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Chiral Complexes Designed to Catalyzed Organic Reactions

设计用于催化有机反应的手性配合物

基本信息

批准号：
10542798
负责人：
ERIC N JACOBSEN
金额：
$ 72.31万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-01-01 至 2023-12-31
项目状态：
已结题

项目摘要

This program is dedicated to the development and elucidation of new principles for stereoselective catalysis, and in the application of those principles to the invention of practical synthetic methods for the preparation of chiral, bioactive compounds. This renewal application is focused on two distinct approaches to the generation and stereocontrolled reaction of highly electrophilic intermediates. Each of the proposed reaction manifolds is based on firm mechanistic hypotheses gleaned from extensive preliminary investigations. The first involves the application of precisely designed chiral ureas, thioureas, and squaramides to catalyze enantioselective reactions via ion-pair intermediates. These dual hydrogen-bond donors can abstract or bind weakly basic anions, such as halides, sulfonates, and carboxylates, to generate chiral ion pairs that remain tightly associated during subsequent selectivity-determining reactions of the prochiral cations. We discovered that the combination of hydrogen-bond donors with achiral Lewis or Brønsted acids generates highly reactive complexes that can promote activation and enantioselective reactions of weakly electrophilic substrates. This new principle is directed to creative new applications including the enantioselective multi-component synthesis of amines from carbonyl compounds and to the asymmetric ring opening of oxetanes. The principle of anion-abstraction catalysis is also applied in a new way to the promotion of enantioselective boronate rearrangements, through a novel chiral recognition mechanism involving discrimination of enantiotopic leaving groups. The boronate rearrangement methodology provides a general approach to the systematic construction of trisubstituted stereocenters from readily available organoboron derivatives. The second distinct approach involves the oxidative fluorofunctionalization of alkenes using hypervalent iodine catalysis. We have discovered that simple C2-symmetric aryl iodides catalyze enantioselective difluorination of simple alkenes via a multistep mechanism involving a highly reactive fluoroalkyl iodane intermediate. That intermediate can be intercepted in a variety of intra- or intermolecular reactions, leading to novel, 1,1-, 1,2-, and 1,3-fluorofunctionalized products in highly enantioenriched form. Efforts are directed toward the mechanistic elucidation of the new reactions, and to their practical enablement through the use of practical fluoride sources.

该计划致力于开发和阐明立体选择性催化的新原理，以及在将这些原理应用于制备手性化合物的实用合成方法的发明中，生物活性化合物。该更新应用程序侧重于两种不同的生成方法和高亲电子中间体的立体控制反应。每个提议的反应流形都是基于基于从广泛的初步调查中收集到的可靠的机械假设。第一个涉及应用精确设计的手性脲、硫脲和方酰胺催化对映选择性反应通过离子对中间体。这些双氢键供体可以提取或结合弱碱性阴离子，例如卤化物、磺酸盐和羧酸盐，以产生手性离子对，这些离子对在反应过程中保持紧密结合随后的前手性阳离子的选择性决定反应。我们发现，组合氢键供体与非手性路易斯酸或布朗斯台德酸生成高反应性络合物，可以促进弱亲电子底物的活化和对映选择性反应。这个新原则是致力于创造性的新应用，包括胺的对映选择性多组分合成羰基化合物和氧杂环丁烷的不对称开环。阴离子提取催化原理还通过一种新颖的方法以新的方式应用于促进对映选择性硼酸酯重排涉及对映体离去基团辨别的手性识别机制。硼酸盐重排方法提供了系统构建三取代的通用方法来自容易获得的有机硼衍生物的立体中心。第二种不同的方法涉及使用高价碘催化进行烯烃的氧化氟官能化。我们发现这么简单 C2-对称芳基碘化物通过多步机制催化简单烯烃的对映选择性二氟化涉及高反应性氟烷基碘中间体。该中间体可以通过多种方式拦截分子内或分子间反应，产生高度新颖的 1,1-、1,2- 和 1,3- 氟官能化产物对映体富集形式。努力的方向是对新反应的机理进行阐明，以及它们的作用通过使用实用的氟化物源来实现实际的能力。