SUBSTITUENT EFFECTS ON THE CLAISEN REARRANGEMENT

脂肪族克莱森重排是最有用的和 有机合成中的强反应。而基本的克莱森 重排通常只在高温下发生， 更一般的“修改的”克莱森重排 已经开发出了实用程序。几乎无一例外地，这些 变体的成功是因为存在一个取代基，该取代基 提供了很强的提速效果。然而， 对取代基效应的认识远远落后于优雅 应用这些效应的综合研究。 该项目的目标有两个：1)提供更多 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， 和媒介效应的研究，以及2)结合这一新的 利用现有知识设计有用的取代基的信息- 受控的克莱森重排。包括合成的和生物有机的 对这些概念的应用进行了展望。建议： 开发简便的Claisen重排的新变体 展示了独特的综合优势。开发一种 一种重要的吡喃并萘二酚的合成方法 抗肿瘤抗生素家族，已经在进步和未来 概述了计划。最后，过渡态的合理设计 分支酸变位酶的抑制剂，这是 提出了莽草酸途径。这种酶催化了唯一的 已知的生物克莱森重排。因为这条路通往 叶酸和重要的芳香氨基酸是必不可少的 低等植物和细菌代谢的元素，而不是 人类新陈代谢元素，新除草剂的发现 可能会产生抗菌剂。

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.