Direct asymmetric α C(sp3)‒H alkylation of benzylamines with MBH acetates enabled by bifunctional pyridoxal catalysts

Organocatalytic allylic substitution of Morita-Baylis-Hillman (MBH) adducts is widely regarded as one of the most powerful transformations in organic synthesis. A range of activated carbon nucleophiles have been successfully employed in this reaction, enabling the incorporation of diverse functional moieties. Despite its potential, the use of inert C-H nucleophiles-critical for broadening the reaction's versatility and synthetic utility-remains a significant challenge in the field. Direct α-C-H functionalization of benzyl amines with MBH adducts offers a promising route to form a new C-C bond while simultaneously establishing a chiral amine moiety, a feature highly attractive from the perspective of organic synthesis. However, this transformation is particularly challenging due to the inherent inertness of the α-C(sp³)-H bonds, significant nucleophilic interference from the NH₂ group, and the complexity of selectivity control. Herein, we have successfully achieved an asymmetric direct α-C-H allylic alkylation of NH₂-unprotected benzylamines with MBH adducts using a bifunctional chiral pyridoxal catalyst, producing biologically important chiral γ-amino acid derivatives in good yields with excellent diastereo- and enantioselectivities. The reaction offers a distinct strategy for synthesizing multiply functionalized compounds from readily available starting materials, significantly expanding access to complex chiral architectures.