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

• Applicant: Professor Dr. Christoph Schneider
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 314974693

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.

• DFG Programme: Research Grants