Enantioselective Single and Dual α-C-H Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer

Cyclic amines are ubiquitous structural motifs found in pharmaceuticals and biologically active natural products, making methods for their elaboration via direct C-H functionalization of considerable synthetic value. Herein, we report the development of an iron-based biocatalytic strategy for enantioselective alpha-C-H functionalization of pyrrolidines and other saturated N-heterocycles via a carbene transfer reaction with diazoacetone. Currently unreported for organometallic catalysts, this transformation can be accomplished in high yields, high catalytic activity, and high stereoselectivity (up to 99:1 e.r. and 20,350 TON) using engineered variants of cytochrome P450 CYP119 from Sulfolobus solfataricus. This methodology was further extended to enable enantioselective alpha-C-H functionalization in the presence of ethyl diazoacetate as carbene donor (up to 96:4 e.r. and 18,270 TON), and the two strategies were combined to achieve a one-pot as well as a tandem dual C-H functionalization of a cyclic amine substrate with enzyme-controlled diastereo-and enantiodivergent selectivity. This biocatalytic approach is amenable to gram scale synthesis and can be applied to drug scaffolds for late-stage C-H functionalization. This work provides an efficient and tunable method for direct asymmetric alpha-C-H functionalization of saturated N-heterocycles, which should offer new opportunities for the synthesis, discovery, and optimization of bioactive molecules.

Automated summary

This study reports the development of an iron-based biocatalytic strategy for enantioselective alpha-C-H functionalization of pyrrolidines and other saturated N-heterocycles, using a carbene transfer reaction with diazoacetone. The method shows high yields, catalytic activity, and stereoselectivity, and is applicable to drug scaffolds synthesis.