Enantioselective Enamine Catalysis with Aldehydes

醛对映选择性烯胺催化

• 批准号: 7258433
• 负责人: David W MacMillan
• 金额: $ 29.53万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-07 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258433
• 关键词: 3-hydroxybutanal; Acids; Adopted; Aerobic; Air; Aldehydes; Alkylation; Amination; Amines; Amino Acids; Architecture; Area; Attention; Aziridines; Basic Science; Benign; Biochemistry; Biological; Biological Factors; Biotechnology; Carbohydrates; Carbon; Catalysis; Cations; Chemicals; Chemistry; Chlorine; Commerce; Complex; Cyclization; Development; Diels Alder reaction; Drug Design; Economics; Electrons; Environment; Epoxy Compounds; Facility Construction Funding Category; Floods; Fluorine; Glucose; Glycobiology; Goals; Grant; Halogens; Hydroxy Acids; In Situ; Industry; Intercept; Mannose; Marketing; Mediating; Metabolism; Metals; Methodology; Methods; Molecular; Molecular Biology; Molecular Probes; Mutation; Names; Nitrogen; Numbers; Object Attachment; One-Step dentin bonding system; Organic Chemicals; Organic Synthesis; Oxidation-Reduction; Oxygen; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Principal Investigator; Process; Production; Protocols documentation; Range; Reaction; Reagent; Research; Research Personnel; Savings; Solvents; Structure; Sulfur; System; Techniques; Technology; Time; Toxic effect; Trace metal; United States Food and Drug Administration; allose; animation; aziridine; base; catalyst; chemical synthesis; chlorination; concept; cost; cycloaddition; design; enantiomer; erythrose; frontier; gulose; idose; in vivo; innovation; interest; novel; novel strategies; oxidation; planetary Atmosphere; polyol; programs; tool; uptake; wasting

DESCRIPTION (provided by applicant): Over the last 30 years, enantioselective catalysis has become one of the most important frontiers in exploratory organic synthetic research with widespread application in biomedical settings. Surprisingly, however, the research area of organocatalysis (the use of small organic molecules as reaction catalysts) has become a field of central importance in chemical synthesis in only the last ten years. This is quite remarkable given the widespread availability of organic chemicals in enantiopure form and the attendant potential for savings in cost, time, energy, operational complexity and chemical waste. This proposal outlines the development of an innovative and general strategy for enantioselective organocatalysis that enables simple aldehydes to participate in a variety of a-functionalization reactions that were previously unknown. As part of these studies, we describe a catalyst design endeavor that should provide inexpensive, robust amine catalysts that engender high levels of asymmetric induction for a broad spectrum of enamine-mediated reactions. During the tenure of this granting period we hope to demonstrate the value of this new enamine activation strategy in the context of the first examples of enantioselective organocatalytic (1) aldehyde-aldehyde cross aldol reactions, (2) a-chlorination reactions, (3) a-aminotosylation reactions, and (4) a-alkylation reactions. We also hope to introduce three new strategies for chemical synthesis that are founded upon enamine organocatalysis that will allow accelerated access to bioarchitectures and functionalities that are not readily available by conventional methods. The first strategy involves a conceptually novel approach to the production of polyol-differentiated carbohydrates in only two chemical transformations (both aldol reactions). This modularity of this sequence will allow the construction of natural and non-natural carbohydrates that can incorporate carbon, nitrogen, halogen or sulfur substituents within the saccharide framework. The second strategy involves the enantioselective catalytic synthesis of reactive intermediates that are suitably versatile to undergo in situ, asymmetric bond transfer. This powerful strategy should enable the production of a diverse range of synthons such as aziridines, epoxides and amino acids (amongst others) from simple aldehydes using the same catalytic induction step in each protocol. Last, we introduce a new activation concept for organocatalysis that we term SOMO activation. This new approach to organocatalysis is based upon the transient formation of aldehyde derived radical cations (the one-electron intermediate that bridges the fields of iminium and enamine catalysis) that can enantioselectively intercept a range of p-nucleophiles. Specifically, we propose that SOMO catalysis will allow the first enantioselective intramolecular a-alkylation of aldehydes, a long standing goal for the field of asymmetric catalysis. Having demonstrated the feasibility of SOMO activation, we hope to launch this new organocatalysis area in the context of several important transforms including intramolecular oxidative cyclizations.

描述（由申请人提供）：在过去的30年中，对映选择性催化已成为探索性有机合成研究中最重要的前沿领域之一，在生物医学环境中具有广泛的应用。然而，令人惊讶的是，有机催化（使用小有机分子作为反应催化剂）的研究领域仅在过去十年中就已成为化学合成中的一个重要领域。考虑到对映体纯形式的有机化学品的广泛可用性以及随之而来的节省成本、时间、能量、操作复杂性和化学废物的潜力，这是相当显著的。该提案概述了一个创新的和一般的战略发展对映体选择性的有机催化，使简单的醛参与各种以前未知的α-官能化反应。作为这些研究的一部分，我们描述了一种催化剂设计的奋进，应该提供廉价的，强大的胺催化剂，产生高水平的不对称诱导的广泛的烯胺介导的反应。在此授权期间，我们希望在对映选择性有机催化的第一个例子的背景下证明这种新的烯胺活化策略的价值：（1）脱氢-醛交叉羟醛反应，（2）α-氯化反应，（3）α-氨基甲苯磺酰化反应，和（4）α-烷基化反应。 我们还希望介绍三种新的化学合成策略，这些策略建立在烯胺有机催化的基础上，这将允许加速获得传统方法不容易获得的生物结构和功能。第一种策略涉及一种概念上新颖的方法来生产多元醇分化的碳水化合物，只有两个化学转化（两个羟醛反应）。该序列的这种模块性将允许构建天然和非天然碳水化合物，其可以在糖框架内掺入碳、氮、卤素或硫取代基。第二种策略涉及反应性中间体的对映选择性催化合成，所述反应性中间体适合于进行原位不对称键转移。这种强有力的策略应该能够在每个方案中使用相同的催化诱导步骤从简单的醛生产各种各样的二氢氮杂环丙烷，环氧化物和氨基酸（等等）。最后，我们介绍了一种新的有机催化活化概念，我们称之为SOMO活化。这种新的有机催化方法是基于醛衍生的自由基阳离子的瞬时形成（单电子中间体，桥接亚胺和烯胺催化的领域），可以对映选择性地拦截一系列的p-亲核试剂。具体而言，我们建议，自组织氧化物催化将允许第一个对映选择性的醛，一个长期存在的目标不对称催化领域的分子内α-烷基化。在证明了SOMO活化的可行性之后，我们希望在包括分子内氧化环化在内的几个重要转化的背景下启动这个新的有机催化领域。