催化不对称氧杂Diels-Alder反应及其在新型手性吡喃(糖)核苷类似物设计合成中的应用研究

Nucleoside analogues as antiviral drugs have received more and more attention because of their outstanding advantages as antimetabolites such as little side-effect, high successful rate and low-risk. As an important content of nucleoside analogues, chiral pyran(osyl) nucleoside compounds play a important role of which many known natural products have shown the unique biological activities. However, the difficulty in constructing chiral pyran(osyl) rings greatly limits the development of this kind of nucleoside analogues. As an important content of Diels-Alder reaction, the catalytic asymmetric oxo-hetero Diels-Alder reaction provides a convenient and effective route to the synthesis of chiral pyran(osyl) compounds. In this project, we would like to carry out the study on catalytic asymmetric oxo-Diels-Alder reaction from the aspects of normal electron demand and inverse electron demand, in which a series of novel chiral pyran(osyl) rings could be constructed with high stereoselectivities through more efficient catalytic system (including concerted catalysis) and applied to the synthesis of chiral pyran(osyl) nucleoside compounds for further biological activity study. Based on this, attempts to apply catalytic asymmetric oxo-hetero Diels-Alder reaction to the total synthesis of several natural products or known bioactive molecules will be also set up.

核苷类似物作为抗代谢药物，具有毒副作用小，成功率高、风险性低等显著优势，其作为抗病毒药物日益受到人们的重视。在众多的核苷类似物中，手性吡喃(糖)核苷类化合物占据着重要地位，已知的这一类天然产物大多都显示了独特的生物活性。但是，手性吡喃(糖)环的构建难度极大地限制了这一类核苷类似物的发展。作为Diels-Alder反应的一个重要内容，催化不对称氧杂Diels-Alder反应为合成手性吡喃(糖)类化合物提供了一条便捷有效的途径。本课题拟从正常电子需求和反电子需求两个方面，对催化不对称氧杂Diels-Alder反应开展研究，通过发展新的高效催化体系（含协同催化），高立体选择性地构建一系列新型手性吡喃(糖)类化合物并将其应用到这一类核苷类化合物的合成中，同时对其开展相关生物活性研究。在此基础上，本课题也将对这一反应在几种手性吡喃(糖)核苷天然产物或已知生物活性分子的全合成中的应用开展研究。

新型手性吡喃(糖)核苷类化合物作为天然核苷类似物日益受到人们的重视。研究主要集中在新型手性吡喃糖基的获取及核苷碱基的修饰上。在联萘酚衍生的手性磷酸的作用下，首次开展了3-甲酰基色酮类化合物与不同乙烯基醚间的催化不对称反电子需求氧杂Diels-Alder反应研究，合成了一系列可作为糖基前体的手性六元氧杂环类化合物；在新的核苷类药物的发现过程中，7-去氮嘌呤是一种碱基修饰理想的模拟物, 研究同时以7-去氮嘌呤为骨架，实现了多种新型核苷碱基的构建；本项目在执行期间虽尚未能通过这些手性吡喃糖基前体和新型核苷碱基实现手性吡喃(糖)核苷的构建，但其中所发展的方法不仅能够丰富不对称氧杂Diels-Alder反应的内容，也为后期开发高效合成手性六元氧杂环类化合物提供了思路。此外，所得的新型嘌呤碱基类似物在药物化学，生物医药等领域具有潜在的应用价值。