Angew. Chem. Int. Ed. 51, 6929–6933 (2012)

Three of the most common justifications for total-synthesis campaigns are (i) as tests for newly developed synthetic methodology, (ii) the interesting biological activity of the natural products and (iii) the presence of synthetically challenging or unusual carbon skeletons in the structure. A rare example now reported by Alois Fürstner and co-workers from the Max-Planck-Institut für Kohlenforschung in Mülheim, Germany includes elements of all three.

Neurymenolide A was first isolated from a species of red algae found in the South Pacific. It exhibits activity against both methicillin- and vancomycin-resistant bacteria — so the structure could be important in the generation of new drug targets. Fürstner and co-workers, however, were most interested in the unusual structure, which contains a 4-hydroxypyrone as part of a macrocycle (pictured). Restricted rotation of this moiety (blue) in combination with the single stereocentre (of unknown configuration) means that the compound exists as a mixture of two diastereomers that interconvert on a timescale of several hours.

The key feature of any synthesis of this target is that the skipped polyene array (red) is likely to isomerize easily to the energetically more favourable conjugated system — so identification of a mild synthetic method was important. Fürstner and co-workers first developed a mild gold-catalysed method for the construction of 4-hydroxypyrones. To construct the natural product, however, it was necessary to use the new cyclization method on a substrate containing no less than six carbon–carbon multiple bonds. Furthermore, the electrophilic catalyst must react fastest at the least electron-rich alkyne.

Following formation of the desired pyrone, the macrocycle was formed using a molybdenum alkyne metathesis catalyst previously developed by the Fürstner group. The selectivity of this catalyst for reaction with two methyl-alkynes in the presence of three other alkenes is remarkable. The synthesis was completed by a selective reduction of the alkyne resulting from this metathesis and a final deprotection to remove an acetyl group introduced during pyrone formation.