The proline-catalyzed direct asymmetric three-component mannich reaction:

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Published on Web 01/10/2002

The Proline-Catalyzed Direct Asymmetric Three-Component Mannich Reaction: Scope, Optimization, and Application to the Highly Enantioselective Synthesis of 1,2-Amino Alcohols
Benjamin List,* Peter Pojarliev, William T. Biller, and Harry J. Martin
Contribution from the Departments of Molecular Biology and Chemistry, The Scripps Research Institute, 10550 North TorreyPines Road, La Jolla, California 92037
Received October 29, 2001

Abstract: We have developed proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines. Several of the studied reactions provide -amino carbonyl compounds (Mannich products) in excellent enantio-, diastereo-, regio-, and chemoselectivities. The scope of each of the three componentsand the influence of the catalyst structure on the reaction are described. Reaction conditions have been optimized, and the mechanism and source of asymmetric induction are discussed. We further present application of our reaction to the highly enantioselective synthesis of 1,2-amino alcohols.


The vast majority of nature’s molecules, including proteins and nucleic acids and mostbiologically active compounds, contain nitrogen. Consequently, developing new synthetic methods for the construction of nitrogenous molecules has defined the frontiers of organic synthesis since its very beginning.1 The Mannich reaction has long been a very useful platform for the development of such methodologies.2 Originally, this reaction produces -amino-carbonyl compounds from three components,an amine and two different carbonyl species. As in the related “direct aldol reaction”, using unmodified carbonyl compounds in direct Mannich reactions has caused severe selectivity problems. Such limitations have been partially overcome through the development of indirect Mannich variants that assign the specific role of each carbonyl component in the reaction mixture. However, additionalsynthetic operations result from the requirement to preform intermediates such as imine and enol equivalents (eq 1).

and enol equivalents.3 We have recently discovered prolinecatalyzed asymmetric three-component Mannich reactions between ketones, aldehydes, and amines that furnish Mannich products in up to 99% ee.4 The scope of this novel catalytic asymmetric carbon-carbon-bond-forming multicomponentreaction and its application to the highly enantioselective synthesis of 1,2-amino alcohols are described herein. Asymmetric Mannich Reactions. Mannich-type reactions that produce enantiomerically enriched products have been reported. Several indirect variants use stoichiometric amounts of chiral enol equivalents, including enamines,5 silyl enolethers,6 boron enolates,7 and lithium enolates.8Alternatively, chiral imine equivalents have been utilized.9 Double stereodifferentiating asymmetric Mannich-type reactions that require two different stoichiometric chiral controllers have also been developed.10,11
(2) Mannich, C.; Krosche, W. Arch. Pharm. (Weinheim, Ger.) 1912, 250, 647. Reviews: (a) Denmark, S. E.; Nicaise, O. J.-C. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999; pp 923-961. (b) Kleinmann, E. F. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol. 2, Chapter 4.1. (c) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044-1070. (3) For an exception, see: (a) Yamasaki, S.; Iida, T.; Shibaski, M. Tetrahedron Lett. 1999, 40, 307-310. (b) Yamasaki, S.;Iida, T.; Shibasaki, M. Tetrahedron 1999, 55, 8857-8867. (4) List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337. (5) (a) Kober, R.; Papadopoulus, K.; Miltz, W.; Enders, D.; Steglich, W.; Reuter, H.; Puff, H. Tetrahedron 1985, 41, 1693-1701. (b) Risch, N.; Esser, A. Liebigs Ann. Chem. 1992, 233-237. (c) Vinkovic, V.; Sunjic, V. Tetrahedron 1997, 53, 689-696. (d) Zarghi, A.; Naimi-Jamal, M. R.;...
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