Department of Chemistry, Tsinghua University, Beijing 100084, People's Republic of China.
J Org Chem. 2011 Apr 15;76(8):2694-700. doi: 10.1021/jo200069m. Epub 2011 Mar 25.
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.
从已知的 Betti 碱衍生物 (+)-(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[2,1-b][1,3]恶嗪出发，分别以 9 步和 55%及 46%的总收率，完成了托烷生物碱（-）可卡因和（-）血根碱的全合成。在这条新路线中，RCM 反应和 1,3-偶极环加成被用作对映选择性构建托烷骨架和区域选择性引入 3-溴-2-异恶唑啉环作为掩蔽的顺式-2,3-二取代基的关键步骤。为了获得所需的 RCM 反应前体（2S,5R）-2-烯丙基-5-乙烯基吡咯烷，我们开发了一种通用且实用的方法，用于制备含有烯烃和/或炔烃取代基的手性纯顺式-2,5-二取代吡咯烷。我们还提供了两种高效的途径，用于将 3-溴-2-异恶唑啉环转化为（-）可卡因和（-）血根碱中所需的顺式-2,3-二取代基。
