UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

The chemistry of thujone : new enantioselective syntheses of Ambrox[Registered trade mark] and Epi-Ambrox Cirera, Carles


This thesis is concerned with the development of a new synthetic approach to(-)-Ambrox® (2) and epi-Ambrox (3) using thujone (1) as an enantiopure building block. Thujone (1), a readily available starting material obtained from Western red cedar, can be efficiently converted to D-cyperone (144), which can be chemically elaborated to obtain the key intermediate, enone 143. As a model study for the synthesis of racemic 2 and 3, a synthetic sequence starting with a cyclohexanone derivative has also been developed to afford the racemic intermediate143. Acid catalyzed Robinson annelation of 2-methylcyclohexanone with1-chloropentan-3-one gave enone 165. Methylation of 165 to 166 with methyl iodide and potassium tert-amylate proceeded in high yield. Wolff-Kishner reduction of 166 gave 167which was then oxidized to racemic 143 with sodium dichromate. At this stage, enantiopure 143, obtained via 144, from thujone (1) was prepared and compared with racemic 143. A novel method for the transposition of the carbonyl function in enantiopure 143 to the isomeric enantiopure enone 172 was developed. Treatment of 143 with manganese(III) acetate allowed introduction of an acetoxy function at the C8 position, to afford a mixture of isomers (185 and 186 4:1 ratio) in excellent yield (86 %). Reduction of 185and 186 with lithium aluminum hydride provided a mixture of alcohols, which without separation, was treated with p-toluenesulfonic acid to yield 172. This 3 step process, 143to 172, could be performed without isolation of intermediates and in an overall yield of64 %. Stereoselective alkylation of 172 with ethyl iodoacetate yielded compound 201exclusively with entry of the side chain in an axial orientation. Hydrogenation of 201 to205 and then ketalization, afforded 215. Reduction of the ester, protection of the alcohol functionality, and deprotection of the carbonyl, finally gave compound 219 in excellent yields. Reaction of 219 with the cerium chloride-methyllithium reagent gave 220, which yielded, after hydrogenolysis, diol 221. p-Toluenesulfonic acid catalyzed cyclization ofdiol 221 provided the potent ambergris odorant (-)-epi-Ambrox (3). Epimerization of the side chain in 219 with sodium methoxide in methanol gave compound 225 which was further converted into (-)-Ambrox® (2) by an identical sequence as for (-)-epi-Ambrox (3).

Item Citations and Data


For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.