Development, Elucidation, and Application of New Principles in Stereoselective Catalysis

立体选择性催化新原理的开发、阐明和应用

基本信息

批准号：
10622995
负责人：
ERIC N JACOBSEN
金额：
$ 40.78万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10622995
关键词：
Acceleration Acids Alcohols Alkali Metals Alkanesulfonates Alkenes Anions Binding Carbon Catalysis Cations Complex Creativeness Development Engineering Environment Friends Fruit Generations Glean Goals Hydrogen Bonding Investigation Ions Methods Outcome Pathway interactions Preparation Public Health Reaction Reagent Site Thiourea Transition Elements Urea Work carboxylate carboxylation catalyst chemical synthesis design glycosylation inorganic phosphate novel novel strategies phosphorus compounds programs small molecule stereochemistry sugar

Acceleration Acids Alcohols Alkali Metals Alkanesulfonates Alkenes Anions Binding Carbon Catalysis Cations Complex Creativeness Development Engineering Environment Friends Fruit Generations Glean Goals Hydrogen Bonding Investigation Ions Methods Outcome Pathway interactions Preparation Public Health Reaction Reagent Site Thiourea Transition Elements Urea Work carboxylate carboxylation catalyst chemical synthesis design glycosylation inorganic phosphate novel novel strategies phosphorus compounds programs small molecule stereochemistry sugar

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项目摘要

PROJECT SUMMARY/ABSTRACT This program is focused on the discovery, application, and mechanistic elucidation of catalytic reactions that are stereoselective, environmentally friendly, and useful for the preparation of chiral, bioactive compounds. We seek to develop novel concepts in catalytic reactivity and selectivity, and apply them to important problems in chemical synthesis. The premise underlying our current and proposed work is that new classes of small-molecule, chiral organic catalysts can promote challenging bond constructions, controlling the absolute and/or relative stereochemistry of the reactions through networks of attractive non-covalent interactions. The overarching goal is to identify simple organic catalysts that are readily accessible, inexpensive, and bear the minimal structural features necessary for inducing high levels of stereocontrol in synthetically interesting transformations. We will pursue several distinct catalytic concepts over the next five-year period, with each of the proposed reactivity manifolds based on firm mechanistic hypotheses gleaned from extensive preliminary investigations. We will apply precisely designed chiral ureas, thioureas, and squaramides to catalysis of enantioselective carbon-carbon and carbon-heteroatom bond-forming reactions. These dual hydrogen-bond donors can abstract or bind weakly basic anions, such as halides, sulfonates, phosphate, and carboxylates, to promote concerted substitution reactions or generate chiral ion pairs that remain tightly associated during subsequent enantioselectivity- 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 promote activation of weakly electrophilic substrates to access highly reactive cationic species. This new principle will be directed to creative applications involving atom-economical carbonyl addition reactions and additions to alkenes. The principle of anion-binding catalysis will also be examined in pathways where the catalyst-bound anion acts as the nucleophile in the enantiodetermining bond construction. Activation of polar reagents is applied in desymmetrizing ring- opening reactions and generation of stereogenic-at-phosphorus compounds. We will also pursue a new strategy aimed at applying anion binding by chiral H-bond donors to enhance the reactivity and control the stereochemical outcome of transition-metal catalyzed reactions, and separately in the context of stereoselective and site- selective glycosylation reactions. We have found that precisely tailored bisthiourea catalysts promote stereospecific, invertive reactions of alcohol nucleophiles with glycosyl phosphates via cooperative activation of both the nucleophile and the electrophile. This cooperative mechanism provides a new approach to achieving control over the site of reaction in minimally protected sugars and other polyfunctional substrates. We also aim to uncover completely new classes of chiral catalysts, such as a new class of alkali metal isothiourea-boronate complexes we uncovered unexpectedly and that promote enantioselective, catalytic reactions with highly basic reacting partners.

项目摘要/摘要该程序的重点是发现，应用和机械阐明催化反应立体选择性，环保，可用于制备手性生物活性化合物。我们寻找开发催化反应性和选择性方面的新颖概念，并将其应用于化学的重要问题合成。我们当前和提议的工作的前提是新的小分子手性有机催化剂可以促进挑战键结构，控制绝对和/或相对通过有吸引力的非共价相互作用网络的反应的立体化学。总体目标是识别易于访问，便宜的简单有机催化剂，并具有最小的结构在合成有趣的转换中引起高水平立体控制所必需的功能。我们将在接下来的五年中追求几个不同的催化概念，每个提议的反应性基于固件的歧管假设从广泛的初步研究中收集的歧管。我们将将精确设计的手性尿素，thioureas和Squareamides应用于对映选择性碳碳的催化和碳杂化键形成反应。这些双氢键供体可以抽象或弱结合基本阴离子，例如卤化物，硫酸盐，磷酸盐和羧酸盐，以促进协同的取代反应或产生手性离子对，在随后的对映选择性期间保持紧密相关 - 确定术前阳离子的反应。我们发现氢键供体的组合使用Achiral Lewis或BrønstedAcids产生高反应性复合物，促进弱的激活亲电底物进入高反应性阳离子物种。这个新原则将针对创意涉及原子经济羰基添加反应和对烷烃的添加的应用。原则阴离子结合催化也将在催化剂结合的阴离子充当核眼的途径中检查在映射键结构中。极性试剂的激活施加在除外环中开放反应和立体基因化合物的产生。我们还将采取新的策略旨在应用手性H键供体的阴离子结合以增强反应性并控制立体化学过渡金属催化反应的结果，并在立体选择性和位置的背景下分别选择性糖基化反应。我们发现，精确量身定制的Bisthiourea催化剂促进醇核磷酸盐与糖基磷酸盐的立体特异性，反转反应，通过合作激活核粉状和电力液。这种合作机制提供了一种新的方法来实现控制最小保护的糖和其他多功能底物中反应部位。我们也瞄准揭示全新的手性催化剂，例如新的碱金属isothiourea-boronate 复合物我们意外发现，并促进具有高碱性的对映选择性，催化反应反应伙伴。