基于动态动力学拆分合成手性非环核苷

Chiral acyclic nucleosides, as the analogues of nucleosides, could connect diverse chiral groups with different stereo configurations in their side chains. Thus, chiral acyclic nucleosides exhibit outstandingly potential antiviral activities. The traditional approach to synthesize chiral acyclic nucleosides is based on chiral pool strategy, which exhibit several disadvantages such as long steps, low total yields, and difficult to obtain chiral starting materials. Therefore, it’s of great importance to develop more effective synthetic methods to construct chiral acyclic nucleosides. To date, there are only few reports to synthesize chiral acyclic nucleosides via asymmetric catalysis. To our knowledge no example of enantioselective construction of chiral acyclic nucleoside via dynamic kinetic resolution reaction has been reported. The applicant focus on the asymmetric synthesis of chiral nucleosides, and have synthesized various of chiral carbocyclic nucleosides, azacyclic nucleosides, and acyclic nucleosides analogues via asymmetric cycloaddition and hydrogenation reactions. Meanwhile, the applicant participated in writing the review about the development for the synthesis of chiral acyclic nucleosides. Based on the applicant’s previous work about the synthesis of chiral nucleosides and asymmetric catalysis, in this project, we will design and synthesize 4-N,N´-dialkylaminopyridine nucleophilic catalysts derived from chiral amino acids, and apply the chiral catalysts in several dynamic kinetic resolution reactions based on acyl transfer to synthesize diverse chiral acyclic nucleoside analogues, which could be transformed into the corresponding chiral acyclic nucleosides and nucleotides. Finally, the antiviral activities of these representative chiral acyclic nucleosides and nucleotides will be evaluated in vitro.

手性非环核苷作为核苷类似物，因其侧链可以连接不同种类、不同立体构型的手性基团，具有显著的抗病毒潜能。手性非环核苷传统的合成方法基于手性源策略，具有反应步骤长、总收率低和手性源不易获得等不足。因此，发展高效的手性非环核苷的合成方法是一个非常有意义的研究课题。到目前为止，通过不对称催化来合成手性非环核苷的报道较少，尚没有基于动态动力学拆分合成手性非环核苷的报道。申请人近年来一直从事手性核苷的不对称合成，通过不对称环加成和氢化反应合成了手性碳环、杂环和非环核苷，参与撰写了手性非环核苷合成进展综述。本项目基于申请人在手性核苷合成及不对称催化方面的研究基础，拟设计合成氨基酸衍生的手性4-氨基吡啶类亲核催化剂，并将其应用到基于酰基转移的系列动态动力学拆分反应，合成手性非环核苷类产物，并进一步衍生得到相应的手性非环核苷（酸），进而在体外开展抗病毒活性筛选。

非环核苷作为核苷类似物，具有抗病毒潜能，因此发展非环核苷的高效合成方法具有重要的研究意义。本项目基于河南师范大学核苷研究团队在手性核苷合成及不对称催化方面的研究基础，设计合成了系列氨基酸衍生的新型手性酰基转移催化剂，包括手性4-二甲氨基吡啶、3,4-二氨基吡啶氮氧、2-取代-4-氨基吡啶氮氧、4-芳基吡啶氮氧等亲核催化剂，首次提出手性DMAP氮氧，以氧原子作为亲核位点，也能作为酰基转移催化剂。发展了系列非环核苷合成方法学，包括通过嘌呤/嘧啶、醛和酸酐三组分动态动力学拆分合成手性非环核苷类似物；通过α-嘌呤取代羧酸与醇的动态动力学拆分合成手性非环核苷类似物；通过不对称双羟化合成手性非环核苷；通过嘧啶与联烯的加成合成非环核苷类似物；通过α-嘧啶取代丙烯酸酯的不对称共轭加成/质子化串联反应合成手性非环核苷类似物；通过嘌呤对氨基环丙烷以及环氧的开环，合成非环核苷类产物。最后对非环核苷类化合物开展抗病毒活性筛选，发现了较好抗HBV-DNA活性的非环核苷类化合物。在本项目支持下共发表研究论文13篇，包括J. Am. Chem. Soc.1篇，Angew. Chem. Int. Ed. 1篇，ACS Catal. 2篇。申请中国发明专利10项，其中7项授权，发展了系列手性酰基转移催化剂和非环核苷合成方法学。