Advancing the Logic of Chemical Synthesis: C−H Activation as Strategic and Tactical Disconnections for C−C Bond Construction

The design of synthetic routes via retrosynthetic logic is decisively influenced by the transformations available. In this context, transition metal-catalyzed C-H activation has emerged as a powerful strategy for C-C bond formation, with myriad methods developed for diverse substrates and coupling partners . Despite its interest and proven efficacy however, its uptake in the total synthesis has been tepid, partially owing to their apparent synthetic intractability and inapplicability, as well as a lack of comprehensive guidelines for their implementation. These issues are addressed in this review, where we guide the identification of retrosynthetic opportunities to incorporate C-H activation processes for the generation of C-C bonds. By comparing and analyzing total syntheses accomplished using traditional approaches against recent C-H activation methods, this review demonstrates how the successful implementation of C-H activation-enabled C-C bond construction has led to the realization of more efficient retrosynthetic strategies, as well as the execution of previously unattainable tactical maneuvers. Finally, we identify shortcomings due to limitations in existing C-H activation processes, and project how some of the total syntheses highlighted in this review can be further economized by adopting emerging next-generation C-H activation technologies.