通过碳-氢活化立体选择性的合成2,6-反-二取代四氢吡喃结构及其在天然产物(-)-Apicularen A全合成中的应用

2,6-二取代的四氢吡喃结构广泛存在于具有重要生物活性的天然产物中。2,6-顺-二取代四氢吡喃的合成方法已经得到了较为深入的研究；但是，对如何高立体选择性的合成其反式异构体的研究仍然十分有限。本课题拟通过调节Prins反应中间体的空间位阻和立体电子效应，设计了2个高立体选择性的构建2,6-反-二取代四氢吡喃的模型。反应通过DDQ介导的氧化C?H活化引发；关环后，三烷基硅基通过去硅基化反应移除而生成2,6-反-二取代四氢吡喃。.我们拟通过对具有显著抗癌活性的天然产物(?)-apicularen A进行全合成研究验证上述发展的模型在合成复杂天然产物中的应用价值。从简单的醛出发，合成可以通过14步完成。除了DDQ介导的氧化C?H活化，合成的关键步骤还有Cr介导的催化不对称炔丙基化、SmI2/ iPrOH介导的立体选择性的酮还原、Ru催化的区域选择性的硅氢化反应、Tamao氧化和Co/Cr介导的

2,6-Disubstituted tetrahydropyrans are core units within a multitude of biologically active natural products, and therefore have attracted great interest in recent years. The stereoselective synthesis of 2,6-cis-tetrahydropyrans has been studied extensively. However, highly selective 2,6-trans isomer synthesis has proven to be much more challenging. In the proposal, two models of Prins reactions are designed to diastereoselectively yield 2,6-trans-tetrahydropyrans through both steric and stereoelectronic tuning. DDQ-mediated oxidative C?H bond cleavage reaction will be employed to initiate Prins reactions, and after cyclizations, trialkylsilyl groups could be removed through simple desilylations. ..Then we will validate the applicability of model developed above in the construction of complex natural products through a total synthesis of (?)-apicularen A. The synthesis will be completed in 14 steps from a simple aldehyde. In addition to the DDQ-mediated C?H cleavage process, key steps in the synthesis include catalytic enantioselective Cr-mediated propargylation, SmI2/iPrOH mediated stereoselective ketone reduction, Ru-catalyzed regioselective hydrosilylation, Tamao oxidation and catalytic enantioselective Co/Cr-mediated allylation.