C-H Functionalization-Enabled 11-Step Semisynthesis of (-)-Veragranine A and Characterization of Synthetic Analogs in Osteoarthritis-related Pain Treatment

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Donghui Ma
  • Paz Duran
  • Reem Al-Ahmad
  • Kristensen, Sara Hestehave
  • Margarita Joa
  • Omar Alsbiei
  • Erick J Rodríguez-Palma
  • Yanrong Li
  • Shilin Wang
  • Rajesh Khanna
  • Mingji Dai

We report an efficient semisynthesis of the cholestane steroidal alkaloid (-)-veragranine A with a 6/6/6/5/6/6 hexacyclic ring system, eight stereocenters, and a unique C12-C23 linkage. Our synthesis features a Schönecker-Baran C-H oxidation at C12, a Suzuki-Miyaura cross-coupling to form the C12-C23 bond, and a hydrogen atom transfer (HAT)-initiated Minisci C-H cyclization to forge the C20-C22 bond with desired stereochemistry at C20. These enabling transformations significantly enhanced the overall synthetic efficiency and delivered (-)-veragranine A in 11 steps and over 200 mg from cheap and readily available dehydroepiandrosterone. In addition, this approach allowed flexible syntheses of novel synthetic analogs for biological evaluations in sensory neurons in vitro and in an in vivo model of arthritic pain, from which two novel lead compounds were identified for further development.

OriginalsprogEngelsk
TidsskriftJournal of the American Chemical Society
ISSN0002-7863
DOI
StatusE-pub ahead of print - 2024
Eksternt udgivetJa

ID: 394713779