Development of New Catalytic and Enantioselective Reactions

描述(由申请人提供)：高效和立体选择性地合成手性有机分子对治疗剂的可用性至关重要。开发能够促进重要的成键反应，并且易于获得、价格低廉、空气稳定的催化剂是现代化学的一个引人注目的目标。在这种背景下，用于有机小分子对映体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的构件中，有对映体纯胺和醇。尽管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，但仍有相当数量的缺点尚未解决。我们将通过创新催化剂设计和提高化学反应能力来解决这些问题。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基保护。这类独特的催化剂提供了一系列原本难以获得的富含对映体的醇；我们的目标是发现能够以非凡的效率促进醇硅化的催化剂(即，2摩尔%催化剂)。高效催化剂的可获得性将使这类重要的转化真正可行，因为这类反应是在空气中进行的，使用试剂级(或无)溶剂。此外，我们将使用相同类别的催化剂，通过相应的醇对甲苯磺化反应对映选择性地活化醇。生成的富含对映体的对甲苯磺酸盐可以很容易地转化为其他有用的有机分子。在我们计划的第二部分，我们将为另一类重要而不发达的过程开发新的催化剂：醛二胺的对映选择性烯丙化反应。通过该方法获得的富含对映体的烯丙基胺可作为其他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，已经发展了许多金属催化的方法来形成它们的对映选择性。我们已经发现了第一套形成C-B键的无金属SET协议；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体选择性C-B键的形成方法，在这种方法中，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铜催化反应中用作配体。 与公众健康相关：高效、实用和立体选择性地制备手性有机分子对治疗剂的可用性至关重要；开发催化对映体选择性方法是现代化学和医学中一个引人注目的目标。有机合成中最有用的中间体是对映体纯胺和醇。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、实用和对映选择性地合成广泛的胺和醇，这些胺和醇是任何其他方法难以制备的。

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.