Asymmetric Synthesis of Cytotoxic Natural Products

细胞毒性天然产物的不对称合成

• 批准号: 6882619
• 负责人: ROBERT S COLEMAN
• 金额: $ 26.26万
• 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 2006-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6882619
• 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.

五味子素是一种结构新颖的木脂素天然产物，具有强大的细胞毒性，是从药用植物五味子中分离出来的。这些试剂是由典型的二苯并环二烯类木脂素通过氧化螺旋环化形成独特的2,4-环己二烯-6-螺旋-3'-（2',3'-二氢苯并[b]呋喃）环体系而得到的。提出了一种天然产物家族的合成方法，该方法基于形成螺二氢苯并[b]呋喃环体系的仿生策略。本文提出了两种联芳基键构建策略，第一种是基于适当取代的1,4-二乙基丁烷体系的分子间偶联，第二种是基于不对称分子间联芳基偶联反应的新合成方法。在第一种策略中，环二烯环的三个立体中心将通过不对称烯基硼化反应引入，1,4-二乙基丁烷的构建将通过立体选择性氢硼化/铃木偶联反应序列完成。在第二种策略中，环二甲苯环将通过适当取代的手性联芳基体系的合环复合反应形成。最后的螺旋环化是基于联芳基体系固有的空间偏压，从二甲氧苄素前体进行区域选择性的。邻胺嘧啶是大环二烯和三烯内酯天然产物，对癌基因转化的细胞具有选择性，具有强大的细胞毒性。研究人员提出了这些试剂的全合成方法，其中包括一种用于形成大内酯的新型分子内Castro-Stephens偶联和一种用于安装酰胺侧链的(Z)-碘化乙烯和内酰胺之间的钯催化偶联。