From Planning to Optimization: Total Synthesis of Valerenic Acid and Some Bioactive Derivatives

Ramharter, Juergen; Mulzer, Johann

Eur. J. Org. Chem. 2012, (10), 2041-2053.

A detailed study of the total synthesis of valerenic acid, a well known GABA_A receptor subtype modulator, is described. Both successful as well as unsuccessful attempts towards the synthesis of the title compound are presented, including four different strategies to synthesize one of the key intermediates. The first two strategies are based on epoxides provided from the chiral pool, whereas the last two approaches rest on stereocontrolled modifications of 2-cyclopentenone. The streamlined synthesis implements a new one-pot reaction, which combines the addition of a Grignard species with an acid-catalyzed isomerization of the intermediate allylic alcohol. Further highlights are a stereo- and regioselective hydroxy-directed Diels–Alder reaction, a hydroxy-directed hydrogenation, and a final Negishi coupling reaction. After optimization of our synthesis, the preparation of several easily available derivatives is also discussed. Amides obtained by functionalization of the carboxyl group are more than twice as active as valerenic acid.