假蕨素家族天然产物的集合式合成及其分子探针的设计和制备

Pseudopterosin family of natural products are structurally and stereochemically complex compounds that display various potent pharmacological activities ranging from anti-inflammatory to anti-tuberculosis. Several members of the pseudopterosin family have been accomplished via a number of different strategies. However, a general route towards these promising natural products has been missing. Based on our careful analysis of the structure features of pseudopterosins, a key synthetic intermediate has been recognized, which would give rise to a variety of bioactive natural products through straightforward transformations. In order to efficiently prepare such an intermediate, we propose to explore a novel cascade reaction of enynes involving a 6-endo-dig cyclization followed by a stereoselective [3,3]-rearrangement. Based on this novel transformation, we aim to realize the collective total synthesis of pseudopterosin family natural products in an efficient and scalable fashion. By preparing unnatural analogs of these privileged skeletons, we will build an extensive compound library that informs us rich structure-activity relationship of pseudopterosins. Our route will also enable the synthesis of specific small-molecule probes for associated biology studies, elucidating the undefined mechanism-of-action of these intriguing natural products.

作为一类具有突出的抗炎和抗肺结核生物活性的复杂小分子，假蕨素家族天然产物一经发现即吸引了广泛的关注。虽然该家族部分成员的化学合成已有相关报道，但是其合成效率还不尽理想。发展一条具有普适性的合成路线、实现对于多个天然产物的集合式合成具有十分重大的意义。经过对这一家族天然产物分子结构的深入剖析，我们提出了一个能快速高效地转化为目标分子的关键中间体，并设计了新颖独特的烯炔关环-重排的串联反应来迅速完成该中间体的制备。我们将以此为基础完成对假蕨素家族天然产物高效、模块化和立体选择性的全合成工作；并围绕这一重要分子骨架构建其类似化合物库，为其构效关系的研究提供有力的工具。在此之上，我们还将设计合成全新而多样的小分子探针，使探索这类高抗炎活性天然产物的作用靶点成为可能，从而在根本上填补假蕨素类天然产物生物活性机理研究上的空白。

假蕨素家族天然产物属于二萜类海洋天然产物，其中的一大类属于在生源上相关的serrulatane和amphilectane骨架化合物，具有独特的化学结构及突出的抗炎、抗肺结核等生物活性，但其作用机制目前还不清楚。本课题针对假蕨素家族天然产物展开不对称全合成研究工作。首先根据其结构特点以及相互关系，提出了全新的逆合成分析。从串联的金催化关环-重排反应的模型研究出发，探索确定了一条以不对称1,4-加成串联酰基化反应、金催化的选择性环化反应、芳构化/共轭驱动的Cope重排反应成功构建α-吡喃酮和呋喃两类关键中间体的方法。在随后的研究中，实现了从α-吡喃酮到苯、酚、邻二酚三种氧化态不同的芳环体系的转化，及金催化的Michael加成反应以完成七元环的构建。最终建立了一条高效、模块化、灵活普适的合成路线，实现了一系列具有代表性结构及重要生物活性的天然产物的集合式合成，为其构效关系和作用机理研究提供了研究材料。