Enantioselective Enamine Catalysis with Aldehydes

醛对映选择性烯胺催化

• 批准号: 7436329
• 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/7436329
• 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边界之一，并在生物医学环境中广泛应用。然而，令人惊讶的是，仅在过去的十年中，有机催化的研究领域（使用小有机分子作为反应催化剂）已成为化学合成中至关重要的领域。鉴于有机化学物质以对映体形式以及节省成本，时间，能源，运营复杂性和化学废物节省的潜力，这是非常了不起的。该提案概述了对对映选择性有机催化的创新和一般策略的发展，该对照式的有机催化使简单的醛可以参与以前未知的各种A官能化反应。作为这些研究的一部分，我们描述了一项催化剂设计努力，该努力应提供廉价，健壮的胺催化剂，从而导致高水平的不对称诱导剂，以实现多种烯胺介导的反应。在此授予期的任期内，我们希望在最初的对映射器官催化的例子（1）醛 - 醛反应，（（2）a-氯化反应（（3）a-氨基化反应和（4）a-α-α-α-α-α-α-α-杀菌反应。 我们还希望引入三种新的化学合成策略，这些策略是基于谜的有机催化建立的，这些策略将允许加速访问生物体系结构和功能，而常规方法不容易获得。第一种策略涉及一种在仅在两种化学转化（均两种化学反应）中生产多元二分化碳水化合物的概念新方法。该序列的这种模块化将允许构建天然和非天然碳水化合物，这些碳水化合物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综合，这些中间体具有广泛使用，可在原位发生不对称的键转移。这种强大的策略应能够从每种方案中使用相同的催化诱导步骤从简单的醛中产生各种合成子，例如氮岛，环氧化物和氨基酸（其他）。最后，我们介绍了一个新的有机刻分析激活概念，该概念我们称为SOMO激活。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（桥梁桥接伊米米尼和磁轴催化场的单电子中间体），可以对构象拦截一系列p-核酚。具体而言，我们建议SOMO催化将允许醛的第一个对映选择性分子内A烷基化，这是不对称催化领域的长期目标。在证明了SOMO激活的可行性之后，我们希望在几种重要的转换（包括分子内氧化循环）的背景下启动这个新的有机催化区域。