ACYCLIC STEREOSELECTION IN NATURAL PRODUCT SYNTHESIS

天然产物合成中的无环立体选择

基本信息

批准号：
2441024
负责人：
CLAYTON H HEATHCOCK
金额：
$ 25.91万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-09-01 至 1998-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2441024
关键词：
alkenes biological products chemical addition chemical substitution conformation drug design /synthesis /production enolate lithium macrolide antibiotics magnesium nuclear magnetic resonance spectroscopy rifamycins stereochemistry thiones

项目摘要

The long term goal of this project is to address the problems introduced into the rational synthesis of complex organic molecules by stereochemistry, both relative and absolute. In the five-year program proposed, several types of studies will be carried out. The most fundamental will be physical organic investigations of lithium and magnesium enolates, important intermediates in organic synthesis. These studies will try to assess the importance of aggregation on reactivity, specifically on stereochemistry. Reseach directed toward the development of a protocol for catalytic, asymmetric aldol reactions using the readily-available boron enolates will also be carried out. The stereochemical personalities of two less-studied classes of reagents--magnesium enolates and metalloenamines--will be systematically investigated. The sterochemistry of the reactions of immonium ions and thionium ions with nucleophilic alkenes will be surveyed. A productive protocol for the stereoselective construction of conformationally-flexible molecules will be further developed. This strategy employs a highly stereoselective aldol reaction, coupled with further reactions that are known to transfer chirality with high selectivity. The specific sequence to be studied will utilize sequential aldol, Claisen, and Mislow/Evans rearrangement ot prepare building blocks having three stereocenters. The method will be appleid to the total synthesis of the natural porducts ACRL toxin IIIA and myxalamide. The use of chiral alpha-silyloxy ketones for asymmetric aldol constructions will be further developed and applied to the synthesis of the rifamycin S ansa chain. Finally, erythronolide A will be synthesized as a exercise in development of aldol strategy. The main theme of this research project is stereochemistry in synthesis, a topic of great relevance to modern medicinal chemistry.

该项目的长期目标是解决问题引入复杂有机物的合理综合分子通过立体化学，无论是相对和绝对的。在提议的五年计划，将有几种类型的研究执行。最基本的是物理有机研究锂和镁烯醇，重要的有机合成中的中间体。这些研究将尝试评估汇总对反应性的重要性，特别是立体化学。指向发展使用催化，非对称醛反应的方案易于使用的硼enolates也将进行。这两个较少研究类的立体化学性格试剂 - 含量烯醇和冶金胺 - 将是系统研究。反应的静态化学用亲核烷烃的原子离子和三元离子将被调查。立体选择性的生产协议构造构象分子的构建将是进一步发展。该策略采用高度立体选择性藻反应，再加上已知的进一步反应以高选择性转移手性。特定序列被研究将利用顺序藻类，克莱森和Misllow/Evans 重排OT准备三个立体中心。该方法将成为总合成的苹果天然porducts Acrl毒素IIIA和粘酰胺。使用用于非对称醛的手性α-硅氧酮酮结构将进一步开发并应用于利福米霉素的ANSA链的合成。最后，Erythronolide a 将合成作为Aldol策略发展的练习。该研究项目的主题是立体化学综合，与现代药物有很大相关的话题化学。