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.
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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)
Ramòn, 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 Vögtle, F., Stoddart, J. F. & Shibasaki, M.) 39–64 (Wiley-VCH, Weinheim, 2000)
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. & Gröger, 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., Franzén, J. & Jørgensen, K. A. Asymmetric multicomponent domino reactions and highly enantioselective conjugated addition of thiols to α,β-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)
Enders, D., Kipphardt, H., Gerdes, P., Breña-Valle, L. J. & Bhushan, V. Large scale preparation of versatile chiral auxiliaries derived from (S)-proline. Bull. Soc. Chim. Belg. 97, 691–704 (1988)
Franzén, J. et al. A general organocatalyst for direct α-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)
List, B., Pojarliev, P. & Martin, H. J. Efficient proline-catalyzed Michael additions of unmodified ketones to nitro olefins. Org. Lett. 3, 2423–2425 (2001)
Enders, D. & Seki, A. Proline-catalyzed enantioselective Michael additions of ketones to nitrostyrene. Synlett, 26–28 (2002)
This work was supported by the Deutsche Forschungsgemeinschaft (SPP Organokatalyse) and the Fonds der Chemischen Industrie (thanked by C.G. for a Kekulé 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.
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.
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Enders, D., Hüttl, M., Grondal, C. et al. Control of four stereocentres in a triple cascade organocatalytic reaction. Nature 441, 861–863 (2006). https://doi.org/10.1038/nature04820
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