Asymmetric Synthesis of Cytotoxic Natural Products

细胞毒性天然产物的不对称合成

• 批准号: 6742115
• 负责人: ROBERT S COLEMAN
• 金额: $ 2.87万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6742115
• 关键词: alkynes; biological products; biomimetics; biotechnology; boron; chemical synthesis; cytotoxicity; free radicals; lactams; lignans; medicinal plants; method development; palladium; stereochemistry

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.

五味子苷是从中药植物五味子的果实中分离出来的结构新颖的木脂素天然产物家族，具有强大的细胞毒性。 这些试剂源自代表性的二苯并环辛二烯类木脂素，通过氧化螺环化形成独特的2,4-环己二烯酮-6-螺-3'-(2',3'-二氢苯并[b]呋喃)环系统。 提出了该天然产物家族的合成方法，该方法基于形成螺二氢苯并[b]呋喃环系统的仿生策略。 提出了两种联芳键构建策略，第一种基于适当取代的 1,4-二芳基丁烷体系的分子间偶联，第二种基于不对称分子间联芳偶联反应的新颖合成方法。 在第一种策略中，环辛二烯环的三个立体中心将通过不对称烯丙基硼化反应引入，并且1,4-二芳基丁烷的构建将通过立体选择性硼氢化/Suzuki偶联反应序列完成。 在第二种策略中，环辛二烯环将通过适当取代的手性联芳基系统的闭环复分解反应形成。 建议基于联芳基系统固有的空间偏向，从二氧杂环己烷前体区域选择性地进行最终的螺环化。肟胺是大环二烯和三烯内酯天然产物，具有对癌基因转化细胞具有选择性的强效细胞毒性。 提出了对这些试剂的全合成的研究，其特征是用于形成大内酯的新型分子内卡斯特罗-斯蒂芬斯偶联以及用于安装烯酰胺侧链的(Z)-乙烯基碘和内酰胺之间的钯催化偶联。