The chemistry of thujone : enantioselective syntheses of drimanetype antifeedants and ambergris fragrances
Creators: name: Chen, Yong-Huang
Publisher: name: University of British Columbia
Year: 2008

description: This thesis is concerned with the development of thujone (3) as an effective chiral building block for natural product synthesis. Treatment of thujone (3) with ozone in solution gave thujonol (94) and thujonone (95) in a good total yield (70%) via oxidation of the tertiary carbon in the isopropyl side chain. This type of selective oxidation with ozone was generally applicable to a series of thujone derivatives, thus providing versatile intermediates for the syntheses of compounds of interest in the fields of insecticides and perfumery chemicals. Studies on acid promoted ring cleavage of cyclopropylcarbinols obtained from ozonation revealed three distinct pathways, depending on substrates and reaction conditions. Treatment of 97 with concentrated hydrochloric acid gave chloride 123 while heating alcohol 130, derived from thujone in five steps, in dioxane:water with a catalytic amount of p toluenesulfonic acid generated homoallylic alcohol 144. On the other hand, concentrated hydrobromic acid treatment of 120, obtained from thujonol (94) by Robinson annulation, resulted in bromide 322. Compound 322 was further reduced with tributyltin hydride to natural (+)-β-cyperone (8), thus completing a new four step synthesis from thujone (3). In a projected synthesis of drimane antifeedants (-)-polygodial (2) and (-)-warburganal (10), a novel radical-mediated ring expansion from 123 to 126 was discovered when the former was treated with tributyltin hydride. However, when a related intermediate 132, derived by treatment of 130 with hydrochloric acid, was reacted in this manner, no rearrangement but simple reduction to 133 was observed. Clearly, the ring expansion process is critically dependent on the nature of functionality in ring A. Generation of 126 and, in turn, subsequent intermediates afforded a convenient route to the exclusion of the original isopropyl side chain in many thujone-derived compounds by ozonolysis. An alternative route developed for the exclusion of the isopropyl side chain involved Baeyer-Villiger oxidation. For example, ketone 131 available from ozonation of alkane 128, when subjected to m-CPBA oxidation, provided acetate 160, which after hydrolysis to cyclopropanol 161 and treatment of the latter with ferric chloride yielded 13-chloroketone 162. The enone 163, obtained from dehydrochlorination of 162, was converted to dienone 168 with phenylselenenyl chloride and hydrogen peroxide. Birch reduction of 168 generated the crucial intermediate 64. Since enone 64 had been previously converted to (-)-polygodial (2) and (-)-warburganal (10), a formal enantioselective synthesis was thus completed. The enone 163 could also serve as an attractive intermediate for the synthesis of (-)- Ambrox® (179). Stereoselective conjugate addition of enone 163 with vinylmagnesium bromide and cuprous iodide yielded compound 245 which was further regioselectively methylated to 246. Introduction of a double bond into 246 via selenium chemistry as noted above furnished 250 which was reduced to the trans-fused decalone 251 by Birch reduction. L-Selectride treatment of 251 produced the axial alcohol 253 and subsequent hydroboration yielded the 1,5-diol 255. p-Toluenesulfonic acid catalyzed cyclization of the 1,5-diol 255 provided the potent ambergris odorants ()Ambrox® (179) and an interesting rearrangement compound 257 as major products. At lower temperature (80°C), 179 was the major product while 257 became predominant at higher temperature (100°C). Ring expansion of thujone was also investigated in order to explore alternative routes leading to the synthesis of (2) and (179). Reaction of thujone (3) with ethyl diazoacetate generated β-Ketoester 270, which upon decarboxylation furnished “’thomothujone (272). Robinson annulation of compound 272 yielded enone 274. Alkane 291 was derived from 274 in three steps and its ozonation reaction was performed. Surprisingly, the normally observed attack at the tertiary carbon of the isopropyl side chain did not occur. Instead, ketone 292 was isolated as the major product.