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.

schiarisanrins是一个结构新颖的木质天然产品家族，表现出有效的细胞毒性，是从中药植物schizandra arisanensis的果实中分离出来的。 这些药物是源自氧化螺旋旋风的良好代表的木糖二烯类，形成独特的2,4- cyclohexadienone-6-Spiro-3' - （2'，3'，3'-二氢苯甲酸[b] furan）。 提出了对这种天然产物家族的合成方法，并基于一种仿生策略，用于形成螺旋形的苯苯甲酸[B]呋喃环系统。 提出了两种用于双键构建的策略，第一种基于适当取代的1,4-二亚丁烷系统的分子间耦合，而第二种基于第二种基于新型的合成方法，用于不对称的内分子间屈偶联反应。 在第一个策略中，将通过不对称的烯丙基反应引入环链二烯环的三个立体生成中心，并将通过立体选择性水机/铃木耦合反应序列来完成1,4-二硫烷的结构。 在第二个策略中，环链环将通过适当取代的手性双子肌系统的环闭合反应形成。 提出了最终的螺旋旋风拟成制，以基于Biaryl系统的固有空间偏置从二Xepin前体进行区域选择性。氧胺是大环二烯和三烯内酯天然产物，它们表现出有效的细胞毒性，对癌基因转化的细胞有选择性。 提出了针对这些药物的总合成的研究，这些试剂具有新型的分子内Castro-Stephens耦合，用于大乳酸酯形成，并在A（Z） - 乙烯基碘化物和乳胶之间催化钯催化耦合，用于安装eNamide侧链。