Origin of the enantioselectivity in organocatalytic Michael additions of β-ketoamides to α,β-unsaturated carbonyls: a combined experimental, spectroscopic and theoretical study

Abstract

The organocatalytic enantioselective conjugate addition of secondary β-ketoamides to α,β-unsaturated carbonyl compounds is reported. Use of bifunctional Takemoto's thiourea catalyst allows enantiocontrol of the reaction leading either to simple Michael adducts or spirocyclic aminals in up to 99 % ee. The origin of the enantioselectivity has been rationalised based on combined DFT calculations and kinetic analysis. This study provides a deeper understanding of the reaction mechanism, which involves a predominant role of the secondary amide proton, and clarifies the complex interactions occurring between substrates and the catalyst.

Keywords: Michael addition; density functional calculations; enantioselectivity; organocatalysis; reaction mechanisms.