基于烯烃的[2+2]环加成反应合成四元碳环核苷类化合物

The carbocyclic nucleosides have been widely used in clinical as anti-virus drugs. Compared with natural occurring nucleosides, carbocyclic nucleosides display good metabolic stability and lipotropy, thus posses broad-spectrum antiviral activity and lower drug resistance. Given that the size and configuration of carbocyclic ring have significant effect on its antiviral activity, the synthesis of carbocyclic nucleosides with different ring size has important research significance on the study of its antiviral activity. However, all the ported methods for the synthesis of four-membered carbocyclic nucleosides needed the preparation of four-membered carbocyclic materials in advance, which had some faults such as multiple steps, low diversity, low yield and cost-consuming. The synthesis of four-membered carbocyclic nucleosides via [2+2] cycloaddition reaction from olefin substituted nucleobases has never been reported up to now. In this project, the synthesis of four-membered carbocyclic nucleosides via [2+2] cycloaddition reaction in the presence of visible light or Lewis catalysts from olefin substituted purines will be accomplished, thus construct four-membered carbocyclic nucleosides, develop the synthetic methodology and diversify the scaffolds of four-membered carbocyclic nucleosides. Subsequently, we will convert them into four-membered carbocyclic nucleosides containing several hydroxyls, and test pharmacological activity of the target compounds, in order to screen out new carbocyclic nucleosides with a better pharmacological activity.

碳环核苷是临床上广泛使用的抗病毒药物，与天然核苷相比，碳环核苷具有更高的代谢稳定性和亲脂性，具有广谱抗病毒活性和较低的耐药性，其中，环的大小及构型大大影响其抗病毒活性，因此合成具有环状大小不同的碳环核苷并研究其抗病毒活性具有重要的研究意义。目前四元碳环核苷的合成需要预先制备取代的四元环状化合物，反应步骤长、产物结构单一、总收率低和成本高等不足。通过环加成反应构建四元碳环核苷类化合物，至今尚未见报道。本项目拟通过光催化或Lewis酸催化合成策略，以N-9位带有不同双键取代基团的嘌呤为原料，通过烯烃的分子间[2+2]环加成反应，构建四元碳环核苷类化合物，发展四元碳环核苷构筑的方法学，丰富四元碳环类化合物的结构类型。并将其衍生为含有多个羟基的四元碳环核苷，用于药理活性的初步研究，总结构型关系，以期筛选出生物活性更高的碳环核苷类化合物。

核苷类化合物是一类重要的抗病毒、抗肿瘤药物，其合成方法一直备受关注。河南师范大学核苷研究团队长期致力于核苷类似物的合成方法研究，发展了系列环核苷、非环核苷合成方法学。本项目以四元碳环核苷的合成为首要目标，以烯基取代的嘌呤和嘧啶为底物开展了系列[2+2]环加成反应的实验研究。遗憾的是，没有获得理想的结果。另外，在该项目的支持下，我们进行其他方面的研究工作，主要包括：1) 烯基取代的嘌呤或嘧啶化合物与乙烯基环氧的不对称[3+2]环加成反应合成手性异核苷；2) 以环氧乙烷和双取代的硫脲为原料合成氢化嘧啶类化合物，为结构多样性氢化嘧啶化合物的合成提供了新的途径；3) 发展了一系列苯并杂环化合物的去芳构化环加成反应，如苯并唑类化合物与D-A环氧乙烷的环加成去芳构化，2-硝基苯并呋喃分别于亚胺甲叶立德和MBH碳酸酯的环加成去芳构化反应，为三环苯并杂环类化合物的合成提供了新的思路。在本项目的支持下共发表研究论文8篇，包括Org. Lett. 3 篇，Chem. Commun. 4 篇，Org. Chem. Front. 1 篇。获授权发明专利8 项。获得省科技进步三等奖1项，省专利一等奖1项。