Trost Barry M, Waser Jerome, Meyer Arndt
Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA.
J Am Chem Soc. 2008 Dec 3;130(48):16424-34. doi: 10.1021/ja806724x.
We report a full account of our work toward the total synthesis of pseudolaric acid B (1a), a diterpene acid isolated from the bark of Pseudolarix kaempferi Gordon (pinaceae). Compound 1a is an antifungal and antifertility agent. Furthermore, its capacity for inhibiting tubulin polymerization makes it a potential lead for cancer therapy. Herein, we describe the use of a Ru- or Rh-catalyzed [5 + 2] intramolecular cycloaddition reaction of an alkyne and a vinylcyclopropane for the construction of the polyhydroazulene core of the molecule. Our first unsuccessful strategy for the introduction of the quaternary center based on an epoxide opening with cyanide led to the discovery of a new TBAF-mediated isomerization of a 1,4-diene to a 1,3-diene and a vinylogous eliminative opening of an epoxide to form a dienol. Our second strategy, based on the cyclization of an alkoxycarbonyl radical upon a diene system, succeeded in forming the quaternary center. Detailed studies showed the dependence of this underutilized approach for the synthesis of lactones on substrate structure and reaction conditions. In the late stage of the synthesis, the unique capacity of cerium organometallic reagents to add to a sensitive, sterically hindered ketone was demonstrated. The easy formation of an oxo-bridged derivative was the major hurdle to the completion of the synthesis and showcased the intriguing reactivity of the complex core of the pseudolaric acids.
我们全面报告了我们在全合成土槿皮酸B（1a）方面的工作，土槿皮酸B是从金钱松（松科）树皮中分离得到的一种二萜酸。化合物1a是一种抗真菌和抗生育剂。此外，它抑制微管蛋白聚合的能力使其成为癌症治疗的潜在先导化合物。在此，我们描述了使用钌或铑催化的炔烃与乙烯基环丙烷的[5 + 2]分子内环加成反应来构建该分子的多氢薁核心。我们基于用氰化物开环氧化合物引入季碳中心的首个未成功策略，导致发现了一种新的四丁基氟化铵介导的1,4 - 二烯异构化为1,3 - 二烯以及环氧乙烷的烯丙型消除开环以形成二烯醇的反应。我们基于在二烯体系上使烷氧羰基自由基环化的第二个策略成功形成了季碳中心。详细研究表明这种未充分利用的内酯合成方法对底物结构和反应条件的依赖性。在合成的后期，展示了有机金属铈试剂加成到一个敏感的、空间位阻较大的酮上的独特能力。易于形成氧桥联衍生物是合成完成的主要障碍，并展示了土槿皮酸复杂核心的有趣反应性。
