基于炔胺的多组分反应合成小分子化合物的研究

多组分反应是一种绿色、原子经济性反应，申请人前期开发了炔胺作为C2合成模块的多组分反应 (Angew. Chem. Int. Ed.等论文)。在此基础上，围绕多组分反应的效率、化学和立体选择性等科学问题，拟开展“基于炔胺的多组分反应合成小分子化合物的研究”：(1)炔胺、吲哚-N-甲酸、亲电试剂的三组分反应合成吲哚衍生物；采用底物替换策略，将炔胺与吲哚-N-甲酸进行高效对接，并利用吲哚环的反应活性。(2)炔胺、酰基羟胺、各类π电子受体(烯烃、炔烃、重氮等)的三组分反应合成β/γ-氨基酸衍生物；将酰基羟胺代替羧酸，并借鉴金属催化的环化反应活性，同时用手性茂基配位的金属催化剂，开发相应的不对称合成模式。(3)炔胺、羧酸、亚胺(或 二氢异喹啉)的不对称三组分反应合成手性小分子；采用手性磷酸作为催化剂，通过氢键活化模式实现。通过以上研究，展示多组分反应的优点，构建化合物库供活性筛选。

Multi-component reactions (MCRs) is defined as a reaction in which three or more reactants react in a single operation to form a single product that contains essentially all the atoms of the starting materials, and therefore is a typical green and atom-economic chemical process. Previously, the applicant disclosed that ynamides are versatile C2 building blocks in MCRs. Based on these results and considering the efficiency, chemical selectivity and stereoselectivity of multi-component reactions, we propose “The Investigation of Multi-Component Reactions of Ynamides Toward Small Molecules Synthesis”: (1) A three component reaction of ynamides, indole-N-carboxylic acid, and electrophiles for synthesis of indole derivatives. Under the reactant replacement strategy, the carboxylic acids could be replaced with indole-N-carboxylic acid which would add to ynamides to form enol ether intermediate, and undergo bifunctionalization of indole ring with electrophiles for accessing indole derivatives. (2) A three component reaction of ynamides, hydroxamic acids, π components (alkenes, alkyes, diazo compounds, etc) for synthesis of β/γ-amino acids. The acidic hydroxamic acids could add to ynamides to form enol ether intermediate, which could undergo transition-metal-catalyzed redox-neutral cyclization with π components to constitute the MCRs process for accessing β/γ-amino acids. Furthermore, we will investigate the asymmetric protocol of these MCRs. (3) The asymmetric multi-component reaction of ynamides, carboxylic acids and imines (or dihydroisoquinolines). The carboxylic acids could add to ynamides to form enol ether intermediate, which could engage in chiral phosphoric acid-catalyzed addition to imines for accessing chiral β-amino acids (or tetrahydroisoquinolines). The applicant would well conduct this project and establish the MCRs protocol. The MCRs process would be featured of readily available starting materials, efficient and atom-economic reaction, structural divergent products. The compound library would be constructed and subject to biological evaluation to discover lead compounds.