Vol 441|15 June 2006|doi:10.1038/nature04820
LETTERS Control of four stereocentres in a triple cascade organocatalytic reaction Dieter Enders1, Matthias R. M. Hu¨ttl1, Christoph Grondal1 & Gerhard Raabe1
Efficient and elegant syntheses of complex organic molecules with multiple stereogenic centres continue to be important in both academic and industrial laboratories1. In particular, catalytic asymmetric multi-component ‘domino’ reactions, used during total syntheses of natural products and synthetic building blocks, are highly desirable2,3. These reactions avoid time-consuming and costly processes, including the purification of intermediates and steps involving the protection and deprotection of functional groups, and they are environmentally friendly and often proceed with excellent stereoselectivities4,5. Therefore, the design of new catalytic and stereoselective cascade reactions is a continuing challenge at the forefront of synthetic chemistry6. In addition, catalytic cascade reactions can be described as biomimetic, as they are reminiscent of tandem reactions that may occur during biosyntheses of complex natural products7,8. Here we report the development of an asymmetric organocatalytic triple cascade reaction for the synthesis of tetra-substituted cyclohexene carbaldehydes. This three-component domino reaction proceeds by way of a catalysed Michael/Michael/aldol condensation sequence affording the products with good to moderate yields (25–58 per cent). During this sequence, four stereogenic centres are formed with high diastereoselectivity and complete enantioselectivity. In addition, variation of the starting materials can be used to obtain diverse polyfunctional cyclohexene derivatives, which can be used as building blocks in organic synthesis. During the past few years, the field of asymmetric catalysis, previously dominated by biocatalysis and metal catalysis, has been complemented by organocatalysis using small organic molecules as a
third powerful tool. Organocatalysts are usually non-toxic, highly efficient and selective, readily available, metal-free and robust, explaining the growing interest in their use for organic synthesis9–11. In particular, secondary amines—capable of both enamine as well as iminium catalysis—can be used to design ‘domino’ processes12. Recently, List13, MacMillan14 and Jørgensen15 showed examples of this property by merging first iminium and then enamine activation. In contrast, we embarked on a reverse strategy using enamine activation of the first substrate to start a triple cascade. The reaction sequence that we have devised is depicted in Fig. 1. This catalytic cascade is a three component reaction comprising a linear aldehyde A, a nitroalkene B, an a,b-unsaturated aldehyde C and a simple chiral secondary amine, which is capable of catalysing each step of this triple cascade. In the first step (Fig. 2), the catalyst (S)-1 activates component A by enamine formation, which then selectively adds to the nitroalkene B in a Michael-type reaction16. The following hydrolysis liberates the catalyst, which is now able to form the iminium ion of the a,b-unsaturated aldehyde C to accomplish the conjugate addition with the nitroalkane 317. In the subsequent third step, a further enamine activation of the proposed intermediate 4 leads to an intramolecular aldol condensation via 5. Hydrolysis returns the catalyst for further cycles and releases the desired tetrasubstituted cyclohexene carbaldehyde 2. It is well known that nitroalkenes B18 are among the most reactive Michael acceptors, explaining the chemoselectivity of the first step of the catalytic cycle. Therefore the enamine of A reacts much faster with B than with the a,b-unsaturated aldehyde C. Once the Michael
Figure 1 | Asymmetric, organocatalytic three component multistep reaction cascade. RT, room temperature.
Figure 2 | Proposed catalytic cycle of the triple cascade. The newly formed bond of each step is shown in red for clarity.
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany.
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Table 1 | Yield and stereoselectivities of reported reactions 2
a§ b c d e f g h i j k l
d.e., e.e.‡ (%)
Me Me Me Me Et i-Pr Bn CH2OTBS Me Me Me Me
Ph o-ClPh p-MeOPh Piperonyl Ph Ph Ph Ph Ph Ph Ph 5-Methyl-furan-2-yl
Ph Ph Ph Ph Ph Ph Ph Ph H Me n-Bu Ph
40 (70) 51 (61) 38 (65) 39 (64) 58 (60) 56 (62) 38 (45) 54 (62) 50 (58) 25 (32) 29 (33) 37 (57)
7.8:2.2 8.4:1.6 8.3:1.7 8.7:1.3 8.0:2.0 7.9:2.1 8.9:1.1 9.9:0.1 8.6:1.4 6.8:3.2 8.0:2.0 8.9:1.1
.99 .99 .99 .99 .99 .99 .99 99 .99 .99 .99 99
Properties of the reported chemo-, diastereo- and enantioselective three component domino reaction affording the tetra-substituted cyclohexene carbaldehydes 2. * Yield of the isolated main diastereomer (in parenthesis: yield of the crude main diastereomer determined by gas chromatography). †The diastereomeric ratio (d.r.) was determined by gas chromatography mass spectrometry. The minor diastereomer was determined as the 5-epimer of 2 (Supplementary Information). ‡ The diastereomeric and enantiomeric excess (d.e., e.e.) was determined by HPLC on a chiral stationary phase (Supplementary Information). §The reaction was carried out on a 20 mmol scale using only 10 mol% of the catalyst without any loss of the enantiomeric purity and slightly lower yield (37%). 2.4 g of 2a were isolated.
adduct 3 is formed, the following steps are so quick that the intermediates 4 and 5 could not be detected by gas chromatography measurements (see Supplementary Fig. 2). The final product 2, also an a,b-unsaturated aldehyde, is sterically too hindered for a further Michael addition compared to C. After optimization of the reaction conditions, we carried out the domino reaction in toluene between 0 8C and room temperature, and the reaction was finished after 16–24 hours. Nearly stoichiometric amounts of all three components were used (A:B:C ¼ 1.20:1.00:1.05). The best results concerning yield and selectivity were obtained with 20 mol% of the OTMS-protected (TMS ¼ trimethylsilyl) diphenylprolinol ((S)-1) which is easily available from the natural amino acid (S)-proline19,20. Employing the (R)-proline derived catalyst (R)-1 affords the enantiomeric products ent-2. The fact that the residues R1–R3 of the precursors A, B and C can be varied (see Table 1) demonstrates the high flexibility of our approach. Use of automation techniques may deliver a huge library of different derivatives (for example, using ten different substrates for each compound A, B and C may provide 1,000 derivatives of 2). As shown in Table 1, R1 of component A can bear simple to demanding residues as well as valuable functional groups (2 h). At present, R2 is limited to aromatic and heteroaromatic (2 l) substituents. Efforts to use aliphatic nitroalkenes B need further optimization; only traces of the cyclohexene carbaldehydes 2 can be obtained so far. The residue R3 of component C allows the broadest diversity. Aliphatic as well as aromatic moieties are tolerated. Furthermore, acrolein (R3 ¼ H) can be used, affording tri-substituted cyclohexene carbaldehydes (2i). The best yields were obtained with aromatic substituents R2 and R3 (38–58%). The replacement of R3 by aliphatic residues led to lower yields (25% and 29%), whereas sterically demanding aldehydes A had less influence on the yield. In contrast, the variation of the residues had only a small impact on the diastereoselectivity (diastereomeric ratio d.r. ¼ 6.8:3.2–9.9:0.1), and we were pleased that in all cases complete enantiocontrol (enantiomeric excess e.e. $ 99%) was obtained. This cascade reaction generates four stereogenic centres, and theoretically could give rise to 24 ¼ 16 different stereoisomers. We note that in fact this asymmetric cascade forms enantioselectively just two diastereomers, which are easy to separate by flash chromatography. The reason for the high stereoselectivity is the first Michael addition, which is known to proceed with high diastereo- and enantioselectivity21,22; clearly this selectivity is kept or enhanced in the second step via a sterically favourable interaction between the iminium species and nitroalkane 317. The relative and absolute 862
Figure 3 | X-ray structure of 2b. Colour coding: white, hydrogen; grey, carbon; blue, nitrogen; red, oxygen; green, chlorine.
configuration of the cyclohexene carbaldehyde 2 was determined by 1 H-NMR nuclear Overhauser effect (NOE) experiments and X-ray crystallography (Fig. 3). The relative and absolute configurations are in agreement with respective related organocatalytic conjugate additions. We have developed a chemo-, diastereo- and enantioselective three component domino reaction, accomplished with the readily available proline derived organocatalyst 1 and low cost, simple starting materials, leading to tetra-substituted cyclohexene carbaldehydes 2. The four stereogenic centres are generated in three consecutive carbon–carbon bond formations with high diastereo- and complete enantiocontrol. Thus, this protocol includes all the advantages of domino reactions as well as asymmetric organocatalysis, and opens up a simple and flexible entry to polyfunctional cyclohexene building blocks. METHODS General procedure for the synthesis of cyclohexene derivatives 2. To a solution of catalyst (S)-1 (65 mg, 0.20 mmol) and nitroalkene B (1.00 mmol, 1.00 equiv.) in toluene (0.8 ml) was added subsequently under stirring aldehyde A (1.20 mmol, 1.20 equiv.) and a, b-unsaturated aldehyde C (1.05 mmol, 1.05 equiv.) at 0 8C. After 1 h the solution was allowed to reach room temperature, and stirred until complete conversion of the starting materials (16–24 h, monitored by gas chromatography). The reaction mixture was directly purified by flash column chromatography (SiO2, ethyl acetate/pentane, 1:8–1:6) to afford the product 2. All new compounds were fully characterized (see Supplementary Information). Characterization of 2a. The title compound 2a, (3S,4S,5R,6R)-3-methyl-5nitro-4,6-diphenylcyclohex-1-ene carbaldehyde, was prepared according to the general procedure described above. The product was obtained as a colourless solid. The e.e. was measured by high-performance liquid chromatography (HPLC) using a chiral stationary phase (Daicel OD, n-heptane/iso-propanol 95:05) relative to the racemic sample: major isomer 13.6 min, minor isomer 3 21 17.3 min. M.p. 126 8C (recrystallized from diethyl ether); [a]22 D (deg cm g dm21) ¼ –52.0 (c ¼ 1.01 g cm23, CHCl3). IR (KBr) 3,057, 2,815, 2,720, 2,361, 1,693, 1,650, 1,548, 1,494, 1,450, 1,365, 1,163, 761, 702 cm–1. 1H-NMR (300 MHz, CDCl3) d 1.23 (d, J ¼ 7.2 Hz, 3H), 2.91 (dd, J ¼ 10.4, 3.5 Hz, 1H), 3.45 (ddq, J ¼ 10.4, 7.2, 1.4 Hz, 1H), 4.48 (s, 1H), 4.86 (s, 1H), 7.0 (m, 2H), 7.19–7.42 (m, 9H), 9.59 (s, 1H) p.p.m. 13C-NMR (75 MHz, CDCl3) d 18.7, 32.2, 43.2, 45.3, 92.4, 127.8 (2C), 128.0 (3C), 128.1, 129.1 (2C), 129.2 (2C), 136.8, 137.2, 138.8, 156.1, 192.0 p.p.m. MS (EI, 70 eV), m/z (%) ¼ 321 (13) [Mþ], 274 (75), 259 (20), 245 (35), 231 (45), 215 (20), 183 (17), 167 (30), 115 (34), 105 (48), 91 (100), 77 (17). Analysis: calcd for C20H19NO3 (321.37) C, 74.75; H, 5.96; N, 4.36; found C, 74.62; H, 6.22; N, 4.36. Received 17 January; accepted 5 April 2006. 1.
2. 3. 4. 5.
Nicolaou, K. C., Montagnon, T. & Snyder, S. A. Tandem reactions, cascade sequences, and biomimetic strategies in total synthesis. Chem. Commun. 551–-564 (2003). Wasilke, J.-C., Obrey, S. J., Baker, R. T. & Bazan, G. C. Current tandem catalysis. Chem. Rev. 105, 1001–-1020 (2005). Ramo´n, D. J. & Yus, M. Asymmetric multicomponent reactions (AMCRs): the new frontier. Angew. Chem. Int. Edn Engl. 44, 1602–-1634 (2005). Tietze, L. F. Domino reactions in organic synthesis. Chem. Rev. 96, 115–-136 (1996). Tietze, L. F. & Haunert, F. in Stimulating Concepts in Chemistry (eds Vo¨gtle, F., Stoddart, J. F. & Shibasaki, M.) 39–-64 (Wiley-VCH, Weinheim, 2000).
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6. 7. 8. 9. 10. 11. 12.
13. 14. 15.
Guo, H.-C. & Ma, J.-A. Catalytic asymmetric tandem transformations triggered by conjugate additions. Angew. Chem. Int. Edn Engl. 45, 354–-366 (2006). Lehninger, A. L. Principles of Biochemistry (Worth, New York, 1993). Mann, J. Chemical Aspects of Biosynthesis (Oxford Chemistry Primers, Oxford Univ. Press, Oxford, 1999). Dalko, P. L. & Moisan, L. In the golden age of organocatalysis. Angew. Chem. Int. Edn Engl. 43, 5138–-5175 (2004). Berkessel, A. & Gro¨ger, H. Asymmetric Organocatalysis (Wiley VCH, Weinheim, 2005). Seayed, J. & List, B. Asymmetric organocatalysis. Org. Biomol. Chem. 3, 719–-724 (2005). Ramachary, D. B. & Barbas, C. F. III Towards organo-click chemistry: Development of multicomponent reactions through combination of aldol, Wittig, Knoevenagel, Michael, Diels-Alder and Huisgen cycloaddition reactions. Chem. Eur. J. 10, 5323–-5331 (2004). Yang, J. W., Hechavarria Fonseca, M. T. & List, B. Catalytic asymmetric reductive Michael cyclization. J. Am. Chem. Soc. 127, 15036–-15037 (2005). Huang, Y., Walji, A. M., Larsen, C. H. & MacMillan, D. W. C. Enantioselective organo-cascade catalysis. J. Am. Chem. Soc. 127, 15051–-15053 (2005). Marigo, M., Schulte, T., Franze´n, J. & Jørgensen, K. A. Asymmetric multicomponent domino reactions and highly enantioselective conjugated addition of thiols to a,b-unsaturated aldehydes. J. Am. Chem. Soc. 127, 15710–-15711 (2005). Hayashi, Y., Gotoh, H., Hayashi, T. & Shoji, M. Diphenylprolinol silyl ethers as efficient organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes. Angew. Chem. Int. Edn Engl. 44, 4212–-4215 (2005). Prieto, A., Halland, N. & Jørgensen, K. A. Novel imidazolidine-tetrazole organocatalyst for asymmetric conjugate addition to nitroalkanes. Org. Lett. 7, 3897–-3900 (2005). Berner, O. M., Tedeschi, L. & Enders, D. Asymmetric Michael-additions to nitroalkenes. Eur. J. Org. Chem. 1877–-1894 (2002).
19. Enders, D., Kipphardt, H., Gerdes, P., Bren˜a-Valle, L. J. & Bhushan, V. Large scale preparation of versatile chiral auxiliaries derived from (S)-proline. Bull. Soc. Chim. Belg. 97, 691–-704 (1988). 20. Franze´n, J. et al. A general organocatalyst for direct a-functionalization of aldehydes: stereoselective C–-C, C-N, C-F, C-Br, and C-S bond-forming reactions. Scope and mechanistic insights. J. Am. Chem. Soc. 127, 18296–-18304 (2005). 21. List, B., Pojarliev, P. & Martin, H. J. Efficient proline-catalyzed Michael additions of unmodified ketones to nitro olefins. Org. Lett. 3, 2423–-2425 (2001). 22. Enders, D. & Seki, A. Proline-catalyzed enantioselective Michael additions of ketones to nitrostyrene. Synlett, 26–-28 (2002).
Supplementary Information is linked to the online version of the paper at www.nature.com/nature. A figure summarizing the main result of this paper is included. Acknowledgements This work was supported by the Deutsche Forschungsgemeinschaft (SPP Organokatalyse) and the Fonds der Chemischen Industrie (thanked by C.G. for a Kekule´ fellowship). We thank BASF AG, Degussa AG, Bayer AG and Wacker-Chemie for the donation of chemicals, and J. Runsink for the NOE measurements. Author Contributions M.R.M.H. and C.G. contributed equally to this work. The X-ray structure analysis was performed by G.R. Author Information Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre, accession number CCDC 295450, and are available via www.ccdc.cam.ac.uk/data_request/cif. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to D.E. ([email protected]
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