UBC Theses and Dissertations

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UBC Theses and Dissertations

Total syntheses of sesquiterpenoids (±)-aristolone, (±)-[alpha]-cubebene, (±)-[beta]-Cubebene Britton, Ronald William


An efficient, 10-step synthesis of (±)-aristolone (7) from 2,3-dimethylcyclohexanone (86) is described. Alkylation with methallyl chloride of 86, via the corresponding n-butylthiomethylene derivative 119, followed by removal of the n-butylthiomethylene blocking group, gave the two ketones 121 and 122. Acid catalyzed isomerization of 121 gave the ketone 136 which, upon treatment with diethyl cyanomethylphosphorane, followed by base hydrolysis of the resulting nitriles 139 and 140, gave carboxylic acid 141. The latter was converted into the corresponding diazoketone 144 which, upon heating with cupric sulfate in cyclohexane, afforded (±)-aristolone (7) and (±)-6,7-epi-aristolone (145) in good yield. The stereochemistry of the ketone 121 was proven unambiguously by converting it into the alkane 133. Authentic 133 was prepared by an alternate route. Thus, ozonolysis of the known octalin 125, followed by chromic acid oxidation and esterification with diazomethane gave the keto ester 126. Baeyer-Villiger oxidation of 126 gave the diester 127, which was treated with methyllithium to afford the diol 128. Dehydration of 128 followed by hydrogenation of the resulting hydroxy alkenes 130 gave the alcohol 131, which was converted to the tosylate 132. Reduction of 152 with lithium aluminum hydride afforded authentic 133. The stereochemistry of aristolone (7) was proven by an unambiguous synthesis of the Birch reduction product of dihydroaristolone (53). Thus, treatment of the known octalone 92 with isopropenylmagnesium bromide in the presence of cuprous chloride afforded the decalone 159 which upon hydrogenation gave 160 identical with the product of the lithium-ammonia reduction of dihydroaristolone (53). An efficient, 12-step synthesis of (±)-ϐ-cubebene (14)from d,l-menthone (171) is described. Thus, 171 was converted into the aldehyde 175, via the corresponding n-butylthiomethylene derivative 173. Thus, sodium borohydride reduction of the latter and acid catalyzed hydrolysis of the resulting ϐ-hydroxy-thioenol ether 174, produced aldehyde 175. Reduction of 175 with sodium borohydride gave the epimeric alcohols 177a,b which were separated via their trimethylsilyl ether derivatives. Pure 177a was converted to the bromide 181 with phosphorous tribromide. Treatment of 181 with carbethoxymethyltriphenylphosphorane, followed by base hydrolysis, gave the acid 186. Acid 186 was converted into the diazoketone 170 which, upon heating with cupric sulfate in cyclohexane, gave (±)-ϐ-cubebene norketone (104) and the epimeric ketone 189. Treatment of 104 with methylenetriphenylphosphorane gave (±)-ϐ-cubebene (14) in quantitative yield. The stereochemistry of the intermediate alcohol 177a was proven by converting 177a into the bromide 181, followed by lithium aluminum hydride reduction of the latter to the alkene 190. Authentic 190 was prepared in the following manner. Treatment of (-)-trans-caran-2-one (108) with methyllithium followed by pyrolysis of the resulting alcohol 195 gave the diene 196. Regioselective hydrogenation of the disubstituted double bond of 196 with the homogeneous catalyst tris(triphenylphosphine)-chlororhodium gave authentic alkene 190. The efficiency of the intramolecular cyclization of the two olefinic diazoketones 144 and 170 illustrates the utility of this synthetic method in the synthesis of natural products.

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