Catalytic enantioselective direct Michael additions of ketones to alkylidene malonates

Enantioselective direct Michael additions of ketones using (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine as a catalyst are described. Michael adducts with up to 91% e.e. were obtained by the reaction of alkylidene malonates with simple unactivated ketones under mild reaction conditions. © 2001 Elsevier Science Ltd. All rights reserved. An increasing demand for optically active compounds has stimulated the development of catalytic asymmetric bond-forming reactions. Of the carbon carbon bond forming reactions, the enantioselective Michael reaction has been one of the most studied in synthetic organic chemistry. Typically, carbon nucleophiles that contain an active methylene center such as malonic acid esters, -keto esters, nitroalkanes, etc. have been studied. Ketones, however, while they are versatile carbon nucleophiles, have generally been used as donors only following their pre-activation by conversion into highly reactive enol or enamine equivalents. In these cases, additional synthetic step(s), stoichiometric amounts of base, additional reagents (silylating agents to form the enol silyl ether or chiral amines to form the enamine derivative) or chiral ligands are required. A potentially more promising strategy would involve catalysis of direct additions of unmodified ketones to Michael-type acceptors. The development of catalytic asymmetric variants of this process would provide access to optically enriched 1,5-dicarbonyl synthons. As part of our ongoing program directed towards identifying small organic molecules as catalysts of asymmetric reactions, we explore here the direct addition of ketones through an enamine-type mechanism to Michael-type acceptors. Chiral amines have been used previously in catalytic asymmetric Michael additions, serving either to activate the Michael donor via formation of an iminium species (I, Scheme 1), or as bases where a complex formed between the amine and the enolate react with the acceptor (II, Scheme 1). A third mechanism could involve transient activation ketone donors through formation of an enamine intermediate (III, Scheme 1). Herein we wish to report our preliminary studies concerning enantioselective direct Michael additions of ketone donors catalyzed by chiral amines that operate using an enamine mechanism. Our previous studies had identified L-proline as a catalyst of direct asymmetric aldol reactions, Mannich reactions, and Robinson annulations. As a model transformation we studied the proline-catalyzed Michael addition of acetone to diethyl benzalmalonate in DMSO. The Michael adduct was isolated albeit in racemic form and together with (E)-PhCHCHCOCH3 as a byproduct. In order to achieve enantioselectivity, we screened a variety of chiral amines as catalysts of the reaction. When (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine was studied as a catalyst of the same reaction we found that the addition product was formed exclusively Scheme 1. Mechanisms for amine-catalyzed Michael reactions.