基于金属卡宾中间体合成α-氟代氨基酸衍生物的研究

α-Amino acids are important structure motifs and subunits in organic molecules with interesting biological activities. The introduction of fluorine atoms leads to a change in the physical properties of a compound, such as solubility and lipophilicity. Inspired by recent reports on Cu and Pd catalyzed aminofluorination of styrenes, in this project, we are aiming to develop a direct approach to α-fluoro-α-amino acid derivativatives by transition metal catalyzed germinal aminofluorination of readily available diazoesters. Although the synthesis of α-amino acid derivativatives by N-H bond insertion of transition metal carbenes have been developed by several research groups, a direct way to α-fluoro-α-amino acid derivativatives through N-F bond insertion of metal carbene intermediates is unknown. The key to realize our goal is the selection of a proper metal complex as catalyst to minimize the dimerization of the diazo compounds, thus leading to an enhanced selectivity of the metal carbene intermediate. Initially, we will focus on the Cu-catalyzed aminofluorination of diazoesters by using N-fluorobenzenesulfonimide (NFSI) as both fluorine source and amine source. We will also investigate the reaction mechanism and pathway. Then, we will apply this strategy to transition metal catalyzed aminofluorination of diazoesters by using other electrophilic fluorine sources and amine sources. In a word, the significance of this project is develop a direct approach for α-fluoro-α-amino acid derivativatives synthesis via transition metal catalyzed aminofluorination of diazoesters, and provide new methods and ideas for difunctionalization of metal carbene intermediates.

许多药物分子中含有α-氨基酸的结构单元。在有机药物分子中引入氟原子，可改变它的溶解性、亲油性等，进而影响它的代谢稳定性。以重氮酯为原料，通过金属卡宾对N-H键的插入反应是合成α-氨基酸衍生物的高效方法。然而，至今金属卡宾对N-F键的插入反应尚未有文献报道。本项目将着重研究过渡金属催化重氮酯的氟胺化反应。受钯和铜催化苯乙烯氟胺化反应研究的启发，我们将首先研究重氮酯与N-氟代双苯磺酰胺(NFSI)的反应，并着重考察吡啶类含氮配体对氟胺化反应的影响，通过调节配体上取代基团的位阻效应、电性、刚性来调控催化剂的催化效果，抑制重氮酯的聚合、调节金属卡宾中间体的反应活性，从而提高氟胺化反应的整体效率。在此基础上，我们还将研究其他氟化试剂、氨基亲核试剂与重氮酯的反应，最终发展一步高效合成α-氟代氨基酸衍生物的新方法。

本项目主要基于芳基重氮酸酯分解产生卡宾，利用卡兵碳上只有两个取代基以及两个未成键的电子的特性，在卡宾碳上同时引入氟与胺官能团，实现一步高效合成α-氟代氨基酸衍生物。研究内容可分以下几个部分：.第一、基于芳基重氮酸酯与N-氟代双苯磺酰胺的反应，合成了一系列α-氟代氨基酸衍生物。.第二、基于芳基重氮酸酯与N-H键的反应，合成了一系列α-双苯磺酰胺酯；.第三、基于金催化炔酰胺与吡啶并[1,2-b]吲唑反应，合成一系列吲哚类化合物；.第四、基于钯催化芳基重氮酸酯与酰基C-H键的反应，合成了一系列异香豆素类化合物；.第五、基于铑活化炔烃产生铑卡宾与叠氮化物反应，合成了一系列5-氨基1,2,3-三氮唑。