Dynamic kinetic asymmetric allylation, propargylation and crotylation of ketones using copper catalysis

Abstract

Chiral tertiary alcohols are privileged structures found in numerous bioactive molecules and pharmaceutical agents. However, general and efficient synthetic methods for forming α,β-stereogenic tertiary alcohols bearing two or more contiguous stereocentres are rare. Here we report the development of an enantioconvergent method for the synthesis of α,β-stereogenic tertiary alcohols in a single step by allylation, propargylation or crotylation of racemic α-amino, α-(hetero)aryl and α,α-dialkyl ketones using readily available boronic ester reagents. The identification of the chiral ligand/copper catalytic system enables rapid interconversion and chiral recognition between two enantiomers of racemic ketones, allowing the dynamic kinetic resolution process to occur. The reaction features high levels of diastereoselectivity and enantioselectivity, a wide scope of heterocycle substrates and high functional group compatibility, and provides a general and efficient synthesis of a variety of complex chiral tertiary alcohols otherwise difficult to access, thereby offering a tool for the rapid modification and synthesis of drug molecules. The synthesis of α,β-stereogenic tertiary alcohols featuring multiple contiguous stereocentres is a challenge. Now, a method for the enantioconvergent copper-catalysed allylation, propargylation and crotylation of racemic ketones is reported. The process provides access to chiral tertiary alcohols bearing multiple contiguous stereocentres.