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

• Published in: Journal of the American Chemical Society Vol. 145; no. 20; pp. 10960 - 10966
• Main Authors: Wright, Brandon A., Matviitsuk, Anastassia, Black, Michael J., García-Reynaga, Pablo, Hanna, Luke E., Herrmann, Aaron T., Ameriks, Michael K., Sarpong, Richmond, Lebold, Terry P.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.05.2023; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; ROUTE; PHOTOCHEMICAL-SYNTHESIS; BINDING; STRAIN; COMPLEXITY
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.3c02616

Azabicyclo­[2.1.1]­hexanes (aza-BCHs) and bicyclo[1.1.1]­pentanes (BCPs) have emerged as attractive classes of sp 3-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.