Direct Formation of Synthetically Useful Silyl-Protected Aldol Adducts via the Asymmetric Reductive Aldol Reaction

Abstract

Examination of different silane reducing agents in the reductive aldol reaction revealed that Me 2 i-PrSiH is highly selective for formation of the silylated aldol adduct versus the derived acylated adduct. This silicon group provides more robust protection for the product b-hydroxyl group than the diethylmethylsilyl group, which was employed previously.In recent years, research in our group has focused on the development of useful catalytic asymmetric transformations. Towards this goal, we previously reported the rhodium-catalyzed asymmetric reductive aldol reaction between an aldehyde and an a,b-unsaturated ester as a tool for stereocontrolled C-C bond formation. 1,2 This reaction provides an attractive alternative to existing catalytic aldol methodologies in that it does not require preformation of metal enolates or silyl enol ethers and proceeds with high enantioselectivities in a procedurally simple manner. Another valuable feature of the reductive aldol reaction lies in its ability to directly provide silyl-protected b-hydroxy carbonyl compounds when silanes are used as the reducing agent (Scheme 1). 3 While our previous work on the asymmetric reductive aldol reaction was carried out with Et 2 MeSiH or Me 2 PhSiH as the reducing agent, neither of the derived silyl ethers functions as a particularly robust hydroxyl protecting group. As a result, when using the reaction in natural product synthesis, it is common to cleave the silyl ether during work up and then reprotect with a more robust protecting group. 4 In an attempt to improve the utility of the reductive aldol reaction in complex molecule synthesis, we have investigated the use of different silane sources that would generate more synthetically useful silyl-protected aldol products. 5 Scheme 1Based on our proposed mechanism for the Rh-BINAPcatalyzed reductive aldol reaction (Scheme 2), it was expected that increased steric encumbrance on the silane would favor acylation of the aldol adduct (to give 2) relative to silylation (to give 1). 6 In order to counteract this undesired side reaction, an increased concentration of silane was employed relative to our original reports. Even with these conditions, the reductive aldol reaction with t-