C(sp3)-H hydroxylation of Broad-Spectrum Alkanes Catalyzed by an Artificial P450 Peroxygenase Driven by ω-Pyridyl Fatty Acyl Amino Acids

Abstract

Selective hydroxylation of C(sp3)–H bonds is a long-standing challenge in the organic synthesis field. We herein report an artificial P450 peroxygenase system facilitated by ω-pyridyl fatty acyl amino acids that can hydroxylate broad-spectrum alkanes, including linear and cyclic alkanes and benzylic and allylic alkane chains. Compared with the previously reported dual-functional small molecule (DFSM) with imidazole as a catalytic group (Im-DFSM), pyridyl DFSM (Pyd-DFSM) produced substantially higher total turnover numbers (TTNs) for the hydroxylation of medium-chain alkanes and cycloalkanes (C6–C8), e.g., 12.0-fold and 17.1-fold increased TTNs of P450 mutant F87A/T268V for heptane and cycloheptane, respectively. In addition, Pyd-DFSM altered the enantioselectivity of benzylic hydroxylation, e.g., it almost inverted the configuration observed in the benzylic hydroxylation of ethylbenzene and tetralin. More importantly, Pyd-DFSM showed excellent regioselectivity for allylic hydroxylation over epoxidation of terminal alkenes and cycloalkenes, e.g., up to 94% allylic hydroxylation of 1-hexene was observed. This work significantly enhances the catalytic toolbox of the DFSM-facilitated P450 peroxygenase system; it not only substantially expands the chemical space of P450 enzymes, but also provides an alternative solution for the selective hydroxylation of C(sp3)–H bonds.