C–H Functionalization as a Powerful Method for Direct Synthesis of Lactones
Olivia Goethe, Daniel K. Zhou, Xiaoyu Zhu, Petr Sevelda, Alex Szyperek, Martin Tomanik
Abstract
High Resolution Image Download MS PowerPoint Slide C–H activation has profoundly impacted synthetic chemistry by expanding the capabilities for the installation of functional groups and useful synthetic handles at otherwise inert C–H positions. In the context of lactone synthesis, advances in transition metal-catalyzed C–H activation have enabled the direct functionalization of unactivated C–H bonds using common, native coordinating functionalities such as carboxylic acids or amides without the need for harsh reaction conditions employed in traditional approaches or removal of strongly coordinating directing groups. This review highlights the evolution of enabling C–H lactonization strategies from initial discoveries of one- and two-electron functionalization reactivity to modern methods that leverage the combination of finely tuned ligands and reaction conditions for regioselective and enantioselective lactone synthesis. Mechanistic insights and synthetic applications are presented for lactones synthesized via C(sp 2 )–H and C(sp 3 )–H activation, with a focus on olefination, alkylation, hydroxylation, direct lactonization, and biocatalytic processes. The application of these methods for the preparation of complex molecules underscores the utility and impact of these methodologies in the toolkit of modern organic synthesis. By showcasing these advancements, this review aims to encourage the use of C–H activation and functionalization strategies for the efficient, regioselective preparation of lactones and the design of synthetic routes to lactones for a myriad of applications.