Total Synthesis of (−)-Cocaine and (−)-Ferruginine

Total synthesis of tropane alkaloids (−)-cocaine and (−)-ferruginine were accomplished in nine steps each and in 55% and 46% overall yields, respectively, starting from the known Betti base derivative (+)-(7aR,10R,12S)-10-(1H-benzotriazol-1-yl)-7a,8,9,10-tetrahydro-12-phenyl-12H-naphtho[1,2-e]pyrrolo[2,1-b][1,3]oxazine. In this novel route, RCM reaction and 1,3-dipolar cycloaddition were employed as key steps for the enantioselective construction of tropane skeleton and the regioselective introduction of 3-bromo-2-isoxazoline ring as masked cis-2,3-disubstituents. To obtain the desired precursor (2S,5R)-2-allyl-5-vinylpyrrolidine for RCM reaction, we developed a general and practical method for the preparation of enantiopure cis-2,5-disubstituted pyrrolidines bearing alkene- and/or alkyne-containing substituents. We also offered two highly efficient pathways for the conversion of the 3-bromo-2-isoxazoline ring into the desired cis-2,3-disubstituted groups in (−)-cocaine and (−)-ferruginine.

以已知的Betti碱（Betti base）衍生物(+)-(7aR,10R,12S)-10-(1H-苯并三唑-1-基)-7a,8,9,10-四氢-12-苯基-12H-萘并[1,2-e]吡咯并[2,1-b][1,3]噁嗪为起始原料，本研究分别通过9步反应完成了莨菪烷类生物碱（tropane alkaloids）(-)-可卡因（(-)-cocaine）与(-)-铁锈碱（(-)-ferruginine）的全合成，总产率分别为55%与46%。在该新颖合成路线中，研究采用闭环复分解反应（Ring-Closing Metathesis, RCM）与1,3-偶极环加成（1,3-dipolar cycloaddition）作为关键步骤，实现了莨菪烷骨架的对映选择性构建，并完成了作为掩蔽型顺式-2,3-二取代基的3-溴-2-异噁唑啉环的区域选择性引入。为获取闭环复分解反应所需的目标前体(2S,5R)-2-烯丙基-5-乙烯基吡咯烷，本研究开发了一种通用且实用的方法，用于制备带有烯基和/或炔基取代基的对映纯顺式-2,5-二取代吡咯烷。此外，本研究还提供了两条高效路径，可将3-溴-2-异噁唑啉环转化为(-)-可卡因与(-)-铁锈碱分子中所需的顺式-2,3-二取代基团。