A.N.Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova, 28, bld. 1, Moscow, 119334, Russia.
Moscow Institute of Physics and Technology (National Research University), Institutskiy per., 9, Dolgoprudny, Moscow Region, 141700, Russia.
Org Biomol Chem. 2023 Nov 22;21(45):9091-9100. doi: 10.1039/d3ob01577g.
Defluorination of the readily available 21,21,21-trifluorothevinone (7) with Mg + MeSiCl allows the preparation of 21,21-difluorothevinone (10) and 21-fluorothevinone (11), which can be used as the starting compounds for syntheses of 21,21-difluoro- and 21-fluoro-substituted relatives of thevinols and orvinols. Taken together, thevinols and orvinols are well known to constitute a family of the highly potent 4,5α-epoxy-18,19--(etheno/ethano)morphinan-type opioid receptor ligands. Alternatively, 10 and 18,19-dihydro-21,21-difluorothevinone (13) have been synthesized by the addition of MeSiCHF to the carbonyl function of thevinal (12) and dihydrothevinal (18) followed by oxidation of the intermediate C(21)-difluorinated secondary alcohols. 21,21-Difluorothevinols were obtained both by the addition of RMgX or RLi to the 21,21-difluoroketones and by the addition of MeSiCHF to the carbonyl function of the non-fluorinated 18,19--(etheno/ethano)morphinan ketones. In general, these addition reactions have been shown to result in mixtures of the C(21)-epimeric alcohols. However, in some cases, the reactions proceeded with high stereoselectivity allowing the isolation of one of the epimeric alcohols by conventional crystallization. Preparations of the 21,21-difluorothevinols bearing an allyl, cyclopropylmethyl, or cyclobutylmethyl group at the N(17) nitrogen are also reported.
用 Mg + MeSiCl 将易得的 21,21,21-三氟硫代戊酮 (7) 脱氟，可以制备 21,21-二氟硫代戊酮 (10) 和 21-氟硫代戊酮 (11)，它们可作为合成 21,21-二氟-和 21-氟取代的硫代戊醇和奥醇的起始化合物。总的来说，硫代戊醇和奥醇是众所周知的具有高度效力的 4,5α-环氧-18,19--(亚乙/亚乙基)吗啡烷型阿片受体配体家族。或者，10 和 18,19-二氢-21,21-二氟硫代戊酮 (13) 通过 MeSiCHF 加成到 vinal (12) 和二氢硫代戊醛 (18) 的羰基官能团，然后氧化中间的 C(21)-二氟化仲醇来合成。通过 RMgX 或 RLi 加成到 21,21-二氟酮，或者通过 MeSiCHF 加成到非氟代的 18,19--(亚乙/亚乙基)吗啡烷酮的羰基官能团，都可以得到 21,21-二氟硫代戊醇。通常，这些加成反应会产生 C(21)-差向异构体醇的混合物。然而，在某些情况下，反应具有高立体选择性，可以通过常规结晶分离出一种差向异构体醇。还报道了在 N(17)氮上带有烯丙基、环丙甲基或环丁基甲基的 21,21-二氟硫代戊醇的制备。
