A Convergent, Flexible, and Stereoselective Total Synthesis of the Dimeric Nuphar Alkaloids 6-Hydroxy-Thionuphlutine and 6-Hydroxy-Thiobinupharidine

二聚体nuphaa生物碱6-羟基硫比乌柳嘌呤和6-羟基硫比乌柳嘌呤具有具有挑战性的分子结构和高度有趣的药理特性，如抗转移、诱导细胞凋亡和免疫抑制活性。因此，这种天然产物类的单一代表的立体选择性全合成将是非常可取的，但迄今尚未完全完成。在这个项目中，我们打算建立一个新的、高度收敛的、立体选择性的合成策略来合成标题化合物。在第一个资助期，我们已经能够开发出一种高度立体选择性的方法来获得完全取代的和功能化的哌啶构建模块——基于一个强大的序列，包括一个vinylologich反应，环化到内酰胺，并通过liebeskin - srogl交叉偶联还原烷基化到2,6-顺式取代的哌啶。其中一种哌啶已转化为双a-烷基化喹啉吡啶，该喹啉吡啶准备提供与中心螺环硫烷的接触。因此，我们建立了一个立体选择性合成路线，以达到天然产物的整个碳主链和9个立体碳中心中的7个具有正确的绝对构型。在接下来的步骤中，我们打算将我们最先进的中间体环化为中心硫烷，为此我们提出了3种不同的策略。随后，硫烷将与第二个哌啶构建块烷基化，这将在硫烷杂环内建立第二个季立体中心。最后，在仅仅2个合成步骤内，烷基化产物将被环合成nuuphar生物碱。合成方案在概念上设计为制备4种可能的非对映异构体偶联生物碱中的至少2种。立体发散预期通过在生成硫烷前体双烷基化喹诺齐啶的过程中烷基化顺序的逆转来实现。设想在硫烷烷基化过程中对第二螺环手性中心的立体化学控制可以通过纯底物或手性辅助控制来建立。

The dimeric Nuphar alkaloids 6-hydroxy-thiobinupharidine and 6-hydroxy-thionuphlutine are characterized by their challenging molecular architecture and their highly interesting pharmacological properties, e. g. anti-metastatic, apoptose-inducing, and immunosuppressive activity. Accordingly, a stereoselective total synthesis of single representatives of this natural product class would be highly desirable, but has not been fully accomplished to this date.In this project we intend to establish a novel, highly convergent, and stereoselective synthetic strategy towards the title compounds. In the first funding period we have been able to develop a highly stereoselective access to the fully substituted and functionalized piperidine building blocks – based upon a powerful sequence comprising a vinylogous Mannich reaction, cyclization to the lactam, and reductive alkylation towards a 2,6-cis-substituted piperidine via Liebeskind-Srogl cross coupling. One of the piperidines has been converted into a doubly a-alkylated quinolizidine which is poised to provide access to the central spirocyclic thiolane. Thus, we have established a stereoselective synthetic route to the entire carbon backbone of the natural product and 7 out of the 9 stereogenic carbon centers with the correct absolute configuration. In the next steps we intend to cyclize our most advanced intermediate to the central thiolane for which we propose 3 different strategies. Subsequently, the thiolane is to be alkylated with the second piperidine building block which would give rise to the establishment of the second quaternary stereogenic center within the thiolane heterocycle. Finally, within merely 2 more synthetic steps the alkylation product will be cyclized into the nuphar alkaloids.The synthesis plan is conceptually devised in such a way as to prepare at least 2 out of the 4 possible diastereomeric nuphar alkaloids. The stereodivergence is expected to be achieved by a reversal of the alkylation order en route to the doubly-alkylated quinolizidine which is the precursor to the thiolane. The stereochemical control over the second spirocyclic chiral center which is set during the alkylation of the thiolane is envisioned to be established either by pure substrate or chiral auxiliary control.