电化学调控的不对称反应合成手性碳环核苷

Compared with the natural nucleosides, carbocyclic nucleosides not only make these derivatives metabolically resistant to the action of phosphorylases and hydrolases, but also show good antiviral or antitumor activities. Therefore, medicinal chemists have focused their attention on designing and preparing new carbocyclic nucleoside analogues. Many different synthetic approaches for carbocyclic nucleosides often required multi-steps or fine asymmetric control, which often had very high wastage in the process. On the other hand, electroorganic synthesis is a green synthesis technology. The oxidant and reducing agent were replaced by electron in the reaction, and the pollution could be eliminated fundamentally. At present the electrochemical asymmetric reactions of aliphatic aldehydes at α position had been reported. However, electrochemical tuning of the asymmetric reaction to synthesize the carbocyclic nucleosides has not been reported. Herein, we intend to synthesize a series of carbocyclic nucleosides using electrochemical technology and SOMO theory. The asymmetric reaction was conducted in the presence of alicyclic ketones as carbonyl substrates and nucleoside bases as nucleophiles. The toxic oxidants were replaced by electron in the process, and the SOMO activation was achieved by electrochemical oxidation. Therefore, the electrochemical tuning of the asymmetric reaction to synthesize the chiral carbocyclic nucleosides could provide novel approach and research directions for the green and efficient syntheses of carbocyclic nucleosides, which had remarkable significance both in fundamental research and practical application.

碳环核苷克服了天然核苷对磷酸化酶和水解酶的代谢不稳定性，同时具有较好的抗病毒、抗肿瘤等生物活性，因而在药物研究中占有重要地位。目前碳环核苷的合成方法都需经过多步合成或者精细不对称控制，过程繁琐，生产成本较高；而电化学有机合成作为一门绿色合成技术，在反应中用电子代替对环境造成污染的氧化剂和还原剂，可从根本上消除污染。目前已有文献报道电化学调控脂肪醛的α-位不对称官能团化，而通过电化学手段制备手性碳环核苷尚未报道。本申请拟借助电化学技术和SOMO理论，巧妙地利用阳极氧化和小分子手性胺催化的协同作用，构筑系列手性碳环核苷。反应以脂肪环酮为羰基底物，核苷碱基作为亲核试剂，用电子代替有毒的氧化剂，即电化学氧化实现SOMO活化，使核苷碱基与脂肪酮α-位发生不对称偶联反应，合成系列手性碳环核苷类似物。本项目利用电化学手段制备碳环核苷为碳环核苷的绿色高效合成提供新的方法和研究方向，具有理论意义和应用前景。

项目围绕手性碳环核苷的合成深入开展工作，以较高的收率和优异的立体选择性共合成五个系列的手性碳环核苷化合物多达200个，其中通过不对称转移氢化反应，合成系列N9-嘌呤，N3-嘌呤和嘧啶取代的手性五元碳环核苷化合物；通过不对称烯丙基胺化反应，合成系列含有C=C双键的手性五元碳环核苷化合物；通过联烯酯/MBH碳酸酯的不对称[3+2]环加成反应合成两类含有季碳的手性五元环核苷化合物；通过不对称[3+3]环加成反应合成系列六元碳环核苷化合物。另外，还开展核苷相关的其他工作，通过环丙烷化反应合成系列螺环核苷化合物；通过环氧乙烷与硫脲的环化反应合成系列嘧啶化合物。申请国家发明专利8项，其中授权2项。共发表标注本项目编号（21602045）的SCI论文8篇，其中影响因子5.0以上的6篇；在国内外学术会议上交流论文1篇；培养硕士研究生3名（在读）。