Rizzacasa, Bunte, Cuzzupe and Daly. ACIEE, 2006, Early View. DOI: 10.1002/anie.200602507.
A short formal synthesis of zaragozic acid C, this paper is a good reminder of the power of the Claisen rearrangement, this time in the Ireland modification. These targets were isolated in the last decade, and are inhibitors of squalene synthase, and thus have cholesterol-lowering properties. The SM shown below was made from a bit of sugar-bashing (L-arabinose), and coupling of the differentially protected unsaturated diol.
Ireland-Claisen, followed by diazomethane methyl-esterification and deprotection returned the terminal olefin, which, upon hydrogenation, cyclised to give the crystalline spiro lactone. However, this reduced the compound excessively, as they require the terminal olefin to stay intact, so alternative conditions were used.
With the desired compound in hand, functional group manipulations and the addition of the side chain left them ready to construct the polycyclic core. This required heating in acid for three days, though admittedly in a rather dilute solution. This created the core in one smooth transformation, allowing a formal synthesis in only a few more steps (an intermediate in Erick Carreira’s synthesis).