Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates. Academic Article uri icon

abstract

  • Modular functionalization enables versatile exploration of chemical space and has been broadly applied in structure-activity relationship (SAR) studies of aromatic scaffolds during drug discovery. Recently, the bicyclo[1.1.1]pentane (BCP) motif has increasingly received attention as a bioisosteric replacement of benzene rings due to its ability to improve the physicochemical properties of prospective drug candidates, but studying the SARs of C2-substituted BCPs has been heavily restricted by the need for multistep de novo synthesis of each analogue of interest. Here we report a programmable bis-functionalization strategy to enable late-stage sequential derivatization of BCP bis-boronates, opening up opportunities to explore the SARs of drug candidates possessing multisubstituted BCP motifs. Our approach capitalizes on the inherent chemoselectivity exhibited by BCP bis-boronates, enabling highly selective activation and functionalization of bridgehead (C3)-boronic pinacol esters (Bpin), leaving the C2-Bpin intact and primed for subsequent derivatization. These selective transformations of both BCP bridgehead (C3) and bridge (C2) positions enable access to C1,C2-disubstituted and C1,C2,C3-trisubstituted BCPs that encompass previously unexplored chemical space.

published proceedings

  • Nat Chem

altmetric score

  • 9.2

author list (cited authors)

  • Yang, Y., Tsien, J., Dykstra, R., Chen, S., Wang, J. B., Merchant, R. R., ... Qin, T.

citation count

  • 5

complete list of authors

  • Yang, Yangyang||Tsien, Jet||Dykstra, Ryan||Chen, Si-Jie||Wang, James B||Merchant, Rohan R||Hughes, Jonathan ME||Peters, Byron K||Gutierrez, Osvaldo||Qin, Tian

publication date

  • October 2023