可控性Beta-环丁内酯Dyotropic重排反应研究及其在天然产物多样性合成中的应用

Development of novel synthetic methodologies, especially those leading to skeletal re-organization via selective cleavages and re-generations of multiple chemical bonds, has ranked among the utmost research subjects for synthetic community. The inherent challenges associated with these topics mainly stem from the complicated chemo-, regio-, and stereoselectivity issues that will lead to undesirable competitive reactions. Wagner-Meerwein type dyotropic rearrangement of beta-lactone engages concurrent migration of two vicinal σ-bonds (one C-O bond and one C-C bond) to generate the ring-enlarged product, gama-butyrolactone.It represents a useful method for constructing gama-butyrolactone that is a ubiquitous motif in the biologically active compounds, however, its synthetic utility was historically overlooked, probably due to its sensitivity to the reaction parameters (e.g. substrates and Lewis acids), which makes the product distributions somewhat unpredictable. In this program, we will conduct a systematic investigation on the dyotropic rearrangement of chiral beta-lactone, which will cover several aspects: 1）identification of new catalytic system (e.g. new Lewis acids) with superior reactivity than the existing conditions to promote dyotropic rearrangement; 2）examination of the substrate scope of the newly developed catalytic system; 3) clarification of the key factors that control the reactivity and selectivity of the reaction. We aim to develop the dyotropic rearrangement of beta-lacotne into a controllable and predictable reaction that would find broad synthetic utility in natural product synthesis. With the synthetic methodology established, we will move towards the enantioselective total syntheses of two family of natural products, the xanthanolides and stemona alkaloids, both of which have amazing structure diversity and remarkable biological profiles. We plan to develop a highly efficient and general method for syntheses of the 5-7 bicyclic core of xanthanolides or the 5-7-5 tricyclic core of stemona alkaloids via the controllable Wagner-Meerwein type dyotropic rearrangement of cis-beta-lactones. Meanwhile, we will apply the diversity-oriented strategy in our study to realize the collective syntheses of a number of the aforementioned natural products as well as their analogs for further biological evaluation.

利用骨架迁移和重排反应快速高效合成目标分子是有机合成化学研究热点之一，其挑战性在于如何有效控制反应中化学键断裂和重组的化学、区域和立体选择性。Beta-环丁内酯在Lewis酸催化下可发生 dyotropic重排反应生成gama-环戊内酯。该反应受底物类型和反应条件影响较大，产物难以控制，因而合成应用价值有限。本课题将系统研究顺式beta-环丁内酯dyotropic重排反应，建立新Lewis酸催化体系，拓展底物普适性，总结反应规律，实现化学、区域和立体选择性可调可控，使其发展成为构建手性gama-环戊内酯的通用方法之一。在此基础上，将对两类具有重要生物活性的天然产物苍耳烷型倍半萜和百部生物碱展开全合成研究。以dyotropic重排反应为关键步骤,简洁高效的构建其特有的5-7双环或5-7-5三环核心骨架，并结合多样性合成策略，完成一系列该家族天然产物的合成，为进一步开展生物功能研究奠定基础。

本项目围绕“可控性Beta-环丁内酯Dyotropic重排反应研究及其在天然产物多样性合成中的应用”这一主题，开展了一系列系统深入的研究工作，取得了丰硕的研究成果，主要内容概括如下：.1) Dyotropic 重排反应方法学研究。本项目对3,4-顺式-环丁内酯dyotropic 重排反应进行了系统研究，使其发展成为构建多取代手性环戊内酯的有效方法之一(Angew. Chem. Int. Ed. 2012, 51, 6984-6988). 。此外，还对其它不同类型的dyotropic 重排反应进行了研究，首次实现了α-亚甲基-β-环丁内酯类底物的dyotropic重排反应和β-环丁内酰胺dyotropic重排反应，可用于高效构建多取代五元环内脂或内酰胺类化合物。部分研究成果尚未发表，相关文章正在撰写当中。 .2) 苍耳烷型倍半萜类天然产物的集群式合成。本项目以dyotropic重排反应为关键步骤，实现了一系列苍耳烷型倍半萜天然产物（如xanthatin和8-epi-xanthatin）的集群式合成。2014年，本课题组以单体xanthatin为前体，通过仿生合成策略实现了多个结构更为复杂的苍耳烷二聚体（如mogolides A-D）的首次全合成（Angew. Chem. Int. Ed, 2014, 53, 14494–14498）。2016年，以另一个单体8-epi-xanthatin为前体，完成了该家族其它一系列单体或二聚体的全合成（如xanthipungolide和pungiolide A-E）。至此，苍耳烷型倍半萜家族中所有代表性的天然产物全合成均以完成。部分研究成果相关论文正在撰写当中。.3) 百部生物碱的集群式合成。我们以的dyotropic重排反应为关键步骤，顺利实现了该家族最具代表性的分子stemoamide的不对称全合成。整条合成路线共9步，是目前关于该分子不对成合成中路线最短、总产率最高的合成路线。在此基础上，我们还完成了该家族其他结构更为复杂的天然产物（如saxorumamide和stemonin）的全合成，相关论文正在撰写当中。.另外，在本项目基金的支持下，我们还完成了其它一些天然产物全合成和方法学研究，相关研究论文也标自然科学基金支持。