含手性单氟甲基非环核苷（酸）类化合物的不对称合成

Some of nucleosides and nucleotides are important anti-cancer and anti-virus drugs. For the side chain of acyclic nucleosides and nucleotides, the introduction of a chiral group, the absolute configuration of the chiral atom and the introduction of a fluorine atom, could change their biological activities significantly. In particular, acyclic nucleosides and nucleotides containing chiral monofluoromethyl group in their side chains, including (S)-FPMPA, (S)-FPMPGp, bisamidate (S)-FPMPA, and (S)-FPMPT, exhibit outstanding anti-virus activities. However, the asymmetric synthesis method for the construction of acyclic nucleosides and nucleotides containing chiral monofluoromethyl group, has never been reported up to now. In this project, based on asymmetric catalysis strategy, we decide to develop the synthetic methods of constructing acyclic nucleosides and nucleotides containing chiral monofluoromethyl group. In order to achieve this goal, we will develop the first example of asymmetric monofluoromethylation of linear ketones and aldehydes. As supplements, we will conduct the ring-opening of epoxides via asymmetric fluorination reaction, and the ring-opening of epoxides bearing monofluoromethyl group via asymmetric amination reaction. As a result, we will realize the first example of asymmetric synthesis of acyclic nucleosides and nucleosides containing chiral monofluoromethyl group. Subsequently, we will build the compound library of acyclic nucleosides and nucleotides containing chiral monofluoromethyl group. By screening their biological activities, we will summarize their structure-activity relationship, and screen out the drug candidate with better biological activities.

非环核苷（酸）中部分化合物是重要的抗癌、抗病毒药物。对于非环核苷（酸）的侧链而言，手性基团的引入、手性原子的绝对构型、氟原子的引入，能显著改变其生物活性。其中，侧链上含手性单氟甲基的非环核苷（酸），包括(S)-FPMPA、(S)-FPMPGp、bisamidate (S)-FPMPA和(S)-FPMPT，具有显著的抗病毒活性。但是，关于构建含手性单氟甲基非环核苷（酸）的不对称合成方法，至今尚未见报道。本项目拟通过不对称催化策略，建立含手性单氟甲基非环核苷（酸）类化合物的合成方法。拟以第一例直链酮（醛）的不对称单氟甲基化反应为主，以环氧化合物的不对称氟化开环反应、含单氟甲基环氧砌块的不对称胺化开环反应为补充，首次实现含手性单氟甲基非环核苷（酸）的不对称合成报道。然后，建立含手性单氟甲基非环核苷（酸）类化合物库，并对其进行生物活性筛选，总结构效关系，以期发现具有更好生物活性的候选药物。

非环核苷作为核苷类似物，因其侧链可以连接不同链长的碳链、不同的杂原子和不同立体构型的手性中心，具有显著的抗病毒潜能。本项目围绕非环核苷的设计与合成，在非环核苷的侧链上引入氟原子、硫原子、氰基以及不同烷基取代的手性片段，发展了新的非环核苷合成方法学。报道了首例联烯类底物与单氟甲基化试剂的加成反应，用于合成系列侧链含氟原子的非环核苷类产物；通过硫代乙酸对嘧啶取代的丙烯酸酯的不对称质子化反应，构建侧链含硫原子的手性非环核苷；通过α-嘌呤取代丙烯酸酯的不对称氢化反应，合成了侧链连接不同烷基取代的手性非环核苷类产物，提出了嘌呤环作为可配位的功能基团促进不饱和烯烃的不对称氢化的新策略。通过筛选部分非环核苷体外抗HSV-I、HSV-II、RSV和HBV病毒活性测试，发现侧链链长为3个碳，1'位为甲基取代的腺嘌呤衍生的非环核苷有一定的体外抑制RSV的作用，为该类非环核苷的结构修饰提供了参考依据。.共发表标注本项目编号（21402041）的论文8篇，均为SCI论文，其中影响因子6.0以上的2篇；申请发明专利4项，获得授权2项；参加国内学术会议交流9次，交流会议论文6篇，做口头报告2次。