手性叔胺催化取代芳杂环羧酸的不对称反应研究

In view of the importance of heteroarylcyclic compounds, the development of economic and efficient methods for the synthesis of such valuable compounds is of highly interesting and significant. Carboxylic acids have been extensively used in organic synthesis because they are readily available building blocks with wide divesrsity. It is known that alphatic carboxylic acid derivatives can undergo a variety of organic transformations based on tertiary amine catalyzed nucleophilic ammonium enolate intermediate, thus realizing the functionalization of α- and γ-positions of carbonyl group. However, such catalytic pathway is still unexplored yet with heteroaryl-carboxylic acids as material because such compounds are lack of α-CH. In this project, we will investigate the formation of acyl ammonium species between tertiary amine and activated heteroaryl-carboxylic acid, which can increase the acidity of benzylic C-H by means of the strong electron-withdrawing effect.Thus the deprotonation and dearomatization of acyl ammonium species might be achieved under mild conditions to form the corresponding formal ammonium enolate. Moreover, we will study the asymmetric addition reactions between the formal ammonium enolate intermediate and a variety of electrophiles including aldehydes, ketones, and imines, thus affording the novel heterocycles in a concise sequence. Our work might provide a novel transition-metal free approach towards the functionalization of benzylic C-H.

鉴于芳杂环化合物的重要性，发展经济和高效的新型有机合成方法具有极大的研究和应用价值。羧酸因其类型多样、稳定易得等优点，已被广泛使用在有机合成中。相关研究表明，脂肪族羧酸衍生物可以在叔胺催化下以生成亲核性铵基烯醇中间体的形式参与多种不同类型的有机反应，实现羧酸α-和γ-位的官能团化，但芳酸因缺乏相应alfa-CH难以通过类似催化途径反应。本项目拟采用叔胺与活化的取代芳杂环羧酸作用生成酰基铵盐中间体，利用其强拉电子效应进一步增强邻位取代基CH的酸性，随后温和条件下去质子得到去芳香化的类似铵基烯醇中间体，并考察其与醛、酮、亚胺等多种亲电性化合物的不对称加成反应，从而能够快速构建多种类型新颖的杂环结构。本项目的成功实现将发展一条新颖的非金属催化活化芳基苄位官能团的方法。

杂环化合物广泛存在于天然产物和生物活性分子中。申请人设计了应用金鸡纳碱衍生的叔胺或相转移催化剂催化的不对称加成反应，得到结构多样的杂环化合物。.1. 研究了叔胺催化剂催化吡啶和吲哚羧酸衍生物与醛、酮、亚胺的反应。但目前实验结果并不理想，仍需继续优化条件以提高产物收率及立体选择性。.2. 用金鸡纳碱叔胺催化了环状氮杂二烯与γ-丁烯酸内酯的不对称[4+2]环加成反应。在反应中应用(DHQD)2PHAL或β-ICD为催化剂，可以以中等收率和较好的立体选择性分别得到内型或外型环加成产物。相关工作发表在Molecules上。.3. 采用金鸡纳碱衍生的相转移催化剂催化环状氮杂二烯与异靛蓝的加成反应，反应可以在三氟甲苯或甲苯溶剂中以优异的收率分别得到螺环或并环产物。相关工作已经完成，论文正在撰写中，将于近期投稿。.