NEW METHODOLOGY FOR THE SYNTHESIS OF ANTITUMOR AGENTS

该提案旨在开发新的 构建天然物质的方法 具有重要的生物活性。 这些研究的目的是， 我们在这里提出的不是复杂有机物的全合成， 分子本身，而是发展新的战略， 合成化学的应用将超越 一种特殊类型的天然产物。 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，并具有 证明了其在合成 不能以其他方式准备。 我们在此建议， 控制绝对立体化学的方法 光化学环化，并涉及天然的 具有重要细胞毒性的化合物。 我们 本文还描述了我们的初步结果与不同的 发色团，一种乙烯基乙酰胺，导致形成 含氮环系。 的一般性研究 本发明的方法及其在合成抗肿瘤药物 本文提出了生物碱。 通过上述研究，我们希望开发新的 用于立体化学控制形成 碳碳键 使用容易获得的手性助剂， 分子内二氧杂环戊烯酮光环加成提供了 实现绝对控制的巨大潜力 立体化学是现代有机合成重要目标 化学. 我们概述的综合战略 天然产物的分子内（2+2）光环加成反应 二氧杂环戊烯酮和乙烯基乙酰胺的对应物， Diels-Alder反应、阳离子多烯环化反应和芳烃- 烯烃环加成 一个以上的碳-碳键， 大量的立体化学信息产生于单个 合成操作 碳纳米管的结构 巨大戟烷和克罗烷二萜、紫杉醇、中萜，和 本提案中概述的长春花生物碱证明了 这种方法在综合方面具有相当大的潜力。

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.