Peptide Catalyzed Conjugate Additions to β-Nitroacrylates – Steric Bulk Increases the Reaction Rate

Abstract

The organocatalytic conjugate addition of aldehydes to beta-nitroacrylates provides direct access to beta-ester-gamma-nitroaldehydes and, thereby, common structural motifs of many bioactive compounds. However, the deactivation of amine-based catalysts by alkylation with the highly electrophilic nitroacrylates hampers this reaction. Here, we show that the peptide H-Mep-dPro-dGlu-NH2, which is reluctant to undergo alkylation, catalyzes this reaction at low catalyst loading (0.5-1 mol %) within short reaction times (15-60 min) to yield a broad range of beta-ester-gamma-nitroaldehydes with high stereoselectivity. Kinetic studies revealed that increased steric bulk on the beta-nitroacrylate enhances the reaction rate by hindering catalyst alkylation.