Synthetic studies on octalones and related systems
Creators: name: Worster, Paul Murray
Publisher: name: University of British Columbia
Year: 2010

description: This thesis describes a number of investigations that culminated in an improved series of practical preparations for substituted octalones. Starting with a study of acid and base catalyzed additions of methyl vinyl ketone to 2-methylcyclohexanone, the preparation of 4a-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (234) was simplified and improved by a one pot reaction that sequentially employed both acid and base. The advantages of this efficient procedure were then demonstrated by the preparation of trans-4a,8-dimethy1-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (235) from 2,6-dimethylcyclohexanone and methyl vinyl ketone. Several approaches to trans-8-acetoxy-4a-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (236) were then undertaken. An efficient two step conversion of octalone 234 to 8,8a-epoxy-2,2-ethylenedioxy-4a-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (284) was followed by an acid hydrolysis which afforded both 86,8aa-dihydroxy-4a3-methyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (292) and the undesireable dione 4a-me thy1-3,4,4a,5,8,8a-hexahydro-1(2H),7(6H)-naph thalenedione (294). The photosensitized oxygenation (¹O₂) of 4a-methyl-3,4,4a,5,6,7-hexahydro-2(lH)-naphthalenone (341), prepared in 96% from 234, was accomplished with Rose Bengal in pyridine or methanol and afforded 4a-methyl-3,4,4a,5-tetrahydro-l(2H),7(6H)-naphthalenedione (343), rather than the expected Y~peracetate, 4a-methyl-8-peracetoxy-4,4a,5, 6,7,8-hexahydro-2(3H)-naphthalenone (344), when acetylation of the product was attempted. Reduction of the intermediate γ-hydroperoxide (342) before acetylation afforded compound 236 in low yield. This work also resulted in the isolation of trans- and cis-4a-methyl-3,4,4a, 5,6,7,8,8a-decahydro-2(lH)-naphthalenone (349 and 350), the dione 294, and 4a-methyl-4,4a,5,6-tetrahydro-2(3H)-naphthalenone (353). The octalone 237, 4a,8,8-trimethyl-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone, was synthesized in an efficient seven step sequence that employed the n-butylthiomethylene blocking group. Octalone 234 was converted in two steps to its 3-n-butylthiomethylene derivative (375). This compound was dialkylated with methyl iodide to afford 3-n-butyl-thiomethylene-1,1,4a-trimethyl-3,4,4a,5,6,7-hexahydro-2(IH)-naphthalenone (376) and then unblocked by exhaustive hydrolysis to afford 1,1,4a-trimethyl-3,4,4a,5,6,7-hexahydro-2(lH)-naphthalenone (356). Successive Wolff-Kishner reduction of 356 and allylic oxidation of the product, l,l,4a-trimethyl-l,2,3,4,4a,5,6,7-hexahydronaphthalene (357), with sodium chromate afforded the desired octalone 237. Cis- and _trans-4a,5-dimethy1-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (238 and 239) were both prepared as pure compounds by employing a sequence that originated from 2,3-dimethylcyclohexanone. Alkylation of the n-butylthiomethylene derivative, 6-n-butylthiomethylene-2,3-dimethylcyclohexanone (400), was studied to determine the stereochemical effect of alkylating agent, solvent and base. Control of the stereoselectivity was demonstrated to be primarily dependent on the choice of alkali metal cation. The most practical means of producing the cis-vicinyl dimethyl derivative, cis-2,3-dimethy1-2(2-ethoxycarbonyl-ethyl)-6-ii-butylthiomethylenecyclohexanone (415), employed ethyl-3-chloro- or bromopropionate as alkylating agent with potassium j^-butoxide in _t-butanol whereas one of the most favourable means of obtaining the trans-vicinyl dimethyl derivative, trans-2,3-dimethyl-2(2-ethoxycarbonyl-ethyl)-6-n-butylthiomethylenecyclohexanone (416) employed lithium _t-butoxide in t-butanol. Hydrolysis of 415 and 416 then yielded the keto acids cis- and trans-2,3-dimethy1-2(2-carboxyethyl)cyclohexanone ( 417 and 418). These compounds were readily dehydrated to their correspound-ing enol lactones, cis- and trans-4a,5-dimethyl-l-oxa-*3,4,4a,5,6,7-hexahydro-2(lH)-naphthalenone (419 and 420). Recrystallization of this mixture gave the cis-dimethyl enol lactone 419 in pure form. The more elusive trans isomer required successive silica chromatographies, hydrolysis of the impure trans enol lactone and crystallization of the pure trans keto acid (418) with subsequent dehydration to the enol lactone. Treatment of 419 and 420 with methyllithium at -25° yielded cis- and trans-2,3-dimethy1-2(3-oxobutyl)cyclohexanone (440a and 440b) which, after base treatment, afforded 238 and 239. A study of the product distribution in the methyllithium reaction showed that stereoisomerism played a hitherto unrecognized role. For example, an 84:16 ratio of enol lactones 419 and 420 yielded an octalone ratio of 95:5 (238:239). Authentic octalone 239 was also prepared in an unambiguous manner by an eight step sequence from octalone 234. Dehydrogenation of 234 to 4a-methyl-5,6,7,8-tetrahydro-2(4aH)-naphthalenone (300) and conjugate addition with lithium dimethylcuprate gave trans-4,4a-dimethy1-4,4a,5, 6,7,8-hexahydro-2(3H)-naphthalenone (381). Deconjugation of 381 gave 467, trans-4,4a-dimethyl-3,4,4a,5,6,7-hexahydro-2(lH)-naphthalenone, hydride reduction of 467 yielded 468, trans-4,4a-dimethyl-2-hydroxy- 1,2,3,4,4a,5,6,7-octahydronaphthalene ., acetylation of 468 and subsequent allylic oxidation with chromic anhydride gave trans-4a,5-dimethyl-7-acetoxy-4,4a,5,6,7,8-hexahydro-2(3H)-naphthalenone (470). Dehydro-acetylation of 470 produced the dienone 471, trans-4a,5-dimethyl-4,4a, 5,6-tetrahydro-2(3H)-naphthalenone, and selective hydrogenation gave octalone 239. Androst-4-en-3-one (240) was prepared as the result of two studies on oxidation and reduction procedures. In the first study, 38-hydroxy-androst-5-en-17-one (473) was nearly quantitatively reduced via the Wolff-Kishner reduction and then oxidized under a variety of conditions to 'octalone' 240. This work led to new insights into the mechanism of chromium trioxide oxidation in dimethylformamide with acid and in dichloromethane with nitrogen bases. Mechanistic explanations from studies on cholesterol oxidation and practical applications to other systems are given. In the second route to 'octalone' 240, testosterone (472) was converted into a series of C-3 derivatives of androst-4-ene-3,17-dione (562). These included the methoxy (602), ethylenedioxy (563), trimethylenedioxy (619), ethylenedithio (598;), trimethylenedithio (600), and 2,2-dimethyltrimethylenedioxy (594) derivatives. The Wolff-Kishner reduction products from these compounds were studied and plausible mechanisms were formulated.