Achieving Regioselectivity for Remote C−H Activation by Substructure Conformations: an Approach of Paralogous Cytochrome P450 Enzymes

Abstract

For advanced synthetic intermediates or natural products with multiple unactivated and energetically similar C(sp3)−H bonds, controlling regioselectivity for the C‐H activation is particularly challenging. The use of cytochrome P450 enzymes (CYPs) is a promising solution to the ‘regioelectivity’ challenge in remote C–H activation. Notably, CYPs and organic catalysts share a fundamental principle: they strive to control the distance and geometry between the metal reaction center and the target C‐H site. Most structural analyses of the regioselectivity of CYPs are limited to the active pocket, particularly when explaining why regioselectivity could be altered by enzyme engineering through mutagenesis. However, the substructures responsible for forming the active pocket in CYPs are well known to display complex dynamic changes and substrate‐induced plasticity. In this context, we highlight a comparative study of the recently reported paralogous CYPs, IkaD and CftA, which achieve different regioselectivity towards the same substrate ikarugamycin by distinct substructure conformations. We propose that substructural conformation‐controlled regioselectivity might also be present in CYPs of other natural product biosynthesis pathways, which should be considered when engineering CYPs for regioselective modifications.