Enantioselective Enamine Catalysis with Aldehydes

醛对映选择性烯胺催化

基本信息

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
项目类别：
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

项目摘要

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 年里，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之一，并在生物医学领域得到广泛应用。然而，令人惊讶的是，有机催化研究领域（使用有机小分子作为反应催化剂）仅在过去十年就已成为化学合成中的核心重要领域。考虑到对映体纯形式的有机化学品的广泛使用以及随之而来的节省成本、时间、能源、操作复杂性和化学废物的潜力，这是相当引人注目的。该提案概述了对映选择性有机催化的创新和通用策略的开发，该策略使简单的醛能够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工作，该设计应提供廉价、坚固的胺催化剂，为广泛的烯胺介导的反应产生高水平的不对称诱导。在本授权期间，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）醛-醛交叉羟醛反应，（2）α-氯化反应，（3） α-氨基甲苯基化反应，和(4)α-烷基化反应。我们还希望引入三种基于烯胺有机催化的化学合成新策略，这将允许加速获得传统方法不易获得的生物结构和功能。第一个策略涉及一种概念上新颖的方法，仅通过两次化学转化（均为羟醛反应）即可生产多元醇分化的碳水化合物。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合成，这些中间体适用于进行原位不对称键转移。这种强大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合成子，例如氮丙啶、环氧化物和氨基酸（等等）。最后，我们引入了有机催化的新激活概念，我们称之为 SOMO 激活。这种新的有机催化方法基于醛衍生的自由基阳离子（桥接亚胺和烯胺催化领域的单电子中间体）的瞬时形成，该阳离子可以对映选择性地拦截一系列p-亲核试剂。具体来说，我们提出SOMO催化将实现醛的第一个对映选择性分子内α-烷基化，这是不对称催化领域的长期目标。在证明了 SOMO 活化的可行性后，我们希望在包括分子内氧化环化在内的几个重要转变的背景下启动这个新的有机催化领域。