Enantioselective C-H Functionalization: Logic and Applications in the Total Synthesis of Natural Products

Abstract

Natural products, with their profound structural diversity and potent bioactivities, represent an invaluable source of inspiration for drug discovery and biomaterial development. The integration of enantioselective C–H functionalization into synthetic planning has emerged as a transformative strategy, offering streamlined and atom-economical routes to complex molecular architectures. This review comprehensively summarizes the pivotal role of these methodologies in the asymmetric total synthesis of natural products. We have organized recent breakthroughs according to three distinct C–H functionalization pathways: (1) radical hydrogen atom abstraction (HAA), (2) metallocarbene C–H insertion, and (3) C–H metalation. Through illustrative case studies, we dissect how these strategies function as key steps to construct stereodefined frameworks, thereby enabling the concise synthesis of target molecules, confirming absolute configurations, and facilitating biological evaluation. We anticipate that the continued maturation of enantioselective C–H activation will further democratize and accelerate the synthesis of complex natural products and their analogs.