Chiral Aldehyde/Palladium Catalysis Enables Asymmetric Branched-Selective Ring-Opening Functionalization of Methylenecyclopropanes with Amino Acid Esters

Abstract

Achieving catalytic asymmetric functionalization of methylenecyclopropanes (MCPs) by selective C–C bond cleavage is a notable challenge due to the intricate reaction partners involved. In this work, we report that chiral aldehyde/palladium combined catalysis enables the asymmetric functionalization of MCPs with NH₂-unprotected amino acid esters. This reaction proceeds through a regiospecific branched ring-opening mechanism, resulting in optically active α,α-disubstituted α-amino acid esters bearing nonconjugated terminal alkene units. Mechanism studies indicate that the ring-opening pathways are irreversible and the ultimate regioselectivity is governed by palladium catalysis. The products can be utilized in the construction of chiral dihydropyrazoles, α-methyl aspartic acid derivatives, and analogues of VPC01091 and BMS-986104.