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.

该提案旨在开发新的 天然物质的构建方法 具有重要的生物活性。 研究的目标是 我们这里提出的并不是复杂有机物的全合成 分子本身，而是新策略的发展 合成化学的应用将超出 构建特定类别的天然产物。 我们有 开发了分子内 (2+2) 光环加成方案， 分子内二氧杂环戊烯酮光环加成，并且有 证明了其在合成化合物中的实用性 不能做其他准备。 我们在此建议应用此 控制绝对立体化学的方法 光化学环化，以及自然制备 具有重要细胞毒性特性的化合物。 我们 在此还用不同的方式描述了我们的初步结果 发色团，一种插烯酰胺，导致形成 含氮环系统。 普遍性研究 该工艺及其在抗肿瘤药物合成中的应用 本文提出了生物碱。 通过上述研究，我们希望开发出新的 立体化学控制形成的方法 碳-碳键。 使用现成的手性助剂， 分子内二氧杂环戊烯酮光环加成提供 实现绝对控制的巨大希望 立体化学是现代有机合成的一个重要目标 化学。 我们概述的合成策略 使用分子内 (2+2) 光环加成法合成天然产物 二氧杂环烯酮和插烯酰胺的对应物 Diels-Alder 反应、阳离子多烯环化和芳烃- 烯烃环加成。 超过一个碳-碳键且 在一个单一的过程中产生大量的立体化学信息 合成操作。 碳骨架的结构 Ingenane 和 clerodane 二萜、紫杉素、mesembrine 和 本提案中概述的长春花生物碱证明 这种方法在合成方面具有巨大的潜力。