Ma Donghui, Duran Paz, Al-Ahmad Reem, Hestehave Sara, Joa Margarita, Alsbiei Omar, Rodríguez-Palma Erick J, Li Yanrong, Wang Shilin, Khanna Rajesh, Dai Mingji
Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.
Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York 10010, United States.
J Am Chem Soc. 2024 Jun 6;146(24):16698-705. doi: 10.1021/jacs.4c04025.
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 and in an model of arthritic pain, from which two novel lead compounds were identified for further development.
我们报道了一种高效半合成具有6/6/6/5/6/6六环体系、八个立体中心和独特C12-C23键联的胆甾烷甾体生物碱（-）-维拉格拉宁A的方法。我们的合成方法的特点包括在C12处进行舍内克-巴兰C-H氧化、通过铃木-宫浦交叉偶联形成C12-C23键，以及通过氢原子转移（HAT）引发的米尼斯奇C-H环化反应在C20处形成具有所需立体化学的C20-C22键。这些关键转化显著提高了整体合成效率，以11步反应从廉价且易于获得的脱氢表雄酮出发，得到了超过200毫克的（-）-维拉格拉宁A。此外，这种方法能够灵活合成新型合成类似物，用于在感觉神经元和关节炎疼痛模型中进行生物学评估，从中鉴定出两种新型先导化合物以供进一步开发。
