Synthesis of macrocyclic shellfish toxins containing ...

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Synthesis of macrocyclic shellfish toxins containing spiroimine moieties Patrick D. O’Connor and Margaret A. Brimble* Received (in Cambridge, UK) 8th January 2007 First published as an Advance Article on the web 2nd April 2007 DOI: 10.1039/b700307m

Downloaded on 20 September 2011 Published on 02 April 2007 on http://pubs.rsc.org | doi:10.1039/B700307M

Covering: 1993–2006 An overview of the structure and biological activity of macrocyclic polyketides derived from dinoflagellates that contain unusual cyclic imine units is provided. The total and partial syntheses of these molecules are discussed with an emphasis on the construction of the spiroimine functionality thought to be the key pharmacophore of these fast-acting shellfish toxins. 1 2 2.1 2.2 2.3 3 3.1 3.2 3.3 4

Introduction—shellfish toxins Synthesis of pinnatoxin A Kishi’s synthesis of (−)-pinnatoxin A Total synthesis of the pteriatoxins Formal synthesis of pinnatoxin A Other synthetic approaches towards the PnTX family of toxins Murai’s approach to the C10–C31 PnTX skeleton Hashimoto’s approach to the C10–C31 PnTX skeleton Zakarian’s approach to the spiroimine unit of PnTX and PtTX Synthetic studies towards the spirolides

Department of Chemistry, The University of Auckland, 23 Symonds Street, Auckland, New Zealand. E-mail: [email protected]; Tel: +64 9 3737599

4.1 Brimble’s synthesis of the bis-spiroacetal moiety of the spirolides 5 Gymnodimine 5.1 Synthesis of the gymnodimine skeleton 5.2 Synthetic studies towards gymnodimine, Murai et al. 5.3 Synthetic studies towards gymnodimine, Romo et al. 5.4 Synthetic studies towards gymnodimine, White et al. 6 Acknowledgements 7 References

1 Introduction—shellfish toxins The isolation of secondary metabolites of marine origin provides a rich source of structurally diverse molecular frameworks with interesting biological activities.1 The unusual molecular architecture often associated with these molecules renders them

Patrick O’Connor completed his BSc (Hons) at Massey University in New Zealand in 2000. He was awarded his PhD in 2004 under the supervision of Professor Lewis N. Mander, at Australia National University upon completing the synthesis of the himandrine skeleton. After a postdoctoral position in the laboratory of Professor Leo A. Paquette, Patrick returned to New Zealand to accept a Foundation of Research, Science and Technology postdoctoral research fellowship with Professor Margaret A. Brimble at the University of Auckland where he is working on the synthesis of marine natural products.

Patrick D. O’Connor

Margaret A. Brimble

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Margaret Brimble was born in Auckland, New Zealand where she was educated and graduated from the University of Auckland with an MSc (1st class) in chemistry. She was then awarded a UK Commonwealth Scholarship to undertake her PhD studies at Southampton University. In 1986 she was appointed as a lecturer at Massey University, NZ. After a brief stint as a visiting Professor at the University of California, Berkeley she moved to the University of Sydney where she was promoted to Reader. In 1999, she returned to New Zealand to take up the Chair in Organic and Medicinal Chemistry at the University of Auckland where her research program continues to focus on the synthesis of spiroacetal containing natural products (especially shellfish toxins), the synthesis of pyranonaphthoquinone antibiotics, the synthesis of alkaloids and peptidomimetics for the treatment of neurodegenerative disorders, and the synthesis of glycopeptides as components for cancer vaccines. She is currently President-Elect of the International Society of Heterocyclic Chemistry and was named the 2007 L’Oréal-UNESCO For Women in Science Laureate for AsiaPacific in Materials Science.

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valuable molecular probes for the investigation of biochemical processes ultimately providing candidates for advanced preclinical and clinical development.2 Marine invertebrates and associated bacteria provide a rich source of polyketides3 containing densely oxygenated macrocyclic arrays, many of which exhibit potent cell growth anti-proliferating activity thus furnishing new lead compounds for the development of anticancer agents. While few in number compared to bacterial polyketides and marine spongederived polyketides, dinoflagellates and unicellular marine algae produce some of the largest and most fascinating polyketide macrolides identified to date. Compounds with potential therapeutic value as anticancer agents, as well as deadly neurotoxins whose production has resulted in notable public health hazards, are represented by this group of secondary metabolites.4 Whilst the syntheses of macrolides of marine origin have been extensively reviewed,5 reviews on the syntheses of macrolide shellfish toxins are more sparse. This article aims to summarize the structure and biological activity of polyketide derived shellfish toxins and to provide a summary of existing syntheses to construct macrocyclic shellfish toxins that also contain an unusual cyclic imine unit. Consumption of shellfish is considered part of a healthy diet, however, numerous cases of shellfish poisoning occur worldwide each year and a significant number of these incidents are associated with natural marine biotoxins produced by microalgae.6 Shellfish toxins are produced by free-living micro-algae, upon which filterfeeding bivalve molluscs such as clams, mussels, oysters, or scallops feed. Depending on the environment surrounding them, these algae may proliferate and aggregate to form a high concentration of cells known as “algal blooms.” Shellfish concentrate the phycotoxins in the edible tissues acting as a vector transferring these toxic compounds further up the food chain where they can be lethal to humans and carnivores such as fish and crabs. In the last few decades, incidences of toxic algal blooms, both in fresh water and the sea, have become increasingly frequent, thus strict monitoring of shellfish to ensure consumer safety is required. Three main species of dinoflagellates that produce the toxins are: Alexandrium spp., Gymnodinium and Pyrodinium.7 Five major classes of shellfish poisoning have been identified: neurotoxic shellfish poisoning (NSP), diarrhetic shellfish poisoning (DSP), paralytic shellfish poisoning (PSP), amnesic shellfish poisoning (ASP) and ciguatera fish poisoning (CSP). Except for ASP all poisoning incidents are caused by biotoxins synthesized by dinoflagellates. The toxins responsible for these syndromes are not single chemical entities but are families of compounds having similar chemical structures and effects. Chemically they range from low molecular weight compounds to high molecular weight, lipophilic substances. Most algal toxins cause human illness by disrupting electrical conductance, uncoupling communication between nerve and muscle, and impeding critical physiological processes. They act by binding to specific membrane receptors, leading to changes in the intracellular concentration of ions such as sodium and calcium. Ion channels play key roles in neurons, and molecules that can modulate their function are useful for the rational design and development of drugs for clinical conditions such as pain, epilepsy, stroke, and cancer.8 Dinoflagellate derived polyketides can be organized into three categories according to their structural type:4 (i) polyether ladders; (ii) linear polyethers and (iii) macrocycles (including macrolides 870 | Nat. Prod. Rep., 2007, 24, 869–885

and non-macrolides). The biosynthetic origins are highly suggestive of a polyketide biogenic pathway.4 The most notorious of the dinoflagellate derived polyketides are the polyether ladder compounds9 typified by brevetoxin B (1), ciguatoxin (2), gambierol (3), and yessotoxin (4) (Fig. 1). These molecules are composed of a series of trans-fused ether rings, with syn stereochemistry across the top and bottom of the molecules resulting in a semi-rigid ladder-like structure. Despite this common polycyclic motif, they exhibit diverse biological activity with high potency mainly by activating voltage dependent sodium channels causing repetitive firing in neurons. The skeletal novelty, complexity and biological activity of these polycyclic ether marine biotoxins have prompted a flurry of activity from synthetic chemists forming the basis for several recent comprehensive reviews in this area.10 Okadaic acid (5) (Fig. 2) is one of the first of the linear polyether shellfish toxins to be isolated from the sponges, Halichondria okadai and H. melanodocia.11 However, it was subsequently established that okadaic acid (5) and the related dinophysis toxins are produced by dinoflagellates of the genera Prorocentrum and Dinophysis.12 Okadaic acid and the related dinophysis toxin DTX-1 are potent tumour promoters and the mechanism of action underlying this activity is their potent ability to inhibit the serine/threonine protein phosphatases PP-1 and PP-2A.13 Notably, the total synthesis of okadaic acid has been reported by several groups.14 Other linear polyethers isolated from planktonic and symbiotic Amphidinium species include the antifungal amphidinols15 e.g. amphidinol 14 (6) from A. klebskii and luteophanols A, B and C16 from Amphidinium sp. (strain Y-52), amphidinin A17 from Amphidinium sp. (strain Y-52) and colopsinol A.18 No significant synthetic studies towards these linear polyether toxins have been initiated to date. One of the most potent toxins known to man, palytoxin, a linear polyketide, was isolated from the soft coral Palythoa toxica19 and subsequently from the benthic dinoflagellate Ostreopsis siamensis.20 Palytoxin has been shown to act on the ouabain site of the Na+ /K+ ATPase receptor.21 The synthesis of palytoxin has been reviewed.22 Azaspiracid-1 (7)23 and its congeners azaspiracids 2–5,24 sonamed because of their unusual azaspiro ring assembly provide interesting examples of linear polyether shellfish toxins. The azaspiracids have been the focus of intensive synthetic studies that have been reviewed recently.25 The original structure of azaspiracid-1 (7), proposed by Yasumoto, has been revised twice. The final corrected structure was elucidated by the impressive total synthesis of azaspiracid-1 (7) by Nicolaou and co-workers.26 The most prolific producers of macrolide-containing shellfish toxins are four strains of Amphidinium, isolated from the Japanese flatworm Amphiscolops sp. From these four strains were isolated 20 macrolides (e.g. amphidinolide N (8), Fig. 3) that exhibited cytotoxicity against several cancer cell lines. In addition amphidinolides B1 , B2 , B3 and B4 , caribenolide I (9) and hoffmaniolide provide further examples of closely related dinoflagellate derived macrolides27 (Fig. 3). Synthetic approaches to the amphidinolides have recently been reviewed by Colby and Jamison.28 A group of macrolide polyether toxins to which outbreaks of diarrhetic shellfish poisoning in Japan were initially attributed are the pectenotoxins exemplified by pectenotoxin-2 (PTX2) (10).29 This journal is © The Royal Society of Chemistry 2007


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Fig. 1

Structures of polyether ladder polyketides derived from dinoflagellates.

Fig. 2 Structures of linear polyether polyketides derived from dinoflagellates.


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Fig. 3 Structures of macrolide polyketides derived from dinoflagellates.

Named after the scallop (Patinopecten yessoensis) from which the toxic extract was first isolated, the pectenotoxins are produced by the toxic dinoflagellate species of the genera Dinophysis (D. acuta and D. fortii). The first pectenotoxins to be isolated were pectenotoxins 1–5 however, since then, more pectenotoxins have been isolated.30–34 The pectenotoxins comprise a macrolide structure containing a spiroacetal, three substituted tetrahydrofurans and 19 (or 20 in the case of PTX11) stereocentres embedded within a 40-carbon chain. PTX2 exhibited selective and potent cytotoxicity against several cancer cell lines at the nanomolar level.35 PTX2 (10) and PTX6 have also been shown to interact with the actin cytoskeleton at a unique site36 thus providing an important research tool for the study of basic cellular behaviour. Synthetic approaches to the pectenotoxin family of toxins have recently been reviewed.37 Goniodomin A (11)38 provides another example of a novel 25membered polyether macrolide isolated from the dinoflagellate Alexandrium hiranoi (formerly Goniodoma pseudogoniaulax) and more recently from Alexandrium monilatum. Goniodomin A (11) was found to exhibit antifungal activity, stimulate ATPase activity by binding to, and altering the conformation of, actin,39 exhibit antiangiogenic activity via inhibition of actin reorganization in endothelial cells40 and increase the fibrous actin content of 1321N1 human astrocytoma cells.41 Despite the significant biological activity reported for goniodomin A (11), somewhat surprisingly no synthetic studies towards this macrolide have been reported. A remarkable group of dinoflagellate derived 62-membered macrolides are the vasoconstrictors zooxanthellatoxins42 and zooxanthellamide.43 These toxins enhance calcium influx in smooth muscle44 and have yet to be the subject of a serious synthetic assault. Of particular interest for the purposes of this review are a group of macrolide shellfish toxins that also contain a cyclic imine unit 872 | Nat. Prod. Rep., 2007, 24, 869–885

that is thought to be a key structural feature for their observed toxicity. Many of these toxins have been classified as “fast-acting toxins” because they cause rapid death within 3–10 minutes when administered intraperitoneally in mice. These toxins also exhibit high oral potency, often with apparent neurological symptoms including piloerection, abdominal muscle spasms, hyperextensions of the back, and arching of the tail to the point of touching the nose. Prorocentrolide A (12) and prorocentrolide B (13, Fig. 4) were isolated from Prorocentrum lima45 and Prorocentrum maculosum,46 respectively. Both macrolides contain a cyclic imine unit and are lethal in the mouse bioassay; however, their mechanism of action has not been elucidated. Synthetic studies towards the procentrolides have been limited to the 12-carbon tetrahydrofuran and tetrahydropyran units.47 Spiroprorocentrimine (14)48 isolated from Prorocentrum sp. possesses a novel spiroimine moiety, a heterocyclic motif that is also present in several related toxins. The marine biotoxin gymnodimine (15)49 was first isolated from oysters (Tiostrea chilensis) collected at Foveaux Strait in the South Island of New Zealand and was found to exhibit neurotoxic shellfish poisoning with a minimum lethal dose (intraperitoneal) of 700 lg mL−1 in the mouse bioassay. Gymnodimine is produced by the dinoflagellate, Karenia selliformis (syn. Gymnodinium selliforme) and its structure was initially elucidated by NMR spectroscopy49 and later confirmed by X-ray crystallographic analysis.50 Gymnodimine has also recently been observed in Tunisia.51 Stewart et al.50 reported the complete loss of toxicity when gymnodimine was reduced to gymnodamine thus suggesting that the cyclic imine functionality is in fact the key pharmacophore of gymnodimine. The effects of gymnodimine and closely related semi-synthetic analogues on cellular viability were also recently examined using a Neuro2A neuroblastoma cell line.52 Several synthetic approaches to gymnodimine (15) are described (vide infra). This journal is © The Royal Society of Chemistry 2007


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Fig. 4

Structure of the spiroimine containing marine toxins.

In 1995 pinnatoxin A (PnTX A) (16) was isolated from the clam Pinna muricata following serious outbreaks of shellfish poisoning in China and Japan.53 Structural elucidation revealed the presence of a 6,5,6-bisspiroacetal motif and a novel 6,7-spiroimine unit. Pinnatoxins B, C and D (17–19) were subsequently reported54 as well as the relative stereochemistry of PnTX A (16)55 that was not able to be determined at the time of isolation. The absolute stereochemistry of PnTX A (16) was finally assigned by the total synthesis of (−)-pinnatoxin A in 199856 and was This journal is © The Royal Society of Chemistry 2007

found to be the antipode of the originally proposed structure. The unique molecular structures of the pinnatoxins and their potent activity as calcium channel activators have prompted a number of other synthetic approaches towards their synthesis (vide infra) and a recent total synthesis of pinnatoxins B and C by the Kishi group has unequivocally established the absolute stereochemistry of these naturally occurring toxins.57 Continued investigation into Japanese shellfish toxins has recently led to the isolation of pteriatoxin A (PtTX A) (20) and a Nat. Prod. Rep., 2007, 24, 869–885 | 873


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1 : 1 mixture of pteriatoxins B (21) and C (22)58 (PtTX B/C) from the viscera of the Okinawan bivalve Pteria penguin. The compounds were obtained in extremely small amounts and found to show acute toxicity, similar to that of the pinnatoxins. Complete structural elucidation confirmed that the pteriatoxins were in fact pinnatoxin analogues containing a methionine a-amino acid moiety in the C-34 side-chain. The absolute stereochemistry of pteriatoxins A, B and C has recently been established unequivocally59 based on an intensive synthetic programme by the Kishi group that afforded a unified total synthesis60 of the pteriatoxins and allowed access to all possible stereoisomers of each member of this class of shellfish toxin. Closely related to the pinnatoxins are the spirolide family of marine biotoxins. Spirolides A–D (23–26) comprise a novel family of pharmacologically active macrocyclic imines found in the polar lipid fraction of the digestive glands of contaminated mussels (Mytilus edulis), scallops (Placopecten magellanicus) and toxic plankton from the eastern coast of Nova Scotia, Canada. Spirolides A–D contain an unusual 5,5,6-bis-spiroacetal moiety together with a rare 6,7-spirocyclic imine.61 Spirolides E and F (30–31), are keto-amine hydrolysis derivatives resulting from ring opening of the cyclic imine unit, and are biologically inactive, thus suggesting that the cyclic imine functionality is the pharmacophore responsible for toxicity.62 Isolation and culture of a toxic clone of the dinoflagellate Alexandrium ostenfeldii, obtained from the same aquaculture site, allowed structural elucidation of several more congeners, spirolides A, C and 13-desmethyl C.63 Recent radiolabeling studies have confirmed both the polyketide biosynthetic origin of 13-desmethyl spirolide C.64 Spirolide G65 and 20-methylspirolide G66 which contain a different 5,6,6-bisspiroacetal ring system have also recently been reported. 13,13,19Didesmethyl spirolide C65 (28), and desmethyl spirolide D (29)67 provide further congeners. The absolute stereochemistry of the spirolide family of toxins has not been established to date, however, a computer-generated relative assignment of 13-desmethyl spirolide C (27) indicating the same relative stereochemistry as the related toxin pinnatoxin A in the region of their common structure has been reported.68 Spirolides A–D cause potent and characteristic symptoms in the mouse bioassay and weakly activate L-type calcium channels. Preliminary pharmacological research into the mode of action of the spirolides suggests they are antagonists of the muscarinic acetylcholine receptor (mAChR).69 More recently research by Gill et al.70 has revealed that gene expression of mAChR11, 4, and 5 and nAChRa2 and b4 as well as the early neural injury markers c-Jun and HSP-72 were all upregulated in the brain stem and cerebellum of rats given a high (and fatal) dose of the spirolide toxins. The unique heterocyclic motifs of both the bis-spiroacetal and spiroimine moieties of the spirolides have prompted several synthetic endeavours that are described in this review (vide infra). The fact that the prorocentrolides, gymnodimine, the pinnatoxins and the spirolides are all fast acting toxins in the mouse bioassay eliciting similar symptoms suggests that they have a common mode of action possibly attributed to the common presence of a cyclic imine function. Given the unique biological activities associated with these compounds synthetic approaches to this family of cyclic imine-containing macrolide shellfish toxins are reviewed herein. 874 | Nat. Prod. Rep., 2007, 24, 869–885

2 Synthesis of pinnatoxin A 2.1 Kishi’s synthesis of (−)-pinnatoxin A Kishi’s convergent synthesis of (−)-pinnatoxin A56,57 (ent-16) hinged on an ambitious late stage biomimetic Diels–Alder macrocyclization (Scheme 1). Based on a biosynthetic pathway postulated by Uemura in 1995,71 this cycloaddition relies on substrate directed stereocontrol to obtain the correct diastereofacial selectivity. The cyclisation precursor 34 was constructed by a highly convergent route using dithiane alkylation, and a series of Nozaki–Hiyama–Kishi (NHK) couplings as key steps.

Scheme 1

Synthesis of pinnatoxin A by Kishi et al.

Key steps in the synthesis of 6,5,6-spiroketal fragment 38 are shown in Scheme 2 and involve asymmetric allylation of aldehyde This journal is © The Royal Society of Chemistry 2007


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Scheme 2 Reagents and conditions: (1) (−)-MeOB(Ipc)2 , allylMgBr, Et2 O, −78 ◦ C; (2) TBSOTf, 2,6-lut., CH2 Cl2 0 ◦ C; (3) DIBAL, THF, −78 ◦ C, 78% (3 steps); (4) I2 , PPh3 , imidazole, CH2 Cl2 –benzene, 86%; (5) t BuLi (2 equiv.) add 43 −78 ◦ C, 50 min, add 44 −78 → 0 ◦ C 82%; (6) AD-mix-a, 0–10 ◦ C, 5 h, 73%; (7) (COCl)2 , DMSO, i Pr2 NEt, 77%; (8) CSA (3 mol%), MeOH, 10 h, 51%; (9) TBSOTf, 2,6-lut., CH2 Cl2 , 0 ◦ C 99%; (10) OsO4 , NMO, acetone–H2 O; (11) NaIO4 , THF–H2 O, pH 7, 85% (2 steps).

42 followed by high yielding alkyllithium addition of 43 to chiral aldehyde 4472 to give an isomeric mixture of allylic alcohols. Selective asymmetric dihydroxylation of the trisubstituted olefin using AD-mix-a gave a triol that was then oxidized to diketone 46. The critical acid catalyzed spiroketalization step afforded a product with an incorrectly configured C19 stereocentre; however, subsequent silyl protection of alcohols 47 resulted in epimerization at C19 to give the desired configuration. Oxidative cleavage of the terminal double bond of 48 provided aldehyde 38 over two steps. Addition of the alkyllithium derived from iodide 39 to aldehyde 38 (Scheme 3), followed by oxidation and methylenation of the resultant alcohol gave the C10 terminal olefin in excellent yield over three steps. Following installation of the dithiane, lithiated 49 was treated with iodide 36 in the presence of HMPA to give coupled product in moderate yield (Scheme 3). PMB ether 51 was then converted to aldehyde 52 in preparation for an NHK coupling. In the presence of CrCl2 –NiCl2 , vinyl iodide 40, prepared from chiral 5372 was added to aldehyde 52 giving a modest yield of an allylic alcohol that was immediately deprotected and oxidized This journal is © The Royal Society of Chemistry 2007

to aldehyde 54 in preparation for the second NHK addition. The second NHK coupling of tert-butyl 2-iodoacrylate (35) to 54 was effected in modest yield under somewhat more elaborate conditions using the bispyridinyl ligand 6-CHIRABIPPY73 yielding, after acetonide removal, allylic alcohols 55 as a 3 : 1 mixture of diastereomers. The masked diene was liberated in an SN 2 reaction by treating mesylate 56 with DABCO followed by NEt3 . The authors noted that similarly carboxylated dienes had a high propensity to dimerize via intermolecular cycloaddition,74,75 and therefore the DA-macrocyclization was carried out under dilute conditions. The facial selectivity of the macrocyclization proved to be critically dependent on the configuration of the C25–C32 backbone. Interestingly, conversion of acetonide 54 to a Diels–Alder precursor followed by heating (toluene 100 ◦ C, 0.2 mmol) gave the desired exo adduct as the sole product in 60% yield. This route however was not pursued because the C29–C30 acetonide could not be removed. The diene derived from mesylate 56 was heated under dilute conditions to effect a DA-macrocyclization. Only three of the eight possible isomers were observed; one endo, and two exo adducts, all of the same regiochemistry. By changing the solvent to dodecane the formation of the undesired endo isomer was suppressed. Further elucidation of factors governing the diastereofacial selectivity of this interesting macrocyclization were investigated in Kishi’s total synthesis of the closely related pteriatoxins (vide infra). Deprotection of 57 gave the amino-ketone 58 which initially proved reluctant to cyclize. Noting that the imine present in PnTX A (16) was stable to acidic conditions, the authors proposed a high energy barrier to form the necessary tetrahedral intermediate due to the presence of a vicinal quaternary centre. Imine formation was eventually accomplished by heating a neat sample of 58 to 200 ◦ C under vacuum. Finally, global deprotection furnished (−)-PnTX A. 2.2 Total synthesis of the pteriatoxins The pteriatoxins (PtTXs) were synthesised by the Kishi group again using an IMDA as the key bond forming reaction (Scheme 4) with the notable difference being the C33 functionalization on the diene precursor 59 (cf. intermediate 55, Scheme 3). Replacement of the conjugated carboxydiene resulted in a synthetic advantage wherein the diene was no longer prone to intermolecular cycloaddition.76 Variation of both the C34–C35 diol protecting group, and the reaction temperature resulted in an optimized 51% yield of the desired isomer 60 along with three other minor isomers. A cysteine unit was introduced from a common C34–35 epoxide intermediate thus providing access to all members of the pteriatoxin family of toxins. Rigorous comparison of the natural and synthetic material allowed complete assignment of the relative and absolute configuration of the pteriatoxins.77 2.3 Formal synthesis of pinnatoxin A In 2004 Hirama et al. secured a formal synthesis of PnTX A (16) by preparing ent-58 (Scheme 5) which was enantiomeric to an intermediate synthesised by the Kishi group en route to PnTX A (cf. Scheme 3).78 With a unique end game strategy (Scheme 5) the Hirama group constructed the entire macrocyclic Nat. Prod. Rep., 2007, 24, 869–885 | 875


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Scheme 3 Reagents and conditions: (1) 39, t BuLi −78 ◦ C, then add 38, −78–0 ◦ C, 15 min, 88%; (2) (COCl)2 , DMSO, i Pr2 NEt, −78 → 0 ◦ C, 92%; (3) PPh3 CH3 Br, n BuLi, 0 ◦ C, 89%; (4) TBAF, THF, 2.5 h, 100%; (5) I2 , Ph3 P, imidazole, DCM–benzene 1 : 1, 15 h, 95%; 1,3-dithiane, t BuLi, THF–HMPA 10 : 1, 92%; (6) t BuLi, THF–HMPA 10 : 1, −78 ◦ C, 5 min then add 36, 2 min, 71% (7) (CF3 CO2 )2 IPh, MeCN–MeOH 5 : 1, −10 ◦ C, 5 min, 82%; (8) 1 mol% NiCl2 –CrCl2 , DMSO, 8.5 h, 55%; (9) HF.py–pyridine–THF 1 : 2 : 8 : 3, 2 h, 91%; (10) DMP, NaHCO3 , DCM, 1 h, 91%; (11) 6-CHIRABIPY, 33 mol% NiCl2 –CrCl2 , THF, 35, and then 54, 88%; (12) DCM–TFA–H2 O, 1 h, 71%; (13) DABCO, NEt3 , benzene, 1 h; (14) diene (0.2 mM), dodecane, 70 ◦ C, 78%; (15) 200 ◦ C, 1–2 Torr, 70%; (16) TFA–DCM 1 : 1, 95%.

Scheme 4

Reagents and conditions: (1) tert-butyl-4-hydroxy-2-methylphenyl sulfide, dodecane, 160 ◦ C, 12 h, 51%.

skeleton from dithiane 62 and iodide 63 over three synthetic steps involving dithiane alkylation, desilylation, and ring closing metathesis (RCM). The C5 quaternary centre of fragment 63 was constructed stereoselectively by intramolecular epoxide alkylation (Scheme 6). Arguably one of the most synthetically challenging aspects of the PnTX synthesis, the C5 quaternary centre, was constructed by 6-exo-tet cyclization of the C5 nitrile anion derived from 64 (Scheme 6) onto the in situ derived C30–C31 epoxide. Model 876 | Nat. Prod. Rep., 2007, 24, 869–885

studies by the same group had shown that the diastereoselectivity of the quaternary C5 centre and tertiary C31 centre in the product could be completely controlled by an anti arrangement in the transition state between the planar nitrile ‘enolate’ equivalent and the epoxide groups.79 Treatment of 64 with excess base resulted in the formation of only one diastereomer 65. Interestingly, the C28 carbinol remained unprotected throughout this reaction sequence. The second key fragment 62 was constructed by bisspiroacetalization of 66. The acetonide function of 66 was first This journal is © The Royal Society of Chemistry 2007


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Scheme 5 Formal synthesis of PnTX A by Hirama et al.78

Stork reagent82 then the bicyclic spiroacetal moiety was formed by sequential deprotection of the acetonide function followed by camphorsulfonic acid induced cyclization. The C10 allylic alcohol moiety was converted to exo-methylene derivative 73 in three steps involving DDQ oxidation to the enone,83,84 1,4-reduction with the Stryker reagent,85 and Wittig methylenation. Eight further steps were required to complete the formal synthesis of pinnatoxin A.

3 Other synthetic approaches towards the PnTX family of toxins 3.1 Murai’s approach to the C10–C31 PnTX skeleton

Scheme 6 Reagents and conditions: (1) KHMDS (2.5 equiv.), THF, 0 ◦ C, then KHMDS (1.5 equiv.), 0 ◦ C → rt, 72%; (2) CSA 10 mol%, MeOH, rt, 3 h, then CSA, toluene, 2 days, 84% (2 steps).

removed using camphorsulfonic acid in methanol, then the solvent was changed to toluene to effect the final acetal rearrangement. Significantly, changing the solvent from methanol to toluene prevented the formation of undesired diastereomers during bisspiroacetalization. The predominance of the desired isomer formed in non-polar solvent was rationalized by the presence of a stabilizing hydrogen bond in the product. A similar hydrogen bond was observed in the crystal structure of a model compound made by the same group.80 Following the alkylation of dithiane 62 with iodide 63 (Scheme 7), it was then necessary to desilylate the allylic and homoallylic carbinols in order to facilitate the ring closing metathesis, presumably for steric reasons. The RCM then proceeded in the presence of Grubbs catalyst 7081 to give diol 71 in high yield. The dithiane was converted to ketal 72 using the This journal is © The Royal Society of Chemistry 2007

The task of synthesizing the C10–C31 carbon skeleton common to the PnTX and PtTX family has been undertaken by several other groups most notably Murai,86–89 Hashimoto,90–92 and Hirama.78–80,93,94 Murai’s approach to the C10–C31 advanced intermediate 75 (Scheme 8) relied on a tandem cyclization to construct the spiroacetal functionality. The tetraketone intermediate 74 was constructed using two additions of sulfonyl anions to aldehydes followed by oxidation and desulfurization to forge the C18–C19 and C25–C26 bonds. Upon selective desilylation, tetraketone 74 underwent tandem cyclization to afford pentacycle 75 in excellent yield. The same group has also disclosed a stepwise route to the same C10–C31 fragment incorporating the C15 tertiary carbinol.87

3.2 Hashimoto’s approach to the C10–C31 PnTX skeleton The approach taken by Hashimoto et al. to the same C10– C31 fragment took advantage of a hemiacetal 1,4-conjugate addition to construct the critical C23–O bond (Scheme 9). The convergent synthesis of cyclization precursor 76 relied on two aldol dehydration reactions and a dithiane alkylation. Selective desilylation at C12 resulted in the formation of a mixture of acetals that were then subjected to basic conditions to effect Michael addition of the derived C19 hemiacetal to the C23 enone moiety of 76. Acidolysis of the acetonide group then afforded 77. Nat. Prod. Rep., 2007, 24, 869–885 | 877


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Scheme 7 Reagents and conditions: (1) t BuLi (1.9 equiv.), THF–HMPA 9 : 1 −78 ◦ C 95%; (2) TBAF, THF, 0 ◦ C, 89%; (3) 70 10 mol%, DCM, reflux, ˚ MS, rt; (4) TFA–MeOH 1 : 20, rt, then CSA, MeOH, rt, 71% (2 steps); (5) DDQ, 1,4-dioxane–DCM 1 : 75%; (4) (CF3 CO2 )2 IPh, MeOH–DCM 20:9, 3 A 1, 40 ◦ C, 67%; (6) {(Ph3 P)CuH}6 10 mol%, toluene–H2 O 100 : 1, rt, 64%; (7) Ph3 PCH3 Br, t BuOK, THF, 0 ◦ C, 64%.

Scheme 8 Reagents and conditions: (1) HF.Py, MeCN, 24 ◦ C, 7.5 h, 83% (after 1 recycle).

3.3 Zakarian’s approach to the spiroimine unit of PnTX and PtTX

Scheme 9 Reagents and conditions: (1) 1 N HCl–THF, 0 ◦ C, 1 h; (2) LiOMe (1 equiv.), THF–MeOH 10 : 1, 4 h, 77%; (3) CSA, DCM, 5 h, 62%.

Zakarian’s innovative approach to the spiroimine moiety of the PnTX and PtTX family of molecules made use of a [3,3]-Claisen rearrangement followed by a [2,3]-Mislow–Evans sigmatropic cascade (Scheme 10).95 Dihydropyran 80 was synthesised using a high yielding sp2 –sp3 Suzuki coupling of vinyl triflate 78 to the hy-

droboration adduct 79. Under optimized conditions,96 microwave irradiation of 80 in the presence of triethyl phosphite effected tandem rearrangement on a multigram scale, thereby installing the C5 quaternary centre in 81 with a high degree of stereocontrol.

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Scheme 11 Reagents and conditions: (1) n BuLi, THF, −78 ◦ C, 30 min, then 85; (2) DMP, NaHCO3 , DCM, 40 min; (3) SmI2 , MeOH, THF, 0 ◦ C, 40 min, 86% (3 steps); (4) RuO2 , NaIO4 , CCl4 –MeCN, H2 O 2 : 2 : 3, 23 ◦ C, 10 h, 74%; (5) HF.Py, MeCN, 23 ◦ C, 8.5 h, 85%; (6) MeLi, THF, −78 ◦ C, 30 min, 99%; (7) TBSOTf, 2,6-lut., CH2 Cl2 , 0 ◦ C → 20 ◦ C, 53%.

4.1 Brimble’s synthesis of the bis-spiroacetal moiety of the spirolides

Scheme 10 Reagents and conditions: (1) Pd(PPh3 )4 (5 mol%), NaOH (3 equiv.), dioxane, 60 ◦ C, 3 h, 91%; (2) P(OEt)3 , s-collidine, MeOCH2 CH2 OCH2 CH2 OH, 50 W, 170 ◦ C, 20 min, 150 ◦ C, 15 h, 82%; (3) PMe3 , rt, 8 h, then 110 ◦ C, 100%.

Following functional group manipulation, Staudinger reduction97 of the C1 azide in 82 gave imine 83 in quantitative yield. It was proposed that alkylation of C31 can then be accomplished using either p-allyl palladium methodology or by allylic substitution using cuprate reagents.

4

Synthetic studies towards the spirolides

Although a total synthesis of the spiroimine unit of these molecules has not yet been reported, the 5,5,6-bis-spiroacetal fragment, encompassing C10–C23 of the natural product, has been synthesized by the Brimble98,99 and the Ishihara groups.100 In the first synthesis of the bis-spiroacetal moiety of the spirolides, the Ishihara group synthesized the carbon skeleton by addition of sulfone 84 to aldehyde 85 (Scheme 11) followed by oxidation and desulfurization to give ketone intermediate 86. Alkyne oxidation101 of 86 to diketone 87 followed by desilylation and subsequent bisspiroacetalization afforded a mixture of C15 isomers of which 88 was the minor product. Stereoselective axial addition of methyllithium to the isomeric mixture of spirocyclic ketones 88 gave, after protection of the C19 alcohol, the desired product 89 as the major product of a mixture of C15 acetals. This journal is © The Royal Society of Chemistry 2007

The Brimble approach to the bis-spiroacetal portion of the spirolides made use of two sequential oxidative radical cyclizations,98,99,102,103 and began with the construction of cis-dihydrofuran 93 using a silyl modified Prins reaction (Scheme 12).104–108 Aldehyde 95 was prepared in five steps from monoprotected propane-1,3-diol (94) in which the key asymmetric step was a Brown crotylboration.109 Grignard coupling of aldehyde 95 to bromide 93 proceeded well under Barbier conditions to give a mixture of epimeric alcohols 96 which, after a sequence of oxidative radical cyclization and protection steps (96 → 99), gave an equal mixture of the four possible bis-spiroacetal isomers. Interestingly, treatment of this isomeric mixture of bis-spiroacetals with commercial mCPBA, containing a small amount of mchlorobenzoic acid, resulted in equilibration to the thermodynamically favored isomer before the epoxidation step delivered oxygen to only one face of the olefin affording 100. It was assumed that facial selectivity during the epoxidation was derived from hydrogen bonding effects in the transition state. Selective opening of epoxide 100, followed by oxidation of the resultant alcohol gave a ketone that was methylated with methylmagnesium bromide. In accordance with Ishihara’s results,100 methylation occurred via the axial trajectory giving the desired isomer 101 as the sole product.

5 Gymnodimine 5.1 Synthesis of the gymnodimine skeleton Kishi et al. reported a biomimetic synthesis of the gymnodimine skeleton 101 based on a Diels–Alder macrocyclization using an Nat. Prod. Rep., 2007, 24, 869–885 | 879


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Scheme 12 Reagents and conditions: (1) InCl3 , DCM, rt, 73%; (2) (COCl)2 , DMSO, NEt3 , DCM, −78 ◦ C, 96%; (3) n BuLi, t BuOK, (Z)-butene, (−)-(Ipc)2 B(OMe), BF3 ·OEt2 , THF, −78 ◦ C, NaOH, H2 O2 , 72% (4) TBDPSCl, imid, DMF, 100 ◦ C, 99%, (5) BH3 ·DMS, THF, rt, then NaOH, H2 O2 , 78%; (6) DMP, Py, DCM, rt, 84%; (7) Mg, Br(CH2 )Br, I2 , Et2 O, rt, 72%; (8) PhI(OAc)2 , I2 , hm, cyclohexane, rt, 81–86%; (9) mCPBA, DCM, 0 ◦ C → rt, 63%; (10) DIBALH, hexane, 0 ◦ C, 54%; (11) DMP, Py, DCM, rt, 88%; (12) MeMgBr, Et2 O, −78 ◦ C, 86%.

Scheme 13

Kishi’s synthesis of the gymnodimine skeleton.110

a,b-unsaturated iminium species 102 as the dienophile component (see retrosynthesis, Scheme 13).110 The concept of using unsaturated imines as dienophiles had been clearly illustrated by MacMillan who found that condensing an a,b-unsaturated ketone with a secondary amine generated a reactive dienophile.111 The key advanced intermediate 103 was constructed via two sequential NHK alkylations of intermediates 104 and 105 respectively to cistetrahydrofuran intermediate 106. The tetrahydrofuran fragment 106 in turn was prepared efficiently by acid mediated cyclization of allyl alcohol 107. The synthesis of the cis-tetrahydrofuran 106 (Scheme 14) commenced with Myers asymmetric alkylation112,113 of epoxide 109 which provided aldehyde 110 after further elaboration. Alkylation 880 | Nat. Prod. Rep., 2007, 24, 869–885

of 110 under NHK conditions gave allylic alcohol 107 as a mixture of epimers. Acidolysis of the epimeric mixture 107 with excess ptoluenesulfonic acid effected cyclization, via an intermediary allyl cation, to give the desired cis-tetrahydrofuran (112) as a 9 : 1 isomeric mixture. As a testament to the reliability of the synthesis, this cyclization could be carried out on a 6.2 g scale. Oxidation then afforded aldehyde 106. The triene fragment 104 was then installed by NHK alkylation of aldehyde 106 (Scheme 15) resulting in a 1 : 1 mixture of allylic alcohols at C10. The stereochemistry of the C10 carbinol was corrected by allylic oxidation followed by asymmetric CBS reduction. A third NHK alkylation followed by allylic oxidation gave the advanced intermediate 115. This journal is © The Royal Society of Chemistry 2007

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formation of a necessary tetrahedral aminal intermediate vicinal to a quaternary spirocyclic centre. It now seems likely that a subtle interplay of steric factors also involving the macrocyclic ring is responsible for the observed hydrolytic stability of gymnodimine and several other spirocyclic imine containing shellfish toxins.


5.2 Synthetic studies towards gymnodimine, Murai et al.

Scheme 14 Reagents and conditions: (1) CrCl2 –NiCl2 , DMF, 86%; (2) PTSA, DCM, 86% (9 : 1 isomeric); (3) (COCl)2 , DMSO, NEt3 , DCM, 80%.

Macrocyclization was attempted using a,b-unsaturated ketone 115 in an organic solvent, but unfortunately this resulted in exclusive formation of the undesired endo isomers. Global deprotection of 115 gave amino ketone 103 which spontaneously cyclized to give a,b-unsaturated imine 102. In a model NMR study, a similar a,b-unsaturated aliphatic imine proved to be surprisingly stable, even for extended periods in acidic media. The macrocyclization was carried at a concentration of 60 lmol in citrate buffer at pH 6.5 and was complete after 48 h at 36 ◦ C giving a 1 : 1 mixture of the desired exo 117 and undesired endo 118 isomers. Fascinatingly, the undesired endo isomer 118 was hydrolytically unstable breaking up to give an amino ketone under the aqueous reaction conditions. In contrast, the desired exo-adduct 117, with the same relative stereochemistry as that of the natural product, retained an imine functionality that was observed to be stable to the aqueous conditions. In his earlier synthesis of PnTX A, Kishi proposed that hydrolytic stability of the imine products was a result of a high energy barrier to the

The Murai114,115 approach to the C1–C19 backbone of gymnodimine draws from the chiral pool to access fragments 120 and 122 which are unified in a Horner–Wadsworth–Emmons (HWE) reaction, carried out under Masamune–Roush116 conditions, to give intermediate 123 (Scheme 16). The critical DA cycloaddition between a-methylene lactam 125 and diene 123 was carried out in the presence of Ellman’s copper bis(sulfinyl)imidoamidine complex (126)117 and proceeded with excellent regio- and diastereofacial selectivity to give only one cycloadduct 127 in good yield. It is interesting to note that the Evans’ ligand (S,S)-t-Bu-BOX failed to give any reaction under the same conditions. 5.3 Synthetic studies towards gymnodimine, Romo et al. The Romo group have developed three independent syntheses for the butenolide, spiroimine and tetrahydrofuran segments of gymnodimine encompassing the entire carbon framework of the molecule.118–122 Similar to the Murai group, Romo et al.120,121 formulated their approach to the spiroimine portion of gymnodimine on the use of an intermolecular Diels–Alder cycloaddition of an a-methylene lactam 135 to alkyne containing dienes 130 and 132 (Scheme 17).120 A three carbon alkyne-containing tether on the diene served as a handle for further functionalization. It was initially predicted that a Z-diene would be required for the Diels–Alder cycloaddition in order to enforce exo-selectivity in the product. However, it was later discovered that both geometric isomers of the diene could be usefully employed. Both Z- and E-dienes were available by either hydrotelluration123 or hydrostannylation of hexa-2,4diyne124 followed by metallation and acylation using Weinreb amide 133 (Scheme 17).

Scheme 15 Reagents and conditions: (1) 106, NiCl2 –CrCl2 , Ni(COD)2 , THF, DMF, t BuPy, 50 ◦ C, 70%; (2) MnO2 , DCM, 50%; (3) (R)-2-methyloxazaborolidine, BH3 ·DMS, tol, −10 ◦ C, 80%; (4) 105, 0.5 mol%, NiCl2 –CrCl2 , DMF, 56%; (5) MnO2 , DCM, 83%; (6) TBAF, THF, 78%; (7) Pd(PPh3 )4 , tol, 1% AcOH, (8) pH 6.5, sodium citrate–HCl, H2 O, 36 ◦ C, 48 h, conc. = 60 lM.


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Scheme 16 Reagents and conditions: (1) LiCl, MeCN, i Pr2 NEt, 0 ◦ C, 2 h, 90%; (2) (R)-2-methyl-oxazaborolidine, BH3 ·DMS, tol, −10 ◦ C, 10 min, 98%; ˚ MS, DCM, 25 ◦ C, 35 h. (3) TBDPSCl, imidazole, DCM, 25 ◦ C, 12 h, 98%; (4) (−)-siam·Cu(SbF6 )2 (1 equiv.), 3 A

Scheme 18 Reagents and conditions: 136 (22 mol%), CuCl2 (20 mol%), ˚ MS, DCM, 25 ◦ C, 10 h, 85%, dr > 19 : 1, 95% ee. AgSbF6 (40 mol%), 3 A

Scheme 17 Reagents and conditions: (1) Bu2 Te2 , NaBH4 , EtOH, reflux, 3 h, 77%; (2) n BuLi, THF, −78 ◦ C, 1 h then 133, 0.75 h, 90%; (3) NaHMDS, TBSOTf, THF, −78 ◦ C, 0.5 h, 82%; (4) (Bu3 Sn)2 CuCNLi2 , MeOH, THF, −78 ◦ C.

Initial experiments using the strong Lewis acid Me2 AlCl demonstrated that the desired relative stereochemistry about the spiroimine unit was obtained irrespective of the initial diene olefin geometry thereby indicating a stepwise, rather than a concerted process. A cationic intermediate for this reaction was thus invoked. In contrast to the use of the strong Lewis acid Me2 AlCl, in the presence of the chiral Evans’ catalyst {Cu[(S,S)t-Bu-BOX]}(SbF6 )2 only the E-diene 132 cyclized. Given that a likely concerted mechanism operates under the latter milder conditions, the lack of reactivity of the Z-diene under Evans catalytic conditions was thought to be due to steric interactions between the alkyne and the BOX ligand 136 in the transition state (Scheme 18). Romo’s approach to the cis-tetrahydrofuran 142 unit of gymnodimine121 makes use of a Heathcock anti-aldol reaction125–127 between ephedrine derived auxiliary 138 and aldehyde 139 to establish the C15–C16 stereocenters (Scheme 19). Acid catalyzed cyclization of the derived enol ether 140 gave the lactol ether 141 as a mixture of epimers which were then allylated 882 | Nat. Prod. Rep., 2007, 24, 869–885

Scheme 19 Reagents and conditions: (1) pTSA cat. MeOH, 25 ◦ C, 86%; (2) allyltrimethylsilane, BF3 ·OEt2 , Et2 O, 0 ◦ C, 95%.

to give the cis-tetrahydrofuran 142 as the major product, albeit as a 4 : 1 mixture of diastereomers that were separated at a later stage. Romo was the first to access the C1–C4 butenolide fragment of gymnodimine118 with a synthesis based on the use of a novel vinylogous Mukaiyama aldol reaction. In a model study using This journal is © The Royal Society of Chemistry 2007

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methylcyclohexanone 143 as the substrate, it was shown that silyloxyfuran 144 approaches the Lewis acid co-ordinated ketone from the equatorial direction in such a way as to minimize steric interactions (Scheme 20). Critically, the relative stereochemistry in the product is governed by the configuration of the starting material in a predictable manner. Elimination of the tertiary carbinol of 145 gave an intermediate 146 containing all the C1–C6 functionality of gymnodimine.

the cis-selective iodoetherification, and had previously been used by Bartlett and Rychnovsky129 to effect such a transformation. Several other alcohol protecting groups including Piv, TBS, and Bn were tested, however inferior results were obtained wherein the trans-tetrahydrofuran was the predominant product. The White group elected to synthesise the two chiral centres of the spirocyclic imine unit via Diels Alder cycloaddition of (S)glyceraldehyde-derived diene 152 to symmetric Meldrum’s acidderived dienophile 153 (Scheme 22).130 Whereas reaction of diene 152 with unsymmetrical dienophiles resulted in the formation of regioisomers and stereoisomers, the use of the doubly activated and symmetric dienophile 153 gave only two chromatographically separable cycloadducts 154 and 155 with complete regioselectivity. Differentiation of the chemically similar carbonyl groups of 154 was achieved by deprotection of the PMB group whereupon cyclization of the primary alcohol to the proximal carbonyl gave lactone 156. Following elaboration to cyano-enone 157, Michael addition of a higher order vinyl cuprate in the presence of TMSCl gave an enol ether. Reduction of the nitrile function with lithium aluminium hydride gave the desired imine 158 upon basic workup.

Scheme 20 Reagents and conditions: (1) TiCl4 , −78 ◦ C; (2) SOCl2 , Py, DCM, −50 ◦ C, 88%, D2,3 : D1,2 = 6 : 1.

5.4

Synthetic studies towards gymnodimine, White et al.

The synthetic plan adopted by the White group for the construction of the cis-tetrahydrofuran moiety of gymnodimine128 is outlined in Scheme 21 and relied on the iodoetherification of olefin 148, itself readily available from 147 in four steps. The 2,6dichlorobenzyl (DCB) protecting group was found to have an ideal combination of steric and electronic properties in order to achieve

Scheme 22 Reagents and conditions: (1) EtOH, HOAc, 25 ◦ C, 48 h, 85%; (2) DDQ, DCM–H2 O; (3) CH2 =CHLi, (2-Th)Cu(CN)Li then Me3 SiCl; (4) LiAlH4 , Et2 O, 10 min, then NaOH, H2 O, 29% (2 steps).

6 Acknowledgements The authors would like to thank the New Zealand Foundation for Research Science and Technology.

7 References Scheme 21 Reagents and conditions: (1) I2 , MeCN, 20 ◦ C, 87%.


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