Periodic Reporting for period 1 - SynWaiXen (Total Synthesis of Waixenicin A and Xenibellol A)
Periodo di rendicontazione: 2020-03-01 al 2022-02-28
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.
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.