Studies related to the (±)-aristolone and total synthesis of (±)-seychellene

William De Waal
In the first part of this thesis an 8-step synthesis of (±)-4-demethylaristolone 16 is described. This synthetic sequence was eventually to provide the basis for the total synthesis of (±)-aristolone 11. Alkylation of the known 2-methyl-6-n-butylthiomethylenecyclohexanone 77 with methallyl chloride gave, after removal of the blocking group, ketone 79. Treatment of 79 with p-toluenesulfonic acid in refluxing benzene yielded a mixture of olefinic ketones, 79 and 80. Reaction of 80 with
more » ... omethylphosphonate yielded a mixture of nitriles, 81 and 82, which upon base hydrolysis afforded in good yield, the β,γ-unsaturated carboxylic acid 83 as the sole product. The latter was converted into the crucial diazoketone 86 via the acid chloride 84. Intramolecular cyclization of 86 in the presence of cupric sulfate gave a mixture of (±)-4-demethylaristolone 16 and (±)-5-epi-4-demethylaristolone 88 in a ratio of 2:1. Employing, in each case, two successive Birch reductions, compounds 16 and 88 were converted into decalones 90 and 111, respectively. An alternate synthesis of compound 90 involved the 1,4-conjugate addition of isopropenylmagnesium bromide to the known octalone 91, followed by catalytic hydrogenation of the addition product 97. The compound obtained from this sequence was identical with 90 prepared from (±)-4-demethylaristolone, thus establishing the stereochemistry of the latter. That the predicted stereochemical outcome of the conjugate addition (to 91) was correct, was shown as follows. Ketalization of 97 yielded compound 104, which was converted into its more stable epimer 107, via keto ketal 106. The olefinic ketal 107 upon catalytic hydrogenation followed by acid catalyzed hydrolysis yielded decalone 108. Since compound 108 was clearly different from decalone 111, prepared from (±)-5-epi-4-demethylaristolone 88, it was established that the Birch reduction of the latter had yielded a product with a cis ring junction. In the second part of this thesis an efficient and very stereoselective 16-step sy [...]
doi:10.14288/1.0059904 fatcat:3jjkbwifargxtj45zd37gvjdyu