Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes
Brandon A. Wright, Anastassia Matviitsuk, Michael J. Black, Pablo García‐Reynaga, Luke Elizabeth Hanna, Aaron T. Herrmann, Michael K. Ameriks, Richmond Sarpong, Terry P. Lebold
Abstract
-rich cores for replacing flat, aromatic groups with metabolically resistant, three-dimensional frameworks in drug scaffolds. Strategies to directly convert, or "scaffold hop", between these bioisosteric subclasses through single-atom skeletal editing would enable efficient interpolation within this valuable chemical space. Herein, we describe a strategy to "scaffold hop" between aza-BCH and BCP cores through a nitrogen-deleting skeletal edit. Photochemical [2+2] cycloadditions, used to prepare multifunctionalized aza-BCH frameworks, are coupled with a subsequent deamination step to afford bridge-functionalized BCPs, for which few synthetic solutions currently exist. The modular sequence provides access to various privileged bridged bicycles of pharmaceutical relevance.