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

项目总结/摘要 该计划的重点是催化反应的发现，应用和机理阐明， 立体选择性的、环境友好的并且可用于制备手性生物活性化合物。我们寻求 发展催化反应性和选择性的新概念，并将其应用于化学领域的重要问题。 合成.我们目前和提出的工作的前提是，新的小分子，手性 有机催化剂可以促进具有挑战性的键结构，控制绝对和/或相对键结构， 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 是确定简单的有机催化剂，容易获得，便宜，并承担最小的结构， 在合成感兴趣的转化中诱导高水平立体控制所必需的特征。我们将 在未来五年内，我将研究几种不同的催化概念， 歧管基于从广泛的初步调查中收集到的坚定的机械假设。我们将 将精确设计的手性脲、硫脲和方酰胺应用于对映选择性碳-碳催化， 和碳-杂原子键形成反应。这些双氢键给体可以与分子发生弱的结合或分离 碱性阴离子，如卤化物、磺酸盐、磷酸盐和羧酸盐，以促进协同取代 反应或产生在随后的对映选择性期间保持紧密缔合的手性离子对。 确定前手性阳离子的反应。我们发现氢键供体的结合 与非手性刘易斯酸或布朗斯特酸产生高度反应性的复合物， 亲电子底物以获得高反应性阳离子物质。这一新的原则将被引导到创造性的 涉及原子经济的羰基加成反应和烯烃加成的应用。原则 阴离子结合催化作用也将在催化剂结合阴离子作为亲核试剂的途径中进行研究 对映体决定键的结构。极性试剂的活化应用于去对称化环- 开环反应和立体异构的at-磷化合物的产生。我们还将采取新的战略 目的是利用手性氢键供体与阴离子结合，提高反应活性， 过渡金属催化反应的结果，并分别在立体选择性和网站的背景下， 选择性糖基化反应。我们已经发现，精确定制的双硫脲催化剂促进 醇亲核试剂与糖基磷酸酯通过协同活化的立体特异性反转反应 亲核试剂和亲电试剂。这一合作机制为实现 控制最低限度保护的糖和其他多官能底物中的反应位点。我们还旨在 发现全新的手性催化剂，例如新的碱金属异硫脲硼酸盐 我们意外地发现了一种复合物，它能促进对映选择性的催化反应， 反应型伴侣

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.