UBC Theses and Dissertations

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UBC Theses and Dissertations

Stereoselective total synthesis of sesquiterpenoids; (-)-copacamphene and (-)-cyclocopacamphene Smillie, Robert Dean


An efficient, 6-step synthesis of the (-)-diketone (122) from (+)-carvomenthone (123) is described. Conversion of 123 Into the corresponding n-butylthiomethylene derivative (131), followed by alkylation of the latter with ethyl 2-iodopropionate and successive removal of the n-butythiomethylene blocking group and esterification of the resulting acid (134) , gave the keto ester (135). Treatment of 135 with sodium bis(trimethylsilyl)amide in dimethoxyethane resulted in an efficient intramolecular Claisen condensation, affording the (-)-diketone 122 in 90% yield. The stereochemistry of the (-)-diketone (122) was proven unambiguously in the following way. Successive subjection of the (+)-ketol (142), of known absolute stereochemistry, to hydrogenation, dehydration, condensation with ethyl formate, and oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone, afforded the (+)-dienone aldehyde (153). Conjugate addition of lithium dimethylcuprate to 153, followed by trapping of the intermediate enolate anion with acetyl chloride gave the keto enol acetate (154). Ozonolysis of the latter, followed by esterification of the resulting acid (157) gave the (+)-keto ester (138), which was clearly epimeric with the previously prepared keto ester (135). Intramolecular Claisen condensation of 135 afforded the (+)-diketone (139), which was clearly different from the (-)-diketone (122). The (-)-diketone (122) was utilized in the synthesis of (-)-copacamphene (23) and of (-)-cyclocopacamphene (24). Several methods for the conversion of the (-)-diketone (122) into the (-)-keto olefin (125) were investigated. The most efficient sequence found was as follows. Reduction of 122 with sodium borohydride gave the (-)-keto alcohol (169) which was readily converted into the corresponding p_-tosylhydrazone (170). Treatment of the latter with methyllithium, followed by Jones oxidation afforded the (-)-keto olefin (125) in good yield. Reaction of 125 with methoxymethylenetriphenylphosphorane gave the isomeric olefinic enol ethers (172). Successive subjection of the latter to acid hydrolysis and base-catalyzed equilibration afforded the (-)-olefinic aldehyde (174). The latter was reacted with methylenetriphenylphosphorane, and the resulting (+)-diene (175) was subjected to hydroboration-oxidation, to produce the (+)-olefinic alcohol (178). Treatment of 178 with p-toluenesulf onyl chloride in pyridine produced the corresponding p-tosylate (180), which underwent a high-yielding eliminative cyclization to afford (-)-copacamphene (23). Although a number of routes directed towards the synthesis of (-)-cyclocopacamphene (24) were investigated, the most efficient sequence employed the (+)-olefinic alcohol (178) as starting material. Oxidation of the latter with Collins reagent afforded the (-)-olefinic aldehyde (194), which was readily converted into the corresponding p_-tosylhydrazone (210). Pyrolysis of the lithium salt of the latter produced the (+)-pyrazoline (213), which, upon photolysis in ether, afforded (-)-cyclocopacamphene (24) in 93% yield.

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