A spiro-annulation approach to the zizaane sesquiterpenes

Abstract

4,4-Dimethyl-2-oxabicyclo[3.2.1]octan-3-one (10), obtained in two steps from norcamphor, was converted to 3-(1,1-dimethyl-2-oxopropyl)cyclopentanone (14), then selectively ketalized. The ketal function underwent Lewis acid catalysed spiro-annulation with 1,2-bis)trimethylsiloxy)cyclobutene (4) yielding 7-(1,1-dimethyl-2-oxopropyl)spiro[4.4]nonane-1,4-dione (21), and intramolecular titanium-induced ketone–ketone coupling and oxidation afforded (±)-isokhusimone (3) in an overall yield of 35% from norcamphor. In an alternative approach, the ethylene ketal of methyl 2-mefhyl-2-(3-oxocyclopentyl)propanoate (27) was prepared from 10. Spiro-annulation proceeded in good yield, but subsequent titanium-induced ketone–ester coupling failed to provide the desired tricyclic product, 7,7-dimefhyltricyclo[6.2.1.01,5]undecane-2,6-dione (30). Keywords: annulation, carbonyl coupling, isokhusimone, terpene.