield: 96% Aspect: white powder Molecular Formula: C19H23NOS Mp: 95-96 °C HRMS (ESI) calcd for C19H24NOS+ [M+H]+: 314.1573; Found 314.1565. 1

H NMR (400 MHz, CDCl3) δ 7.36-7.22 (m, 8H CHAr 1-5, 7-9), 7.07-7.05 (m, 2H CHAr 6,10), 5.42 (br s, 1H NH), 4.32 (t, J = 7.7 Hz, 1H CH 4), 3.53-3.44 (m, 1H CH2 7), 3.41-3.33 (m, 1H CH2 3), 2.74-2.54 (m, 4H CH2 3, 8), 2.39-2.29 (m, 2H CH2 11), 1.16 (t, J = 7.4 Hz, 3H CH3 12) 13

C NMR (100 MHz, CDCl3) δ 169.9 (C2), 141.9 (C5), 138.8 (C9), 128.8, 128.7, 128.6, 127.7 (C6, 7, 9, 10, 11, 12, 14, 15), 127.4, 126.5 (C8, 13), 45.6 (C4), 44.3 (C3), 40.7 (C7), 35.6 (C8), 25.5 (C11), 14.4 (C12) IR: υ (cm-1) 3300, 2924, 2345, 2193, 2056, 1635, 1550, 1452, 1343, 1061, 756, 703

1.6b) 3-(benzylthio)-N-phenethyl-3-phenylpropanamide 175

Yield: 73% (procedure E), 75% (procedure F) Aspect: white solid Molecular Formula: C24H25NOS Mp: 54-57 °C HRMS (ESI) δ calcd for C24H26NOS+ [M+H]+: 376.1730; Found 376.1730 1

H NMR (400 MHz, CDCl3) δ 7.45-7.20 (m, 13H CHAr 1-6, 23-25, 23-27), 7.12-7.04 (m, 2H CHAr 12, 16), 5.49 (br s, 1H NH), 4.23 (m, 1H CH 9), 3.61-3.43 (m, 3H CH2 20 7), 3.38-3.29 (m, 1H CH2 20), 2.76-2.54 (m, 4H CH2 10, 21)

13

C NMR (100 MHz, CDCl3) δ 169.7 (C17), 141.4 (C11), 138.9 (C22), 137.9 (C5), 129.0, 128.8, 128.7, 128.6, 128.5, 127.9 (1, 3, 4, 6, 12, 13, 15, 16, 23, 24, 26, 27), 127.6, 127.1, 126.5 (C 2, 14, 25), 45.7 (C9), 44.0 (C10), 40.7 (C20), 35.9 (21), 35.6 (C7) IR: υ (cm-1) 3292, 2931, 2361, 1713, 1649, 1497, 1366, 1163, 1028, 748, 699

1.6c) N-phenethyl-3-phenyl-3-(phenylthio)propanamide

Yield: 69% (procedure E), 63% (procedure F) Aspect: clear oil 176

Molecular Formula: C23H23NOS HRMS (ESI) δ calcd for C23H24NOS+ [M+H]+ 362.1573; found 362.1582 1

H NMR (400 MHz, CDCl3) δ 7.32-7.21 (m, 13H CHAr 2-6, 16-18, 22-26), 7.07-7.02 (m, 2H CHAr 15, 19), 5.37 (br s, 1H NH) 4.72 (dd, J = 8.3, 6.7 Hz, 1H CH 13), 3.53-3.44 (m, 1H CH2 8), 3.41-3-31 (m, 1H CH2 8), 2.80 (dd, J = 14.4, 6.7 Hz, 1H CH2 12), 2.75-2.56 (m, 3H CH2 7, 12)

13

C NMR (100 MHz, CDCl3) δ 169.8 (C10), 141.0 (C14), 138.7 (C1), 134.0 (C21), 132.6 (C22, 26), 128.9, 128.8, 128.7, 128.6, 127.7, 127.6, 127.5, 126.5 (C2-6 15-19, 23-25), 49.5 (C13), 43.6 (12), 40.7 (8), 35.5 (7) IR: υ (cm-1) 3327, 3029, 2934, 1645, 1544, 1455, 1254, 1153, 1027, 751, 691

1.6d) 3-(tert-butylthio)-N-phenethyl-3-phenylpropanamide

Yield: 70% Aspect: clear oil Molecular Formula: C21H27NOS HRMS (ESI) calcd for C21H28NOS+ [M+H]+ : 342.1813; Found 342.1881 1

H NMR (400 MHz, CDCl3) δ 7.41-7.38 (m, 2H CHAr 12, 14), 7.35-7.21 (m, 6H CHAr 13, 20-24), 7.08-7.04 (m, 2H CHAr 11, 15), 5.44 (br s, 1H NH), 4.39 (t, J = 7.6 Hz, 1H CH 4), 3.53-3.44 (m, 1H CH2 17), 3.40-3.30 (m, 1H CH2 17), 2.76-2.55 (m, 3H CH2 3, 18), 2.51 (dd, J = 14.2, 7.6 Hz, 1H CH2 3), 1.22 (s, 9H CH3 7-9) 13

C NMR (100 MHz, CDCl3) δ 170.0 (C2), 144.5 (C10), 139.0 (C19), 128.9, 128.7, 128.7, 127.7, 127.1 (11, 12, 14, 15, 20, 21, 23, 24), 126.5 (C1, 16), 46.6 (C4), 44.6 (C6), 44.3 (C3), 40.8 (c17), 35.7 (C18), 31.4 (C79) IR: υ (cm-1) 3667, 3292, 2970, 2901, 2361, 1643, 1551, 1454, 1068, 748, 698

177

1.6e-f) methyl 2-((tert-butoxycarbonyl)amino)-3-((3-oxo-3-(phenethylamino)1-phenylpropyl)thio)propanoate

Yield: 70% (from D-cysteine), 72% (from L-cysteine) Aspect: colorless oil Molecular Formula: C26H34N2O5S From D-cysteine, mixture of 2 diastereoisomers HRMS (ESI) calcd for C26H35N2O5S + [M+H]+ : 487.2261; Found 487.2267 1

H NMR (400 MHz, CDCl3) δ 7.39-7.18 (m, 6H CHAr 22-24, 30-34), 7.10-7.01 (m, 4H CHAr 21,25), 5.61-5.35 (m, 3H NH), 5.18 (m, 1H NH), 4.53-4.39 (m, 2H CH 7), 4.36 (t, J = 7.5 Hz, 1H CH 4), 4.30 (t, J = 7.5 Hz, 1H CH 4), 3.76 (s, 3H CH3 18), 3.69 (s, 3H CH3 18), 3.54-3.30 (m, 4H CH2 27), 2.88-2.51 (m, 12H CH2 3, 6, 28), 1.47 (s, 9H CH3 12-14), 1.43 (s, 9H CH3 12-14) 13

C NMR (100 MHz, CDCl3) δ 171.5, 171.4 (C16), 169.6, 169.4 (C2), 155.4, 155.1 (C9), 141.2, 141.1 (C20), 138.9, 138.9 (C29), 128.9, 128.7, 127.8, 126.6 (C21-25, 30-34), 80.3, 80.2 (C11), 53.6, 53.2 (C7), 52.8, 52.7 (C18), 46.9, 46.5 (C4), 44.4, 44.0(C6), 40.9 (C27), 35.7 (C28), 34.0, 33.7 (C3), 28.5, 28.4 (12-14) IR: υ (cm-1) 3275, 2930, 2857, 1647, 1495, 1365, 1163, 1109, 736, 699 SFC analysis: Solvent flow 4 mL/min, co-solvent 15% MeOH, column chiralpak IA. Retention times: 3.38 min, 3.73 min. From L-cysteine, mixture of 2 diastereoisomers HRMS (ESI) calcd for C26H35N2O5S+ [M+H]+: 487.2261; found 487.2263 1

H NMR (400 MHz, CDCl3) δ 7.38-7.18 (m, 6H CHAr 22-24, 30-34), 7.09-7.03 (m, 4H CHAr 21,25), 5.61-5.51 (m, 1 H NH), 5.51-5.44 (m, 1H NH), 5.44-5.37 (m, 1H CH 7), 5.23-5.12 (m, 1H), 4.53-4.38 (m, 2H CH 4), 4.35 (t, J = 7.6 Hz, 1 H CH 4), 4.30 (t, J = 7.5 Hz, 1 H CH 4), 3.76 (s, 3H CH3 18), 3.69 (s, 3H CH3 18), 3.533.31 (m, 4H CH2 27), 2.85-2.51 (m, 12H CH2 3, 6, 28), 1.46 (s, 9H CH3 12-14), 1.42 (s, 9H CH3 12-14).

178

13

C NMR (100 MHz, CDCl3) δ 171.5, 171.4 (C16), 169.6, 169.4 (C2), 155.4, 155.1 (C9), 141.2, 141.1 (C20), 138.9, 138.9 (C29), 128.9, 128.7, 127.8, 126.6 (C21-25, 30-34), 80.3, 80.2 (C11), 53.6, 53.2 (C7), 52.8, 52.7 (C18), 46.9, 46.5 (C4), 44.4, 44.0(C6), 40.9 (C27), 35.7 (C28), 34.0, 33.7 (C3), 28.5, 28.4 (12-14) IR: υ (cm-1) 3275, 2930, 2857, 1647, 1495, 1163, 1101, 736, 699 SFC analysis: Solvent flow 4 mL/min, co-solvent 15% MeOH, column chiralpak IA. Retention times: 6.15 min, 6.78 min. Racemic

From D-cysteine

179

From L-cysteine

180

1.6g) 3-(benzylthio)-N-phenethylbutanamide

Yield: 72% Aspect: transparent oil Molecular Formula: C18H21NOS HRMS (ESI) calcd for C18H22NOS+ [M+H]+: 300.1417; Found 300.1420 1

H NMR (400 MHz, CDCl3) δ 7.40-7.17 (m, 10H CHAr 5-9, 16-20), 5.64 (br s, 1H NH), 3.66 (hept, J = 7.2 Hz, 1H CH 2), 3.53 (q, J = 6.8 Hz, 2H CH2 13), 2.81 (t, J = 6.8 Hz, 2H CH2 14), 2.45 (dd, J = 14.6, 6.2 Hz, 1H CH2 10), 2.20 (dd, J = 14.6, 7.6 Hz, 1H CH2 10), 1.30 (d, J = 6.8 Hz, 3H CH3 1) 13

C NMR (100 MHz, CDCl3) δ 170.4 (C11), 138.8 (C15), 132.3 (C4), 129.0, 128.8, 128.7 (C 5, 6, 8, 9. 16, 17, 19, 20), 127.3, 126.6 (C7 18), 43.8 (C2), 40.6 (C13), 39.8 (C10), 35.6 (C14), 21.0 (C1) IR: υ (cm-1) 3292, 2924, 2342, 1642, 1550, 1438, 1089, 1026, 742, 693

1.6h) 3-(benzylthio)-N-phenethylbutanamide

Yield: 76% Aspect: white powder Molecular Formula: C19H23NOS Mp: 87-88 °C 181

HRMS (ESI) calcd for C19H24NOS+ [M+H]+ 314.1573; Found 314.1584. 1

H NMR (400 MHz, CDCl3) δ 7.34-7.16 (m, 10H CHAr 6-10, 17-21), 5.29 (br s, 1H NH), 3.75 (ABq, J = 10.7 Hz, 1H CH2 4), 3.73 (ABq, J = 10.7 Hz, 1H CH2 4), 3.57-3.43 (m, 2H CH2 14), 3.16-3.06 (m, 1H CH 2), 2.80 (t, J = 6.9 Hz, 2H CH2 15), 2.36 (dd, J = 14.5, 6.9 Hz, 1H CH2 11), 2.22 (dd, J = 14.5, 6.9 Hz, 1H CH2 11), 1.26 (d, J = 6.9 Hz, 3H CH3 1) 13

C NMR (100 MHz, CDCl3). δ 170.5 (C12), 138.9, 138.4 (C5, 16), 128.8, 128.8, 128.7, 128.6 (C 6, 7, 9, 10, 17, 18, 20, 21), 127.1, 126.6 (C8, 19), 44.27 (C2), 40.63 (C14), 36.7 (C4), 35.7 (C11), 35.97 (C15), 21.45 (C1) IR: υ (cm-1) 3305, 2928, 1638, 1546, 1453, 1176, 1072, 695

1.6i) 3-(ethylthio)-N-phenethylbutanamide

Yield: 95% Aspect: white crystals Molecular Formula: C14H21NOS Mp: 42–45 °C HRMS (ESI) calcd for C14H22NOS+ [M+H]+ 252.1417; Found 252.1421 1

H NMR (400 MHz, CDCl3) δ 7.32-7.19 (m, 5H CHAr 12-16), 5.81 (br s, 1H NH), 3.57-3.51 (m, 2H CH2 9), 3.27-3.17 (m, 1H CH 2), 2.83 (t, J = 7.0 Hz, 2H CH2 10), 2.60-2.51 (m, 2H CH2 4), 2.39 (dd, J = 14.6, 7.0 Hz, 1H CH2 6), 2.25 (dd, J = 14.6, 7.0 Hz, 1H CH2 6), 1.23 (t, J = 7.0 Hz, 3H CH3 5), 1.27 (d, J = 7.0 Hz, 3H CH3 1) 13

C NMR (100 MHz, CDCl3) δ 170.8 (C7), 138.9 (C11), 128.8, 128.7 (C12, 13, 15, 16), 126.6 (C14), 44.5, (C2) 40.7 (C9), 36.5 (C6), 35.8 (C10), 25.0 (C4), 21.7 (C1), 14.9 (C5) IR: υ (cm-1) 3298, 2965, 2927, 2869, 2338, 1638, 1551, 1178, 697

182

1.6j) 3-(benzylthio)-3-(4-bromophenyl)-N-phenethylpropanamide 26

Br 24 23 21 20 19

16

15

17

S 14

25

22 13

27 8

1 28

12

7

O 2

9

4

N H

5

6

10 11

3

18

Yield: 88% Aspect: viscous clear oil Molecular Formula: C24H24NOBrS HRMS (ESI) calcd for C24H25NOBrS+ [M+H]+ 454.0835; Found 454.0837 1

H NMR (400 MHz, CDCl3) δ 7.48-7.42 (m, 2H CHAr 24, 27), 7.32-7.15 (m, 10H CHAr 7-11, 17-21), 7.05-7.0 (m, 2H CHAr 23, 28), 5.31 (br s, 1H NH), 4.16 (dd, J = 8.2, 6.9 Hz, 1H CH 13), 3.58-3.41 (m, 3 H CH2 4, 15), 3.40-3.27 (m, 1H CH2 4), 2.74-2.57 (m, 3H CH2 5, 11), 2.46 (dd, J = 14.5, 8.3 Hz, 1H CH2 11) 13

C NMR (100 MHz, CDCl3) δ 169.3 (C2), 140.7, 138.8, 137.7 (C6, 16, 22), 131.9, 129.8, 129.0, 128.8, 128.8, 128.7 (C7, 8, 10, 11, 17, 18, 20, 21, 23, 24, 27, 28), 127.3, 126.7 (C9, 19), 121.4 (C25), 45.1 (C13), 44.0 (C12), 40.8 (C4), 36.0 (C15), 35.6 (C5) IR: υ (cm-1) 3281, 3060, 2959, 1651, 1455, 1072, 1010, 700

1.6k) 3-(ethylthio)-N-(4-methoxyphenyl)-3-(4-nitrophenyl)propanamide

Yield: 80% Aspect: orange oil 183

Molecular Formula: C18H20N2O4S HRMS (ESI) calcd for C18H21N2O4S + [M+H]+: 361.1217; Found 361.1224 1

H NMR (400 MHz, CDCl3) δ 8.22-8.14 (m, 2H CHAr 19, 22), 7.64-7.53 (m, 2H CHAr 18, 23), 7.43-7.27 (m, 2H CHAr 5, 11), 7.12 (brs, 1H NH), 6.86-6.78 (m, 2H CHAr 6, 10), 4.52 (t, J = 7.4 Hz, 1 H CH 13), 3.77 (s, 3H CH3 9), 2.91 (dd, J = 14.9, 7.1 Hz, 1H CH2 12), 2.79 (dd, J = 14.9, 7.7 Hz, 1H CH2 12), 2.45-2.35 (m, 2H CH2 15), 1.19 (t, J = 7.4 Hz, 3H CH3 16) 13

C NMR (100 MHz, CDCl3) δ 167.3 (C2), 156.9 (C7), 149.9 (C17), 147.3 (C20), 130.4 (C4), 128.8 (C18, 23), 124.1 (C19, 21), 122.1 (C5, 11), 114.3 (C6, 7), 55.6 (C9), 45.1 (C13), 44.4 (C12), 25.9 (C15), 14.5 (C16). IR: υ (cm-1) 3295, 2962, 1655, 1603, 1511, 1344, 1244, 1034, 828, 733

1.6l) N-cyclopropyl-3-(4-methoxyphenyl)-3-(phenylthio)propanamide

Yield: 58% (reaction done at 35 °C) Aspect: white powder Molecular Formula: C19H21NO2S HRMS (ESI) calcd for C19H22NO2S+ [M+H]+: 328.1293 Found 328.1371 Mixture of rotamers, 91:9 Major: 1H NMR (400 MHz, CDCl3) δ 7.42-7.17 (m, 7H CHAr 18, 22, 11-17) 6.86-6.77 (m, 2H, CHAr 17, 23), 5.54 (br s, 1H NH), 4.65 (dd, J = 8.7, 6.5 Hz, 1H CH 8), 3.79 (s, 3H CH3 21), 2.75 (dd, J = 14.3, 6.5 Hz, 1H CH2 7), 2.66-2.53 (m, 2H CH2 7, CH 4), 0.72-0.62 (m, 2H CH2 5, 6), 0.38-0.22 (m, 2H CH2 5, 6) Minor (discernible) 1H NMR (400 MHz, CDCl3) δ 4.85 (dd, J = 8.8, 6.0 Hz, 0.1H), 3.77 (s, 0.3H), 3.16 (dd, J = 15.6, 8.8 Hz, 0.1H), 3.02 (dd, J = 15.6, 6.0 Hz, 0.1H). 2.49-2.46 (m, 0.1H), 0.87-0.77 (m, 0.2H), 0.58-0.38 (m, 0.2H)

184

Major 13C NMR (100 MHz, CDCl3) δ 171.3 (C2), 158.9 (C19), 134.2 (C10), 132.9 (C16), 132.5, 128.9, 128.7(C 11, 12, 14, 15, 17, 23), 127.4 (C13), 114.1 (C18, 22), 55.3 (C21), 49.0 (C8), 43.7 (C/), 22.5 (C4), 6.7, 6.6 (C5, 6). Minor (discernible) 13C NMR (100 MHz, CDCl3) δ 174.3, 132.3, 127.2, 113.8, 48.3, 39.8, 23.7, 8.5 IR: υ (cm-1) 2977, 1604, 1571, 1514, 1427, 1251, 1178, 1027, 956, 824

1.6n) 3-(tert-butylthio)-N-(4-methoxyphenyl)-3-phenylpropanamide

Yield: 61% Aspect: yellow oil Molecular Formula: C20H25NO2S HRMS (ESI) calcd for C20H26NO2S+ [M+H]+ 344.1679; Found 344.1677 1

H NMR (400 MHz, CDCl3) δ 7.43-7.22 (m, 8H CHAr 6, 10, 20-24), 6.82-6.80 (m, 2H CHAr 5, 22), 4.42 (t, J = 7.5 Hz, 1H CH 13), 3.77 (s, 3H CH3 9), 2.80 (dd, J = 14.4, 7.5 Hz, 1H CH2 12), 2.73 (dd, J = 14.4, 7.5 Hz, 1H CH2 12), 1.23 (s, 9H CH3 16-18). 13

C NMR (100 MHz, CDCl3) δ 168.3 (C2), 156.6 (C7), 144.5 (C19), 130.8 (C4), 128.8, 127.7 (C20-21, 23-24), 127.3 (C 22), 122.1 (C C5, 11), 114.2 (C6, 10), 55.6 (C9), 47.4 (C13), 44.8 (C15), 44.4 (C12), 31.4 (C16-18) IR: υ (cm-1) 3281, 2959, 1651, 1511, 1241, 1034, 827, 700

1.6o) 3-((2-hydroxyethyl)thio)-N-phenethyl-3-phenylpropanamide

185

Yield: 61% Aspect: clear oil Molecular Formula: C19H23NO2S HRMS (ESI) calcd for C19H24NO2S + [M+H]+: 330.1449; Found 330.1525 1

H NMR (400 MHz, CDCl3) δ 7.36-7.17 (m, 8H CHAr 11-13, 19-23), 7.11-7.06 (m, 2H CHAr 10, 14), 5.49 (br s, 1H NH), 4.38 (t, J = 7.3 Hz, 1H CH 4), 3.73-3.58 (m, 2H CH2 7), 3.55-3.37 (m, 2H CH2 16), 2.79-2.53 (m, 6H CH2 3, 6, 17) 13

C NMR (100 MHz, CDCl3) δ 170.0 (C2), 141.9 (C4), 138.9 (C13), 128.9, 128.9, 128.8, 127.7, 127.7, 126.6 (C 10-14, 19-23), 60.9 (C7), 45.5 (C4), 44.2 (C3), 40.9 (C16), 35.6 (C17), 34.7 (C6). IR: υ (cm-1) 3675, 3293, 2970, 2918, 2358, 1644, 1552, 1454, 1047, 749, 698

1.6p) 3-((2-((tert-butyldiphenylsilyl)oxy)ethyl)thio)-N-phenethyl-3phenylpropanamide

Yield: 83% Aspect: clear oil Molecular Formula: C35H41NO2SSi HRMS (ESI) calcd for C35H42NO2SSi + [M+H]+: 568.2627; Found:568.2707 1

H NMR (400 MHz, CDCl3) 7.66-7.58 (m, 4H CHAr 15, 19, 21, 25), 7.46-7.33 (m, 6 H CHAr 16-17, 22-24), 7.30-7.18 (m, 8H CHAr 28-30, 36-40), 7.00-7.05 (m, 2H CHAr 27, 31), 5.37 (br s, 1 H NH), 4.25 (t, J = 7.8 Hz, 1H CH 4), 3.61-3.69 (m, 2 H CH2 7), 3.50-3.40 (m, 1H CH2 33), 3.37-3.27 (m, 1H CH2 33), 2.47-2.70 (m, 6H CH2 3, 6, 34), 1.02 (s, 9H CH3 11-13).

186

13

C NMR (100 MHz, CDCl3) 169.6 (C2), 141.7 (26), 138.8 (C35), 135.6 (C15, 19, 21, 25), 133.5 (C14, 20), 129.7, 128.7, 128.6, 127.7 (C16-18, 22-24, 28, 30, 36, 37, 39, 40), 127.5 (C29), 126.5 (C38), 63.3 (C7), 46.2 (C4), 44.3 (C3), 40.6 (C33), 35.5 (34), 33.6 (C6), 26.8 (C11-13), 19.2 (C10) IR: υ (cm-1) 3277, 2931, 2857, 2330, 1641, 1560, 1428, 1109, 1068, 822, 739, 697

Iminonitriles 1.36) N-phenylbenzimidoyl cyanide

Yield: 99%, mixture of isomers Aspect: Yellow solid Molecular Formula: C14H10N2 1

H NMR (400 MHz, CDCl3) δ 8.23-8.09 (m, 2.6H), 7.65-7.59 (m, 2H), 7.59-7.53 (m, 3H), 7.51-7.44 (m, 2.6H), 7.36-7.30 (m, 1.1H), 7.23-7.17 (m, 2H), 7.17-7.04 (m, 0.8H). 13

C NMR (100 MHz, CDCl3) δ 149.3, 148.1, 140.4, 140.0, 133.8, 133.5, 133.3, 133.0, 132.6, 129.4, 129.3, 129.2, 128.5, 128.4, 127.5, 122.3, 121.1, 120.5, 111.0, 110.8.

1.140) N-phenethylcinnamimidoyl cyanide

Yield: 92% Aspect: Yellow crystals Molecular formula: C18H16N2 1

H NMR (400 MHz, CDCl3) δ 7.56-7.25 (m, 11H CH 5 CHAr 7-11, 16-20), 6.98 (d, J = 16 Hz, 1H CH 4), 4.17 (t, J = 8.0 Hz, 2H CH2 13), 3.09 (t, J = 8.0 Hz, 1H CH2 14).

187

13

C NMR (100 MHz, CDCl3) δ 142.8 (C3), 142.6 (C5), 138.7 (C15), 134.5 (C6), 130.3 (C9), 129.1, 129.0, 128.6, 128.4, 127.8 (C7, 8, 10, 11, 16, 17, 19, 20), 126.6 (C4), 125.8 (C16), 109.0 (C3), 60.3 (C13), 36.9 (C14)

1.97a) N-phenethyl-3-phenylpropanimidoyl cyanide

Yield: 95% Aspect: Light yellow oil Molecular Formula: C18H18N2 1

H NMR (400 MHz, CDCl3) δ 7.32-7.17 (m, 10H CHAr 1-4, 6, 15-19), 3.99 (m, 2H CH2 11), 2.97-2.93 (m, 4H CH2 8, 13), 2.83-2.79 (m, 2H CH2 7).

13

C NMR (100 MHz, CDCl3) δ 143.8 (C12), 139.6 (C5), 138.7 (C14), 129.1, 128.8, 128.6, 128.6, 126.7 (C14, 6, 15-19), 110.4 (C12), 60.1 (C11), 40.3 (C8), 36.6 (C13), 31.8 (C7).

1. 97b) (2E)-N-benzyl-3-(4-methoxyphenyl)acrylimidoyl cyanide

Yield: 77% Aspect: Orange crystals Molecular formula: C18H16N2O Mp: 68.4-75.1 °C HRMS (ESI) calcd for C18H17N2O+ [M+H]+ 277.1335; found 277.1333. 188

1

H NMR (400 MHz, CDCl3) δ 7.50 -7.30 (m, 8H CH 5 CHAr 7, 13, 17-21), 6.94-6.90 (m, 3H CH 4, CHAr 8, 12), 5.05 (s, 2H CH2 15), 3.85 (s, 3H C11).

13

C NMR (100 MHz, CDCl3) δ 161.6 (C9), 143.1 (C3), 142.9 (C5), 137.8 (C16), 129.6 (C7, 13), 128.9, 128.3 (C 17, 18, 20, 21), 127.7 (C19), 127.4 (C6), 123.9 (C4), 114.7 (C8, 12), 109.5 (C3), 62.5, 55.6. IR: υ (cm-1) 2930, 2839, 2363, 1604, 1579, 1513, 1248, 1174, 1031, 824.

1. 97c) N-cyclopropylbenzimidoyl

Yield: 87% Aspect: Clear oil Molecular Formula: C11H10N2 HRMS (ESI) calcd for C11H11N2+ [M+H]+ 171.0917; found 171.0919. 1

H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 8.1, 2.0 Hz, 2H CHAr 8, 9), 7.51-7.41 (m, 3H CHAr 9-11), 3.68-3.62 (m, 1H CH 1), 1.32-1.25 (m, 2H CH2 6, 7), 1.25-1.19 (m, 2H CH2 6,7). 13

C NMR (100 MHz, CDCl3) δ 138.7 (C4), 133.7 (C3), 131.6 (C10), 128.9, 127.0 (C8, 9, 10, 11, 12), 110.8 (C5), 41.3 (C1), 12.1 (C6,7). IR: υ (cm-1) 3014, 2216, 1575, 1443, 1268, 1181, 1008, 949, 771, 690.

1. 97d) 2-(2-(1,3-dioxolan-2-yl)ethyl)-N-phenethylbenzimidoyl cyanide

189

Yield: 88% Aspect: Yellow oil Molecular formula: C21H22N2O2 HRMS (ESI) calcd for C21H23N2O2+ [M+H]+ 335.1754; found 335.1760. 1

H NMR (400 MHz, CDCl3) δ 7.66-7.61 (m, 1H CHAr 5), 7.45-7.20 (m, 8H CHAr 6-8, 21-25), 4.81 (t, J = 4.7 Hz, 1H CH 12), 4.26 (t, J = 7.3 Hz, 2H CH2 18), 4.02-3.92 (m, 2H CH2 14, 15), 3.91-3.83 (m, 2H CH2 14, 15), 3.14 (t, J = 7.3 Hz , 2H CH2 19), 2.99 (m, 2H CH2 12), 1.96-1.88 (m, 2H CH2 11). 13

C NMR (100 MHz, CDCl3) δ 142.5 (C3), 141.7 (C9), 139.0 (C20), 132.7 (C4), 131.5, 131.1, 130.5 (C5, 7, 8), 129.1, 128.7 (C 21, 22, 24, 25), 126.7, 126.6 (C6, 23), 110.3 (C2), 104.0 (C12), 65.1 (C13, 16), 60.7 (C18), 36.7 (C19), 34.9 (C11), 28.2 (C19). IR: υ (cm-1) 3027, 2951, 2880, 1604, 1494, 1454, 1250, 1139, 1030, 945, 898, 769, 749, 700.

1. 97e) N-(2-((trimethylsilyl)oxy)propyl)benzimidoyl cyanide

Yield: 57% Aspect: Clear oil Molecular formula: C14H20N2OSi HRMS (ESI) calcd for C14H21N2OSi+ [M+H]+ 261.1418; found 261.1427. 1

H NMR (400 MHz, CDCl3) δ 8.02-7.98 (m, 2H CHAr 4, 6), 7.56-7.42 (m, 3H CHAr 1-3), 4.22 (m, 1H CH 10), 3.96 (d, J = 6.0 Hz, 2H CH2 9), 1.31 (d, J = 6.0, 3H CH3 13), 0.09 (s, 9H CH2 11).

13

C NMR (100 MHz, CDCl3) δ 142.8 (C7), 133.8 (C5), 132.4 (C2), 129.1, 127.8 (C1, 3, 4, 6), 110.1 (C12), 68.1 (C10), 66.6 (C9), 22.4 (13), 0.4 (C11). IR: υ (cm-1) 2960, 1605, 1452, 1251, 1096, 1006, 839, 689.

190

1. 97f) (2E)-2-methyl-N-phenethylbut-2-enimidoyl cyanide

Yield: 63% Aspect: Yellow oil Molecular formula: C14H16N2 1

H NMR (400 MHz, CDCl3) δ 7.36-7.19 (m, 5H CHAr 10-14), 6.65-6.55 (m, 1H C15), 4.09 (t, J = 7.4 Hz, 1H CH2 7), 3.03 (t, J = 7.4 Hz, 1H CH2 8), 1.94-1.89 (m, 6H CH3 1, 16).

13

C NMR (100 MHz, CDCl3) δ 145.2 (C3), 139.2 (C9), 137.8 (C15), 135.2 (C2), 129.1, 128.5 (C 10, 11, 13, 14), 126.5 (C12), 109.3 (C4), 59.7 (C7), 37.0 (C8), 14.9 (C16), 12.0 (C1).

1. 97g) 3-methyl-N-phenethylbut-2-enimidoyl cyanide

Yield: 76% Aspect: Clear oil Molecular formula: C14H16N2 HRMS (ESI) calcd for C14H17N2+ [M+H]+ 213.1386; found 213.1389. 1

H NMR (400 MHz, CDCl3) δ 7.35-7.20 (m, 5H CHAr 12-16), 5.99-5.96 (m, 1H CH 4), 4.07 (t, J =7.3 Hz, 2H CH2 9), 3.03 (t, J = 7.3, 2H CH2 10), 2.11 (s, 3H CH3 1), 1.94 (s, 3H CH3 3). 13

C NMR (100 MHz, CDCl3) δ 149.7 (C5), 140.1 (C2), 139.1 (C11), 129.1, 128.6 (C 12, 13, 15, 16), 126.5 (C14), 121.7 (C4), 111.0 (C5), 59.6 (C9), 36.9 (C10), 28.0 (C3), 20.3 (CC1). IR: υ (cm-1) 2923, 2215, 1643, 1591, 1453, 1269, 1032, 746, 699. 191

1. 97h) N-benzylpentanimidoyl cyanide

Yield: 78% Aspect: Clear oil Molecular formula: C13H16N2 1

H NMR (400 MHz, CDCl3) δ 7.41-7.28 (m, 5H CHAr 10-14), 4.93 (s, 2H CH2 8), 2.61 (t, J = 7.5 Hz, 2H CH2 7), 1.74-1.67 (m, 2H CH2 6), 1.44-1.35 (m, 2H CH2 5), 0.96 (t, J = 7.4 Hz, 3H CH3 4) 13

C NMR (100 MHz, CDCl3) δ 145.0 (C2), 137.4 (C9), 128.7, 128.0, 127.6 (C10-14), 110.7 (C3), 62.3 (C8), 38.5 (C7), 27.7 (C6), 22.0 (C5), 13.7 (C4).

1. 97i) N-benzylpivalimidoyl cyanide

Yield: 93% Aspect: Clear oil Molecular Formula: C13H16N2 HRMS (ESI) calcd for C13H17N2+ [M+H]+ 201.1386; found 201.1381. 1

H NMR (400 MHz, CDCl3) δ 7.49-7.20 (m, 5H CHAr 11-15), 4.96 (s, 2H CH2 9), 1.30 (s, 9H CH3 1,3,4).

13

C NMR (100 MHz, CDCl3) δ 152.9 (C5), 137.8 (C10), 128.6, 127.7 (C11, 12, 14, 15), 127.4 (C13), 109.7 192

(C6), 61.7 (C9), 39.5 (C2), 27.0 (C1, 3, 4). IR: υ (cm-1) 2969, 1699, 1631, 1456, 1367, 1261, 1161, 1088, 736, 696.

1. 97j) (Z)-4-methoxy-N-phenethylbenzimidoyl cyanide

Yield: 59% Aspect: colorless oil Molecular Formula: C17H16N2O 1

H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 9.0 Hz, 2H CHAr 8, 12), 7.25-7.35 (m, 5H CHAr 14-18), 6.99 (d, J = 9.0 Hz, 2H CHAr 9, 11), 4.21 (t, J = 7.2 Hz, 2H CH2 5), 3.90 (s, 3H CH3 13), 3.11 (t, J = 7.2 Hz, 2H CH2 6), 13

C NMR (100 MHz, CDCl3) δ 162.8 (C10). 141.3 (C2), 139.0 (C7), 129.3, 129.1, 129.1, 128.5, 128.5 (C, 8, 12, 14, 15, 17, 18), 126.5, 126.5 (C3, 16), 114.3 (C9, 11), 109.7 (C4), 60.00 (C5), 55.5 (C13), 36.9 (C6).

1. 97k) N-cyclopropylcinnamimidoyl cyanide

Yield: 88% Aspect: White crystals Molecular formula: C13H12N2 1

H NMR (400 MHz, CDCl3) δ 7.52-7.49 (m, 2H CHAr 7, 11), 7.42-7.36 (m, 3H CHAr 8-10), 7.32 (d, J = 16.0 Hz, 193

1H CHAr CH 5), 6.91 (d, J = 16.0 Hz, 1H CH 4), 3.56-3.51 (m, 1H CH 13), 1.29-1.21 (m, 2H CH2 14, 15), 1.201.14 (m, 2H CH2 14, 15). 13

C NMR (100 MHz, CDCl3) δ 140.3 (C5), 139.6 (C3), 134.9 (C6), 129.6 (C4), 129.1, 127.7 (C 7, 8, 10, 11), 126.0 (C9), 110.1 (C2), 41.3 (C13), 12.4 (C14, 15).

1. 97l) 4-((tert-butyldimethylsilyl)oxy)-3-methoxy-N-phenethylbenzimidoyl cyanide

Yield: 75% Aspect: Clear oil Molecular formula: C23H30N2O2Si HRMS (ESI) calcd for C23H31N2O2Si+ [M+H]+ 395.2149; found 395.2156. 1

H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 2.1 Hz, 1H CHAr 28, 7.42 (dd, J = 8.2, 2.1 Hz, 1H CHAr 14), 7.31-7.19 (m, 5H CHAr 23-27), 6.89 (d, J = 8.2 Hz, 1H CHAr 13), 4.16 (t, J = 7 Hz, 2H CH2 20), 3.06 (t, J = 7 Hz, 2H CH2 21), 3.85 (s, 3H CH3 1), 0.99 (s, 9H CH3 10-12), 0.17 (s, 6H CH3 7, 8). 13

C NMR (100 MHz, CDCl3) δ 151.6 (C3), 149.4 (C4), 141.6 (C16), 139.1 (C22), 129.2, 128.6 (C23, 24, 26, 27), 127.6 (C15), 126.6 (C25), 122.2, 120.9 (C13, 14), 109.8 (C17), 109.7 (C28), 60.0 (C1), 55.6 (C20), 37.0 (C21), 25.8 (C7, 8), 18.6 (C10-12), -4.4 (C9). IR: υ (cm-1) 2931, 2858, 2337, 2226, 1699, 1594, 1509, 1288, 912, 841.

1. 97m) 2,6-dichloro-N-phenethylbenzimidoyl cyanide 194

Yield: 84% Aspect: Clear oil Molecular Formula: C16H12Cl2N2 1

H NMR (400 MHz, CDCl3) δ 7.40-7.22 (m, 8H CHAr 3-5, 16-20), 4.36 (t, J = 7.2 Hz, 2H CH2 13), 3.17 (t, J = 7.2 Hz, 2H CH2 14). 13

C NMR (100 MHz, CDCl3) δ 138.4 (C9), 137.8 (C8), 134.4 (C15), 132.3 (C2, 6), 131.9 (C4), 129.0, 128.8, 128.4 (C3, 5, 16, 17, 19, 20), 126.8 (C18), 109.1 (C10), 60.8 (C13), 36.4 (14).

1. 97n) N-(4-methoxyphenyl)-3-(4-nitrophenyl)acrylimidoyl cyanide

Yield: 74% Aspect: orange crystals Molecular Formula: C17H13N3O3 Mp: 135-138 °C HRMS (ESI) calcd for C17H14N3O3+ [M+H]+: 308.0957; Found 308.1030

195

1

H NMR (400 MHz, CDCl3) δ 8.32-8.27 (m, 2H CHAr 1,3), 7.76-7.70 (m, 2H CHAr 4, 6), 7.56 (d, J = 16.4 Hz, 1H CH 8), 7.41-7.36 (m, 2H CHAr C14, 18), 7.27 (d, J = 16.4 Hz, 1H CH 9), 7.02-6.96 (m, 2H CHAr 15, 17) 3.89 (s, 3H CH3 20) 13

C NMR (100 MHz, CDCl3) δ 160.5 (C16), 148.4 (C2), 141.3 (C10), 140.9 (C5), 139.3 (C8), 135.3 (C13), 131.3 (C9), 128.5 (C1, 3), 124.5 (C 4, 6), 124.0 (C14, 18), 114.7 (C15, 17), 111.2 (C12), 55.7 (C20). IR: υ (cm-1) 2933, 2842, 2215, 1724, 1599, 1516, 1343, 1253, 1024, 837, 750.

1. 97o) 3-(4-bromophenyl)-N-phenethylacrylimidoyl cyanide

Yield: 92% Aspect: white crystals Molecular Formula: C18H15N2Br Mp: 57-61 °C HRMS (ESI) calcd for C18H16N2Br+ [M+H]+: 339.0491; Found 339.0488 1

H NMR (400 MHz, CDCl3) δ 7.54 (m, 2H CHAr 15, 19), 7.40-7.36 (m, 2H CHAr 16, 18), 7.34-7.28 (m, 4H CHAr 9-13 CH 1), 7.26-7.21 (m, 4H CHAr 9-13), 6.93 (d, J = 16.4 Hz, 1H CH 2), 4.14 (t, J = 7.2 Hz, 2H CH2 6), 3.06 (t, J = 7.3 Hz, 2H CH2 7) 13

C NMR (100 MHz, CDCl3) δ 142.7 (C3), 141.3 (1), 138.7 (C8), 133.5 (C14), 132.4 (C15, 19), 129.3, 129.1, 128.6, 126.7 (C 9, 10, 12, 13, 16, 18), 126.5 (C 2, 11), 124.7 (C17), 108.9 (C4), 60.3 (C6), 36.9 (C7) IR: υ (cm-1) 3027, 2927, 2855, 2342, 2220, 1579, 1489, 1256, 1072, 812, 699

196

1. 97y) 2-allyl-N-phenethylbenzimidoyl cyanide

Starting from 2-allylbenzaldehyde190. Yield: 65% Aspect: Yellow oil Molecular formula: C19H18N2 HRMS (ESI) calcd for C19H19N2+ [M+H]+ 275.1543; found 275.1548. 1

H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.7 Hz, 1H CHAr 5), 7.39-7.18 (m, 8H CHAr 6-8, 17-21), 5.94-5.76 (m, 1H CH2), 5.01 (d, J = 10.2 Hz, 1H CH 1), 4.94 (d, J = 17.0 Hz, 1H CH 1), 4.23 (t, J = 7.1 Hz, 2H CH2 14), 3.59 (d, J = 6.3 Hz, 2H CH2 3), 3.11 (t, J = 7.1 Hz, 2H CH2 15).

13

C NMR (100 MHz, CDCl3) δ 142.6 (C10), 139.7 (C16), 138.9 (C4), 136.9 (C2), 132.8, 131.3, 131.1, 130.3, 129.1, 128.7, 126.8, 126.7 (CH aromatics), 116.2 (C1), 110.3 (C11), 60.6 (C3), 37.7 (C14), 36.7 (C15). IR: υ (cm-1) 3065, 3019, 2921, 1604, 1454, 1254, 1032, 914, 746, 699.

1.141) (2E)-N-phenethylbut-2-enimidoyl cyanide

Yield: 93% Aspect: Yellow oil Molecular formula: C13H14N2 190

S. Arai, Y. Koike, H. Hada, A. Nishida, J. Org. Chem 2010, 75, 7573-7579.

197

1

H NMR (400 MHz, CDCl3) δ 7.37-7.22 (m, 5H CHAr 11-15), 6.70 (dq, J = 16.1, 6.8 Hz, 1H CH 2), 6.34 (dd, J = 16.1, 1.4 Hz, 1H CH 3), 4.09 (t, J = 7.2 Hz, 1H CH 8), 3.04 (t, J = 7.2 Hz, 2H CH 9), 1.99 (d, J = 6.8 Hz, 3H CH1). 13

C NMR (100 MHz, CDCl3) δ 142.6 (C4), 142.2 (C2), 138.8 (C10), 129.9 (C3), 129.0, 128.6 (C11, 12, 14, 15), 126.6 (C13), 109.0 (C5), 59.8 (C8), 36.8 (C9), 18.6 (C1).

1.156) 2-iodobenzyl acetate

To a solution of 2-iodobenzyl alcohol (8 g, 34 mmol, 1 equiv), DMAP (250 mg, 2 mmole, 0.06 equiv) and NEt3 (7.15 ml, 51 mmol, 1.5 equiv) in DCM (85 ml, 0.4 M) at 0°C was added Ac2O (3.8 ml, 40.8 mmol, 1.2 equiv). After full conversion of the starting material the reaction mixture was diluted with AcOEt, washed with NH4Cl, NaHCO3, Brine, dried over Na2SO4 and concentrated. The residue was filtered on a pad of silica (AcOEt) to give 2-iodobenzyl acetate cleanly (quantitative). Yield: quantitative Aspect: clear oil Molecular Formula: C9H9IO2 1

H NMR (400 MHz, CDCl3) δ 7.86 (m, 1H CHAr 6), 7.42-7.31 (m, 2H CHAr 4, 7), 7.07-6.98 (m, 1H CHAr 5), 5.13 (s, 2H CH2 8), 2.15 (s, 3H CH3 1).

13

C NMR (100 MHz, CDCl3) δ 170.8 (C10), 139.7 (C6), 138.4 (C12), 130.0, 129.5, 128.4 (C4, 5, 7), 98.5 (C11), 70.2 (C8), 21.1 (C1).

1.157) 2-(3-oxopropyl)benzyl acetate

198

To a solution of 2-iodobenzyl acetate (100mg, 0.36 mmol, 1 equiv), allyl alcohol (61 μl, 0.9 mmole, 2.5 equiv), NaHCO3 (75.6 mg, 0.9 mmol, 2.5 equiv) and TBAC (100mg, 0.36 mmol, 2.5 equiv) in DMF (0.72 ml, 0.5 M) was added Pd(OAc)2 (4 mg, 0.018 mmol, 5%). The reaction mixture was heated to 50°C till full conversion, cooled to r.t and filtered over a pad of silica (AcOEt). The solution was concentrated under vacuuo and the residue purified by FCC (PE/AcOEt 85/15) to give 63 mg of pure 2-(3oxopropyl)benzyl acetate (85%). Yield: 88% Aspect: clear oil Molecular Formula: C12H14O3 1

H NMR (400 MHz, CDCl3) δ 9.83 (t, J = 1.42 Hz, 1H CH 13), 7.36-7.19 (m, 4H CHAr 6-9), 5.15 (s, 2H CH2 4), 3.01 (t, J = 7.6 Hz, 2H CH2 11), 2.79 (dt, J = 7.6, 1.42 Hz CH2 12), 2.09 (s, 3H CH3 1) 13

C NMR (100 MHz, CDCl3) δ. 201.1 (C13), 170.8 (C2), 139.5 (C5), 133.6 (C10), 130.3, 129.3, 129.0, 126.7 (C6-9), 64.4 (C4), 45.0 (C12), 24.6 (C11), 21.0 (C1).

1.158) 2-(2-(1,3-dioxolan-2-yl)ethyl)benzaldehyde

To a solution of 2-(3-oxopropyl)benzyl acetate (63 mg, 0.3 mmol, 1 equiv) and ethylene glycole (33.51 μl, 0.6 mmole, 2 equiv) in toluene (1.2 ml, 0.25 M) was added PTSA (5.7 mg, 0.03 mmol, 20%) and an excess of Na2SO4. The reaciton mixture was refluxe for four hours before being filtered over NaHCO3 and concentrated under vacuuo. The residue was then dissolved in methanol/water (1:1 mix, 2 ml). K2CO3 was added and the solution stired for 2 hours. The methanol was then evaporated and material the reaction mixture was diluted with Et2O, washed with NH4Cl, Brine, dried over Na2SO4 and concentrated. The residue was dissolved in DCM (0.5 ml, 0.5 M) and PCC (77 mg, 0.36 mmol, 1.5 equiv) was added. The reaction mixture was stirred till full conversion. The mixture was then filtered on silica (PE/AcOEt, 9/1) to give 35 mg of pure 2-(2-(1,3-dioxolan-2-yl)ethyl)benzaldehyde (55 % three steps) Yield: 55% Aspect: clear oil Molecular Formula: C12H14O3

199

1

H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H CH 2), 7.82 (d, J = 7.6 Hz, 1 H CHAr 4), 7.50 (t, J = 7.4 Hz, 1H CHAr 6), 7.37 (t, J = 7.6 Hz, 1H CHAr 5), 7.31 (d, J = 7.6 Hz, 1H CHAr 7), 4.92 (t, J = 4.6 Hz, 1H CH 11), 4.05-3.94 (m, 2H CH2 13, 14), 3.94-3.82 (m, 2H CH2 13, 14), 3.20-3.12 (m, 2H CH2 9), 2.02-1.93 (m, 2H CH2 10). 13

C NMR (100 MHz, CDCl3) δ. 192.5 (C2), 144.5 (C8), 134.0 (C6), 133.9 (C3), 132.1, 131.1, 126.8 (C 4, 5, 7), 103.8 (C11), 65.1 (C13, 14), 35.8 (C19), 27.0 (C11).

1.204a) N-cyclopropyl-3-(4-methoxyphenyl)acrylimidoyl cyanide

Yield: 74% Aspect: yellow crystals Molecular Formula: C14H14N2O Mp: 79-80 °C HRMS (ESI) calcd for C14H15N2O+ [M+H]+ 227.1106; Found 227.1190 1

H NMR (400 MHz, CDCl3) δ 7.45-7.43 (m, 2H CHAr 5, 16), 7.26 (d, J = 16.4 Hz, 1H CH 7), 6.92-6.90 (m, 2H CHAr 4, 17), 6.79 (d, J = 16.4 Hz, 1H CH 8), 3.83 (s, 3H CH3 1), 3.53-3.48 (m, 1H CH 13), 1.25-1.21 (m, 2H CH2 14, 15), 1.14-1.10 (m, 2H CH2 14, 15) 13

C NMR (100 MHz, CDCl3) δ 161.1 (C3), 140.0 (C7), 139.8 (C9), 129.3 (C5, 16), 127.8 (C6), 123.8 (C8), 114.6 (C4, 17), 110.2 (C10), 55.5 (C1), 41.0 (C13), 12.1 (C14, 15) IR: υ (cm-1) 3055, 3025, 2934, 1625, 1602, 1501, 1442, 1299, 1245, 1195, 1165, 1034, 961, 829, 756, 689

200

1.204b) N-(4-methoxyphenyl)cinnamimidoyl cyanide

Yield: 70% Aspect: light orange crystals Molecular Formula: C17H14N2O Mp: 79-80 °C HRMS (ESI) calcd for C17H15N2O+ [M+H]+ 263.1106; Found 263.1171 1

H NMR (400 MHz, CDCl3) δ 7.59-7.54 (m, 3H CH 9, CHAr 4, 6), 7.45-7.42 (m, 3H CHAr 1-3), 7.31-7.23 (m, 2H CHAr 15, 19), 7.17 (d, J = 16.3 Hz, 1 H CH 10), 6.99-6.96 (m, 2 H CHAr 16, 18), 3.86 (s, 3H CH3 21) 13

C NMR (100 MHz, CDCl3) δ 159.6 (C17), 143.0 (C11), 141.8 (C9), 137.4 (C14), 134.7 (C5), 130.4 (C2), 129.1 (C4, 6), 128.0 (1, 3), 127.2 (C10), 123.3 (C15, 19), 114.5 (C16, 18), 111.1 (C13), 55.6 (C21). IR: υ (cm-1) 3041, 2977, 1604, 1571, 1514, 1427, 1310, 1250, 1178, 1022, 956, 824, 806

1.204c) (Z)-N-(4-methoxyphenyl)benzimidoyl cyanide

Molecular Formula: C15H12N2O Yield: 95% Aspect: yellow solid 1

H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.5 Hz, 2H CHAr 14, 18), 7.60-7.50 (m, 3H CHAr 15-17), 7.36 (d, J = 9.0 Hz, 2H CHAr 8, 12), 7.02 (d, J = 9.0 Hz, 2H CHAr 9, 11), 3.89 (s, 3H CH3 11).

201

13

C NMR (100 MHz, CDCl3) δ 159.5 (C8), 141.7 (C2), 136.8 (C3), 134.1 (C5), 132.3 (C14), 128.9, 127.9 (C12, 13, 15, 16), 123.0 (C6, 10) 114.4 (C7, 9), 111.6 (C4), 55.5 (C11).

1.204d) N-benzylbenzimidoyl cyanide

Yield: 92% Aspect: yellow oil Molecular Formula: C15H12N2 HRMS (ESI) calcd for C15H13N2+ [M+H]+: 220.1000; Found 221.1080 1

H NMR (400 MHz, CDCl3) δ 8.07-8.01 (m, 2H CHAr 4, 6), 7.57-7.26 (m, 8H CHAr 1-3, 12-16), 5.17 (s, 2H CH2 10) 13

C NMR (100 MHz, CDCl3) δ 142.3 (C7), 137.7 (C5), 133.5 (C11), 132.5 (C2), 129.1, 128.9, 128.2, 127.9 (C1, 3, 4, 5, 12, 13, 15, 16), 127.7 (C14), 109.9 (C9), 62.5 (C10). IR: υ (cm-1) 3062, 3029, 2848, 2217, 1641, 1605, 1575, 1993, 1449, 1267, 1025

1.204e) (Z)-N-phenethylbenzimidoyl cyanide 1

N

15 14

2 9 8

4

3

N 5

7

16

11 10

12

13

17 18

6

Chemical Formula: C16H14N2 Aspect: yellow oil

202

Yield: 90% (procedure A) 1

H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.5 Hz, 2H CHAr 5, 9), 7.57-7.49 (m, 3H CHAr 6-8), 7.36-7.26 (m, 5H CHAr 14-18), 4.27 (t, J = 7.2 Hz, 2H CH2 11), 3.15 (t, J = 7.2 Hz, 2H CH2 12). 13

C NMR (100 MHz, CDCl3) δ 142.1 (C3).138.8 (C13), 133.4 (C4), 132.2 (C7), 129.1, 128.9, 128.5, 127.6 (C5, 6, 8, 9, 14, 15, 17, 18), 126.6 (C16), 109.5 (C2), 60.2 (C11), 36.8 (C12). IR: υ (cm-1) 3027, 2925, 2859, 2217, 1605, 1577, 1494, 1449, 1269.

1.204f) (Z)-N-phenethylisobutyrimidoyl cyanide

Aspect: colorless oil Yield: 60% Molecular Formula: C13H16N 2; 1

H NMR (400 MHz, CDCl3) δ 7.21-7.34 (m, 5H CHAr 10-14). 4.02 (t, J = 7.0 Hz, 2H CH2 5), 3.02 (t, J = 7.0 Hz, 2H CH2 6), 2.71 (m, 1H CH 3), 1.19 (d, J = 7.0 Hz, 6H CH3 8,9), 13

C NMR (100 MHz, CDCl3) δ 150.1 (C2), 138.6 (C7), 129.0, 128.29 (C10, 11, 13, 14), 126.50 (C12), 109.57 (C4), 59.53 (C5), 36.88 (C3), 36.31 (C6), 18.88 (C8, 9).

1.204g) 4-methoxy-N-phenethylbenzimidoyl cyanide

Yield: 70% Aspect: White powder 203

Molecular Formula: C17H16N2O 1

H NMR (400 MHz, CDCl3) δ 7.92-7.90 (m, 2H CHAr 5, 11), 7.32-7.23 (m, 5H CHAr 16-20), 6.98-6.95 (m, 2H CHAr 6, 10), 4.18 (t, J = 8.0 Hz, 2H CH2 13), 3.87 (s, 3H CH3 9), 3.09 (t, J = 8.0 Hz, 2H CH2 14)

13

C NMR (100 MHz, CDCl3) δ 162.9 (C7), 141.4 (C3), 139.1 (C4), 129.4, 129.2, 128.6 (C 5, 11, 16, 17, 19, 20), 126.6 (C18), 126.5 (C15), 114.4 (C6, 10), 109.8 (C2), 60.1 (C9), 55.7 (C13), 37.0 (C14).

204

Desymmetrization General Procedures: Unless otherwise stated the following procedures were used for the synthesis of the designated compounds. The procedures for the intermediates used in the total synthesis are given under the corresponding entries.

General procedure for the synthesis of bislactones: 2a) Methyl acrylate MeOH reflux

1) O

R

N H drying agent

N

R

O O

2b) AcOH/H2O

O R

O

O

2.100 3) KOH MeOH/H2O 4) Ac2O, NaHCO3

O

O

H

O

O

R 2.101

1) The aldeyhde (1 equiv) was added dropwise to pyrrolidine (1.5 equiv) cooled at 0 °C under stirring and argon. K2CO3 (excess) or Na2SO4 (excess) was then added and the suspension was stirred overnight at room temperature. The suspension was then filtered, washed with Et2O and concentrated. The residue was distilled to give the pure enamine which was immediately used in the following step. 2) To the enamine in methanol ( c = 1.7 M) was added methyl acrylate (2 equiv) at 0 °C. The mixture was then refluxed for 72 h, before a 1:1 mixture of water/ AcOH was added. After refluxing for another 4h, the mixture was concentrated and the residue purified by FCC with PE/AcOEt (85/15) to yield the desired diester. 3) To the diester (1 equiv) in MeOH (c = 0.5 M) was added KOH (2.5 equiv) in water (c = 0.29 M) and the mixture was stirred till disappearance of the starting material. Methanol was then removed in vacuum and the remaining aqueous solution was washed with DCM. To the aqueous phase was then added AcOEt, acidified to pH 3 and the aqueous phase further extracted with AcOEt. The combined organic phases were washed with brine, dried and concentrated to give the diacid which was used as such in the next step without purification. 4) To the diacid (1 equiv) was added acetic anhydride (c = 0.1 M) and NaHCO3 (4 equiv). The suspension was stirred at 80 °C for 3 hours. The excess acetic anhydride was evaporated under reduced pressure and the residue was purified by FCC (PE:AcOEt 1:1) to yield the corresponding bislactone 2.101. 205

General procedure desymmetrization of bislactones:

To the corresponding bislactone ( 0.1 mmol, 1 equiv) in the indicated solvent (1 mL, c = 0.1 M) was added the alcohol (0.2 mmol, 2 equiv) and the catalyst (10 μmol, 0.1 equiv). The mixture was stirred till complete conversion of the bislactone. The solvent was evaporated to dryness and the residue evaporated to dryness and purified by FCC (PE/AcOEt/AcOH 73/25/2) to yield the corresponding acid 2.111.

General procedure for the determination of the enantiomeric ratio of monoacids:

Being insufficiently UV active, compounds 2.111 were converted to the esters 2.41 for SFC determination of the enantiomeric ratio according to the following procedure. Optical rotations were also preferably measured on the ester derivatives. To a solution of acid 2.111 (0.1 mmol, 1 equiv), alcohol (21 μL, 0.2 mmol, 2 equiv), triethylamine (38 μL, 0.3 mmol, 3 equiv) and DMAP (12.2 mg, 0.15 mmol, 1.5 equiv) in DCM (0.4 mL, c = 0.25 M) was added EDC.HCl (23 mg, 0.12 mmol, 1.2 equiv). The mixture was stirred for 2 hours before being partitioned between AcOEt and aqueous NH4Cl. The aquous phase was further extracted with AcOEt. The combined organic phases were washed with NaHCO3, brine, dried and concentrated. The residue was purified by FCC (PE/AcOEt 9/1) to yield the corresponding ester 2.41.

206

Enzymatic Desymmetrisation General Procedure and Screening

R= O

R = Acetal

Entry

Enzyme

Yields (%)

e.r

Yields (%)

e.r

1

Lipase from aspergillus niger

18

51 : 49

trace

n.a

2

Novozyme 435

50

52.5 : 47.5

20

51 : 49

3

Lipase from aspergillus niger (expressed differently)

62

51.5 : 48.5

34

49.5 : 50.5

4

Esterase from porcine liver

26

52 : 48

15

51 : 49

5

Esterase immobilised on resin

29

58 : 42

26

51.5 : 48.5

6

Lipase amano PS

6

51 : 49

16

51 : 49

7

Chemotrypsin

trace

n.a

n.a

n.a

To a solution of diester 1 (0.1 mmol, 1 equiv) in a mixture of phosphate buffer and acetone (c = 0.1 M, 9/1 V/V) was added the indicated enzyme. The mixture was then incubated at 40 °C at 1500 rpm in a shaker for 72 h. The reaction mixture was filtered over a thick pad of Celite, washed with AcOEt and concentrated under vacuuo. The residue was purified by FCC (PE/AcOEt/AcOH 73/25/2) to yield the corresponding acid.

207

Desymetrization: Spectroscopic Data 2.37) Dimethyl 4-ethyl-4-formylheptanedioate (Kuehne’s aldehyde)

Yield: 50% Aspect: yellow oil Molecular Formula: C12H20O5 1

H NMR (400 MHz, CDCl3): δ 9.44 (s, 1H CH 4), 3.70 (s, 6H CH3 13, 15), 2.23-2.18 (m, 4H CH2 16, 17), 1.831.87 (m, 4H CH2 7, 6), 1.58 (q, J = 7.5 Hz, 2H CH2 2), 0.86 (t, J = 7.5 Hz, 3H CH3 1).

13

C NMR (100 MHz, CDCl3): δ 205.2 (C4), 173.4 (C8, 9), 51.9 (C13, 15), 50.2 (C3), 28.4 (C16, 17), 26.1 (C7, 6), 23.3 (C2), 7.8 (C1).

2.38) 4-(1,3-dioxolan-2-yl)-4-ethylheptanedioic acid From Dimethyl 4-(1,3-dioxolan-2-yl)-4-ethylheptanedioate

To dimethyl 4-(1,3-dioxolan-2-yl)-4-ethylheptanedioate (0.5 g, 1.7 mmol, 1 equiv) in MeOH (3.5 ml, c = 0.5 M) was added NaOH (173 mg, 4.34 mmol, 2.5 equiv) in water (3.5 ml, c = 1.25 M) and stirred till disappearance of the starting material. The Methanol was then remouved in vacuu and the remaining solution transferred to an extraction flask and washed with DCM. The aquous phase was then partitined with AcOEt and acidified to pH 3. The organic phase was washed with brine, dried and concentrated to yield cleanly 4-(1,3-dioxolan-2-yl)-4-ethylheptanedioic acid as a white solid (430 mg, 97%). From Dimethyl 4-ethyl-4-formylheptanedioate To kuhene’s aldehyde (1 g, 4.1 mmol, 1 equiv) in hexanes (16 ml, c = 0.25 M) was added ethylene glycol (0.92 ml, 16.4 mmol, 4 equiv) and TsOH (76 mg, 0.4 mmol, 0.1 equiv). The mixture stirred under 208

argon at 95 °C with a dean-stark trap till full conversion. The reaction was poured over NaHCO3 and partitioned with AcOEt, the organic phase was washed with brine, dried and concentrated under vacuuo. The polymer obtained as a clear oil was then dissolved in methanol (5 ml, c = 0.8 M) to which was added dropwise NaOH (410 mg, 10.25 mmol, 2.5equiv) in water (5 ml, c = 0.8 M). The solution was stirred for 4 hours before remouval of the methanol in vacuu and the transfer of the remaining solution to an extraction flask. The solution was then washed with DCM and then the aquous phase was partitined with AcOEt and acidified to pH 3. The organic phase was washed with brine, dried and concentrated to yield cleanly 4-(1,3-dioxolan-2-yl)-4-ethylheptanedioic acid as a white solid (850 mg, 80%). Aspect: white solid Molecular Formula: C12H20O6 HRMS calcd for C12H21O6+ [M+H]+ 261.1333; found 261.1324. 1

H NMR (400 MHz, CDCl3): δppm = 4.60 (s, 1 H CH 4), 3.98-3.86 (m, 2 H CH2 6, 7), 3.86-3.77 (m, 2 H CH2 6, 7), 2.53-2.36 (m, 4 H CH2 10, 15), 1.79-1.68 (m, 4 H CH2 9, 14), 1.51-1.38 (m, 2 H CH2 2), 0.94-0.83 (m, 3 H CH3 1).

13

C NMR (100 MHz, CDCl3): δppm = 180.6 (C11, 16), 108.4 (C4), 64.8 (C6, 7), 40.5 (C3), 29.1 (C10, 15), 27.7 (C9, 14), 25.9 (C2), 7.8 (C1). IR: υ (cm-1) = 2960, 2937, 2880, 1723, 1416, 1311, 1216, 1090, 972, 900, 689.

2.39) 5-(1,3-dioxolan-2-yl)-5-ethyloxocane-2,8-dione

To 4-(1,3-dioxolan-2-yl)-4-ethylheptanedioic acid ( 26 mg, 0.1 mmol. 1 equiv) was added acetic anydride ( 0.3 mL, c = 0.33 M) in a sealed tube which was heated to 50 °C for 2 h. The mixture was cooled, evaporated to dryness, and then co-evaporated twice with xylenes to remove the excess acetic anhydride to give anhydride 10 containing trace xylene as a slightly yellow oil (quant) which was immediately used as such. 1

H NMR (400 MHz, CDCl3): δ 4.57 (s, 1H Ch 4), 3.98-3.87 (m, 2H CH2 6, 7), 3.87-3.76 (m, 2H CH2 6, 7), 2.582.49 (m, 4H CH2 10, 16), 1.80-1.68 (m, 4H CH2 9, 17), 1.45 (q, J = 7.5 Hz, 2H CH2 2), 0.81 (t, J = 7.5 Hz, 3H CH3 1) 209

2.48) Dimethyl 4-(1,3-dioxolan-2-yl)-4-ethylheptanedioate

To a solution of Kuehne’s aldehyde (1 g, 4.1 mmol, 1 equiv) in toluene (16 mL, c = 0.25 M) was added ethylene glycol (0.92 mL, 16.4 mmol, 4 equiv), TsOH (76 mg, 0.4 mmol, 0.1 equiv) and Na2SO4 (10 g). The mixture was stirred under argon at 100 °C till full conversion. The mixture was poured onto aq NaHCO3 and extracted with AcOEt, the organic phases were washed with brine, dried and concentrated under vacuuo. The residue was purified by FCC (PE/AcOEt 85/15) to yield dimethyl 4-(1,3-dioxolan-2-yl)4-ethylheptanedioate 9 as a pale oil (0.86 g, 76%). Aspect: colourless oil Molecular Formula: C14H24O6 HRMS calcd for C14H25O6+ [M+H]+ 289.1646; found 289.1653. 1

H NMR (400 MHz, CDCl3): δ 4.53 (s, 1H CH 4), 3.92-3.77 (m, 4H CH2 6, 7), 3.59 (s, 6H CH3 14, 20), 2.392.34 (m, 4H CH2 10, 16), 1.72-1,68 (m, 4H CH2 9, 15), 1.36 (q, J = 7.5 Hz, 2H CH2 2), 0.81 (t, J = 7.5 Hz, 3H CH3 1). 13

C NMR (100 MHz, CDCl3): δ 174.6 (C11, 17), 108.4 (C4), 64.7 (C6, 7), 51.6 (C14, 20), 40.4 (C3), 29.0 (C10, 16), 28.1 (C9, 15), 25.7 (C2), 7.7 (C1). IR: υ (cm-1) 2955, 2883, 1733, 1434, 1195, 1171, 1100, 998, 887.

2.40) 4-(1,3-dioxolan-2-yl)-4-ethyl-7-methoxy-7-oxoheptanoic acid 12

18

O

19

HO

17

16 1

15

3

4 2 8

O

9

10

14 11

O5

O

O 13

6 7

To 5-(1,3-dioxolan-2-yl)-5-ethyloxocane-2,8-dione (24.3 mg, 0.1 mmol, 1 equiv) in DCM (1 ml, c = 0.1 M) was added methanol ( 8 μl, 0.2 mmol, 2 equiv) and the corresponding chinchona alkaloid catalyst (0.01 mmol, 0.1 equiv). The mixture was stirred till disappearance of the starting material before being 210

evaporated to dryness and purified by FCC PE/AcOEt/AcOH (73/25/2) to yield 4-(1,3-dioxolan-2-yl)-4ethyl-7-methoxy-7-oxoheptanoic acid as a viscous oil (9 mg, 33%). Aspect: Viscous oil. Molecular Formula: C13H22O6 HRMS: calcd for C13H23O6+ [M+H]+ 275.1489; found 275.1481. 1

H NMR (400 MHz, CDCl3): δppm = 4.60 (s, 1 H CH 4), 3.98-3.86 (m, 2 H CH2 6, 7), 3.86-3.75 (m, 2 H CH2 6, 7), 3.66 (s, 3 H CH3 14), 2.49-2.30 (m, 4 H CH2 10, 16), 1.78-1.64 (m, 4 H CH2 9, 15), 1.43 (q, J = 7.5 Hz, 2 H CH2 2), 0.88 (t, J = 7.5 Hz , 3 H CH3 1). 13

C NMR (100 MHz, CDCl3): δppm = 179.6 (C17), 174.7 (C11), 108.5 (C4), 64.8 (C6, 7), 51.7 (C14), 40.5 (C3), 29.0, 28.9 (C10, 16), 28.2, 27.9 (C9, 15), 25.7 (C2), 7.8 (C1). IR: υ (cm-1) = 2952, 2884, 2357, 2341, 1733, 1708, 1437, 1175, 1100, 954.

2.53) 4-ethyl-4-formylheptanedioic acid

Isolated as a side product of 2.98a Yield: Quantitative Aspect: White solid Molecular Formula: C10H16O5 HRMS calcd for C10H17O5+ [M+H]+ 217.1076; found 217.1067. 1

H NMR (400 MHz, CDCl3): δ 9.39 (s, 1H CH 4), 2.36-2.31 (m, 4H CH2 14, 15), 1.88 (t, J = 7.5 Hz, 4H CH2 6, 7), 1.58 (q, J = 7.6 Hz, 3H CH2 2), 0.80 (t, J = 7.5 Hz, 3H CH3 1).

13

C NMR (100 MHz, CDCl3): δ 205.2 (C4), 179.4 (C8, 9), 52.1 (C3), 28.5 (C14, 15), 26.2 (C6, 7), 24.5 (C2), 8.3 (C1). IR: υ (cm-1) 2935, 2715, 2614, 1713, 1464, 1416, 1308, 1274, 1219, 896, 681.

211

2.55) 3-(3-ethyl-6-oxotetrahydro-2H-pyran-3-yl)propanoic acid

Yield: 80% Aspect: White solid Molecular formula: C10H16O4 HRMS calcd for C10H17O4+ [M+H]+ 201.1121; found 201.1119. 1

H NMR (400 MHz, CDCl3): δ 4.03 (d, J = 11.5 Hz, 1H CH2 8), 3.99 (d, J = 11.6 Hz, 1H CH2 8), 2.53 (dt, J = 7.5, 1 Hz, 2H CH2 11), 2.32 (m, 2H CH2 5), 1.81-1.63 (m, 4H CH2 4, 10), 1.49-1.29 (m, 2H CH2 2), 0.88 (t, J = 7.5 Hz, 3H CH3 1). 13

C NMR (100 MHz, CDCl3): δ 178.9 (C6), 172.7 (C12), 75.1 (C8), 34.6 (C3), 29.1 (C4), 28.7 (C10), 28.4 (C5), 27.1 (C11), 26.9 (C2), 7.5 (C1). IR: υ (cm-1) 3147, 2965, 2340, 1729, 1708, 1461, 1403, 1192, 1059.

2.94) methyl 7-((2-bromophenyl)amino)-4-(1,3-dithiolan-2-yl)-4-ethyl-7oxoheptanoate

Yield: 75% Aspect: clear oil Molecular formula: C19H26BrNO3S2

212

HRMS calcd for C19H26BrNNaO3S2+ [M+Na]+ 482.0430; found 482.0425. 1

H NMR (400 MHz, CDCl3): δ 8.40-8.26 (m, 1H CHAr 24), 7.66 (brs, 1H NH), 7.53 (dd, J = 8.0, 1.3 Hz, 1H CHAr 21), 7.30 (m, 1H CHAr 22), 6.97 (m, 1H CHAr 23), 4.71 (s, 1H CH 10), 3.67 (s, 3H CH3 8), 3.31-3.11 (m, 4H CH2 12, 13), 2.62-2.51 (m, 2H CH2 5), 2.50-2.41 (m, 2H CH2 16), 2.02-1.92 (m, 2H CH2 4), 1.92-1.82 (m, 2H CH2 5), 1.55 (q, J = 7.6 Hz, 2H CH2 2), 0.95 (t, J = 7.5 Hz, 3H CH3 1). 13

C NMR (100 MHz, CDCl3): δ 174.3 (C17), 171.3 (C6), 135.8 (C19), 132.3 (C21), 128.5 (C22), 125.2 (C23), 122.0 (C24), 113.4 (C20), 63.4 (C10), 51.9 (C8), 42.0 (C16), 38.7 (C12, 13), 33.3 (C3), 31.7, 31.1 (C5, 15), 29.8, 29.5 (C2, 4), 8.6 (C1). IR: υ (cm-1) 3313, 2925, 1730, 1681, 1591, 1516, 1434, 1291, 1172, 1025, 752.

2.95) 4-((2-(2,4-dinitrophenyl)hydrazono)methyl)-4-ethyl-7-methoxy-7oxoheptanoic acid

Aspect: orange solid Molecular Formula: C17H22N4O8 HRMS: (ESI) calcd for C17H23N4O8+ [M+H]+ 411.1510; found 411.1506. 1

H NMR (400 MHz, CDCl3): δppm = 11.02 (brs, 1H NH 175), 9.11 (d, J = 2.6 Hz, 1H CHAr 23), 8.32 (dd, J = 2.5 Hz, 1H CHAr 20), 7.91 (d, J = 9.6 Hz, 1H CHAr 19), 7.29 (s, 1H NH 15), 3.67 (s, 3H CH3 13), 2.42-2.25 (m, 4H CH3 5, 10), 2.02-1.82 (m, 4H CH3 4, 9), 1.61 (q, J = 7.5 Hz, 2H CH3 2), 0.90 (t, J = 7.4 Hz, 3H CH3 1).

13

C NMR (100 MHz, CDCl3): δppm = 178.1 (C6), 173.8 (C11), 156.2 (C15), 145.2 (C18), 138.3 (21), 130.3 (C20), 129.0 (C24), 123.5 (C23), 116.8 (C19), 52.1 (C13), 43.8 (C3), 29.2, 29.2 (C4, 9), 28.7, 28.5 (C5, 10), 27.4 (C2), 7.9 (C1). IR: υ (cm-1) = 3290, 2932, 1732, 1703, 1615, 1515, 1332, 1306, 1219, 1135.

213

2.96) methyl 4-(1,3-dithiolan-2-yl)-4-ethyl-7-((4-nitrophenyl)amino)-7oxoheptanoate

Yield: 78% Aspect: orange oil Molecular formula: C19H26N2O5S2 1

H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 9.2 Hz, 2H CHAr 21, 26), 7.99 (brs, 1H NH), 7.72 (d, J = 9.2 Hz, 2H CHAr 20, 27), 4.68 (s, 1H CH 3), 3.68 (s, 3H CH3 1), 3.29-3.11 (m, 4H CH2 12, 13), 2.65-2.37 (m, 4H CH2 4, 16), 2.03-1.80 (m, 4H CH2 4, 15), 1.52 (q, J = 7.6 Hz, 2H CH2 2), 0.93 (t, J = 7.5 Hz, 3H CH3 1). 13

C NMR (100 MHz, CDCl3): δ 174.8 (C17), 172.0 (C6), 144.1, 143.5 (C19, 22), 125.2 (C21, 26), 119.0 (C20, 27), 63.3 (C10), 52.0 (C8), 42.0 (C16), 38.6, 38.6 (nonequivalent S-CH2-CH2-S), 33.3, 31.6 (C5, 16), 30.9, 30.0 (C4, 15), 29.4 (C2), 8.5 (C1). HRMS calcd for C19H26N2NaO5S2+ [M+Na]+ 449.1175; found 449.1174.

IR: υ (cm-1): 3327, 2919, 1698, 1548, 1504, 1330, 1256, 1170, 1111, 854, 731.

2.97) 1-(4'-bromo-[1,1'-biphenyl]-4-yl) 7-methyl 4-ethyl-4formylheptanedioate

Aspect: white needles Yield: 85%

214

Molecular formula: C23H25BrO5 1

H NMR (400 MHz, CDCl3): δ 9.47 (s, 1H CH 4) , 7.60-7.50 (m, 4H CHAr 18, 21, 15, 28), 7.46-7.39 (m, 2H CHAr 24, 29), 7.19-7.12 (m, 2H CHAr 18, 22), 3.68 (s, 3H CH3 11), 2.53-2.45 (m, 2H CH2 13), 2.31-2.21 (m, 2H CH2 7), 2.03-1.88 (m, 4H CH2 8, 12), 1.62 (q, J = 7.5 Hz, 2H CH2 2), 0.88 (t, J = 7.5 Hz, 3H CH2 1). 13

C NMR (100 MHz, CDCl3): δ 205.2 (C4), 173.5 (C8), 171.7 (C15), 150.3 (C17), 139.3, 137.9 (C20, 23), 132.0 (C25, 28), 128.8, 128.1 (C18, 21, 24, 29), 122.0 (C16, 22), 118.6 (C25), 52.0 (C11), 51.3 (C3), 28.9, 28.5 (C7, 13), 26.3, 26.0 (C6, 12), 24.6 (C2), 7.9 (C1). IR: υ (cm-1) 2953, 1750, 1725, 1589, 1483, 1315, 1194, 1169, 1139, 996, 807. HRMS: (ESI) calcd for C23H25BrNaO5+ [M+Na]+ 483.0778; found 483.0774.

2.98a) (S)-4-ethyl-4-formyl-7-methoxy-7-oxoheptanoic acid

Yield: 95% Aspect: colourless oil Molecular Formula: C11H18O5 HRMS: (ESI) calcd for C11H17O5 [M-H]+ 229.1081; found 229.1079 1

H NMR (400 MHz, CDCl3): δ 9.42 (s, 1H CH 9), 3.67 (s, 3H CH2 2), 2.28-2.19 (m, 4H CH2 5, 11), 1.88-1.83 (m, 4H CH2 4, 10), 1.56 (q, J = 7.5 Hz, 2H CH2 2), 0.84 (t, J = 7.5 Hz, 3H CH2 1).

13

C NMR (100 MHz, CDCl3): δ 205.2 (C9), 178.2 (C6), 173.5 (C15), 52.0 (C15), 51.2 (C13), 28.5, 28.3 (C5, 11), 26.3, 25.8 (C4, 10), 24.6 (C2), 7.9 (C1). IR: υ (cm-1) 2923, 2852, 1730, 1438, 1287, 1177, 785. [ ]

= −2.0 (c 0.2, CHCl3,)

e.r. = 91.5:8.5 determined through the 1-benzyl 7-methyl 4-ethyl-4-formylheptanedioate derivative

215

2.98b) (S)-4-ethyl-4-formyl-7-isopropoxy-7-oxoheptanoic acid

Yield: 75% Aspect: colourless oil Molecular formula: C13H22O5 HRMS: (ESI) calcd for C13H23O5+ [M+H]+ 259.1540; found 259.1551. 1

H NMR (400 MHz, CDCl3): δ 9.41 (s, 1H CH 9), 4.98 (hept, J = 6.3 Hz, 1H CH 16), 2.29-2.22 (m, 2H CH2 5), 2.19-2.13 (m, 2H CH2 12), 1.93-1.75 (m, 4H CH2 4, 11), 1.55 (q, J = 7.6 Hz, 2H CH2 2), 1.22 (d, J = 6.3 Hz, 6H CH3 17, 18), 0.83 (t, J = 7.5 Hz, 3H CH3 1). 13

C NMR (100 MHz, CDCl3): δ 205.3 (C9), 178.6 (C6), 172.7 (C13), 68.3 (C16), 51.2 (C3), 29.0 (C12), 28.4 (C5), 26.4, 25.7 (C4, 11), 24.6(C2), 21.9 (C17, 18), 7.9 (C1). IR: υ (cm-1) 2969, 2882, 1715, 1457, 1377, 1298, 1187, 1107, 940, 784. e.r. = 91.7:8.3 measured on 1-benzyl 7-isopropyl 4-ethyl-4-formylheptanedioate

2.98c) (S)-7-(benzyloxy)-4-ethyl-4-formyl-7-oxoheptanoic acid

Yield: 80 % Aspect: colourless oil Molecular formula: C17H22O5 HRMS: (ESI) calcd for C13H23O5+ [M+H]+ 259.1540; found 259.1551.

216

1

H NMR (400 MHz, CDCl3): δ 9.41 (s, 1H CH 9), 7.48-7.29 (m, 5H CHAr 18-22), 5.11 (s, 2H CH2 16), 2.372.16 (m, 4H CH2 5, 12), 1.99-1.78 (m, 4H CH2 4, 11), 1.55 (q, J = 7.6 Hz, 2H CH2 2), 0.83 (t, J = 7.5 Hz, 3H CH2 1). 13

C NMR (100 MHz, CDCl3): δ 205.2 (C9), 178.1 (C6), 172.9 (C13), 135.8 (C17), 128.7, 128.5, 128.5 (C1822), 66.8 (C16), 51.2 (C3), 28.7, 28.3 (C5, 12), 26.3, 25.8 (C4, 11), 24.6 (C2), 7.8 (C1). IR: υ (cm-1) 2967, 2719, 1725, 1465, 1387, 1173, 964, 914, 746, 699. e.r. = 94.7:5.3 measured on 1-benzyl 7-methyl 4-ethyl-4-formylheptanedioate derivative, for racemic see: 1-benzyl 7-methyl 4-ethyl-4-formylheptanedioate

217

2.100e) Dimethyl 4-formyl-4-phenylheptanedioate

Yield: 15% Aspect: colourless oil Molecular formula: C16H20O5 HRMS: (ESI) calcd for C16H20NaO5+ [M+Na]+ 315.1203; found 315.1201. 1

H NMR (400 MHz, CDCl3): δ 9.53 (s, 1H CH 8), 7.44-7.37 (m 2H CHAr 1, 5), 7.31 (m, 1H CHAr 3), 7.24-7.19 (m, 2H CHAr 2, 4), 3.63 (s, 6H CH3 15, 21), 2.35-2.06 (m, 8H CH2 10, 11, 16, 17).

13

C NMR (100 MHz, CDCl3): δ 201.5 (C8), 173.4 (C12, 18), 137.5 (C6), 129.3, 128.0, 127.5 (C1-5), 56.3 (C7), 51.9 (C15, 21), 28.9 (C11, 17), 27.5 (C10, 16). IR: υ (cm-1) 2953, 1730, 1437, 1260, 1197, 1175, 989, 915, 765, 733, 702.

2.100f) Dimethyl 4-formyl-4-isopropylheptanedioate

Yield: 15 % Aspect: colourless oil Molecular formula: C13H22O5 HRMS: (ESI) calcd for C13H22NaO5+ [M+Na]+ 281.1359; found 281.1361. 1

H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H CH 17), 3.67 (s, 6H CH3 10, 16), 2.36-2.15 (m, 4H CH2 6, 12), 2.021.78 (m, 5H CH2 5, 11 CH 3), 0.98 (d, J = 7.0 Hz, 6H CH2 1, 2). 218

13

C NMR (100 MHz, CDCl3): δ 206.1 (C17), 173.7 (C7, 13), 52.6 (C4), 51.9 (C10, 16), 31.6 (C3), 28.7 (C6, 12), 24.9 (C5, 11), 17.7 (C1, 2). IR: υ (cm-1) 2953, 1729, 1437, 1300, 1260, 1197, 1175, 989, 764, 736, 702.

2.100g) dimethyl 4-(3-(benzyloxy)propyl)-4-formylheptanedioate

Yield: 17% Aspect: colourless oil Molecular formula: C20H28O6 HRMS: (ESI) calcd for C20H28NaO6+ [M+Na]+ 387.1778; found 387.1785. 1

H NMR (400 MHz, CDCl3): δ 9.34 (s, 1H CHAr 13), 7.31-7.20 (m, 5H CHAr 1-5), 4.41 (s, 2H CH2 7), 3.59 (s, 6H CH3 20, 26), 3.34 (t, J = 6.0 Hz, 2H CH2 9), 2.21-2.11 (m, 4H CH2 16, 22), 1.84-1.74 (m, 4H CH2 715, 21), 1.57-1.48 (m, 2H CH2 10, 11), 1.48-1.36 (m, 2H CH2 10, 11). 13

C NMR (100 MHz, CDCl3): δ 204.9 (C13), 173.4 (C17, 23), 138.3 (C6), 128.4, 127.6, 127.6 (C1-5), 73.0 (C7), 70.0 (C9), 51.9 (C20, 26), 50.7 (C12), 28.4, 28.3 (C10, 16, 22), 26.6 (C15, 21), 23.8 (C11) IR: υ (cm-1) 2957, 2862, 1737, 1437, 1199, 1176, 1100.

2.101a) Cis-4a-ethyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione

Yield: 95% 219

Aspect: white crystals Molecular Formula: C10H14O4 HRMS (ESI) calcd for C10H15O4+ [M+H]+ 199.0965; found 199.0967. 1

H NMR (400 MHz, CDCl3): δ 5.62 (s, 1H CH 13), 2.65-2.52 (m, 4H CH2 5, 9), 1.86-1.73 (m, 4H CH2 4, 8), 1.59 (q, J = 7.5 Hz, 2H CH2 2), 0.97 (t, J = 7.5 Hz, 3H CH2 1).

13

C NMR (100 MHz, CDCl3): δ 168.3 (C6, 10), 103.5 (C12), 33.8 (C3), 27.9 (C2), 26.6 (C5, 9), 24.8 (C4, 8), 7.2 (C1). IR: υ (cm-1) 2941, 1749, 1409, 1239, 1151, 1109, 999, 910 722.

2.101b) 4a-(2-(phenylthio)ethyl)tetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)dione

From dimethyl 4-formyl-4-(2-(phenylthio)ethyl)heptanedioate192. Yield: 76% Aspect: viscous yellowish oil Molecular formula: C16H18O4S HRMS: (ESI) calcd for C16H19O4S+ [M+H]+ 307.0999; found 307.1000. 1

H NMR (400 MHz, CDCl3): δ 7.39-7.21 (m, 5H CHAr 1-5), 5.62 (s, 1H CH 17), 2.98-2.87 (m, 2H CH2 8), 2.702.48 (m, 4H CH2 12, 21), 1.94-1.74 (m, 6H CH2 9, 11, 22).

13

C NMR (100 MHz, CDCl3): δ 167.6 (C13, 20), 134.8 (C6), 130.3, 129.3, 127.1 (C1-5), 102.8 (C16), 35.1 (C8), 34.1 (C10), 28.2 (C9), 26.4 (C12, 21), 25.3 (C11, 22). IR: υ (cm-1) 2931, 1752, 1582, 1439, 1198, 1115, 1013, 912, 742, 693.

220

2.101c) 4a-allyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione

From dimethyl 4-allyl-4-formylheptanedioate191. Yield: 70% Aspect: viscous oil

Molecular formula: C11H14O4 HRMS: (ESI) calcd for C11H15O4+ [M+H]+ 211.0965; found 211.0961. 1

H NMR (400 MHz, CDCl3): δ 5.87-5.70 (m, 1H CH 14), 5.65 (s, 1H CH 16), 5.30-5.20 (m, 2H CH 15), 2.702.57 (m, 4H CH2 2, 8), 2.31 (d, J = 7.3 Hz, 2H CH2 13), 1.91-1.79 (m, 4H CH2 3, 7).

13

C NMR (100 MHz, CDCl3): δ 168.3 (C1, 9), 130.5 (C14), 121.4 (C15), 103.0 (C5), 40.0 (C13), 34.0 (C4), 26.6 (C2, 8), 25.5 (C3, 7). IR: υ (cm-1) 2936, 1756, 1460, 1401, 1350, 1193, 1146, 1115, 1012, 922.

2.101d) 4a-vinyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione

From dimethyl 4-formyl-4-vinylheptanedioate192. Yield: 76% Aspect: viscous oil 191 192

G. Costello, J. Edwin Saxton, Tetrahedron 1986, 42, 6047-6069. J. W. Blowers, J. Edwin Saxton, A. G. Swanson, Tetrahedron 1986, 42, 6071-6095.

221

Molecular formula: C10H12O4 HRMS: (ESI) calcd for C10H12NaO4+ [M+Na]+ 219.0628; found 219.0624. 1

H NMR (400 MHz, CDCl3): δ 5.90-5.79 (m, 2H CH 2 CH 13), 5.43 (d, J = 11.1 Hz, 1H CH2 1), 5.38 (d, J = 17.6 Hz, 1H CH2 1), 2.66 (t, J = 7.3 Hz, 4H CH2 5, 9), 2.05-1.95 (m, 2H CH2 4, 8), 1.94-1.82 (m, 2H CH2 4, 8). 13

C NMR (100 MHz, CDCl3): δ 167.5 (C 6, 10), 137.8 (C2), 117.4 (C11), 102.1 (C12), 36.8 (C3), 26.6 (C5, 9), 25.9 (C4, 8). IR: υ (cm-1) 2937, 2342, 1749, 1478, 1400, 1345, 1127, 1006, 917.

2.101e) 4a-phenyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione

Yield: 85% Aspect: viscous yellowish oil Molecular formula: C14H14O4 HRMS: (ESI) calcd for C14H15O4+ [M+H]+ 247.0965; found 247.0974. 1

H NMR (400 MHz, CDCl3): δ 7.48-7.30 (m, 5H CHAr 1-5), 6.38 (s, 1H CH 14), 2.73-2.65 (m, 2H CH2 18, 9), 2.53-2.44 (m, 2H CH2 18, 9), 2.34-2.26 (m, 2H CH2 8, 19), 2.23-2.12 (m, 2H CH2 8, 19). 13

C NMR (100 MHz, CDCl3): δ 167.4 (C10, 16), 140.4 (C7), 129.7, 128.2, 125.6 (C 1-5), 101.8 (C13), 38.7 (C7), 28.6 (C9, 18), 27.2 (C8, 19). IR: υ (cm-1) 2948, 1759, 1400, 1396, 1239, 1121, 1008, 766, 703.

222

2.101f) 4a-isopropyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione

Yield: 80 % Aspect: viscous oil Molecular formula: C11H16O4 HRMS: (ESI) calcd for C11H17O4+ [M+H]+ 213.1121; found 213.1123. 1

H NMR (400 MHz, CDCl3): δ 5.81 (s, 1H CH 6), 2.71-2.51 (m, 4H CH2 10, 13), 2.01-1.85 (m, 4H CH2 11, 12), 1.69 (dt, J = 14.4, 7.8 Hz, 2H CH 3), 1.00 (d, J = 6.8 Hz, 6H CH3 1, 2).

13

C NMR (100 MHz, CDCl3): δ 168.6 (C8, 14), 101.8 (C5), 37.0 (C4), 30.3 (C3), 27.0 (C10, 13), 23.4 (C11, 12), 16.8 (C1, 2). IR: υ (cm-1) 2960, 1754, 1412, 1241, 1136, 1074, 1005, 980, 950.

2.101g) 4a-(3-(benzyloxy)propyl)tetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)dione

Yield: 70%

223

Aspect: colourless oil Molecular formula: C20H28O6 HRMS: (ESI) calcd for C18H23O5+ [M+H]+ 319.1540; found 319.1539. 1

H NMR (400 MHz, CDCl3): δ 7.41-7.29 (m, 5H CHAr 1-5), 5.62 (s, 1H C19), 4.50 (s, 2H CH2 7), 3.56-3.43 (m, 2H CH2 9), 2.69-2.53 (m, 4H CH2 14, 23), 1.91-1.73 (m, 4H CH2 13, 24), 1.69-1.62 (m, 4H CH2 10, 11).

13

C NMR (100 MHz, CDCl3): δ 168.1 (C15, 21), 138.2 (C6), 128.6, 127.9, 127.8 (C1-5), 103.5 (C18), 73.4 (C7), 69.8 (C9), 33.7 (C12), 32.1 (C10), 26.7 (C14, 23), 25.4 (C13, 24), 23.6 (C11). IR: υ (cm-1) 2943, 2864, 1758, 1496, 1363, 1146, 1100, 1008

2.101h) 4a-methyl-8a-phenyltetrahydropyrano [2,3-b]pyran-2,7(3H,8aH)dione

A solution of 4-benzoyl-4-methylheptanedioic acid193 (1.14 g, 4.1 mmol, 1 equiv) and sodium bicarbonate (1.4 g, 16.4 mmol, 4 equiv) in acetic anhydride (40 mL, c = 0.1 M) was heated at 80 °C until no starting material remained. The acetic anhydride was evaporated and the mixture was partitioned between AcOEt and aq NaHCO3, the aqueous phase was extracted with AcOEt. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated. The residue was then recrystallized in AcOEt to yield 4a-methyl-8a-phenyltetrahydropyrano [2,3-b]pyran-2,7(3H,8aH)-dione as white crystals. Yield: 54% Aspect: white crystals Molecular formula: C15H16O4 HRMS: (ESI) calcd for C15H17O4+ [M+H]+ 261.1121; found 261.1114. 1

H NMR (400 MHz, CDCl3): δ 7.47-7.37 (m 3H CHAr 16-18), 7.35-7.27 (m, 2H CHAr 15, 19), 3.00-2.76 (m, 4H CH2 4, 10), 2.00-1.87 (m, 2H CH2 3, 9), 1.79-1.6 (m, 2H CH2 3, 9), 1.05 (s, 3H CH3 1).

193

H. A. Bruson, T. W. Riener, J. Am. Chem. Soc. 1942, 64, 2850-2858.

224

13

C NMR (100 MHz, CDCl3): δ 168.4 (C5, 11), 136.2 (C14), 129.7, 128.2, 126.9 (C15-19), 110.8 (C8), 34.1 (C2), 27.8 (C4, 10), 26.8 (C3, 9), 23.0 (C1). IR: υ (cm-1) 2959, 1743, 1423, 1262, 1080, 1018, 972, 763, 704.

2.101j) 8a-methyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione

To a solution of di-tert-butyl 4-acetylheptanedioate194 (1.3 g, 4.1 mmol 1 equiv) in DCM (32 ml, 0.13 M) is added TFA (8 ml). The reaction solution is stirred untill full conversion of the starting material and then concentrated under vacuum. The residue is then suspended in Ac2O (40 ml, 0.1M) and NaHCO3 (1.4 g, 16.4 mmol, 4 equiv) is added. The suspention is stirred at 80°C till disapearance of the intermediate. The solution is then concentrated under vacuuo and the residue purified by FCC (PE/AcOEt, 6/4) to yield pure 8a-methyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione (30%). Yield: 30% Aspect: White solid Molecular formula: C9H12O4 HRMS: calcd for C9H13O4+ [M+H]+ 185.0808; found 185.0810. 1

H NMR (400 MHz, CDCl3): δ 2.74-2.54 (m, 4 H CH2 5, 12), 2.34-2.25 (m, 1 H CH 3), 2.10-1.99 (m, 2H CH2 4, 13), 1.98-1.84 (m, 2H CH24, 13), 1.74 (s, 3H CH3 1). 13

C NMR (100 MHz, CDCl3): δ 168.1 (C6, 10), 107.5 (C2), 33.6 (C3), 27.5 (C5, 12), 26.9 (C4, 13), 21.3 (C1).

IR: υ (cm-1) 2967, 1734, 1202, 1137, 1046, 932.

194

Y. Hirayama, T. Nakamura, S. Uehara, Y. Sakamoto, K. Yamaguchi, Y. Sei, M. Iwamura, Org. Lett. 2005, 7, 525528.

225

2.101l) (4as,8ar)-benzyl 8a-methyl-2,7-dioxooctahydropyrano[2,3-b]pyran4a-carboxylate

To a solution of 3-benzyl 1,5-di-tert-butyl 3-acetylpentane-1,3,5-tricarboxylate194 (1g, 2.05 mmol 1 equiv) in DCM (16 ml, 0.13 M) is added TFA (4 ml). The reaction solution is stirred until full conversion of the starting material and then concentrated under vacuum. The residue is then suspended in Ac2O (20 ml, 0.1M) and NaHCO3 (689 mg, 8.2 mmol, 4 equiv) is added. The suspention is stirred at 80°C till disapearance of the intermediate. The solution is then concentrated under vacuuo and the residue purified by FCC (PE/AcOEt, 6/4) to yield (4as,8ar)-benzyl 8a-methyl-2,7-dioxooctahydropyrano[2,3b]pyran-4a-carboxylate (45%). Yield: 45% Aspect: White solid Molecular formula: C17H18O6 HRMS: calcd for C17H18NaO6 [M+Na] 341.1001; found 341.0997. 1

H NMR (400 MHz, CDCl3): δ 7.46-7.30 (m, 5H CHAr 9-13), 5.21 (s, 2H CH2 7), 2.86-2.63 (m, 4H CH2 15, 22), 2.42-2.28 (m, 2H CH2 14, 23), 2.03-1.89 (m, 2H CH2 14, 23), 1.63 (s, 3H CH3 1).

13

C NMR (100 MHz, CDCl3): δ 171.0 (C 4), 167.7 (C20), 134.5 (C8), 129.1, 129.0, 128.8 (C9-13), 106.0 (C2), 68.5 (C7), 45.0 (C3), 26.0 (C15, 22), 24.5 (C1), 24.0 (C14, 23). IR: υ (cm-1) 2934, 1748, 1731, 1218, 956, 740.

2.111a) (R)-4-formyl-4-isopropyl-7-methoxy-7-oxoheptanoic acid (2f)

Yield: 82% 226

Aspect: colourless oil Molecular formula: C12H20O5 HRMS: (ESI) calcd for C12H21O5+ [M+H]+ 245.1384; found 245.1376. 1

H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H CH 16), 3.67 (s, 3H CH3 15), 2.47-2.14 (m, 4H CH2 6, 10), 2.041.75 (m, 5H CH 3 CH2 5, 10), 0.98 (d, J = 7.0 Hz, 6H CH3 1, 2). 13

C NMR (100 MHz, CDCl3): δ 206.1 (C16), 178.6 (C7), 173.8 (C12), 52.6 (C4), 52.0 (C15), 31.6 (C3), 28.7, 28.6 (C6, 11), 24.9, 24.5 (C5, 10), 17.7, 17.6 (C1, 2). IR: υ (cm-1) 2961, 1713, 1438, 1376, 1293, 1179. e.r. = 92.5:7.5; determined on 1-benzyl 7-methyl 4-formyl-4-isopropylheptanedioate

2.111b) (R)-4-formyl-7-methoxy-7-oxo-4-vinylheptanoic acid

Yield: 94% Aspect: colourless oil Molecular formula: C11H16O5 HRMS: (ESI) calcd for C11H16NaO5+ [M+Na]+ 251.0890; found 251.0901. 1

H NMR (400 MHz, CDCl3): δ 9.40 (s, 1H CH 9), 5.72 (dd, J = 18.1, 11.0 Hz, 1H (CH 2), 5.43 (dd, J = 11.1, 1.5 Hz, 1H CHcis 1), 5.20 (dd, J = 18.1, 1.5 Hz, 1H CHtrans 1), 3.67 (s, 3H CH3 16), 2.38-2.19 (m, 4H CH2 5, 12), 2.08-1.91 (m, 4H CH2 4, 11). 13

C NMR (100 MHz, CDCl3): δ 201.6 (C9), 177.8 (C6), 173.5 (C13), 136.0 (C2), 119.2 (C1), 54.8 (C16), 52.0 (C3), 28.8, 28.6 (C5, 12), 27.7, 27.2 (C4, 11). IR: υ (cm-1) 2934, 2358, 1733, 1439, 1296, 1175, 1005, 914.

E.r = 91: 9 determined on 1-benzyl 7-methyl 4-formyl-4-vinylheptanedioate

227

2.111c) (R)-4-formyl-4-(3-methoxy-3-oxopropyl)hept-6-enoic acid

Yield: 95% Aspect: colourless oil Molecular formula: C12H18O5 HRMS: (ESI) calcd for C12H17O5 [M+] 241.1076; found 241.1084. 1

H NMR (400 MHz, CDCl3): δ 9.40 (s, 1H CH 5), 5.73-5.59 (m, 1H CH 2), 5.16-5.12 (m, 2H CH2 1), 3.67 (s, 3H CH3 16), 2.34-2.19 (m, 6H CH2 3, 7, 12), 1.96-1.79 (m, 4H CH2 6, 11). 13

C NMR (100 MHz, CDCl3): δ 204.6 (C5), 178.5 (C8), 173.4 (C13), 131.6 (C2), 119.7 (C1), 52.0 (C16), 50.9 (C4), 36.2 (C3), 28.5, 28.3 (C7, 12), 27.1, 26.6 (C6, 11). IR: υ (cm-1) 2930, 2852, 1731, 1432, 1307, 1179, 1005, 924.

e.r. = 91.2:8.8 determind on 1-benzyl 7-methyl 4-allyl-4-formylheptanedioate

2.111d) (R)-4-formyl-7-methoxy-7-oxo-4-(2-(phenylthio)ethyl)heptanoic acid

Yield: 91% Aspect: colourless oil

228

Molecular formula: C17H22O5S HRMS: (ESI) calcd for C17H23O5S+ [M+H]+ 339.1261; found 339.1260. 1

H NMR (400 MHz, CDCl3): δ 9.40 (s, 1H CH 11), 7.38-7.27 (m, 4H CHAr 1, 2, 4, 5), 7.25-7.18 (m, 1H CHAr 3), 3.67 (s, 3H CH3 18), 2.86-2.65 (m, 2H CH2 8), 2.32-2.09 (m, 4H CH2 14, 20), 1.95-1.76 (m, 6H CH2 9, 13, 19).

13

C NMR (100 MHz, CDCl3): δ 203.9 (C11), 177.8 (C21), 173.2 (C15), 135.3 (C6), 130.1, 129.3, 126.9 (C1-5), 52.1 (C18), 51.2 (C10), 31.8 (C8), 28.5, 28.3, 28.1 (C9, 14, 20), 26.6, 26.1 (C13, 19). IR: υ (cm-1) 2943, 1730, 1439, 1300, 1201, 1175, 742. [ ]

= 0.45 (c 0.2, CHCl3)

e.r. = 93.2:6.8

229

2.111e) (R)-4-formyl-7-methoxy-7-oxo-4-phenylheptanoic acid

Yield: 90% Aspect: colourless oil Molecular formula: C15H18O5 HRMS: (ESI) calcd for C15H18NaO5+ [M+Na]+ 301.1046; found 301.1041 230

1

H NMR (400 MHz, CDCl3): δ 9.54 (s, 1H C8), 7.43-7.36 (m, 2H CHAr 1, 5), 7.36-7.29 (m, 1H CHAr 3), 7.247.17 (m, 2H CHAr 2, 4), 3.63 (s, 3H CH3 15), 2.44-2.07 (m, 8H CH2 10, 11, 16, 17).

13

C NMR (100 MHz, CDCl3): δ 201.3 (C8), 177.6 (C18), 173.3 (C12), 137.3 (C6), 129.3, 128.0, 127.4 (C1-5), 56.1 (C7), 51.9 (C15), 28.8, 28.6 (C11, 17), 27.4, 27.2 (C10, 16). IR: υ (cm-1) 2932, 1726, 1436, 1301, 1201, 702, 649. [ ]

= 0.5 (c 0.2, CHCl3,)

e.r. = 96.3:3.7

231

2.111f) (S)-4-(3-(benzyloxy)propyl)-4-formyl-7-methoxy-7-oxoheptanoic acid

Yield: 95% Aspect: colourless oil Molecular formula: C19H26O6 232

HRMS: (ESI) calcd for C19H26NaO6+ [M+Na]+ 373.1622; found 373.1623. 1

H NMR (400 MHz, CDCl3): δ 9.41 (s, 1H C13), 7.45-7.28 (m, 5H CHAr 1-5), 4.49 (s, 2H CH2 7), 3.66 (s, 3H CH2 20), 3.45 (t, J = 6.0 Hz, 2H CH2 9), 2.29-2.17 (m, 4H CH2 16, 22), 1.92-1.81 (m, 4H CH2 15, 21), 1.66-1.55 (m, 2H CH2 10), 1.55-1.43 (m, 2H CH2 11). 13

C NMR (100 MHz, CDCl3): δ 204.9 (C13), 178.2 (C23), 173.5 (C17), 138.4 (C6), 128.5, 127.8, 127.7 (C1-5), 73.1 (C7), 70.0 (C9), 52.0 (C20), 50.7 (C12), 28.5, 28.5, 28.3 (C10, 16, 22), 26.7, 26.2 (C15, 21), 23.8 (C11). IR: υ (cm-1) 2949, 2862, 1733, 1455, 1292, 1178, 1102, 741, 700 e.r. = 94.7:5.3 determined on 1-(4'-bromo-[1,1'-biphenyl]-4-yl) 7-methyl 4-(3-(benzyloxy)propyl)-4formylheptanedioate. [ ]

= −2.6 (c 0.2, CHCl3,)

2.111g) (S)-4-benzoyl-7-methoxy-4-methyl-7-oxoheptanoic acid

Yield: 66% Aspect: colourless oil Molecular formula: C16H20O5 HRMS: calcd for C16H20NaO5+ [M+Na]+ 315.1203; found 315.1198. 1

H NMR (400 MHz, CDCl3): δ 7.75-7.63 (m, 2H CHAr 6, 10), 7.55-7.45 (m, 1H CHAr 8), 7.45-7.35 (m, 2H CHAr 7, 9), 3.63 (s, 3H CH2 19), 2.40-2.14 (m, 6H CH2 11, 12, 17, 18), 2.10-1.88 (m, 2H CH2 17, 11), 1.29 (s, 3H CH3 1). 13

C NMR (100 MHz, CDCl3): δ 207.0 (C3), 178.9 (C19), 173.7 (C13), 138.6 (C5), 131.6, 128.6, 127.6 (C6-10), 51.9 (C16), 50.1 (C2), 33.9, 33.6 (C12, 18), 29.4, 29.4 (C11, 17), 22.7 (C1). IR: υ (cm-1) 3000, 2952, 1733, 1669, 1200, 1176, 913, 729. e.r. = 90.7:9.3 determined on 1-(4'-bromo-[1,1'-biphenyl]-4-yl) 7-methyl 4-benzoyl-4methylheptanedioate 233

2.111h) 4-acetyl-7-methoxy-7-oxoheptanoic acid

Yield: 69% Aspect: clear oil Molecular formula: C18H22O7 HRMS: calcd for C10H16NaO5+ [M+Na]+ 239.0890; found 239.0887. 1

H NMR (400 MHz, CDCl3): δ 3.66 (s, 3H CH3 10), 2.76-2.49 (m, 1H CH 4), 2.46-2.22 (m, 4 H CH2 6, 12), 2.17 (s, 3 H CH3 1), 2.03-1.86 (m, 2 H CH2 5, 11), 1.86-1.64 (m, 2 H CH2 5, 11). 13

C NMR (100 MHz, CDCl3): δ 211.3 (C3), 178.5 (C13), 173.5 (C7), 51.8 (C10), 50.8 (C4), 31.8, 31.4 (C6, 12), 29.1 (C1), 25.8, 25.7 (C5, 11). IR: υ (cm-1) 2956, 1733, 1709, 1441, 1359, 1164.

2.111l) 4-acetyl-4-((benzyloxy)carbonyl)-7-methoxy-7-oxoheptanoic acid

Yield: 56% Aspect: clear oil Molecular formula: C18H22O7 HRMS: calcd for C18H21O7 [M+H-1] 349.1287; found 349.1296. 1

H NMR (400 MHz, CDCl3): δ 7.47-7.29 (m, 5H CHAr), 5.17 (s, 2 H CH2 7), 3.65 (s, 3H CH3 19), 2.30-2.08 (m, 8H CH2 14, 15, 20, 21), 2.07 (s, 3H CH3 6).

234

13

C NMR (100 MHz, CDCl3): δ 204.4 (C2), 178.1 (22), 173.4 (C16), 171.5 (C4), 135.1 (C8), 128.8, 128.8, 128.7 (C9-13), 67.5 (C7), 62.2 (3), 52.0 (C19), 29.0, 28.7 (C15, 21), 26.8 (C6), 26.7, 26.6 (C14, 20). IR: υ (cm-1) 2955, 2359, 1737, 1711, 1439 1177, 985.

2.41) (R)-1-benzyl 7-methyl 4-ethyl-4-formylheptanedioate and (S)-1-benzyl 7-methyl 4-ethyl-4-formylheptanedioate

Yield: 84% Aspect: colourless oil Molecular Formula: C18H24O5 HRMS: (ESI) calcd for C18H25O5+ [M+H]+ 321.1697; found 321.1693. 1

H NMR (400 MHz, CDCl3): δ 9.40 (s, 1H CH 9), 7.37-7.32 (m, 5H CHAr 11-15), 5.11 (s, 2H CH2 9), 3.66 (s, 3H CH3 22), 2.27-2.18 (m, 4H CH2 5, 18), 1.88-1.82 (m, 4H CH2 4, 17), 1.54 (q, J = 7.5 Hz, 2H CH2 2), 0.82 (t, J = 7.5 Hz, 3H CH2 1). 13

C NMR (100 MHz, CDCl3): δ 205.2 (C9), 173.5 (C19), 172.9 (C6), 135.8 (C10), 128.7, 128.5, 128.4 (C1115), 66.7 (C9), 52.0 (C22), 51.2 (C6), 28.7, 28.5 (C5, 18), 26.2, 26.1 (C4, 17), 24.5 (C2), 7.9 (C1). IR: υ (cm-1) 2921, 2365, 1730, 1456, 1170, 990, 737, 699. (R)-1-benzyl 7-methyl 4-ethyl-4-formylheptanedioate [ ] (S)-1-benzyl 7-methyl 4-ethyl-4-formylheptanedioate [ ]

= −3.2 (c 0.2, CHCl3,) = 3.0 (c 0.2, CHCl3)

235

236

2.41b) (S)-1-benzyl 7-isopropyl 4-ethyl-4-formylheptanedioate

Yield: 86% Aspect: colourless oil Molecular formula: C20H28O5 HRMS: (ESI) calcd for C20H29O5+ [M+H]+ 349.2010; found 349.2013. 1

H NMR (400 MHz, CDCl3): δ 9.41 (s, 1H CH 9), 7.45-7.29 (m, 5H CHAr 23-27), 5.11 (s, 2H CH2 20), 4.98 (hept, J = 6.2 Hz, 1H CH 16), 2.37-2.22 (m, 2H CH2 5), 2.22-2.10 (m, 2H CH2 12), 1.93-1.78 (m, 4H CH2 4, 12), 1.54 (q, J = 7.6 Hz, 2H CH2 2), 1.22 (d, J = 6.3 Hz, 6H CH3 17, 18), 0.82 (t, J = 7.5 Hz, 3H CH3 1).

13

C NMR (100 MHz, CDCl3): δ 205.4 (C9), 173.0 (C6), 172.6 (C13), 135.9 (C22), 128.7, 128.5, 128.4 (C2327), 68.2 (C16), 66.7 (C20), 51.3 (C3), 29.0, 28.7 (C5, 12), 26.3, 26.1 (C4, 11), 24.5 (C2), 21.9 (C17, 18), 7.9 (C1). IR: υ (cm-1) 2976, 2927, 1728, 1456, 1378, 1260, 1179, 1109, 964, 750, 699. [ ]

= −1.3 (c 0.2, CHCl3,)

237

238

2.41c) (S)-1-benzyl 7-methyl 4-formyl-4-vinylheptanedioate

Yield: 86% Aspect: colourless oil Molecular formula: C18H22O5 HRMS: (ESI) calcd for C18H23O5+ [M+H]+ 319.1540; found 319.1538. 1

H NMR (400 MHz, CDCl3): δ 9.39 (s, 1H CH 9), 7.47-7.28 (m, 5H CHAr 19-23), 5.71 (dd, J = 17.9, 11.0 Hz, 1H CH 2), 5.39 (d, J = 11.0 Hz, 1H CHcis 1), 5.18 (d, J = 17.9 Hz, 1H CHtrans 1), 5.10 (s, 2H CH2 17), 3.66 (s, 3H), 2.42-2.15 (m, 4H CH2 5, 12), 2.10- 1.88 (m, 4H CH2 4, 11). 13

C NMR (100 MHz, CDCl3): δ 201.6 (C9), 173.5 (C13), 172.9 (C6), 136.1 (C1), 135.8 (C18), 128.7, 128.5, 128.5 (C19-23), 119.1 (C2), 66.7 (C17), 54.8 (C16), 51.9 (C3), 29.0, 28.8 (C5, 12), 27.7, 27.6 (C4, 11). IR: υ (cm-1) 2957, 1730, 1438, 1259, 1168, 1084, 1011, 793, 750, 699. [ ]

= −3 (c 0.2, CHCl3,)

239

240

2.41d) (S)-1-benzyl 7-methyl 4-allyl-4-formylheptanedioate

Yield: 82% Aspect: colourless oil Molecular formula: C19H24O5 HRMS: (ESI) calcd for C19H24NaO5+ [M+Na]+ 355.1516; found 355.1517. 1

H NMR (400 MHz, CDCl3): δ 9.44 (s, 1H CH 5), 7.43-7.29 (m, 5H CHAr 13-17), 5.73-5.58 (m, 1H CH 2), 5.18-5.07 (m, 4H CH2 1, 11), 3.66 (s, 3H CH3 24), 2.35-2.18 (m, 6H CH2 3, 7, 20), 1.96-1.79 (m, 4H CH2 6, 19). 13

C NMR (100 MHz, CDCl3): δ 204.6 (C5), 173.4 (C21), 172.8 (C8), 135.8 (C12), 131.8 (C2), 128.7, 128.5, 128.5 (C13-17), 119.6 (C1), 66.7 (C11), 52.0 (C24), 51.0 (C4), 36.1 (C3), 28.7, 28.5 (C7, 20), 27.0, 27.0 (C6, 19). IR: υ (cm-1) 2921, 2851, 1732, 1456, 1438, 1303, 1171, 1001, 924. [ ]

= −2.6 (c 0.2, CHCl3,)

241

242

2.41e) (S)-1-benzyl 7-methyl 4-formyl-4-isopropylheptanedioate

Yield: 85% Aspect: colourless oil Molecular formula: C19H26O5 HRMS: (ESI) calcd for C19H27O5+ [M+H]+ 335.1853; found 335.1849. 1

H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H CH 17), 7.43-7.29 (m, 5H CHAr 12-16), 5.11 (s, 2H CH2 10), 3.66 (s, 3H CH3 24), 2.47-2.14 (m, 4H CH2 6, 20), 2.04-1.72 (m, 5H CH 3 CH2 5, 19), 0.97 (d, J = 7.0 Hz, 6H CH3 1, 2).

13

C NMR (100 MHz, CDCl3): δ 206.0 (C17), 173.7 (C21), 171.6 (C7), 135.9 (C11), 128.7, 128.4, 128.4 (C1216), 66.7 (C10), 52.6 (C4), 51.9 (C24), 31.6 (3), 28.9, 28.7 (C6, 20), 24.9, 24.8 (C5, 20), 17.7 (C1, 2). IR: υ (cm-1) 2957, 1735, 1469, 1376, 1300, 1258, 1171, 991. [ ]

= −6.9 (c 0.2, CHCl3,)

243

244

2.41f) (R)-1-(4'-bromo-[1,1'-biphenyl]-4-yl) 7-methyl 4-(3(benzyloxy)propyl)-4-formylheptanedioate

Yield: 82% Aspect: colourless oil Molecular formula: C31H33O6Br HRMS: (ESI) calcd for C31H33BrNaO6+ [M+Na]+ 603.1353; found 603.1370. 1

H NMR (400 MHz, CDCl3): δ 9.47 (s, 1H CH 13), 7.55 (m, 4H CHAr 28, 30, 33, 36), 7.42 (d, 2H, J = 8.4 Hz CHAr 32, 27), 7.38-7.27 (m, 5H CHAr 1-5), 7.14 (d, 2H, J = 8.6 Hz CHAr 27, 31), 4.50 (s, 2H CH2 7), 3.68 (s, 3H CH3 20), 3.48 (t, 2H, J = 6.0 Hz CH2 9), 2.54-2.47 (m, 2H CH2 22), 2.31-2.23 (m, 2H CH2 16), 2.03-1.89 (m, 4H CH2 15, 21), 1.73-1.63 (m, 2H CH2 C10), 1.61-1.50 (m, 2H C11). 13

C NMR (100 MHz, CDCl3): δ 204.9 (C13), 173.4 (C17), 171.6 (C23), 150.3 (C26), 139.4, 138.4, 138.0 (C26, 29, 35), 132.1 (C33, 36), 128.8, 128.6, 128.2, 127.8, 127.7 (C1-5, 28, 30, 32, 37), 122.1 (C27, 31), 121.8 (C34), 73.2 (C7), 70.1 (C9), 52.0 (C20), 50.9 (C12), 28.9, 28.5, 28.5 (C10, 16, 22), 26.8, 26.5 (C15, 21),, 23.9 (C11). IR: υ (cm-1) 2950, 2858, 2362, 2338, 1735, 1481, 1205, 1168, 1139, 1005

245

246

2.41g) (R)-1-(4'-bromo-[1,1'-biphenyl]-4-yl) 7-methyl 4-benzoyl-4methylheptanedioate

Yield: 66% Aspect: colourless oil Molecular formula: C28H27BrO5 HRMS: calcd for C28H27BrNaO5+ [M+Na]+ 545.0934; found 545.0931. 1

H NMR (400 MHz, CDCl3): δ 7.77-7.68 (m, 2H CHAr 20, 33), 7.61-7.36 (m, 9H CHAr 6-10, 24, 26, 29, 34), 7.17-7.07 (m, 2H CHAr 23, 27), 3.65 (s, 3H CH2 16), 2.71-2.48 (m, 2H CH2 18), 2.48-2.23 (m, 4H CH2 11, 12, 17), 2.22-1.96 (m, 2H CH2 11, 17), 1.43-1.34 (m, 3H). 13

C NMR (100 MHz, CDCl3): δ 207.0 (C3), 173.7 (C13), 171.8 (C19), 150.4 (C22), 139.4, 138.6, 137.9 (C5, 25, 28), 132.0 (C30, 33), 131.7, 128.8, 128.6, 128.1, 127.7 (C6-10, 24, 26, 29, 34), 122.1 (C23, 27), 121.8 (C31), 51.9 (C16), 50.2 (C2), 34.0, 33.8 (C12, 18), 29.9, 29.5 (C11, 17), 22.9 (C1). IR: υ (cm-1) 2917, 1735, 1671, 1481, 1168, 1004, 730. [ ]

= −9.1 (c 0.2, CHCl3)

247

248

2.41h) 1-benzyl 7-methyl 4-acetylheptanedioate

Yield: 95% Aspect: clear oil Molecular formula: C17H22O5 HRMS: calcd for C17H23O5+ [M+H]+ 307.1540; found 307.1542. 1

H NMR (400 MHz, CDCl3): δ 7.43-7.28 (m, 5H CHAr 18-22), 5.11 (s, 2H CH2 16), 3.66 (s, 3H CH3 10), 2.612.50 (m, 1H CH 4), 2.46-2.18 (m, 4H CH2 6, 12), 2.15 (s, 3H CH3 1), 2.05-1.87 (m, 2H CH2 5, 11), 1.84-1.66 (m, 2H CH2 165, 11). 13

C NMR (100 MHz, CDCl3): δ 211.0 (C3), 173.5 (C7), 172.8 (C13), 135.9 (C17), 128.7, 128.5, 128.4 (C1822), 66.5 (C16), 51.8 (C10), 50.8 (4), 31.7, 31.5 (C6, 12), 29.4 (C1), 25.9 (C5,11). IR: υ (cm-1) 2954, 1734, 1711, 1437, 1359, 1155.

249

250

2.41i) 3-benzyl 1-(4'-bromo-[1,1'-biphenyl]-4-yl) 5-methyl 3-acetylpentane1,3,5-tricarboxylate

Yield: 64% Aspect: colourless oil Molecular formula: C30H29BrO7 HRMS: calcd for C30H29BrNaO7+ [M+Na]+ 603.0989; found 603.0999. 1

H NMR (400 MHz, CDCl3): δ 7.63-7.51 (m, 4H CHAr 33, 36, 27, 29), 7.47-7.38 (m, 2H CHAr 32, 37), 7.407.32 (m, 5H CHAr 9-13), 7.18-7.10 (m, 2H CHAr 26, 30), 5.21 (s, 2H CH2 7), 3.67 (s, 3H CH2 19), 2.55-2.2 (m, 8H CH2 14, 15, 20, 21),2.12 (s, 3H CH2 6). 13

C NMR (100 MHz, CDCl3): δ 204.1 (C2), 173.0 (C16), 171.4 (C4), 171.2 (C22), 150.3 (C25), 139.3, 137.9, 135.0 (C8, 28, 31), 132.0 (33, 36), 128.8, 128.8, 128.7, 128.1, 122.1 (C9-13, 27, 29, 32, 37), 121.8 (C34), 67.7 (C7), 62.0 (C3), 52.0 (C19), 29.3, 28.9 (C15, 21), 27.0, 26.9 (C14, 20), 26.6 (C6). IR: υ (cm-1) 2922, 2360, 1737, 1709, 1482, 1206, 1169.

251

252

2.41j) 1-benzyl 7-methyl 4-(1,3-dioxolan-2-yl)-4-ethylheptanedioate

To a solution of 4-(1,3-dioxolan-2-yl)-4-ethyl-7-methoxy-7-oxoheptanoic acid (28.8 mg, 0.1 mmol, 1 equiv) and benzyl alcohol (21 μl, 0.2 mmol, 2 equiv) and DMAP (12.2 mg, 0.15 mmol, 1.5 equiv) in DCM (0.4 ml, c = 0.25 M) was added EDC (as HCl salt) (23 mg, 0.12 mmol, 1.2 equiv). The mixture was stirred for 2 hours before being partitioned between AcOEt and NH4Cl aq, the organic phase was washed with NaHCO3, brine, dried and concentrated. The residue was purified by FCC PE: AcOEt 9:1 to yield 1benzyl 7-methyl 4-(1,3-dioxolan-2-yl)-4-ethylheptanedioate as a clear oil ( 30.2 mg, 84%) Molecular Formula: C20H28O6 HRMS: calcd for C20H29O6+ [M+H]+ 365.1959; found 365.1975. 1

H NMR (400 MHz, CDCl3): δppm = 7.33-7.22 (m, 5 H CHAr 22-26), 5.04 (s, 2 H CH2 20), 4.52 (s, 1 H CH2 4), 3.88-3.78 (m, 2 H CH2 6, 7), 3.76-3.68 (m, 2 H CH2 6, 7), 3.58 (s, 3 H CH3 14), 2.39-2.27 (m, 2 H CH2 10, 16), 1.70-1.60 (m, 4 H CH2 9, 15), 1.35 (q, J = 7.5 Hz, 2 H CH2 2), 0.80 (t, J = 7.5 Hz, 3 H CH2 1). 13

C NMR (100 MHz, CDCl3): δppm = 174.7 (C11), 174.1 (C17), 136. 1 (C21), 128.7, 128.4 128.2 (C22-26), 108.5 (C4), 66.3 (C20), 64.8 (C6, 7), 51.7 (C14), 40.5 (C3), 29.3, 29.1 (C10, 16), 28.2, 28.1 (C9, 15), 25.8 (C2), 7.8 (C1). IR: υ (cm-1) = 2952, 2881, 2356, 2342, 1737, 1457, 1259, 1172, 1104, 1000, 616.

253

2.120) 3-benzoyl-5-(benzyloxy)-5-oxopentanoic acid

From 6a-phenyldihydrofuro[2,3-b]furan-2,5(3H,6aH)-dione195 Yield: 47% (88% BRSM) Aspect: clear oil Molecular formula: C19H18O5 HRMS: (ESI) calcd for C19H17O5 [M+] 325.1076; found 325.1078. 1

H NMR (400 MHz, CDCl3): δ 8.04-7.92 (m, 2 H CHAr 1, 5), 7.63-7.53 (m, 1 H CHAr 3), 7.53-7.42 (m, 2 H CHAr 2, 4), 7.42-7.22 (m, 5 H CHAr 20-24), 5.09 (d, 1H, J = 12.3 Hz CH2 18), 5.05 (d, 1H, J = 12.3 Hz CH2 18), 4.31 (quint, 1 H, J = 6.9 Hz CH 9), 2.89 (m, 2 H CH2 10, 14), 2.51-2.64 (m, 2 H CH2 10, 14). 13

C NMR (100 MHz, CDCl3): δ 200.6 (C7), 177.1 (C11), 171.3 (C15), 135.5, 133.6 (C6, 19), 128.9, 128.7, 128.5, 128.4 (C1-5, 20-24), 67.0 (C18), 38.7 (C9), 35.9, 35.5 (C10, 14). IR: υ (cm-1) = 2927, 1733, 1710, 1686, 1167, 957, 699. E.r. = 81:19

195

K. Chung, T. Takata, T. Endo, Macromolecules 1995, 28, 3048-3054.

254

255

2.121) 3-acetyl-5-(benzyloxy)-5-oxopentanoic acid

From 6a-methyldihydrofuro[2,3-b]furan-2,5(3H,6aH)-dione196 Yield: 60% (85 BRSM) Aspect: clear oil Molecular formula: C14H16O5 HRMS: (ESI) calcd for C14H16NaO5+ [M+Na]+ 287.0890; found 287.0886. 1

H NMR (400 MHz, CDCl3): δ 7.43-7.30 (m, 5 H CHAr 14-18), 5.12 (s, 2 H CH2 12), 3.34 (q, 1 H, J = 8 Hz CH 3), 2.84-2.73 (m, 2 H CH2 8, 4), 2.57-2.44 (m, 2 H CH2 8, 4), 2.26 (s, 3 H CH3 1). 13

C NMR (100 MHz, CDCl3): δ 208.7 (C2), 177.1 (C5), 171.3 (C9), 135.5 (C13), 128.8, 128.6, 128.5 (C14-18), 67.0 (C12), 43.8 (C3), 35.4, 35.0 (C4, 8), 29.3 (C1). IR: υ (cm-1) = 2934, 1733, 1714, 1357, 1161. E.r. = 76:23

196

A. Tadokoro, T. Takata, T. Endo, Macromolecules 1993, 26, 4400-4406.

256

257

Procedures and Spectroscopic Data: Total Synthesis 3.48) methyl 4-(1,3-dioxolan-2-yl)-4-ethyl-7-hydroxyheptanoate

To 4-(1,3-dioxolan-2-yl)-4-ethyl-7-methoxy-7-oxoheptanoic acid (100 mg, 0.36 mmol, 1 equiv) in THF ( 1.8 ml, c = 0.2 M) was added BH3.Me2S (0.2 ml, 0.4 mmol, 1.11 equiv, 2 M in THF) at 0 °C. The reaction was left to stir at this temperature till full conversion when water (4 ml) was added. The solution was extracted with AcOEt, washed with brine, dried and concentrated in vacuuo. The residue was purified by FCC PE:AcOEt (2:1) to yield methyl 4-(1,3-dioxolan-2-yl)-4-ethyl-7-hydroxyheptanoate as a clear oil ( 68 mg, 86 %), Aspect: Clear oil Molecular Formula: C13H24O5 HRMS: (ESI) calcd for C13H24NaO5+ [M+Na]+ 283.1516; found 283.1516. 1

H NMR (400 MHz, CDCl3): δppm = 4.64 (s, 1H CH 4), 3.98-3.86 (m, 2 H CH2 6, 7), 3.87-3.75 (m, 2 H CH2 6, 7), 3.66 (s, 3 H CH3 14), 3.62 (t, J = 6.4 Hz, 2 H CH2 17), 2.48-2.30 (m, 2 H CH2 10), 1.82-1.66 (m, 2 H CH2 9), 1.66-1.53 (m, 2 H CH2 16), 1.52-1.34 (m, 4 H CH2 2, 15), 0.87 (t, J = 7.5 Hz, 3 H CH3 1). 13

C NMR (100 MHz, CDCl3): δppm = 174.9 (C11), 108.7 (C4), 64.7 (C17), 63.8 (C6, 7), 51.6 (C14), 40.4 (C3), 29.2, 28.9 (C10, 16), 28.3, 26.7 (C8, 15), 25.9 (C2), 8.9 (C1). IR: υ (cm-1) = 3447, 2949, 2880, 2359, 2341, 1736, 1438, 1198, 1106, 1056.

3.49) methyl 7-azido-4-(1,3-dioxolan-2-yl)-4-ethylheptanoate

258

To methyl 4-(1,3-dioxolan-2-yl)-4-ethyl-7-hydroxyheptanoate (16 mg, 0.055 mmol, 1 equiv) in toluene (0.1 ml, c = 0.6 M) was added N3PO(OPh)2 (14 μl, 0.066 mmol, 1.2 equiv) and DBU (10 μl, 0.066 mmol, 1.2 equiv). The mixture was stirred for an hour before being heated to 60° overnight. Once cooled to r.t the solution was diluted with AcOEt and washed with HCl aq 1M, brine, concentrated in vacuo and purified by FCC to yield methyl 7-azido-4-(1,3-dioxolan-2-yl)-4-ethylheptanoate as a clear oil (19.4 mg 63 %). To methyl 4-(1,3-dioxolan-2-yl)-4-ethyl-7-hydroxyheptanoate (26 mg, 0.1 mmol, 1 equiv) and NEt3 (42 μl, 0.3 mmol, 3 equiv) in DCM (0.33 ml, c = 0.3 M) was added slowly MsCl (11.6 μl, 0.15 mmol, 1.5 equiv) at 0°C. The reaction was stirred for 1 hour before being patitioned between AcOEt and NH4Cl aq, washed with brine, dried and concentrated. The residue was redissolved in DMF (0.25 ml, c = 0.4) with NaN3 (26 mg, 0.4 mmol, 4 equiv) and stirred at 70°C for 2 hours. Once cooled to r.t the solution was diluted with AcOEt and washed with HCl aq (1 M), brine, concentrated in vacuo and purified by FCC to yield methyl 7-azido-4-(1,3-dioxolan-2-yl)-4-ethylheptanoate as a clear oil (25.6 mg 83 %). Aspect: Clear oil Molecular Formula: C13H23N3O4 HRMS: calcd for C13H23N3NaO4+ [M+Na]+ 308.1581; found 308.0619. 1

H NMR (400 MHz, CDCl3): δppm = 4.61 (s, 1 H CH 4), 3.94-3.89 (m, 2 H CH2 6, 7), 3.85-3.76 (m, 2 H CH2 6, 7), 3.66 (s, 3 H CH3 14), 3.24 (t, J = 6.8 Hz, 2H CH3 14), 2.39-2.35 (m, 2 H CH2 10), 1.73-1.69 (m 2H CH2 9), 1.62-1.59 (m, 2 H CH2 16), 1.46-1.38 (m, 4 H CH2 2, 15), 0.87 (t, J = 7.6 Hz, 3 H CH3 1). 13

C NMR (100 MHz, CDCl3): δppm = 174.7 (C11), 108.5 (C4), 64.7 (C6, 7), 52.4 (C17), 51.6 (C14), 40.6 (C3), 30.2, 29.1 (C10, 16), 28.3, 25.8 (C9, 15), 23.2 (C2), 7.8 (C1). IR: υ (cm-1) = 2951, 2880, 2360, 2339, 2095, 1737, 1455, 1262, 1173, 1105, 1003, 660.

3.52) methyl 7-amino-4-(1,3-dioxolan-2-yl)-4-ethylheptanoate

To a solution of methyl 7-azido-4-(1,3-dioxolan-2-yl)-4-ethylheptanoate ( 28.5 mg, 0.1 mmol, 1 equiv) in THF (1 ml, c = 0.1 M) was first added PPh3 (79 mg, 0.3 mmol, 3 equiv) then H2O (0.18 ml, 10 mmol, 10 equiv) and heated to 65 °C. After disappearance of the starting material the solvent was removed in

259

vacuuo and the residue purified by FCC DCM/MeOH/NEt3 (98/1/1) to yield methyl 7-amino-4-(1,3dioxolan-2-yl)-4-ethylheptanoateas a clear oil (22 mg, 84 %) Aspect: clear oil Molecular Formula: C13H25NO4 HRMS: calcd for C13H24N3O4 [M-N2]+ 258.1705; found 258.1698. 1

H NMR (400 MHz, CDCl3): δppm = 4.62 (s, 1 CH 4), 3.93-3.89 (m, 2 H CH2 6, 7), 3.84-3.78 (m, 2 H CH2 6, 7), 3.66 (s, 3 H CH3 14), 2.68 (t, 2 H, J = 6.9 Hz CH2 17), 2.40-2.36 (m, 2 H CH2 10), 1.90 (bs, 2 H NH2 18), 1.731.71 (m, 2 H CH2 9), 1.50-1.34 (m, 6 H CH2 2, 15, 16, ), 0.86 (t, 3 H, J = 7.5 Hz CH3 1) 13

C NMR (100 MHz, CDCl3): δppm = 175.0 (C11), 108.8 (C4), 64.8 (C6, 7), 51.7 (C14), 42.9 (C17), 40.6 (C3), 30.3, 29.4 (C10, 16), 28.5, 26.7 (C9, 15), 26.0, (C2) 8.0 (C1).

3.53) methyl 4-(1,3-dioxolan-2-yl)-4-ethyl-7-(1H-indole-2carboxamido)heptanoate

To a solution of methyl 7-amino-4-(1,3-dioxolan-2-yl)-4-ethylheptanoate (120 mg, 0.46 mmol, 1 equiv) in CH2Cl2 (2.3 ml, c = 0.2M) was added in sequence indol-2-carboxylic acid (90 mg, 0.56 mmol, 1.2 equiv), NEt3 (138 μl, 0.92 mmol, 2 equiv), DMAP (5.6 mg, 0.05 mmol, 0.1 equiv) and EDC (107 mg, 0.56 mmol, 1.2 equiv). The solution was stirred at r.t until disappearance of the starting material. The solution was then washed with HCl 1M aq, NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by FCC PE:AcOEt 6:4 to yield the desired compound (147 mg, 79%) Aspect: yellowish oil Molecular Formula: C22H30N2O5 HRMS: (ESI) calcd for C22H31N2O5+ [M+H]+ 403.2227; found 403.2256. 1

H NMR (400 MHz, CDCl3): δppm = 9.47 (bs, 1 H NH 22), 7.65 (d, 1 H, J = 8.0 Hz CHAr 24), 7.45 (d, 1 H, J = 8.0 Hz CHAr 27), 7.30-7.26 (m 1H CHAr 25), 7.14 (t, 1H, J = 8.0 Hz CHAr 26), 6.83 (d, 1 H, J = 1.4 Hz CHAr 29), 6.33 (bt, 1 H, J = 5.4 Hz NH 18), 4.63 (s, 1 H CH 4), 3.94-3.90 (m, 2 H CH2 6, 7), 3.87-3.78 (m, 2 H CH2 6, 7), 3.66 (s, 3 H CH3 14), 3.45 (q, 2 H, J = 6.8 Hz CH2 17), 2.40-2.36 (m, 2 H CH2 10), 1.74-1.63 (m, 4 H CH2 9, 16), 1.48-1.41 (m, 4 H CH2 2, 15), 0.86 (t, 3 H, J = 7.5 Hz CH3 1). 260

13

C NMR (100 MHz, CDCl3): δppm = 174.9 (C11), 161.6 (C19), 136.2 (C23), 130.9 (C28), 127.7 (C21), 124.4 (C25), 121.9 (C27), 120.6 (C26), 112.0 (C24), 108.6 (C4), 101.7 (C29), 64.7 (C6, 7), 51.6 (C14), 40.6, 40.5 (C3, 17), 30.4, 29.2 (C10, 16), 28.3, 25.8 (C9, 15), 23.7 (C2), 7.9 (C1). IR: υ (cm-1) = 3263, 2945, 2868, 1728, 1636, 1555, 1421, 1310, 1264, 1106, 1014, 749.

3.60) methyl 3-(3-ethyl-2-(1H-indol-3-yl)piperidin-3-yl)propanoate

A solution of methyl 3-(3-ethyl-3,4,5,6-tetrahydropyridin-3-yl)propanoate (19.7 mg, 0.1 mmol, 1 equiv) and indol (47 mg, 0.4 mmol, 4 equiv) in degassed AcOH (0.1 ml, c = 0.1 M) was stirred at 110°C for 72 h (about 80% conversion, longer reaction times lead to degradation). The solution is then cooled to r.t and diluted in EtOAC, and aqous NaHCO3 are then added until the aqueous phase becomes basic. The aqueous phase was further extracted and the combined organic phases were washed with brine, dried with Na2SO4 and concentrated under vacuum. The residue is purified by FCC DCM/MeOH/NH3 (95/5, the DCM was pre-extracted with 2% V/V of a 25% ammonia solution) to yield methyl 3-(3-ethyl-2-(1H-indol3-yl)piperidin-3-yl)propanoate as a mixture of diasteroisomers as a brown oil (22.5 mg, 70%, 80% BRSM). Aspect: brown oil Molecular formula: C19H26N2O2 HRMS: (ESI) calcd for C19H27N2O2+ [M+H]+ 315.2067; found 315.2060. 1

H NMR (400 MHz, CDCl3): (two diastereoisomers 1:1 mixture) δ 8.80 (s, 0.5 H NH 1), 8.75 (s, 0.5 H NH 1), 7.71 (d, 0.5 H, J = 10.0 Hz CHAr 3), 7.68 (d, 0.5 H, J = 10.0 Hz CHAr 6), 7.36 (d, 0.5 H, J = 5.0 Hz CHAr 3), 7.34 (d, 0.5 H, J = 5.0 Hz CHAr 6), 7.19-7.06 (m, 3 H CHAr 4, 5, 9), 3.98 (s, 0.5 H CH 16), 3.95 (s, 0.5 H CH 16), 3.63 (s, 1.5 H CH3 23), 3.54 (s, 1.5 H CH3 23), 3.17-3.08 (m, 1 H CH2 12), 2.75-2.57 (m, 1 H CH2 12), 2.42 (td, 0.5 H, J = 13.3, 5.4 Hz CH3 20), 2.29-2.03 (m, 2H CH2 17, 19), 1.96 (ddd, 0.5 H, J = 15.5, 11.8, 5.4 Hz CH2 19), 1.80-1.10 (m, 7 H CH2 13, 14, 17, 20), 0.75 (t, 1.5 H, J = 7.5 Hz CH3 18), 0.74 (t, 1.5 H, J = 7.5 Hz CH3 18) 13

C NMR (100 MHz, CDCl3): δppm = 175.0 (C21), 174.6 (C21), 135.4 (C2), 135.3 (C2), 127.6 (C7), 127.3 (C7), 123.4 (C9), 123.2 (C9), 121.7 (C4), 121.5 (C4), 119.4 (C6), 119.3 (C6), 119.2 (C5), 119.2 (C5), 115.9 (C8), 115.1 (C8), 111.1 (C3), 111.1 (C3), 62.2 (C10), 61.4 (C10), 51.4 (C23), 51.3 (C23), 47.8 (C12), 47.5 (C12),

261

38.7 (C15), 38.6 (C15), 32.5 (C13), 32.5 (C13), 32.1 (C17), 30.3 (C17), 29.1 (C19), 28.8 (C19), 25.9 (C20), 22.0(C17), 21.9 (C17), 8.2 (C18), 7.7 (C18). IR: υ (cm-1) = 3734, 3385, 3201, 2973, 2802, 2223, 1726, 1435, 1173, 1059, 909, 821, 730

3.71) (S)-4-(1,3-dithiolan-2-yl)-4-ethyl-7-methoxy-7-oxoheptanoic acid

To a solution of 4-ethyl-4-formyl-7-methoxy-7-oxoheptanoic acid (1.0 g, 4.3 mmol, 1 equiv) in DCM ( 9.6 mL, c = 0.5 M) and Hf(OTf)4 (168 mg, 0.2 mmol, 0.05 equiv) at 0 °C was added slowly 1,2ethandithiol (0.73 mL, 8.7 mmol, 2 equiv). The reaction mixture was stirred till no starting material remained upon which the reaction mixture was filtered through a thick pad of Celite with ethyl acetate. The filtrate was concentrated under vacuuo, and the residue was purified by FCC (PE/EtOAc/AcOH 78/20/2) to yield 4-(1,3-dithiolan-2-yl)-4-ethyl-7-methoxy-7-oxoheptanoic acid as a colourless oil (1.28 g, 97%). Aspect: colourless oil Molecular Formula: C13H22O4S2 HRMS: (ESI) calcd for C13H22NaO4S2+ [M+Na]+ 329.0852; found 329.0854. 1

H NMR (400 MHz, CDCl3): δ 4.66 (s, 1H CH 4), 3.67 (s, 3H CH3 14), 3.19-3.14 (m, 4H CH2 6, 7), 2.50-2.40 (m, 4H CH2 10, 16), 1.86-1.81 (m, 4H CH2 9, 15), 1.5 (q, J = 7.5 Hz, 2H CH2 2), 0.91 (t, J = 7.5 Hz, 3H CH2 1). 13

C NMR (100 MHz, CDCl3): δ 179.6 (C17), 174.2 (C11), 63.17 (C4), 51.9 (C14), 41.8 (C4), 38.7 (6, 7), 31.1, 30.7 (C10, 16), 29.6 (C2), 29.5 (C9, 15), 8.5 (C1). IR: υ (cm-1) 2949, 1731, 1706, 1436, 1278, 1173, 913, 732. [ ]

= −1.5 (c 0.2, CHCl3,)

262

3.72) (R)-methyl 4-(1,3-dithiolan-2-yl)-4-ethyl-7-hydroxyheptanoate 18

O

17

O 16

15

14 1

13

9

3

4 2 8

11

10

S5

S

OH 12

6 7

For (R)-methyl 4-(1,3-dithiolan-2-yl)-4-ethyl-7-hydroxyheptanoate: To a solution of 4-(1,3dithiolan-2-yl)-4-ethyl-7-methoxy-7-oxoheptanoic acid (2.25g, 7.35 mmol, 1 equiv) in THF (70 mL, c = 0.1 M) at 0 °C was added slowly LiBH4 (647 mg, 29.4 mmol, 4 equiv). The mixture was stirred till no starting material remained. The reaction mixture was then diluted with EtOAc and HCl aq (1 M) was added. The reaction mixture was stirred for a further 15 minutes. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with water, brine, dried with Na2SO4 and concentrated under vacuum. The residue was dissolved in methanol and TMS-diazomethane was added dropwise at 0 °C until the solution remained yellow and no more gas evolved (about 1.2 equiv). AcOH was then added to destroy the excess diazomethane and the solution was evaporated to dryness. The residue was purified by (FCC PE/EtOAc 2/1) to yield methyl 4-(1,3-dithiolan-2-yl)-4-ethyl-7-hydroxyheptanoate as a colourless oil (2.2 g, 95%) For the synthesis of the enantiomer of Leucomidine B the following procedure was used to obtain (S)-methyl 4-(1,3-dithiolan-2-yl)-4-ethyl-7-hydroxyheptanoate, further steps were identical. To a solution of 4-(1,3-dithiolan-2-yl)-4-ethyl-7-methoxy-7-oxoheptanoic acid (1.2 g, 4 mmol, 1 equiv) in THF (20 mL, c = 0.2 M) at 0 °C was added slowly BH3-Me2S (2M solution in THF, 2.2 mL, 4.4 mmol, 1.1 equiv). The mixture was stirred till no starting material remained. The mixture was then diluted with 10 mL EtOAc, 1 mL of water was then added dropwise and when no more gas evolved, HCl aq (1 M) was then added and the reaction mixture was stirred for a further 15 minutes. The aqueous phase was further extracted with EtOAc. The combined organic layers were washed with water, brine, dried with Na2SO4 and concentrated under vacuum. The residue was purified by FCC (PE/EtOAc 2/1) to yield methyl 4-(1,3-dithiolan-2-yl)-4-ethyl-7-hydroxyheptanoateas a colourless oil (1.13 g, 95%) Aspect: colourless oil Molecular Formula: C13H24O3S2 HRMS: (ESI) calcd for C13H24NaO3S2+ [M+Na]+ 315.1059; found 315.1060. 1

H NMR (400 MHz, CDCl3): δ 4.71 (s, 1H CH 4), 3.67 (s, 3H CH3 17), 3.63 (t, J = 6.1 Hz, 2H CH2 11), 3.253.09 (m, 4H CH2 6, 7), 2.52-2.40 (m, 2H CH2 14), 1.92-1.81 (m, 2H CH2 13), 1.67-1.47 (m, 6H CH2 2, 9, 10), 0.91 (t, J = 7.5 Hz, 3H CH3 1). 13

C NMR (100 MHz, CDCl3): δ 174.6 (C15), 63.8 (C4), 63.7 (C11), 51.8 (C17), 41.9 (C3), 38.6 (C6, 7), 32.6, 31.2 (C13, 14), 29.8, 29.8 (9, 10), 27.5 (C2), 8.7 (C1). 263

IR: υ (cm-1) 3439, 2926, 2877, 1732, 1436, 1260, 1173, 1056, 797.

3.73) (R)-methyl 7-azido-4-(1,3-dithiolan-2-yl)-4-ethylheptanoate

To a solution of methyl 4-(1,3-dithiolan-2-yl)-4-ethyl-7-hydroxyheptanoate (100 mg, 0.34 mmol, 1 equiv) and NEt3 (140 μL, 1.0 mmol, 3 equiv) in DCM (3.5 mL, c = 0.1 M) at 0° C was added MsCl (40 μL, 0.51 mmol, 1.5 equiv) and the reaction mixture was stirred until no starting material remained. The solution was then partitioned between NH4Cl and EtOAc, the aqueous phase was extracted and the combined organic phases were washed with brine, dried with Na2SO4 and concentrated under vacuum to obtain crude 21 which was then used immediately. The residue was dissolved in DMF (3.5 mL, c = 0.1 M) and NaN3 (45 mg, 0.68 mmol, 2 equiv) was added. The mixture was heated to 50 °C until no more mesylate was detected. The mixture was then partitioned between Et2O and water, the aqueous phase was further extracted and the combined organic phases were washed with brinz, dried with Na2SO4 and concentrated under vacuum. The residue was then purified by FCC (PE/EtOAc 9/1) to yield methyl 7azido-4-(1,3-dithiolan-2-yl)-4-ethylheptanoate as a colorless oil (90 mg, 83% over two steps) Aspect: colourless oil Molecular Formula: C13H23N3O2S2 HRMS: (ESI) calcd for C13H24NO2S2+ [M+H]+ 290.1243; found 290.1246. 1

H NMR (400 MHz, CDCl3): δ 4.67 (s, 1H CH 4), 3.66 (s, 3H CH3 17), 3.25 (t, J = 6.5 Hz, 2H CH2 11), 3.233.07 (m, 4H CH2 6, 7), 2.49-2.38 (m, 2H CH2 14), 1.87-1.78 (m, 2H CH2 13), 1.70-1.59 (m, 2H CH2 10), 1.561.46 (m, 4H CH2 2, 9), 0.89 (t, J = 7.5 Hz, 3H CH3 1). 13

C NMR (100 MHz, CDCl3): δ 174.3 (C15), 63.5 (C4), 52.3 (C11), 51.8 (C17), 42.0 (C3), 38.6 (C6, 7), 33.5, 31.1 (C13, 14), 29.6, 29.6 (C2, 9), 23.9 (C10), 8.6 (C1). IR: υ (cm-1) 2927, 2878, 2093, 1735, 1436, 1257), 1172, 1017, 734.

264

3.46) (R)-methyl 3-(3-ethyl-3,4,5,6-tetrahydropyridin-3-yl)propanoate

To a solution of methyl 7-azido-4-(1,3-dithiolan-2-yl)-4-ethylheptanoate (144 mg, 0.45 mmol, 1 equiv) in a 8/1/1 DMSO/H2O/AcOH mixture (4.5 mL, c = 0.1M) was added portionwise over 10 minutes a mixture of IBX (382 mg, 1.36 mmol, 3 equiv) and TBAB (438 mg, 1.36 mmol, 3 equiv). The reaction mixture was stirred until no starting material remained. The mixture was then partitioned between NaHCO3 and Et2O, the aqueous phase was extracted with Et2O (5x) and the combined organic phases were washed with brine, dried with Na2SO4 and concentrated under vacuum to yield a mixture of 23 with TBAB. This mixture was then dissolved in 9/1 THF/H2O (4.5 mL, c = 0.1 M), PPh3 (471 mg, 1.8 mmol, 4 equiv) was added and the mixture was stirred at reflux until no more intermediate remained. The mixture was then concentrated under vacuum. The residue was partitioned between 1 M HCl and DCM, the organic phase was extracted twice with 1 M HCl. To the combined aqueous phases was then added EtOAc and the whole was basified with potassium carbonate. The aqueous phase was further extracted with EtOAc. The combined organic phases were washed with brine, dried with Na2SO4 and concentrated under vacuum to yield methyl 3-(3-ethyl-3,4,5,6-tetrahydropyridin-3-yl)propanoate (16.4 mg, 60% over two steps) Aspect: colourless oil Molecular Formula: C11H19NO2 HRMS: (ESI) calcd for C11H20NO2+ [M+H]+ 198.1489; found 198.1491. 1

H NMR (400 MHz, CDCl3): δ 7.47 (brs, 1H CH 1), 3.67 (s, 3H CH3 14), 3.49 (app. brs, 2H CH2 3), 2.36-2.32 (m, 2H CH2 10), 1.67-1.51 (m, 2H CH2 9), 1.60-1.35 (m, 6H CH2 4, 5, 7), 0.88 (t, J = 7.5 Hz, 3H CH3 8).

13

C NMR (100 MHz, CDCl3): δ 174.1 (C11), 169.4 (C1), 51.9 (C14), 49.5 (C3), 39.1 (C6), 32.3 (C5), 30.4 (C10), 29.1 (C7), 27.7 (C9), 19.4 (C4), 8.2 (C8). IR: υ (cm-1) 2934, 2860, 2336, 1737, 1650, 1437, 1171, 1019.

[ ]

= −13.5 (c 0.2, CHCl3)

265

3.82) (R)-methyl 3-(8-ethyl-1-(2-nitrophenyl)-5,6,7,8-tetrahydroindolizin-8yl)propanoate

A solution of methyl 3-(3-ethyl-3,4,5,6-tetrahydropyridin-3-yl)propanoate (50 mg, 0.25 mmol, 1 equiv) and 1-(3-bromoprop-1-en-1-yl)-2-nitrobenzene197 (67 mg, 0.28 mmol, 1.1 equiv) in DMF (0.25 mL, 1 M) was heated at 110 °C for 1 hour. The mixture was cooled to room temperature. Et2O (10 mL) was added and the mixture was stirred for a further 30 minutes. The precipitate was filtered and coevaporated three times with toluene before being re-dissoved in degassed toluene. Freshly prepared Ag2CO3 (119 mg, 0.43 mmol, 2 equiv) was added and the mixture was refluxed for one hour protected from light. The mixture was then filtered through Celite with AcOEt and purified by FCC (PE/AcOEt 9/1) to yield methyl 3-(8-ethyl-1-(2-nitrophenyl)-5,6,7,8-tetrahydroindolizin-8-yl)propanoate as a yellow oil (46 mg, 60% over two steps). Aspect: yellow oil Molecular Formula: C20H24N2O4 HRMS: (ESI) calcd for C20H25N2O4+ [M+H]+ 357.1809; found 357.1812. 1

H NMR (400 MHz, CDCl3): δ 7.79 (dd, J = 8.0, 1.1 Hz, 1H CHAr 22), 7.54-7.35 (m, 3H CHAr 19-21), 6.54 (d, J = 2.7 Hz, 1H CH 15), 6.02 (d, J = 2.7 Hz, 1H CH 16), 3.98-3.83 (m, 2H CH2 12), 3.60 (s, 3H CH3 1), 2.28-2.13 (m, 2H CH2 5), 2.04-1.82 (m, 2H CH2 11), 1.83-1.48 (m, 6H CH2 6, 10, 8), 0.85-0.64 (m, 3H CH3 9). 13

C NMR (100 MHz, CDCl3): δ 174.4 (C3), 150.7 (C23), 133.8 (C20), 133.5 (C18), 131.3 (C19), 130.5 (C14), 127.7 (C21), 123.8 (C22), 119.0 (C15), 114.7 (C17), 110.7 (C16), 51.7 (C1), 46.2 (C12), 39.4 (C7), 36.1 (C6), 35.0 (C8), 30.1 (C5, 10), 21.3 (C11), 9.19 (C9). IR: υ (cm-1) 2930, 2858, 1698, 1574, 1485, 1226, 1071, 826, 781.

197

P. Magnus, T. Rainey, Tetrahedron 2001, 57, 8647-8651.

266

3.45) (R)-methyl 3-(1-(2-aminophenyl)-8-ethyl-5,6,7,8-tetrahydroindolizin-8yl)propanoate

To a solution of methyl 3-(8-ethyl-1-(2-nitrophenyl)-5,6,7,8-tetrahydroindolizin-8-yl)propanoate (35 mg, 0.1 mmol, 1 equiv) in methanol ( 1 mL, c = 0.1 M) was added Pd/C 10% (catalytic amount). The solution was placed under H2 atmosphere and stirred until no starting material remained. The mixture was filtered through Celite and evaporated to give methyl 3-(1-(2-aminophenyl)-8-ethyl-5,6,7,8tetrahydroindolizin-8-yl)propanoate (32 mg, quantitative, mixture of rotamers). Aspect: colourless oil Molecular Formula: C20H26N2O2 1

H NMR (400 MHz, CDCl3): δ (Presence of rotamers) 7.21-7.04 (m, 2H CHAr 19, 21), 6.92-6.71 (m, 2H CHAr 20, 22), 6.62-6.50 (m, 1H CHAr 15), 6.16-5.94 (m, 1H CHAr 16), 4.64-4.10 (m, 2H NH2 24), 4.03-3.80 (m, 2H CH2 12), 3.65 (s, 1. 5H CH3 1), 3.58 (s, 1. 5H CH3 1), 2.40-2.09 (m, 2H CH2 5), 1.85-1.29 (m, 8H CH2 6, 8, 10, 11), 0.82 (t, J = 6.4 Hz, 1.5 H CH 9), 0.73 (t, J = 6.4 Hz, 1.5 H CH 9). 13

C NMR (100 MHz, CDCl3): δ (Presence of rotamers) 174.7 (C3), 174.5 (C3), 143.8 (C23), 143.5 (C23), 131.7 (C19), 131.3 (C14), 128.1 (C21), 125.6 (C18), 125.4 (C18), 119.2(C15), 118.9(C15), 118.7 (C20), 115.9(C22), 115.7 (C17), 115.6 (C17), 110.3 (C16), 110.2 (C16), 51.7 (C1), 46.3 (C12), 39.5 (C7), 39.3 (C7), 36.1 (C6), 34.8 (C6), 34.6 (C8), 33.4 (C8), 30.6 (C10), 30.4(10), 29.8 (C5), 29.7 (C5), 21.4 (C11), 21.2 (C11), 9.4 (C9), 9.3 (C9).

3.2) (-)-Rhazinilam

To a solution methyl 3-(1-(2-aminophenyl)-8-ethyl-5,6,7,8-tetrahydroindolizin-8-yl)propanoate (32 mg, 0.1 mmol, 1 equiv) in methanol (c = 0.1M) was added KOH ( 55 mg, 1 mmol, 10 equiv) in water (c 267

= 0.1 M) and the mixture stirred overnight. The mixture was partitioned between DCM and 1M HCl and the aqueous phase was extracted with DCM (9x). The combined organic phases were dried and concentrated to dryness. The residue was dissolved in DCM and NEt3 (57 μL, 0.4 mmol, 4 equiv), EDC (28.8 mg, 0.15 mmol, 1.5 equiv), HOBT (19.85 mg, 0.15 mmol, 1.5 equiv) were added. The mixture was left to stir for 3 hours and then partitioned between AcOEt and 1 M HCl. The aqous phase was extracted with AcOEt. The combined organic phases were washed with brine, dried and concentrated in vacuuo. The residue was purified by FCC (PE/AcOEt, 3/7) to give Rhazinilam (23 mg, 80%). Molecular Formula: C19H22N2O HRMS: (ESI) calcd for C19H23N2O+ [M+H]+ 295.1805; found 295.1807. 1

H NMR (400 MHz, CDCl3): δ 7.43 (dd, J = 7.2, 1.7 Hz, 1H CHAr 16), 7.37-7.28 (m, 2H CHAr 14, 15), 7.21 (dd, J = 7.2, 1.7 Hz, 1H CHAr 13), 6.61 (brs, 1H NH 18), 6.5 (d, J = 2.7 Hz, 1H CH 11), 5.75 (d, J = 2.7 Hz, 1H CH 10), 3.94 (dd, 1 H, J = 12.2, 5.5 Hz CH2 6)., 3.79 (td, J = 12.2, 4.8 Hz, 1H CH2 6), 2.52-2.33 (m, 2H CH2 21), 2.45-2.34 (m, 1H CH2 5), 2.00-1.91 (m, 1H CH2 22), 1.90-1.81 (m, 1H CH2 5), 1.72 (td, J = 13.4, 3.1 Hz, 1H CH2 5), 1.59-1.41 (m, 3H CH2 2, 5, 22), 1.27-1.22 (m, 1H CH2 2), 0.72 (t, J = 7.3 Hz, 3H CH3 1). 13

C NMR (100 MHz, CDCl3): δ 176.3 (C19), 139.4 (C17), 137.0 (C8), 130.4 (C12), 129.6 (C15), 127.0 (C13), 126.2 (C14), 125.8 (16), 118.1 (C11), 116.3 (C9), 108.5 (C10), 45.1 (C4), 37.9 (C3), 35.6 (C21), 32.1 (C2), 29.1 (C22), 27.1 (C24), 18.4 (C5), 7.2 (C1). IR: υ (cm-1) 2953, 2930, 2858, 1697, 1574, 1424, 1347, 1226, 1070, 891, 825, 780.

e.r. = 93:7 [ ]

198

= −351.8 (c 0.973, CHCl3) lit198: –421 (c 0.973, CHCl3)

H. H. A. Linde, Helv. Chim. Acta 1965, 48, 1822-1842.

268

269

3.79) methyl 3-((8R)-8-ethyl-2-hydroxy-1-(2-nitrophenyl)-3-oxo-3,5,6,7,8,8ahexahydroindolizin-8-yl)propanoate

A solution of methyl 3-(3-ethyl-3,4,5,6-tetrahydropyridin-3-yl)propanoate and methyl 3-(2nitrophenyl)-2-oxopropanoate199 in toluene is stirred at 90 °C for 24 hours to give the desired product as a mixture of diastereoisomers. The mixture is evaporated and the residue purified by FCC (DCM/MeOH 99/1)to yield methyl 3-((8R)-8-ethyl-2-hydroxy-1-(2-nitrophenyl)-3-oxo-3,5,6,7,8,8a-hexahydroindolizin8-yl)propanoate and methyl3-((8S)-8-ethyl-2-hydroxy-1-(2-nitrophenyl)-3-oxo-3,5,6,7,8,8ahexahydroindolizin-8-yl)propanoate as a yellow oil (80% combined yield). Diasteroisomers can be separated via preparative TLC using the same conditions. Aspect: yellow oil Molecular formula: C20H24N2O6 (8R, 8aS)

HRMS: (ESI) calcd for C20H24N2NaO6+ [M+Na]+ 411.1527; found 411.1486 1

H NMR (400 MHz, CDCl3): (Presence of rotamers) δ 8.76-8.51 (m, 1H OH 17), 8.22-7.92 (m, 1H CHAr 23), 7.76-7.41 (m, 3H CHAr 20-22), 4.44-4.23 (m, 2H CH2 12), 3.57 (s, 3H CH3 9), 2.87 (td, 1H, J = 3.9 Hz CH 29), 2.31-2.08 (m, 2H CH2 5), 1.72-1.42 (m, 4H CH2 4, 10), 1.42-1.16 (m, 4H CH2 2, 11), 0.70 (t, J = 7.4 Hz, 3H CH3 9). 199

C. Granchi, S. Roy, C. Giacomelli, M. Macchia, T. Tuccinardi, A. Martinelli, M. Lanza, L. Betti, G. Giannaccini, A. Lucacchini, N. Funel, L. G. León, E. Giovannetti, G. J. Peters, R. Palchaudhuri, E. C. Calvaresi, P. J. Hergenrother, F. Minutolo, J. Med. Chem. 2011, 54, 1599-1612.

270

13

C NMR (100 MHz, CDCl3): (Presence of rotamers) δ 173.5 (C6), 164.6(C14), 147.8, 145.4(C16, 24), 133.9, 128.8, 128.8, 125.5 (C19-23), 118.2 (C18), 63.0, 51.7, 40.7, 39.8, 30.8, 29.4, 28.3, 22.3, 20.4, 7.3. IR: υ (cm-1) 3114, 2947, 2869, 1734, 1659, 1526.

(8R, 8aR)

HRMS: (ESI) calcd for C20H24N2NaO6+ [M+Na]+ 411.1527; found 411.1533. 1

H NMR (400 MHz, CDCl3): (Presence of rotamers) δ 8.11-7.94 (m, 1H OH 17), 7.70-7.33 (m, 4H CHAr 2023), 4.32-4.21 (m, 2H CH2 12), 3.59 (s, 3H CH3 9), 2.93-2.78 (m, 1H CH 29), 2.12-1.88 (m, 2H CH2 5), 1.671.33 (m, 7 H CH2 2, 4, 10, 11), 0.9-0.8 (m, 1H CH2 11), 0.71-0.54 (m, 3H CH3 9). 13

C NMR (100 MHz, CDCl3): (Presence of rotamers) δ 174.0(C6), 164.4 (C14), 147.8, 145.1 (C16, 24), 134.1, 132.3, 129.0, 128.7 (C19-23), 125.5 (C18), 62.6, 52.0, 40.7, 39.9, 29.7, 28.9, 28.6, 25.7, 20.5, 7.7. IR: υ (cm-1) 3116, 2935, 2867, 1736, 1663, 1528, 1384.

271

3.1) (-)-Leucomidine B (11R, 11aS)-

Methyl 3-(-8-ethyl-2-hydroxy-1-(2-nitrophenyl)-3-oxo-3,5,6,7,8,8a-hexahydroindolizin-8yl)propanoate (26 mg, 0.067 mmol, 1 equiv) was dissolved in methanol ( 0.7 mL, c = 0.1 M) and Pd/C 10% (catalytic amount) was added. The solution was placed under H2 atmosphere and stirred until no starting material remained. The mixture was filtered over Celite and evaporated to give a mixture of the cyclized and non-cyclized form. The residue was dissolved in toluene and heated to reflux for 6 hours. After evaporation the residue was purified by FCC (DCM/MeOH 98/2) to give Leucomidine B as a whitish solid ( 18 mg, 80%). Aspect: white solid Molecular formula: C20H24N2O3 HRMS: (ESI) calcd for C20H25N2O3+ [M+H]+ 341.1860; found 341.1858. 1

H NMR (600 MHz, CDCl3): δ 10.55 (s, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.31 (t, J = 8.1 Hz, 1 H), 7.21 (t, J = 8.1 Hz, 1 H), 4.48 (dd, J = 12.8, 4.8 Hz, 1 H), 4.33 (s, 1 H), 3.80 (s, 3 H), 2.99 (td, J = 12.8, 4.8 Hz, 1 H), 2.75-2.70 (m, 1 H), 2.61-2.56 (m, 1 H), 2.2 (t, J = 5.6 Hz, 2 H), 1.78-1.60 (m, 3 H), 1.55 (td, J = 12.8, 4.8 Hz, 1 H), 1.16 (dq, J = 14.6, 7.4 Hz, 1 H), 0.71 (dq, J = 14.6, 7.4 Hz, 1 H), 0.58 (t, J = 7.4 Hz, 3 H). 13

C NMR (151 MHz, CDCl3): δppm = 174.3, 161.9, 141.7, 135.5, 126.9, 124.3, 122.2, 121.1, 120.8, 113.9, 63.3, 52.1, 39.7 (2C), 32.4, 29.9, 29.0, 23.4, 20.9, 7.5

1

H NMR (400 MHz, CD3OD-CDCl3 1:1): δ 7.67 (d, J = 8.2 Hz, 1H ), 7.49 (d, J = 8.2 Hz, 1H ), 7.26 (ddd, J = 8.2, 7.1, 1 Hz, 1H ), 7.16 (dd, J = 8.2, 7.1, 7.2, 1Hz, 1H ), 4.35 (s, 1H), 4.30 (br d, J = 12.6 Hz, 1H), 3.78 (s, 3H), 3.02-2.92 (m, 1H), 2.78-2.66 (m, 1H), 2.65-2.53 (m, 1H), 2.17 (t, J = 8.6 Hz, 2H ), 1.79-1.52 (m, 4H), 1.12 (dq, J = 14.5, 7.6 Hz, 1H), 0.67 (dq, J = 14.5, 7.6 Hz, 1H), 0.58 (t, J = 7.6 Hz, 3H). 13

C NMR (100 MHz, CD3OD-CDCl3 1:1): δ 175.4, 162.8, 127.6, 135.2, 122.5, 121.4, 121.5, 124.8, 114.09, 142.3, 63.7, 52.4, 40.2, 40.1, 32.8, 30.2, 29.2, 23.7, 21.3, 7.6.

272

Position 2 3a 3b 5 6 7 8 9 10 11 12 13 14a 14b 15a 15b 16a 16b 17a 17b 18 19a 19b 20 21 OMe

1H (ppm)

Isolated

Synthetic

Variation

2.98 4.3

2.98 4.3

0 0 0 0 0 0 0 0.02 0 0 0 0.02 0 0.01 0.01 0.02 0.02 0 0 0 0.01 0.01 0 0.01 0

7.68 7.16 7.27 7.49

7.68 7.14 7.27 7.49

1.6 1.69 1.59 1.76 2.6 2.74 2.18

1.58 1.69 1.58 1.75 2.58 2.72 2.18

0.58 0.67 1.12

0.58 0.66 1.11

4.36 3.78

4.35 3.78

13C (ppm)

Isolated 175.3 40.1

Synthetic 175.4 40.1

162.8 127.6 135.2 128.2 121.4 122.5 124.8 114.1 142.5 21.2

162.8 127.6 135.2 122.5 121.4 121.5 124.8 114.09 142.3 21.3

30.1

30.2

29.2

29.2

32.7

32.8

7.6 23.7

7.6 23.7

40.2 63.8 52.4

40.2 63.7 52.4

Variation 0 0 0 0 0 5.7 a) 0 1 0 0.01 0.2 -0.1 0 -0.1 0 0 0 -0.1 0 0 0 0 0 0.1 0

a)

2D correlation evidence supports the assignation of carbon 8 to 122.5 ppm rather than 128.2 ppm.

IR: υ (cm-1) 3400, 2925, 1665, 1428, 1282, 1016, 753 (11R, 11aS) Enantiomer [ ]

= −15.1 ( c 0.3, CHCl3) (lit200: –18 (c 0.3, CHCl3)

e.r. = 94:6

200

M. Motegi, A. E. Nugroho, Y. Hirasawa, T. Arai, A. H. A. Hadi, H. Morita, Tetrahedron Lett. 2012, 53, 1227-1230.

273

274

(-)-Leucomidine B was purified to 100% ee by semi-preparative SFC: [ ]

= −18.6 (c 0.1, CHCl3) (lit200: –18 (c 0.3, CHCl3)

275

(+)-Leucomidine B (ent-8) (11S, 11aR)

e.r. = 91:9 [ ]

= 14.3 (c 0.3, CHCl3)

276

(11R, 11aR) Diastereoisomer of Leucomidine B

Aspect: grey solid Molecular formula: C20H24N2O3 HRMS: (ESI) calcd for C20H25N2O3+ [M+H]+ 341.1860; found 341.1852. 1

H NMR (600 MHz, CDCl3): δ 10.09 (s, 1H), 7.58 (dd, 2H, J = 8.2, 2.4 Hz), 7.32 (t, 1H, J = 7.6 Hz), 7.19 (t, 1H, J = 7.6 Hz), 4.49-4.45 (m, 1H), 4.41 (s, 1H), 3.50 (s, 3H), 3.04-2.96 (m, 1H), 2.06-1.91 (m, 3H), 1.83 (td, 1H, J = 14.7, 7.7 Hz), 1.79-1.62 (m, 4H), 1.51 (ddd, 1H, J = 13.9, 11.9, 5.4 Hz),1.25 (t, 3H, J = 7.7 Hz) ,1.05 (ddd, 1H, J = 13.9, 11.9, 5.4 Hz) 13

C NMR (151 MHz, CDCl3): δ 174.1, 161.7, 141.6, 135.5, 126.9, 124.4, 122.2, 121.0, 120.6, 113.9, 62.8, 51.7, 39.7, 39.7, 30.1, 30.0, 28.7, 26.5, 20.8, 8.0 1

H NMR (400 MHz, CD3OD-CDCl3 1:1): δ 7.55 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.27 (ddd, J = 8.3, 7.11, 1 Hz), 7.15 (ddd, J = 8.3, 7.11 1 Hz, 1H), 4.42 (s, 1H), 4.36-4.28 (m, 1H), 3.50 (s, 3H), 3.05-2.95 (m, 1H), 2.09-1.60 (m, 8H), 1.42 (ddd, J = 11.8, 14.3, 5.7 Hz, 1H), 1.24 (t, J = 7.6 Hz, 3H), 0.99 (ddd, J = 11.8, 14.3, 5.7 Hz, 1H),

13

C NMR (100 MHz, CD3OD-CDCl3 1:1): δ 175.2, 162.7, 142.3, 135.2, 127.5, 124.9, 122.5, 121.3, 120.9, 114.1, 63.4, 51.9, 40.2, 40.1, 30.4, 30.3, 28.9, 26.8, 21.2, 8.0 IR: υ (cm-1) 3166, 3074, 2937, 2865, 1735, 1660, 1427, 1281, 734. (11R, 11aR); [ ]

= 48.3 (c 0.3, CHCl3)

e.r. = 95:5

277

278

(11S, 11aS) Diastereoisomer of Leucomidine B

[ ]

= −44 (c 0.3, CHCl3)

e. r. = 92:8

279

X-ray Data for 2.97 and 2.101a 2.97) 1-(4'-bromo-[1,1'-biphenyl]-4-yl) 7-methyl 4-ethyl-4formylheptanedioate

280

2.101a) Cis-4a-ethyltetrahydropyrano[2,3-b]pyran-2,7(3H,8aH)-dione

Table 1. Crystal data and structure refinement for jbgdoc341. Identification code

jbgdoc341

Empirical formula

C10H14O4

Formula weight

198.21

Temperature

293(2) K

Wavelength

1.54178 Å

Crystal system

Monoclinic

Space group

P21/c

Unit cell dimensions

a = 12.6494(6) Å

α= 90°.

b = 10.1071(5) Å

β= 94.702(5)°.

c = 7.7146(4) Å

γ = 90°.

Volume

982.98(8) Å3

Z

4

Density (calculated)

1.339 Mg/m3

Absorption coefficient

0.864 mm-1

F(000)

424

Crystal size

0.51 x 0.45 x 0.38 mm3

Theta range for data collection

3.51 to 73.25°.

Index ranges

-15