Modular synthesis of complex benzoxaboraheterocycles through chelation-assisted Rh-catalyzed [2+2+2]cycloaddition

Abstract

Benzoxaboraheterocycles (BOBs) are moieties of increasing interest in the pharmaceutical industry; however, the synthesis of these compounds is often difficult or impractical due to the sensitivity of the boron moiety, the requirement for metalation-borylation protocols, and lengthy syntheses. We report a straightforward, modular approach that enables access to complex examples of the rare BOB framework through a Rh-catalyzed [2+2+2]cycloaddition using MIDA-protected alkyne boronic acids. Key to the development of this methodology was overcoming the steric barrier to catalysis by leveraging chelation assistance. We show the utility of the method through synthesis of a broad range of BOB scaffolds, mechanistic information on the chelation effect, intramolecular alcohol-assisted BMIDA hydrolysis, and the linear/cyclic BOB limits, as well as comparative binding affinities for the new BOB frameworks for ribose-derived biomolecules.