Synthesis of the Palmerolides

The palmerolides are a family of 20-membered macrolides isolated from the Antarctic tunicate Synoicum adareanum, which display unprecedented selectivity towards human melanoma cells. We initiated a programme in late 2007 initially targeting the synthesis of palmerolide A. By incorporating all the necessary functional groups and stereocentres in our advanced fragments, the number of post-coupling transformations was essentially minimised, and the C15-C24 subunit is common to other members of the palmerolide family, including palmerolide C. Utilising convergent strategies we developed efficient syntheses of the fully elaborated C1-C14 and C15-C24 subunits. The C1-C14 subunit utilised HWE coupling at C8-C9 and DIPCl asymmetric reduction at C10. For the synthesis of the C15-C24 sulfone we opted to install the C24 vinyl iodide at an early stage in the synthesis and carry this sensitive motif through all the remaining steps which included an ambitious vinylogous Mukaiyama aldol reaction under Felkin-Anh control to install the 1,2-syn motif at C19-C20 which proceeded in excellent yield and with high levels of both regio- and diastereoselectivity. At this stage, following the completed synthesis and stereochemical assignment of palmerolide A by the groups of De Brabander, Nicolaou and Hall, we opted to revise our target and focus on the synthesis of the regioisomeric family member palmerolide C due to its unresolved stereochemistry. In collaboration with the isolation group of Prof Bill Baker (University of South Florida) a series of diastereomeric C7-C14 fragments were prepared for comparison with the naturally-derived degradation fragment and which enabled in part the assignment of the relative and absolute configuration of the C8-C10 stereotriad. With this information in hand, the stereocontrolled preparation of the requisite fully elaborated C1-14 aldehyde was completed in 17 synthetic steps. The Julia-Kocienski olefination of this subunit with C15-C24 sulfone proceeded in excellent yield to install the C14-C17 E,E-diene, this intermediate was progressed to the C1-C24 seco-acid which underwent classical Yamaguchi macrolactonisation to provide the 20-membered macrolide. Deprotection of the silyl groups at C8-C9 has enabled access to the direct precursor which underwent enamide formation at C24 is required to deliver the proposed structure of palmerolide C. Comparsion of the NMR spectra for our synthetic material with the natural product revealed significant differences prompting our reassignment of the proposed initially proposed structure. The completion of the initially proposed structure of palmerolide Cdemonstrates the applicability of our flexible coupling strategy, initially proposed for palmerolide A, using fully elaborated subunits in key couplings. This enables a short endgame strategy of 5 steps and the outcomes were disclosed in Chemistry- A European Journal.

Concurrently with the research directed towards the palmerolides the PDRA contributed to an additional project concerned with the synthesis and structure elucidation of chamuvarinin, a unique acetogenin containing an adjacently linked bis-THF-THP ether array. His contribution enabled the confident assignment of the relative configuration of this array and ultimately paved the way for the first total synthesis of this novel metabolite, confirming the absolute configuration and gaining access to further material for biological assays against the parasite T. brucei and its potential as a lead compound in the search for new treatments for West African sleeping sickness. This research was published in Organic Letters in February 2011 and followed by a full paper in Chemistry – A European Journal, detailing a revised synthetic strategy an biological studies.