Development of New Catalytic and Enantioselective Reactions

描述(申请人提供)：手性有机分子的高产率和选择性制备对治疗剂的可用性至关重要。发展催化、对映体选择性的合成方法是化学和医学领域的一个迫切目标。在有机合成中最有用的构件是光学纯胺和醇；我们的计划将解决关于这些重要类别的分子的对映选择性制备的问题。我们将建立新的、实用、高效和高对映选择性的方法来合成高产率和光学纯度难以获得的仲胺和叔胺和醇。我们计划的一个主要目标是开发新的手性配体和催化剂，所有这些都是基于氨基酸的。基于氨基酸的分子的一个关键优势是它们可以很容易地制备和修饰，允许快速(机制驱动)合成和筛选变体，从而可以快速确定最适合特定转化集的催化剂。我们将开发新的基于氨基酸的手性配体和实用方法，用于烯醇硅烷和硝基烷烃与乙二胺的高效不对称加成(Mannich反应)。催化剂的发现将由机械原理指导，并将通过本计划中开发的筛选方案来完成。新的合成方法将提供实用的(蒸馏溶剂，不需要空气过滤)和独特的程序来合成各种用替代催化对映体选择性方法无法制备的无环胺和环胺。我们还将开发新的基于氨基酸的手性配体和有效地将碳亲核试剂与酮亚胺进行对映选择性加成的方法。上述原则将用于开发催化不对称烷基化和曼尼希反应，从而获得光学富集型α-和β-季胺酸。我们还将开发新的基于手性氨基酸的配体、催化剂和方法，用于高效地对映选择性合成醇。基于氨基酸的手性配体将被开发，以影响银催化的不对称羟醛加成反应，使一系列烯醇硅烷与各种酮发生不对称加成反应。最后，开发了一类新型的低相对分子质量、易得的氨基酸型手性催化剂，用于醇类的不对称硅烷化反应。在所有的研究中，都将展示在制备高光学纯度的生物活性化合物方面的实用性。

DESCRIPTION (provided by applicant): High yielding and selective preparation of chiral organic molecules is critical to the availability of therapeutic agents. Development of catalytic, enantioselective synthetic methods is a compelling objective in chemistry and medicine. Among the most useful building blocks in organic synthesis are optically pure amines and alcohols; our program will address issues regarding enantioselective preparation of these important classes of molecules. We will establish new, practical, and efficient and highly enantioselective methods for the synthesis of secondary and tertiary amines and alcohols that are otherwise difficult to obtain in high yield and optical purity. One main goal of our program is the development of new chiral ligands and catalysts, all of which are amino acid-based. A crucial advantage of amino acid-based molecules is that they can be easily prepared and modified, allowing for rapid (mechanism-driven) synthesis and screening of variants so that catalysts that best fit a specific set of transformations can be identified expeditiously. We will develop new amino acid-based chiral ligands and practical methods for efficient enantioselective additions of enolsilanes and nitroalkanes to aldimines (Mannich reactions). Catalyst discovery will be guided by mechanistic principles and will be accomplished by screening protocols developed in this program. The new synthetic methods will offer practical (distilled solvents, air exclusion not required) and unique procedures for the synthesis of various acyclic and cyclic amines that cannot be prepared by alternative catalytic enantioselective methods. We will also develop new amino acid-based chiral ligands and methods for efficient enantioselective additions of carbon nucleophiles to ketoimines. The aforementioned principles will be used in the development of catalytic asymmetric alkylations and Mannich reactions that provide access to optically enriched alpha- and beta-quaternary amino acids. We will also develop new chiral amino acid-based ligands, catalysts and methods for efficient enantioselective synthesis of alcohols. Amino acid-based chiral ligands will be developed that effect Ag-catalyzed asymmetric aldol additions for a range of enolsilanes to various ketones. Finally, a new class of low molecular weight and easily available amino acid-based chiral catalysts will be developed for enantioselective silylations of alcohols. In all studies utility in the preparation of biologically active compounds in high optical purity will be demonstrated.