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Total Synthesis of Waixenicin A and Xenibellol A

Periodic Reporting for period 1 - SynWaiXen (Total Synthesis of Waixenicin A and Xenibellol A)

Reporting period: 2020-03-01 to 2022-02-28

The realization of the first total syntheses of the two marine natural products waixenicin A and xenibellol A is the aim of this proposal. For this purpose, a N-heterocyclic carben (NHC)-catalyzed bicyclization shall be employed as key transformation. Both target structures are members of the Xenia diterpenoids family and exhibit cytotoxicity against human cancer cell lines. Despite these highly desirable, promising biological properties and unique structural features, therapeutic applications have been prevented by the circumstance that no synthetic access has been achieved until this day. Using retrosynthetic pattern recognition, we realized that the central fused lactone motif (of both natural products) could be efficiently accessed via a recently reported NHC-catalyzed bicyclization reaction. This organocatalytic methodology enables a rapid creation of molecular complexity and, therefore, its application to these total syntheses should save time and other resources. If a therapeutic potential can be corroborated, a synthetic access would provide this family of Xenia diterpenoids (or their derivatives) as possible anticancer drugs. As a result, this project could potentially lead to an improvement of medical care for future cancer patients, thereby also addressing a UN sustainable development goal.
For Waixenicin A, we synthesized a three different substrates for the desired N-heterocyclic carben (NHC)-catalyzed bicyclization. Unfortunately, a screening of reaction conditions (including high pressure) showed that the desired 9-membered ring could not be made via this method. Heating of the reaction mixture led to slow decomposition, while different solvents showed still no conversion to the desired product. We also sent some material to our collaborator Prof. Berkessel (University of Cologne), who is also the inventor of the tested NHC methodology. He confirmed via computational studies that the formation of the 9-membered ring might be possible, however, as no desired reaction was experimentally found, there appears to be a kinetic barrier.

Since three different substrates showed no conversion for the NHC-catalyzed bicyclization towards Waixenicin A, we decided to follow a different synthetic route to our second natural product Xenibellol A. Accordingly, we envisioned a coupling of two advanced fragments (for a convergent synthesis) followed by a late-stage radical cyclization to furnish the last ring of Xenibellol A. While we managed to prepare a variety of different radical precursors, the desired radical cyclization has not been achieved yet. Therefore, we managed to make three of the four rings of Xenibellol A, which is fairly close to the core structure of this molecule.
We strongly believe that total synthesis is critical to evaluate the generality of a given methodology. Only when a method is put under a test, its true value for scientists and society can be determined. For Waixenicin A, we tested a novel NHC-catalyzed bicyclization reaction in order to validate its utility in the context of the synthesis of a complex natural product.
Although this catalytic method is very efficient for making nepetalactone, it appears to be not applicable to the generation of (more challenging) 9-membered ring systems. Therefore, we also see our results as an encouragement to further improve NHC-catalyzed bicyclizations (via e.g. more active catalysts, lower reaction temperatures etc..) in order to render them fully useful for new, efficient, and economic synthetic routes.

For Xenibellol A, with our different radical precursors (and their syntheses in hand), we now have a platform to further test a variety of cyclization strategies. The properties of a compound are often more thoroughly understood if multiple synthesis strategies are attempted. Together with Prof. Danishefsky's previous results, we hope that our findings will ease any further effort to make this biologically unique natural product. Xenibellol A and Waixenicin A (or their derivatives) could both still improve patient treatment when used as novel drugs.
Attempted key steps