Asymmetric Synthesis of Cytotoxic Natural Products

五味子皂苷是一类结构新颖的木脂素类天然产物，从中草药五味子果实中分离得到，具有很强的细胞毒性。这些试剂是由具有良好代表性的二苯并环辛二烯类木脂素通过氧化螺环反应形成独特的2，4-cyclohexadienone-6-spiro-3‘-(2’，3‘-dihydrobenzo[b]furan)环系。提出了一种合成这一系列天然产物的方法，并基于形成螺二氢苯并呋喃环系的仿生策略。提出了两种构筑联芳键的策略，一种是基于适当取代的1，4-二芳基丁烷体系的分子间偶联反应，另一种是基于不对称联芳偶联反应的新的合成方法。在第一种策略中，环辛二烯环上的三个立体生成中心将通过不对称的烯丙基硼反应引入，而1，4-二芳基丁烷的构建将通过立体选择性的氢化硼/铃木偶联反应来完成。在第二种策略中，通过适当取代的手性联芳基体系的闭环歧化反应形成环辛二烯环。最终的螺环化反应是基于联芳基体系固有的空间偏向，区域选择性地从二恶英前体开始的。草亚胺是大环二烯和三烯内酯的天然产物，具有很强的细胞毒性，对癌基因转化的细胞具有选择性。建议对这些试剂的全合成进行研究，其特征是用于形成大内酯的新型分子内Castro-Stephens偶联，以及用于烯胺侧链安装的(Z)-乙烯基碘和内酰胺之间的钯催化偶联。

The schiarisanrins are a structurally novel family of lignan natural products that exhibit potent cytotoxicity that were isolated from the fruit of the Chinese medicinal plant Schizandra arisanensis. These agents are derived from the well- represented dibenzocyclooctadiene class of lignans by an oxidative spirocyclization to form the unique 2,4- cyclohexadienone-6-spiro-3'-(2',3'-dihydrobenzo[b]furan) ring system. A synthetic approach to this family of natural products is proposed and is based on a biomimetic strategy for the formation of the spirodihydrobenzo[b]furan ring system. Two strategies for biaryl bond construction are proposed, the first based on an intermolecular coupling of an appropriately substituted 1,4-diarylbutane system, and the second based on novel synthetic methodology for an asymmetric intermolecular biaryl coupling reaction. In the first strategy, the three stereogenic centers of the cyclooctadiene ring will be introduced by an asymmetric allylboration reaction, and 1,4-diarylbutane construction will be completed by a stereoselective hydroboration/Suzuki coupling reaction sequence. In the second strategy, the cyclooctadiene ring will be formed by a ring- closing metathesis reaction of an appropriately substituted chiral biaryl system. The final spirocyclization is proposed to proceed regioselectively from a dioxepin precursor based on an inherent steric bias of the biaryl system. The oximidines are macrocyclic diene and triene lactone natural products that exhibit potent cytotoxicity that is selective for oncogene transformed cells. Studies are proposed for the total synthesis of these agents that feature a novel intramolecular Castro-Stephens coupling for macrolactone formation and a palladium catalyzed coupling between a (Z)-vinyl iodide and a lactam for installation of the enamide side chain.