Optimizing the Structure of 4‐Dialkylamino‐α,α‐diarylprolinol Ethers as Catalysts for the Enantioselective Cyclopropanation of α,β‐Unsaturated Aldehydes in Water

Abstract

AbstractWe optimized the structure of a new family of chiral diarylprolinol‐type organocatalysts with improved performances in conjugate addition reactions performed in water and proceeding under the iminium activation manifold. The principles behind the catalyst design were, firstly, the incorporation of a tertiary amino group at the 4‐position of the pyrrolidine scaffold, which can facilitate the reaction by providing a basic site that favors deprotonation of the pronucleophile, and, secondly, a bulky diaryltrialkylsilyloxymethyl group maintained at the 2‐position to control the iminium ion geometry and to provide the required steric bias for face stereoselection. The nature of this 4‐dialkylamino group and the relative 2,4‐configuration was optimized and the resulting catalyst proved its efficiency in the catalytic enantioselective cyclopropanation of α,β‐unsaturated aldehydes using water as the reaction solvent. Moreover, the reaction was studied by computational methods, which indicated that the overall transformation proceeded through a cascade Michael/α‐alkylation sequence, in which the first iminium‐mediated Michael addition reaction was the rate‐determining step and also the step at which stereochemical information was transferred from the catalyst to the products.