Development of New Catalytic and Enantioselective Reactions

描述（由申请人提供）：手性有机分子的高效和立体选择性合成对于治疗剂的可用性至关重要。开发促进重要的键形成反应的催化剂，并且这些催化剂容易获得，便宜且空气稳定，是现代化学的一个引人注目的目标。在这方面，小有机分子的对映选择性形成所需的手性催化剂具有特别高的价值。在制备大量生物活性和医学相关分子所需的最普遍存在的结构单元中，是对映体纯的胺和醇。虽然这两类重要分子的对映选择性合成已经从最近的进展中受益，但是大量的缺点仍然没有得到解决。我们将通过催化剂设计的创新和化学反应性的进步来解决这些问题。 在我们计划的第一部分，我们将设计和开发基于氨基酸的催化剂用于醇的对映选择性硅保护。这类独特的催化剂提供了一系列以其他方式难以获得的对映体富集的醇;我们的目标是发现以优异的效率促进醇甲硅烷基化的催化剂（即，<2mol%催化剂）。高效催化剂的可用性将使这类重要的转化真正实用，因为这类反应是在空气中使用试剂级（或无）溶剂进行的。此外，我们将使用相同类型的催化剂通过相应的醇甲苯磺酰化反应对映选择性活化醇。所得对映体富集的甲苯磺酸酯可以容易地转化为其它有用的有机分子。在我们计划的第二部分，我们将为另一类重要的和欠发达的过程开发新的催化剂：醛亚胺的对映选择性烯丙基化。得到的对映体富集的烯丙基胺可作为合成各种有用的含氮分子的前体。我们计划的第三个目标涉及催化C-B键形成的创新。碳-硼键是有机化学中最有用的实体之一，并且已经开发了许多金属催化的方法来不对称地形成它们。我们已经发现了第一组用于形成C-B键的无金属固定方案;这些反应通过与金属催化变体完全不同的机制进行。我们将开发无金属对映选择性C-B键形成的方法，容易获得的小有机分子作为催化剂。用作催化剂的实体也将在相应的Cu催化反应中用作配体。 公共卫生相关性：手性有机分子的高效、实用和立体选择性制备对于治疗剂的可用性至关重要;催化对映选择性方法的发展是现代化学和医学的一个引人注目的目标。在有机合成中最有用的中间体是对映体纯的胺和醇。本提案中概述的研究旨在设计和引入新的催化剂和方案，用于高效，实用和对映选择性合成各种胺和醇，这些胺和醇难以通过任何其他方法制备。

DESCRIPTION (provided by applicant): Efficient and stereoselective synthesis of chiral organic molecules is critical to the availability of therapeutic agents. Development of catalysts that promote important bond forming reactions, and which are readily accessible, inexpensive, and air stable is a compelling goal of modern chemistry. In this context, chiral catalysts, required for enantioselective formation of small organic molecules, are of particularly high value. Among the most ubiquitous building blocks needed for preparation of a large assortment of biologically active and medicinally relevant molecules are enantiomerically pure amines and alcohols. Although enantioselective syntheses of these two important classes of molecules have benefited from recent advances, a significant number of shortcomings remain unresolved. We will address such issues through innovations in catalyst design and by advances in chemical reactivity. In the first segment of our program, we will design and develop amino acid-based catalysts for enantioselective silyl protection of alcohols. This unique class of catalysts delivers a range of otherwise difficult-to-access enantiomerically enriched alcohols; our goal is to discover catalysts that promote alcohol silylations with exceptional efficiency (i.e., <2 mol % catalyst). The availability of highly efficient catalysts would render this important class of transformations truly practical, as this class of reactions is performed under air, with reagent grade (or no) solvents. Moreover, we will use the same class of catalysts for enantioselective activation of alcohols through the corresponding alcohol tosylations. The resulting enantiomerically enriched tosylates can be readily converted to other useful organic molecules. In the second part of our program, we will develop new catalysts for another important and underdeveloped class of processes: enantioselective allylations of aldimines. The enantiomerically enriched allylic amines obtained through serve as precursors that various other useful nitrogen-containing molecules. The third objective of our program involves innovations in catalytic C-B bond formation. Carbon-boron bonds are among the most useful entities in organic chemistry, and a number of metal-catalyzed method for their enantioselective formation of have been developed. We have discovered the first set of metal-free set protocols for formation of C-B bonds; these reactions proceed by an entirely different mechanism versus the metal-catalyzed variants. We will develop methods for metal-free enantioselective C-B bond formation where readily available small organic molecule serve as catalysts. The entities used as catalysts will also be utilized as ligands in the corresponding Cu-catalyzed reactions. PUBLIC HEALTH RELEVANCE: Efficient, practical and stereoselective preparation of chiral organic molecules is critical to the availability of therapeutic agents; development of catalytic enantioselective methods is a compelling objective in modern chemistry and medicine. Among the most useful intermediates in organic synthesis are enantiomerically pure amines and alcohols. The investigations outlined in this proposal aim to design and introduce new catalysts and protocols for efficient, practical and enantioselective synthesis of a wide range of amines and alcohols, which are difficult to prepare by any other method.