Organocatalyzed Reductive Amination with Trichlorosilane and its Synthetic Applications

Pavel Kocovsky

Abstract

 The amino acid-derived N-methyl formamides, such as the Sigamide (now commercially available), have been eveloped as Lewisbasic organocatalysts for asymmetric reduction of imines with Cl3SiH (≤97% ee at ≥1 mol% loading). Their application will be highlighted by the enantioselective synthesis of N-acetyl colchinol (a potent anti-cancer agent with a mode of action similar to that of taxol) and SCH 48461 and its analogue Ezetimibe (drugs reducing the intake of cholesterol from food). The key reaction also works as a direct, one-pot reductive amination, starting from the corresponding ketone, with no need for isolation of the imine. In the case of aldehydes, the reaction does not require a sophisticated chiral entity and proceeds perfectly well with both primary and secondary amines and DMF as the Lewis-basic catalyst. Tolerance to a wide range of functional groups and heteroaromatic moieties can be demonstrated, e.g., by the reductive amination of keto aldehydes, where the aldehyde group reacts with excellent chemoselectivity. Another notable feature is, e.g., retention of the azido group. Being not experimentally demanding, the method is particularly suitable for parallel chemistry, generating libraries of secondary and tertiary amines.