EXTRACYCLIC STEREOCONTROLLED ALKYLATION OF (1R,5S)-4-ETHYL-6,6-DIMETHYL-3-(PHENYLSULFONYL)BICYCLO[3.1.1]HEPT-3-EN-2-ONE - A HIGHLY STEREOCONTROLLED SYNTHESIS OF (-)-KANSHONE-A

(1R,5S)-4-Ethyl-6,6-dimethyl-3-(phenylsulfonyl)bicyclo[3.1.1]hept-3-en-2-one (7) was prepared from (+)-nopinone (1) in six steps and 70% overall yield via (1R,5R)-6,6-dimethyl-3-(phenylthio)bicyclo-[3.1.l]hept-3-en-2-one (2). Alkylation reactions of 7 with alkyl bromides 16 (a, allyl; b, 3-methyl-2-butenyl; c, propargyl; d, benzyl bromide) in the presence of K2CO3 in MeCN proceeded in regio- and extracyclic stereocontrolled fashion to give, as the major product, mixtures of gamma-alkylated products 17a-d possessing a new chiral center of R configuration adjacent to a ring and 18a-d possessing that of S configuration, whose ratios are 17a-18a, 10:1, 17b-18b, 7:1; 17c-18c, 13:1; and 17d-18d, 18:1, along with alpha-alkylated products 19a-d and 0-alkylated products 20a,b on reactions with 16a,b. In addition, reaction of 7 with methyl bromoacetate (16e) provided 17e as the sole product. In the presence of a combined reagent, K2CO3-Cs2CO3 (9:1), in MeCN, considerably high diastereoselection was detected, i.e., reactions of 7 with 16a,b produced mixtures of 17a and 18a, and 17b and 18b, in 20:1 and 12:1 ratios, respectively. Reaction products were separated by chromatography on silica gel, while the major diastereomers 17a,c-e, highly crystalline themselves, were readily obtained as pure crystals by recrystallization. Mechanism of diastereoselection and the scope and limitations of the extracyclic stereocontrolled alkylation are briefly discussed. In the application of 17 as the synthetic intermediate for the asymmetric synthesis, starting with (1R,5S)-6,6-dimethyl-4-[(1R)-1-methyl-3-butenyl]-3-(phenylsulfonyl)bicyclo[3.l.l]hept-3-en-2-one (17a), (-)-kanshone A (8), a nardosinane sesquiterpene, was synthesized in a highly stereoselective fashion in 12 steps via (1R,4R,5R)-4,6,6-trimethyl-4-[(1R)-l-methyl-3-butenyl]bicyclo[3.1.1]heptan-2-one (30) and its cyclobutane-ring opening product, (4S,4aR,5R)-1-acetoxy-4-isopropenyl-4a,5-dimethyl-3,4,4a,5,6,7-hexahydronaphthalene (34).