Five-membered ring annulation via thermal rearrangement of β-cyclopropyl α,β-unsaturated ketones. A formal total synthesis of the sesquiterpenoid (±)-zizaene

Abstract

Treatment of the β-iodo enones 7–10 with lithium (phenylthio)(cyclopropyl)cuprate provided excellent yields of the corresponding β-cyclopropyl α,β-unsaturated ketones 11–14, respectively. When 3-isopropenyl-2-cyclohexen-1-one (16) was allowed to react with dimethyloxosulfonium methylide in dimethyl sulfoxide – tetrahydrofuran, 3-(1-methylcyclopropyl)-2-cyclohexen-1-one (17) was produced in 59% yield. Although thermal rearrangement (~425–450 °C) of compounds 11 and 17 produced high yields of the annulation products 19 and 22, respectively, similar reactions involving the β-cyclopropyl enones 12 and 13 were not efficient in terms of production of the corresponding bicyclic systems (23, 26, and/or 27, respectively). In these cases, predominant (24 + 25 from 12) or significant (28 + 29 from 13) amounts of monocyclic dienones were formed. The annulation product 22 served as a convenient starting material for a new formal total synthesis of the sesquiterpenoid (±)-zizaene (30). Conjugate addition of lithium divinylcuprate to 22 afforded the ketone 36 which was converted by standard methods (via 38 and 39) into the enone 40. Treatment of the latter substance with thiophenol in the presence of tetra-n-butylammonium fluoride gave 41, which was transformed via ketalization (41 → 42), hydroboration(42 → 43), tosylation (43 → 44), and oxidation (44 → 45) into the sulfone 45. When the latter compound was treated with potassium tert-butoxide in hexamethylphosphoramide, the tricyclic ketal sulfone 46 was produced in 85% yield. Reduction of 46 with sodium amalgam afforded the ketal 47, which upon hydrolysis under mild conditions gave the ketone 32. Treatment of the latter substance with sodium methoxide in methanol provided a 1:2 mixture of the epimeric ketones 31 and 32, which had been converted previously by Coates and Sowerby into (±)-zizaene (30).