可见光驱动光氧化还原1,5-氢迁移策略构建手性α-季碳氮杂芳基化合物

Nitrogen-containing aromatic heterocylces (azaarenes) are ubiquitous in pharmaceuticals, agrochemicals, and biologically active natural products. The construction of azaarene-bearing chiral building blocks from readily available starting substrates under mild reaction conditions is of high synthetic and industrial interest. Up to now, exploiting the electronic properties of the azaarene itself to trigger the reaction with a direct, expedient and complementary manner has received considerable attention of chemists. As a result, azaarenes with an embedded imine (C=N) featuring electron-withdrawing properties have allowed 2-alkylazaarenes as nucleophiles and 2-alkenylazaarenes as electrophiles in catalytic enantioselective reactions to access valuable α- and/or β-functionalized chiral azaarenes. However, the ability of these azaarenes to functionalize chiral quaternary carbon stereogenic centers at α-position has yet been underexplored, while these chiral motifs are key frameworks in a number of compounds with interesting biological activities. In view of our research interest in asymmetric organo-catalysis and visible light-driven photoredox catalysis, we are intrigued to challenge this formidable task through cooperative photoredox and Brønsted/Lewis acid catalysis based on 1,5-hydrogen atom transfer strategy. We will develop the enantioselective trifluoromethylation/α-amino-alkylation of 4-(azaarene)-4-substituted-N-acyl amines with trifluoromethyl-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole/ α-amino acid-derived and α-alkylation of 4-(azaarene)-4-substitituted N-phthaloyl alkyl ethers with aryl/alkyl alkene, leading to three series of valuable chiral azaarenes with α-CF3-based, α-alkyl amine-based, and α-alkyl based quaternary stereocenters. We anticipate that this project would provide a direct and expedient approach to access diverse α-quaternary azaarenes, and inspire the development of novel synthetic methods for other kinds of useful chiral azaarenes.

基于氮杂芳烃的重要生物活性价值，构建光学纯氮杂芳基化合物已成为不对称催化的研究热点。作为一种直接、简便且应用广泛的不对称合成策略，直接利用氮杂芳基电子性质驱动的不对称反应近年来备受关注。但由于缺电子氮杂芳基的弱拉电子性，通过该手段构建含α-手性季碳中心的氮杂芳基化合物迄今仍缺乏有效与通用的合成策略。申请人基于不对称有机催化及光催化的研究基础，提出利用光氧化还原1,5-氢迁移策略并结合手性布朗斯特/路易斯酸催化挑战这一难题。研究内容包括4-氮杂芳基-4-取代-N-酰基胺的不对称三氟甲基/胺烷基化反应及4-氮杂芳基-4-取代-N-邻苯二甲酰亚胺基烷基醚的不对称烷基化反应，以期在氮杂芳基的α-位高对映选择性构建三氟甲基、胺烷基与烷基取代的手性季碳中心。通过开展本课题，将为含α-手性季碳中心氮杂芳基化合物的合成提供一种高效且较为通用策略，并为其它类型手性氮杂芳基化合物的合成给予思路。

缺电子氮杂芳基（如吡啶、喹啉等）结构单元广泛存在于具有生物活性的天然与非天然产物以及药物分子结构中，其催化不对称合成研究是有机化学研究的前沿领域；其中利用氮杂芳基的缺电子特性引发并实现其高立体选择性的不对称催化反应是构建手性氮杂芳烃的最直接的方法之一，然其相关探索非常有限。本项目发展光氧化还原协同手性催化平台，利用1,5氢迁移策略驱动化学反应，实现氮杂芳烃立体选择性构筑。发展了DPZ协同氢键催化平台：开展了不对称自由基—自由基交叉偶联反应，为手性氮杂芳烃精准合成开辟全新路径；实现自由基共轭加成不对称质子化，为氮杂芳烃远程手性中心构建提供直接方法；设计开发分子内Beckwith-Enholm环化、还原质子化及串联反应，实现了氮杂芳烃不同位置手性立体中心的构筑。同时，利用发展的协同催化平台，本申请项目—1,5氢迁移策略的氮杂芳烃立体选择性构筑课题也取得突破性进展。此外，在项目的支持下，以DPZ为光氧化还原催化剂，使用易于制备的N-芳基甘氨酸酯和α-氟代芳基乙酸氧化还原酯为起始原料，通过自由基偶联实现羰基α-位与β-位相连接C−C键构建的新合成途径，高产率制备一系列β-氟代-α-氨基酸酯。