TY - JOUR
T1 - C-H Functionalization-Enabled 11-Step Semisynthesis of (−)-Veragranine A and Characterization of Synthetic Analogs in Osteoarthritis-related Pain Treatment
AU - Ma, Donghui
AU - Duran, Paz
AU - Al-Ahmad, Reem
AU - Hestehave, Sara
AU - Joa, Margarita
AU - Alsbiei, Omar
AU - Rodríguez-Palma, Erick J.
AU - Li, Yanrong
AU - Wang, Shilin
AU - Khanna, Rajesh
AU - Dai, Mingji
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.
PY - 2024/6/19
Y1 - 2024/6/19
N2 - 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.
AB - 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.
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U2 - 10.1021/jacs.4c04025
DO - 10.1021/jacs.4c04025
M3 - Article
C2 - 38843262
AN - SCOPUS:85195795147
SN - 0002-7863
VL - 146
SP - 16698
EP - 16705
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 24
ER -