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

Abstract

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 > 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.

Synthesis of pentasubstituted 2-aryl pyrroles from boryl and stannyl alkynes via one-pot sequential Ti-catalyzed [2 + 2 + 1] pyrrole synthesis/cross coupling reactions

“…Thus, the b-stabilization from the alkyne substituent does not play a dominant role in determining relative selectivity, and other factors such as the relative strength of the forming Ti-C Si bond vs. Ti-C M bond may also be involved: for example, Micalizio has demonstrated that insertion into 2-silyl-3-stannyltitanacyclopropenes will occur on the Ti-C Sn bond compared to the Ti-C Si bond. 45,46…”

Synthesis of Pentasubstituted 2-Aryl Pyrroles from Boryl and Stannyl Alkynes via One-Pot Sequential Ti-Catalyzed [2+2+1] Pyrrole Synthesis/Cross Coupling Reactions

“…Thus, the b-stabilization from the alkyne substituent does not play a dominant role in determining relative selectivity, and other factors such as the relative strength of the forming Ti-CSi bond vs Ti-CM bond may also be involved: for example, Micalizio has demonstrated that insertion into 2-silyl-3-stannyltitanacyclopropenes will occur on the Ti-CSn bond compared to the Ti-CSi bond. 35,36 Figure 5. Directing group strength comparisons.…”

Dative Directing Group Effects in Ti-Catalyzed [2+2+1] Pyrrole Synthesis: Chemo- and Regioselective Alkyne Heterocoupling

“…Pendent alkoxide directing groups have been used extensively in Ti-catalyzed and mediated reactions to engender regio-, chemo-, and enantioselective transformations . For example, Sharpless’ catalytic asymmetric alkene epoxidation relies on alkoxide directing groups to engender enantiofacial selectivity, while more recently Micalizio has used alkoxides to direct alkyne insertion regioselectivity in Ti-mediated reductive coupling reactions (Figure , middle), ,,− and Burns has used alkoxides to direct stereoselective alkene dihalogenation and haloazidation reactions. − Alkoxide-directed coupling reactions have also served as a platform for heterocycle syntheses, such as pyridines and indolizidines. , …”