Stereocontrolled Synthesis of (+)-Nootkatone from (-)-β-Pinene

Article abstract of DOI:10.1021/jo00145a003

A stereocontrolled synthesis of (+)-nootkatone (1) starting from (-)-β-pinene is described.Methyl (1R,3R,5R)-3,6,6-trimethyl-2-oxobicyclo<3.1.1>heptane-3-carboxylate (3) prepared from nopinone (2a) was converted into (1R,2S,5S,8S,10R)-5,8,11,11-tetramethyl-7-methylene-3-oxatricyclo<8.1.1.0^2,8>dodecan-4-one (8a), a key intermediate for the introduction of the vicinal cis-dimethyl group by the following procedures: (1) borohydride reduction of 3 followed by methylation to give the corresponding 3-(1-hydroxy-1-methylethyl) 2-ol compound 6a, (2) propionylation of 6a followed by dehydration to give (1R,2S,3S,5R)-3,6,6-trimethyl-3-isopropenyl-bicyclo<3.1.1>hept-2-yl propionate (7a), and (3) allylic bromination of 7a with NBS followed by intramolecular alkylation.Lithium-ethylamine reduction of enol ether 14 prepared from 8a afforded (1R,2S,7R,8S,10R)-5,7,8,11,11-pentamethyl-4-(1-methylpropyl)-3-oxatricyclo<8.1.1.0^2,8>dodec-4-ene (15a), bearing the desired vicinal cis-dimethyl group.In contrast, catalytic hydrogenation of 8a yielded the trans isomer 9.The conversion of 15a into (+)-1 in ca. 16percent overall yield (from 2a) was achieved by ozonolysis of 15a, leading to (1R,2S,5R)-3-<(1R)-1-methyl-3-oxobutyl>-3,6,6-trimethylbicyclo<3.1.1>heptan-2-one (17b), and subsequent intramolecular aldol cyclization of 17b followed by dehydrochlorination.