NEW METHODOLOGY FOR THE SYNTHESIS OF ANTITUMOR AGENTS

抗肿瘤药物合成的新方法

• 批准号: 3071854
• 负责人: JEFFREY D WINKLER
• 金额: $ 7.03万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3071854
• 关键词: Diels Alder reaction; alkenes; antineoplastics; carbon; chromophore; diterpenes; drug design /synthesis /production; epoxide hydrolase; photochemistry; polyvinyls; stereochemistry; vinca alkaloids

This proposal is directed towards the development of new approaches to the construction of naturally occurring substances with important biological activity. The goal of the studies that we propose herein is not the total synthesis of complex organic molecules per se, but rather the development of new strategies in synthetic chemistry which will have applications beyond the construction of a particular class of natural products. We have developed an intramolecular (2+2) photocycloaddition protocol, the intramolecular dioxolenone photocycloaddition, and have demonstrated its utility in the synthesis of compounds which cannot be otherwise prepared. We propose herein to apply this methodology to the control of absolute stereochemistry in the photochemical cyclization, and to the preparation of naturally occurring compounds with important cytotoxic properties. We also describe herein our preliminary results with a different chromophore, a vinylogous amide, which leads to the formation of nitrogen-containing ring systems. A study of the generality of this process, and its application to the synthesis of antitumor alkaloids is proposed herein. Through the studies outlined above, we hope to develop new methodology for the stereochemically-controlled formation of carbon-carbon bonds. Using readily available chiral auxiliaries, the intramolecular dioxolenone photocycloaddition offers considerable promise for achieving absolute control of stereochemistry, an important goal in modern synthetic organic chemistry. The strategy that we have outlined for the synthesis of natural products using intramolecular (2+2) photocycloadditions of dioxolenones and vinylogous amides has counterparts in the Diels-Alder reaction, cationic polyene cyclization, and arene- olefin cycloaddition. More than one carbon-carbon bond and considerable stereochemical information is generated in a single synthetic operation. The constructions of the carbon skeleta of the ingenane and clerodane diterpenes, taxusin, mesembrine, and the vinca alkaloids outlined in this proposal attest to the considerable potential for this methodology in synthesis.

该提议针对新的发展 建造天然物质的方法 具有重要的生物学活性。 研究的目标 我们在这里提出的不是复杂有机物的总合成 分子本身，而是发展新策略 合成化学反应将超出 建造特定类别的天然产品。 我们有 开发了分子内（2+2）光循环载体方案， 分子内二氧酮光钙载体，并具有 证明了其在合成化合物中的实用性 无法做好准备。 我们建议在此应用 控制绝对立体化学的方法 光化学环化，并自然准备 发生具有重要细胞毒性特性的化合物。 我们 还以不同的方式描述我们的初步结果 发色团，一种乙烯基酰胺，导致形成 含氮环系统。 一项研究的一般性 这个过程及其应用于抗肿瘤的合成 本文提出了生物碱。 通过上面概述的研究，我们希望开发新的 立体化学控制形成的方法 碳碳键。 使用随时可用的手性辅助机， 分子内二氧酮光钙载体提供 实现绝对控制的巨大希望 立体化学，现代合成有机物的重要目标 化学。 我们概述了合成的策略 使用分子内（2+2）光钙载体的天然产物 二氧化苯甲酮和乙烯基酰胺的酰胺中有对应物 Diels-Alder反应，阳离子多烯环化和Arene- 烯烃环加成。 多个碳碳键和 单个立体化学信息是在一个单一中生成的 合成操作。 碳骨架的结构 Ingenane和Clerodane diterpenes，Taxusin，Mesembrine和 该提案中概述的VINCA生物碱证明了 合成中这种方法的巨大潜力。