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Totally Synthetic by Paul H. Docherty, 30 August 2006

Total Synthesis of Zaragozic Acid C


J. O. Bunte, A. N. Cuzzupe, A. M. Daly, M. A. Rizzacasa, Angew. Chem. Int. Ed. 2006, 45, 6376-6380.

DOI: 10.1002/anie.200602507

A short formal total 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 starting material shown below was made from modified L-arabinose and coupled with a differentially protected unsaturated diol.

Ireland-Claisen, followed by methyl esterification using diazomethane 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, 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).