Asymmetric Synthesis of Cytotoxic Natural Products

细胞毒性天然产物的不对称合成

• 批准号: 6624122
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6624122
• 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.

五味子醇甲是从中国药用植物五味子果实中分离的一类结构新颖的木脂素类天然产物，具有很强的细胞毒性。 这些试剂通过氧化螺环化作用从代表性很好的二苯并环辛烯类木脂素衍生，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。 提出了一种天然产物的合成方法，该方法基于螺二氢苯并[B]呋喃环系统形成的仿生策略。 提出了两种策略的联芳基键的建设，第一个基于适当取代的1，4-二芳基丁烷系统的分子间耦合，第二个基于新的合成方法的不对称分子间联芳基耦合反应。 在第一种策略中，环辛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，通过适当取代的手性联芳基系统的闭环复分解反应形成环辛环。 最后的螺环化建议进行区域选择性地从二氧杂环庚三烯前体的基础上的联芳基系统的固有的空间位阻。肟是大环二烯和三烯内酯天然产物，其表现出对癌基因转化细胞具有选择性的强效细胞毒性。 提出了这些试剂的全合成研究，其特征在于用于大环内酯形成的新型分子内Castro-Stephens偶联和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。