A Catalyst Designed for the Enantioselective Construction of Methyl- and Alkyl-Substituted Tertiary Stereocenters

Abstract

Tertiary methyl-substituted stereocenters are present in numerous biologically active natural products. Reported herein is a catalytic enantioselective method for accessing these chiral building blocks using the Mukaiyama-Michael reaction between silyl ketene thioacetals and acrolein. To enable remote enantioface control on the nucleophile, a new iminium catalyst, optimized by three-parameter tuning and by identifying substituent effects on enantioselectivity, was designed. The catalytic process allows rapid access to chiral thioesters, amides, aldehydes, and ketones bearing an α-methyl stereocenter with excellent enantioselectivities, and allowed rapid access to the C4-C13 segment of (-)-bistramide A. DFT calculations rationalized the observed sense and level of enantioselectivity.

Keywords: asymmetric catalysis; density functional calculations; diastereoselectivity; natural products; organocatalysis.