The Development of Alkoxide‐Directed Metallacycle‐Mediated Annulative Cross‐Coupling Chemistry

Alkoxide-directed metallacycle-mediated cross-coupling is a rapidly growing area of reaction methodology in organic chemistry. Over the last decade, developments have resulted in more than thirty new and highly selective intermolecular (or “convergent”) C−C bond-forming reactions that have established powerful retrosynthetic relationships in stereoselective synthesis. While early studies were focused on developing transformations that forge a single C−C bond by way of a functionalized and unsaturated metallacyclopentane intermediate, recent advances mark the ability to employ this organometallic intermediate in additional stereoselective transformations. Among these more advanced coupling processes, those that embrace the metallacycle in subsequent [4+2] chemistry have resulted in the realization of a number of highly selective annulative cross-coupling reactions that deliver densely functionalized and angularly substituted carbocycles. This review discusses the early development of this chemistry, recent advances in reaction methodology, and shares a glimpse of the power of these processes in natural product synthesis.