Enantioselective synthesis of α-functionalized phenylpyrrolidine via photo-enzymatic cascade multi-component reaction

Abstract

Cyclic amines serve as versatile building blocks in pharmaceuticals; however, their modification through enantioselective sp³ C–H functionalization presents significant challenges. In this study, we present a one-pot photo-enzymatic cascade process that enables the enantioselective C(sp³)–H functionalization of saturated N-heterocyclic scaffolds. This innovative approach integrates a light-driven C–N cross-coupling reaction with biocatalytic carbene transfer. Specifically, we employed an efficient photocatalytic system to couple various aryl bromides with cyclic secondary amines, yielding saturated N-heterocycles in the presence of dual Ni/PC in DMSO under blue LED irradiation. The saturated N-heterocyclic compounds generated in situ were subsequently catalytically converted into the corresponding chiral α-functionalized phenylpyrrolidine compounds by engineered SD-VHb_CH carbene transferase within a whole-cell system. Compared to previous methods, this approach demonstrates superior stereoselectivity (up to 99% ee) and a more sustainable catalytic system for the synthesis of various α-functionalized phenylpyrrolidine compounds. Computational studies were conducted to elucidate the critical role of active pocket repositioning in the stereoselective regulation of the reaction but also demonstrate that the binding pocket of the VHb_CH offers a more stable reaction environment, thereby further enhancing enantioselectivity.