Origin of the Enantioselectivity in Organocatalytic Michael Additions of β-Ketoamides to α,β-Unsaturated Carbonyls: A Combined Experimental, Spectroscopic and Theoretical Study

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. From theory to practise: The mechanism of asymmetric organocatalysed Michael addition of β‐ketoamides to enones was studied theoretically, demonstrating for the first time the unique role of the hydrogen atom of the amide in controlling both the reactivity and the enantioselectivity (see scheme). Additional reactions afforded original spiro hemiaminals, taking advantage of the reactivity of the Michael adducts with acrolein. Post‐functionalisation led to valuable enantioenriched glutarimides and pyridones.