A total synthesis of the unique tris-oxazole macrolide ulapualide A produced by the marine nudibranch Hexabranchus sanguineus
A total synthesis of ulapualide A (1), whose relative stereochemistry was assigned on the basis of an earlier molecular mechanics study of its hypothetical metal chelated complex 9, is described. The synthesis is based on: i, elaboration of the double functionalised tris-oxazole 11; ii, synthesis and installation of the top side chain 16 (C-26–C-41) via a stereoselective Wittig reaction, leading to 17; iii, conversion of 17 into 73a and attachment of the C-1–C-9 portion 18; iv, macrocyclisation of 19 by an intramolecular Wadsworth–Emmons olefination leading to the macrolide 20; v, incorporation of the C-9 methyl group (to 80) and, finally vi, manipulation of the side chain functionality in 80 and introduction of the terminal formyl enamine residue. The synthetic ulapualide A showed NMR spectroscopic data which were almost identical to those described for the natural product, and did not separate from the natural material in HPLC analysis. Small differences in the 13C NMR spectroscopic data however lead us to conclude that the stereochemistry of the synthetic ulapualide differs from that in the natural product at one or more of the stereogenic centres along the C-28–C-33 portion of the side chain.