COAP-Pd Catalyzed Asymmetric Ring-Opening Allylic Alkylation for Linear Unsaturated Quaternary Amino Acid Derivatives

Abstract

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 ³¹P 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.

Keywords

Asymmetric catalysis / Ring-opening allylic alkylation / Non-natural amino acid / Functional allylic side chains / Enantioselectivity / γ,δ-Unsaturated quaternary amino acid / COAP-Pd catalysis / Chirality

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