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Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes.

ABSTRACT: Azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) have emerged as attractive classes of sp3-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.

SUBMITTER: Wright BA 

PROVIDER: S-EPMC10281541 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes.

Wright Brandon A BA   Matviitsuk Anastassia A   Black Michael J MJ   García-Reynaga Pablo P   Hanna Luke E LE   Herrmann Aaron T AT   Ameriks Michael K MK   Sarpong Richmond R   Lebold Terry P TP  

Journal of the American Chemical Society 20230505 20

Azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) have emerged as attractive classes of <i>sp</i><sup>3</sup>-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 h  ...[more]

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