基于单电子转移的不对称交叉脱氢偶联反应及在多肽药物研究中的应用

基于单电子转移途径的不对称交叉脱氢偶联具有较高的原子经济性和操作简便性。目前，对于此类反应的研究仍未取得较大突破，所涉及的反应类型和底物类型较为单一。其原因是：目前常用的手性催化策略对于反应底物立体控制能力不强；缺乏全面系统的高效手性诱导模式研究。本申请拟开展的针对反应中两种底物，采用手性离子对立体控制策略结合双功能手性催化剂的高效作用模式，有望解决目前此反应中的手性控制难题，建立该反应全面系统的不对称催化模式和理论，拓宽反应的适用范围。项目中拟开展的可见光催化氧化模式替代目前常用的有机过氧化物氧化剂将极大提高该反应的安全性，建立安全实用的手性合成方法。该项目将深入研究无金属参与的不对称交叉脱氢偶联，避免手性药物合成中的有毒重金属残留。此外，本项目将利用不对称催化交叉脱氢偶联的优势，开发非天然氨基酸MeBmt及其系列结构多样性衍生物的高效手性合成方法，应用于环孢菌素类多肽药物研发。

The asymmetric cross dehydrogenative coupling (CDC) reactions via single-electron-transfer pathway have the merits of high atom economy and easy operation. However, the study of these reactions was very limited in point of the reaction types and substrate scopes. So far, the most common used strategy for the stereo control is not very efficient in the reactions. The study to set up a comprehensive asymmetric catalysis mode for this reaction is highly desired but not realized. In this study, the chiral-ion-pair catalysis combining with the dual-function chiral control strategy will be systematic studied in the asymmetric CDC reactions. The project is expected to establish a solid asymmetric catalysis theory for the reaction and broaden the reaction types and substrate scopes. The visible light promoted single-electron oxidation will be carried out to replace the usually used organic peroxide oxidants, which will greatly improve the security of CDC reaction and lead to a more practical method for asymmetric synthesis. The project will also study the transition metal free conditions to avoid the toxic heavy metal residues in chiral drugs synthesis. In addition, the project will develop an efficient method for the asymmetric synthesis of unnatural amino acid, namely MeBmt, and its analogues by using asymmetric CDC reaction. These unnatural amino acids will be applied in the chemical modification of cyclosporin A and provide lead compounds for the discovery of new peptide drugs.