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

项目摘要/摘要 本课程侧重于催化反应的发现、应用和机理阐明。 立体选择性，环境友好，可用于手性生物活性化合物的制备。我们在寻找 发展催化反应性和选择性的新概念，并将它们应用于化学中的重要问题 综合。我们当前和拟议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 通过吸引的非共价相互作用网络的反应的立体化学。首要目标是 是找出简单的有机催化剂，这些催化剂容易获得，价格低廉，并且具有最小的结构 在综合有趣的转换中诱导高水平立体控制所必需的特征。我们会 在接下来的五年内追求几个不同的催化概念，每个提议的反应性 基于坚定的机械论假设的流形是从广泛的初步调查中收集的。我们会 精细设计的手性脲、硫脲和方酰胺在对映体选择性碳-碳催化中的应用 碳-杂原子键形成反应。这些双氢键施主可以抽象或弱结合。 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 反应或产生手性离子对，在随后的对映选择性过程中保持紧密结合- 测定前手性阳离子的反应。我们发现氢键供体的结合 与无手性Lewis或Brnsted酸生成高活性的络合物，促进弱 亲电底物，以获得高活性阳离子物种。这一新原则将引导到创造性 涉及原子经济的羰基加成反应和烯烃加成反应的应用。三、原则 阴离子结合催化也将在催化剂结合的阴离子作为亲核剂的途径中被考察。 在确定对映体的键结构中。将极性试剂活化应用于脱对称环氧化反应。 开环反应与立体生磷化合物的生成。我们还将推行一项新战略 目的是通过手性氢键供体结合阴离子来提高反应活性和控制立体化学 过渡金属催化反应的结果，并分别在立体选择性和位置- 选择性糖基化反应。我们发现，精确定制的双硫脲催化剂可以促进 通过协同激活醇亲核试剂与糖基磷酸酯的立体专一性的可逆反应 无论是亲核分子还是亲核分子。这一合作机制提供了一种新的方法来实现 对最小保护的糖和其他多功能底物中反应部位的控制。我们还瞄准了 发现全新的手性催化剂，例如一种新的碱金属异硫脲-硼酸盐 我们出人意料地发现了促进高碱性的对映选择性催化反应的络合物 反应伙伴。

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.