UBC Theses and Dissertations

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UBC Theses and Dissertations

Intramolecular alkylation of α,β-unsaturated ketones, an approach to the synthesis of zizaane type sesquiterpenoids and the total synthesis of (±) isolongifolene Zbozny, Michael


In the first part of this thesis an intramolecular alkylation study involving 4a-(3-chloropropy1)-4,4a,5,6,7,8— hexahydro-2-(3H) -napthalenone (77a) , 4 a- ( 3-iodopropy 1) - 4,4a,5,6,7, 8,-hexahydro-2(3H)-napthalenone(77b) and 4a-(mesylate methyl)— 4,4a,5,6,7,8,hexahydro-2(3H)-napthalenone(95) is described. Bicyclic a, ^-unsaturated ketones (77a), (77b) and (95) were prepared and their cyclizations via intramolecular alkylation under a variety of reaction conditions was investigated. In the case of ketone (77a) high selectivity for a or d'-alkyla-tion was achieved by varying certain reaction parameters. The reaction parameters studied were solvent, base, complexing agent and leaving group. The action of potassium t-butoxide in t-butyl alcohol on octalone (77a) afforded ketone (90) as the major product and ketone (91) as the minor product. A change in the solvent system to a 60/40 mixture of THF/t-BuOH combined with the addition of 18-crown-6 afforded selectively ketone (90). The action of potassium t-butoxide in t-butyl alcohol on octalone (77b) however, afforded the ketone (91) exclusively. Exclusive formation of ketone (91) was also achieved by the action of lithium diisopropylamide in THF on ketone (77a). At no time was ketone (92) detected. Bicyclic ketone (95) having a mesylate methyl group at the angular position was subjected to a number of reaction conditions. The position of alkylation was found to be dependent on solvent and the presence of 18-crown-6. The action of lithium t-butoxide or potassium t-butoxide in t-butyl alcohol or THF on ketone (95) afforded exclusively ketone (66). The ketone (95) in HMPA, with or without 18-crown-6, however afforded ketone (104) as the major product and ketone (66) as the minor product. Ketone (103) was not detected. In the second part of this thesis a 15-step synthesis of (±) isolongifolene (114) from 4a-(carbomethoxy)-4a,4,5,6,7,8— hexahydro-2-(3H) -napthalenone (97) is described. Alkylation with methyl iodide of (97) afforded the dimethylated octalone (146). Octalone (146) was transformed into octalone (147) via a Wittig reaction using methylenetriphenylphosphorane. Diene (147) was hydroborated using disiamylborane in THF and the resultant mixture of alcohols (148) and (149) was acetylated with acetic anhydride and pyridine to afford acetates (153) and (154). The latter mixture was allylically oxidized by the action of N— bromosuccinimide in dioxane in the presence of light to yield keto acetates (155) and (156). Decarbomethoxylation of the keto acetates followed by ketalization of resultant mixture afforded ketal acetate (160). Lithium aluminum hydride reduction of (160) followed by tosylation of the resultant alcohol (161) afforded ketal tosylate (162). Acid hydrolysis of (162) followed by intramolecular alkylation of the resultant keto tosylate (163) afforded the tricyclic octalone (165). Dehydro-genation of the latter using DDQ yielded dienone (166) which when treated with lithium dimethylcuprate in ether afforded octalone (167). Treatment of (167) with pyridinium hydrobromide perbromide followed by dehydrobromination of the resultant crude bromide (168) afforded the cross conjugated ketone (169). The latter was converted into octalone (124) via a methyl cuprate reaction. Octalone (124) was not converted into (±) isolongifolene since this transformation had already been reported. Dienone (166) was converted into α, β-unsaturated keto nitrile (172) by the action of diethyl aluminum cyanide on the former. This transformation was to eventually provide an entry into the zizaane class of sesquiterpenoids.

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