The Acidity of a Carbon Nucleophile Dictates Enantioselectivity and Reactivity in Michael Additions to Aromatic and Aliphatic Enals via Iminium Activation

Abstract

The Michael addition of activated methylenes to β-substituted α,β-unsaturated aldehydes (enals) via iminium catalysis takes place following reactivity and enantioselectivity patterns which depend on the electronic nature of the substituent in the β position (β-aryl or β-alkyl). Application of the same reaction conditions to both families of enals may result in erratic levels of asymmetric induction in the reactions of β-aryl enals or low reactivity with β-alkyl enals. A systematic analysis of this behavior using phenylacetic acid derivatives as case studies has led us to find a general trend: the different problems found for β-aryl and β-alkyl enals depend on the acidity of the nucleophile, and the outcome of the reaction for both types of enals can be improved substantially by careful choice of catalyst, solvent, and additive. Furthermore, this study has allowed us to understand subtle aspects of this transformation and has enabled the formulation of a general and reliable protocol to obtain high yields and enantioselectivities consistently, regardless of the acidity of the nucleophile and the nature of the substituent (aromatic or aliphatic) at the β position