Development of New Catalytic and Enantioselective Reactions

新催化和对映选择性反应的发展

• 批准号: 7099934
• 负责人: AMIR H HOVEYDA
• 金额: $ 34.18万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099934
• 关键词: alcohols; alkylation; amines; aminoacid; carbonyl compound; catalyst; chemical synthesis; epoxides; imines; method development; optics; peptide chemical synthesis; silver; stereochemistry

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.

描述（由申请人提供）：手性有机分子的高产率和选择性制备对于治疗剂的可用性至关重要。开发催化、对映选择性合成方法是化学和医学领域的一个引人注目的目标。有机合成中最有用的构建单元是光学纯胺和醇；我们的计划将解决有关这些重要分子类别的对映选择性制备的问题。我们将建立新的、实用的、高效的和高度对映选择性的方法来合成仲胺和叔胺和醇，否则这些方法很难以高产率和光学纯度获得。我们计划的主要目标之一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轻松制备和修饰，从而可以快速（机制驱动）合成和筛选变体，从而可以快速识别最适合一组特定转化的催化剂。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醛亚胺的有效对映选择性加成（曼尼希反应）。催化剂的发现将遵循机械原理，并通过该计划中开发的筛选方案来完成。新的合成方法将为合成各种无环和环状胺提供实用的（不需要蒸馏溶剂，不需要空气排除）和独特的程序，而这些胺是无法通过替代催化对映选择性方法制备的。我们还将开发新的基于氨基酸的手性配体和方法，用于将碳亲核试剂有效地对映选择性加成到酮亚胺上。上述原理将用于开发催化不对称烷基化和曼尼希反应，从而提供光学富集的α-和β-季氨基酸。我们还将开发新的基于手性氨基酸的配体、催化剂和方法，以有效地对映选择性合成醇。将开发基于氨基酸的手性配体，以实现一系列烯醇硅烷与各种酮的银催化不对称羟醛加成。最后，将开发一类新型低分子量且易于获得的基于氨基酸的手性催化剂，用于醇的对映选择性硅烷化。在所有研究中，将证明制备高光学纯度的生物活性化合物的实用性。