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

Nuphar二聚体生物碱6-羟基-硫代-大黄素和6-羟基-硫代-大黄素具有挑战性的分子结构和非常有趣的药理活性，如抗转移、诱导细胞凋亡和免疫抑制活性。因此，这类天然产物的单一代表的立体选择性全合成将是非常理想的，但到目前为止还没有完全完成。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。在第一个资助期，我们已经能够开发一种高度立体选择性地获得完全取代的和功能化的哌啶构筑块-基于一个强大的序列，包括乙烯基曼尼希反应、环化到内酰胺，以及通过利贝斯金德-绍尔交叉偶联还原烷基化得到2，6-顺式取代的哌啶。其中一种哌啶类化合物已被转化为双α-烷基喹唑烷，可提供中心螺环硫杂环戊烷的通道。因此，我们已经建立了一条立体选择性的合成路线，通向天然产物的整个碳骨架和9个具有正确绝对构型的立体生成碳中心中的7个。在接下来的步骤中，我们打算将我们最先进的中间体环化到中心硫代戊烷，我们对此提出了3种不同的策略。随后，硫代戊烷将与第二个哌啶构筑块烷基化，这将导致在硫代戊烷杂环内建立第二个四元立体生成中心。最后，在仅仅两个合成步骤中，烷基化产物将被环化成nuphar生物碱。合成计划的概念设计是这样一种方式，即制备4个可能的非对映异构体nuphar生物碱中的至少2个。立体分歧预计是通过颠倒烷基化顺序来实现的，该烷基化顺序是在生成双烷基喹啉的途中实现的，双烷基喹啉是硫杂环己烷的前体。在硫杂环烷基化过程中，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.