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A full account of catalytic direct asymmetric Mannich-type reactions is presented describing the scope of amino acid-catalyzed additions of unmodified ketones to a large variety of imines. These reactions are performed under very mild, operationally simple, and environmentally friendly and benign conditions employing a one-pot, three-component protocol as well as preformed imines. Typically, products were obtained with high regio- and diastereoselectivities and excellent enantioselectivities. The methodology developed was applied as a powerful approach toward the synthesis of enantiomerically pure functionalized α-amino acids, γ-lactones, oxime-functionalized amino acids as well as pharmacologically important targets such as (R)-cyclohexylglycine.

A long-standing problem in organic synthesis is the catalytic asymmetric addition of alkyl groups to ketones to establish chiral quaternary centers. Such compounds are valuable chiral building blocks that can be further elaborated. In this account, we describe the previously unreported story of the development of the first effective catalyst for the enantioselective addition of dialkyl- and diphenylzinc reagents to ketones. The scope of this reaction is outlined, including a tandem enantioselective addition to cyclic enones/diastereoselective epoxidation protocol that establishes three contiguous stereocenters in a one-pot procedure.

— Enantioselective direct Michael additions of ketones using ( S )-1-(2-pyrrolidinylmethyl)-pyrrolidine as a catalyst aredescribed. Michael adducts with up to 91% e.e. were obtained by the reaction of alkylidene malonates with simple unactivatedketones under mild reaction conditions. © 2001 Elsevier Science Ltd. All rights reserved. An increasing demand for optically active compoundshas stimulated the development of catalytic asymmetricbond-forming reactions. 1 Of the carbon carbon bondforming reactions, the enantioselective Michael reactionhas been one of the most studied in synthetic organicchemistry. 2 Typically, carbon nucleophiles that containan active methylene center such as malonic acid esters, -keto esters, nitroalkanes, etc. have been studied. 3 Ketones, however, while they are versatile carbonnucleophiles, have generally been used as donors onlyfollowing their pre-activation by conversion into highlyreactive enol or enamine equivalents. 4 In these cases,additional synthetic step(s), stoichiometric amounts ofbase, additional reagents (silylating agents to form theenol silyl ether or chiral amines to form the enaminederivative) or chiral ligands are required. A potentiallymore promising strategy would involve catalysis ofdirect additions of unmodified ketones to Michael-typeacceptors. The development of catalytic asymmetricvariants of this process would provide access to opti-cally enriched 1,5-dicarbonyl synthons.As part of our ongoing program directed towardsidentifying small organic molecules as catalysts ofasymmetric reactions, we explore here the direct addi-tion of ketones through an enamine-type mechanism toMichael-type acceptors. Chiral amines have been usedpreviously in catalytic asymmetric Michael additions

— Enantioselective direct Michael additions of ketones using ( S )-1-(2-pyrrolidinylmethyl)-pyrrolidine as a catalyst aredescribed. Michael adducts with up to 91% e.e. were obtained by the reaction of alkylidene malonates with simple unactivatedketones under mild reaction conditions. © 2001 Elsevier Science Ltd. All rights reserved. An increasing demand for optically active compoundshas stimulated the development of catalytic asymmetricbond-forming reactions. 1 Of the carbon carbon bondforming reactions, the enantioselective Michael reactionhas been one of the most studied in synthetic organicchemistry. 2 Typically, carbon nucleophiles that containan active methylene center such as malonic acid esters, -keto esters, nitroalkanes, etc. have been studied. 3 Ketones, however, while they are versatile carbonnucleophiles, have generally been used as donors onlyfollowing their pre-activation by conversion into highlyreactive enol or enamine equivalents. 4 In these cases,additional synthetic step(s), stoichiometric amounts ofbase, additional reagents (silylating agents to form theenol silyl ether or chiral amines to form the enaminederivative) or chiral ligands are required. A potentiallymore promising strategy would involve catalysis ofdirect additions of unmodified ketones to Michael-typeacceptors. The development of catalytic asymmetricvariants of this process would provide access to opti-cally enriched 1,5-dicarbonyl synthons.As part of our ongoing program directed towardsidentifying small organic molecules as catalysts ofasymmetric reactions, we explore here the direct addi-tion of ketones through an enamine-type mechanism toMichael-type acceptors. Chiral amines have been usedpreviously in catalytic asymmetric Michael additions

The development of syntheses providing enantiomerically pure α-amino acids has intrigued generations of chemists and been the subject of intense research. This report describes a general approach to functionalized α-amino acids based on catalytic asymmetric synthesis. Proline catalyzed Mannich-type reactions of N-PMP-protected α-imino ethyl glyoxylate with a variety of unmodified ketones to provide functionalized α-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. Study of seven examples yielded six with product ee values of ≥99%. In reactions involving ketone donors where diastereoisomeric products could be formed, two adjacent stereogenic centers were created simultaneously upon carbon−carbon bond formation with complete syn-stereocontrol. Significantly, this methodology utilizes readily available and rather inexpensive starting materials, does not require any preactivation of substrates or metal ion assistance, and can be carried out on a gram scale under operation...

The Michael additions of a number of ketones and aldehydes to alkylidene malonates and nitro olefins were studied. The reactions employ small organic molecules as catalyst under mild reaction conditions and do not requirepreactivation of the carbonyl donors. These reactions afforded a variety of highly functionalized products in good yields with moderate to good enantioselectivity.

The development of syntheses providing enantiomerically pure alpha-amino acids has intrigued generations of chemists and been the subject of intense research. This report describes a general approach to functionalized alpha-amino acids based on catalytic asymmetric synthesis. Proline catalyzed Mannich-type reactions of N-PMP-protected alpha-imino ethyl glyoxylate with a variety of unmodified ketones to provide functionalized alpha-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. Study of seven examples yielded six with product ee values ofor = 99%. In reactions involving ketone donors where diastereoisomeric products could be formed, two adjacent stereogenic centers were created simultaneously upon carbon-carbon bond formation with complete syn-stereocontrol. Significantly, this methodology utilizes readily available and rather inexpensive starting materials, does not require any preactivation of substrates or metal ion assistance, and can be carried out on a gram scale under operationally simple reaction conditions. The keto-functionality present in the products provides a particularly attractive site for versatile modifications. This study compliments and extends our bioorganic approach to asymmetric synthesis to a versatile synthon class. Given that we have shown that a variety of optically active amino acids can be synthesized with proline catalysis, where an L-amino acid begets other L-amino acids, our results may stimulate thoughts concerning prebiotic syntheses of optically active amino acids based on this route.