Enantioselective Enamine Catalysis with Aldehydes

描述(申请人提供)：在过去的30年里，对映体选择性催化已经成为探索性有机合成研究的最重要的前沿之一，在生物医学环境中得到了广泛的应用。然而，令人惊讶的是，有机催化(使用有机小分子作为反应催化剂)的研究领域在最近十年才成为化学合成中的一个重要领域。考虑到对映体形式的有机化学品的广泛可获得性，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，这一点相当值得注意。这项提案概述了一种创新的、通用的对映选择性有机催化策略的发展，该策略使简单的醛能够参与各种以前未知的a-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努力，它应该提供廉价、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。在本授权期内，我们希望在第一批对映选择性有机催化(1)醛-醛交叉Aldol反应、(2)a-氯化反应、(3)a-氨基酰化反应和(4)a-烷基化反应的背景下证明这种新的烯胺活化策略的价值。 我们还希望引入基于烯胺有机催化的三种新的化学合成策略，这三种策略将允许更快地获得传统方法无法获得的生物结构和功能。第一种策略涉及一种概念上的新方法，只需两次化学转化(两次Aldol反应)就可以生产出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结合碳、氮、卤素或硫取代基。第二种策略涉及反应中间体的对映选择性催化合成，这些中间体具有合适的通用性，可以进行原位不对称键转移。这一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不同范围的合成子，如氮杂环、环氧化物和氨基酸(以及其他)。最后，我们介绍了有机催化的一种新的活化概念，我们称之为SOMO活化。这种有机催化的新方法是基于醛衍生自由基阳离子(连接亚胺和烯胺催化领域的单电子中间体)的瞬时形成，它可以对映体选择性地拦截一系列对核亲核试剂。具体地说，我们提出SOMO催化将允许醛的第一次不对称分子内α-烷基化反应，这是不对称催化领域的一个长期目标。在论证了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推出这一新的有机催化领域。

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.