<scp>COAP</scp> ‐Pd Catalyzed Asymmetric Ring‐Opening Allylic Alkylation for Linear Unsaturated Quaternary Amino Acid Derivatives

Comprehensive Summary Unsaturated quaternary amino acids are essential building blocks for the construction of non‐natural peptides and proteins. Herein, ring‐opening allylic alkylation between vinyl(hetero)cyclopropanes and 4‐substituted azlactones was developed, which was catalyzed by our designed COAP‐Pd complexes. Several series of γ , δ ‐ unsaturated quaternary amino acid derivatives were obtained in good yields with high regio‐ and enantioselectivity. The transformations exhibited good tolerance toward a variety of azlactone substrates, enabling the efficient synthesis of a diverse library of chiral γ,δ ‐ unsaturated quaternary amino acid derivatives with functional allylic side chains. The synthetic utility of this protocol was validated through gram‐scale reactions and subsequent functional group transformations, including hydrolysis under acidic condition to afford non‐natural quaternary amino acids, alcoholysis under basic conditions to give quaternary amino acid esters, as well as epoxidation of the pendent alkenyl groups. In addition, the chiral 4,5‐dihydrooxazole scaffolds with potential pharmaceutical value were also constructed via further cyclization of the corresponding quaternary amino alcohol derivatives, which were prepared from reductive ring‐opening of the corresponding azlactone moieties in the presence of reducing reagents. Moreover, the coordination models and the active catalytic species were further deduced by X ‐ray crystallographic analysis and 31 P NMR experiments. Notably, the resulting γ,δ ‐ unsaturated quaternary amino acid derivatives featured unique linear side chains and quaternary carbon centers. And that, the linear allylic side chains held the promise as a linkage for modifying drugs and natural products, as it allowed for the conjugation of two bioactive scaffolds.