SUBSTITUENT EFFECTS ON THE CLAISEN REARRANGEMENT

脂肪族Claisen重排是最有用和最有效的方法之一。 有机合成中的强反应。 虽然基本的克莱森 重排通常只在高温下发生， “修改”克莱森重排更一般 实用程序已经开发。 几乎无一例外，这些 变体的成功是因为存在取代基， 提供了强的速率加速效应。 但 对取代基效应的理解远远落后于 应用这些效应的综合研究。 该项目的目标是双重的：1）提供一个更 详细了解取代基效应的起源， 速率研究，取代基性质和位置的变化， 和介质效应的研究; 2）将这种新的联合收割机 利用现有知识设计有用取代基的信息- 控制克莱森重排。 合成和生物有机 可以预见这些概念的应用。 建议 开发出简单的克莱森重排的新变体， 呈现出独特的合成优势。 发展 合成方法的吡喃萘醌，一个重要的 抗肿瘤抗生素家族，已经在发展和未来 计划已经制定。 最后，过渡态的合理设计 分支酸酯酶的抑制剂，分支酸酯酶的关键环节， 莽草酸途径。 这种酶催化唯一的 已知的生物学克莱森重排。 因为这条通往 叶酸和重要的芳香族氨基酸是一种必需的 植物和细菌代谢的元素，而不是 人类新陈代谢的元素，新除草剂的发现 和抗菌剂。

The aliphatic Claisen rearrangement is one of the most useful and powerful reactions in organic synthesis. While the basic Claisen rearrangement usually occurs only at high temperatures, a variety of "modified" Claisen rearrangements of much more general utility have been developed. Virtually without exception, these variants succeed because of the presence of a substituent which provides a strong rate accelerating effect. However, the understanding of substituent effects lags far behind the elegant synthetic studies which apply these effects. The goals of this project are twofold: 1) to provide a more detailed understanding of the origins of substituent effects by rate studies, variation of the nature and location of substituents, and study of medium effects, and 2) to combine this new information with existing knowledge to design useful substituent- controlled Claisen rearrangements. Both synthetic and bioorganic applications of these concepts are envisioned. Proposals to develop facile new variants of the Claisen rearrangement with unique synthetic advantages are presented. Development of a synthetic approach to the pyranonaphthoquinones, an important family of antitumor antibiotics, is already in progress and future plans are outlined. Finally, the rational design of transition state inhibitors of the enzyme chorismate mutase, a key link in the shikimate pathway, is proposed. This enzyme catalyzes the only known biological Claisen rearrangement. Since this pathway to folic acid and important aromatic amino acids is an essential element of lower plant and bacteria metabolism and not an element of human metabolism, the discovery of new herbicides and antibacterial agents could result.