The known tricyclic ketone (I) is protected as the ethylene ketal (II) by treatment with ethylene glycol in the presence of pyridinium p-toluenesulfonate. Subsequent oxidation of the secondary alcohol function of (II) employing CrO3/pyridine provides ketone (III). Carboxylation of (III) by means of Stiles' reagent, followed by esterification of the resultant keto acid (IV) with ethereal diazomethane leads to the alpha-keto ester (V). The keto group of (V) is then reduced with NaBH4 to produce a diastereomeric mixture of alcohols (VI). Further deprotection of the ethylene ketal of (VI) furnishes ketone (VII). The hydroxyl group of (VII) is then subjected to a two-step dehydration process via mesylation, followed by elimination of the mesylate group in the presence of DBU, to yield the unsaturated ester (VIII).

Claisen condensation of ketone (VIII) with ethyl formate leads to (IX), which is further cyclized to isoxazole (X) upon treatment with hydroxylamine. Allylic oxidation of (X) with CrO3/pyridine gives dienone (XI). Subsequent isoxazole ring cleavage under alkaline conditions produces keto nitrile (XII). Dehydrogenation of (XII) with DDQ gives rise to enone (XIII). The methyl ester group of (XIII) is then subjected to ammonolysis in methanolic ammonia, to generate amide (XIV), which is finally dehydrated to the corresponding nitrile by employing SOCl2 in toluene.

In an alternative, more efficient synthesis of the title compound, condensation of 2-methylcyclohexanone (I) with 1-chloro-3-pentanone (II) in the presence of 2-naphthalenesulfonic acid (NSA), followed by cyclization in the presence of KOH gives rise to the bicyclic enone (III), along with minor amounts of the tricyclic compound (IV). Treatment of the reaction product with a further amount of chloro ketone (II) in the presence of KOH increases the proportion of the tricyclic enone adduct (IV). Reduction of enone (IV) with lithium metal in liquid ammonia, followed by alkylation of the intermediate lithium enolate with iodomethane leads to the alpha,alpha-dimethyl ketone (V). Allylic oxidation of (V) by means of tert-butyl hydroperoxide in the presence of a catalytic amount of CrO3 furnishes the enedione (VI). Subsequent reaction of (VI) with tosyl cyanide and LDA leads to dinitrile (VII). This is finally dehydrogenated employing DDQ to furnish the title compound.