(±)-Thujopsene

For my inaugural blog post, I thought I'd take a look at an oldie, but a goodie–a (semi?) total synthesis from the groovy 1960s, that of racemic thujopsene. This one comes to you courtesy of the now-deceased Prof. William G. Dauben (a fellow original Ohioan like myself) and crew from the University of California at Berkeley. I like to look back at classic synthesis papers not because I'm old (I'm 32, I'm not that old yet!), but because they often contain instructional chemistry that's no longer utilized but still very useful. Thujopsene is a sesquiterpene that really has little bioactivity to speak of. Being one of the essential oils of some conifer trees, it does have a nice scent, though.

I put the semi part in there because it's not clear what the origin of their octalin starting material 1 is. Either way, their first reported step provides a nice contrast between reaction kinetics and thermodynamics. Enolate formation* from 1 with tert-butoxide and addition of iodomethane to 2 provides the less thermodynamically stable alkene in dimethylated 3 (the alkene conjugated with the ketone takes that title). Dimethylation at the a-position leads to the kinetic product. A little redox manipulation followed; Wolff-Kishner reduction (a reaction analagous to the Shapiro reaction) of ketone 3 followed by allylic oxidation to the ketone 5 with Cr(VI). The mechanism of allylic oxidation with chromium is said to proceed via allylic hydride abstraction, followed by trapping of the allylic cation by the reduced chromium reagent.

The powerful reducing agent lithium aluminum hydride was utilized to accomplish a diastereoselective 1,2-reduction of the enone 5 from the convex face to give allylic alcohol 6 in a 95:5 d.r. The authors also attempted Meerwein-Ponndorf reduction of the enone using Al(Oi-Pr)₃. However, nearly a 1:1 ratio of stereoisomers was obtained in this case (58:42). Honestly, given the choice of reducing agent, it's surprising the molecule wasn't completely reduced, alkene and ketone. Nowadays, the Luche reduction is commonly employed when one wants to selectively 1,2-reduce an enone, and this method makes use of the much less reactive sodium borohydride.

The next step was essentially the crux of the paper, as they mentioned in the opening paragraphs their recent studies on cyclopropanation of allylic alcohols (JACS, 1963, 86, 468). Specifically, they found that cis-selectivity was observed, a fact that is crucial to the stereochemistry obtained in the conversion of 6 to cyclopropyl-containing 7. Thus, usage of the Simmons-Smith organozinc reagent gave 7 as a single isomer, but in relatively low yield. A look at the experimental section shows that quite a bit of work was necessary to get the fully purified material, including a spinning band column distillation, recrystallization and flash chromatography over alumina.

Jones oxidation of the hydroxyl group in 7 gave 8 in expectedly high yield, and addition of MeMgBr followed by a workup with ammonium chloride resulted in facile dehydration to alkene 9, with intermediate alcohol 8 not being isolated. The authors mention that a characteristic reaction of thujopsene (9) is its rearrangement to the ring-expanded widdrol (10), and that was accomplished by treatment with oxalic acid in wet ethanol as a final proof of synthesis.

Overall it’s a nice synthesis. Typically when an organic chemist sees a decalin ring structure with a distal alkene, they immediately think of employing a Diels-Alder reaction. However, the presence of the cyclopropyl group necessitates a slightly different synthetic plan. The cyclopropanation reaction wasn’t quite as efficient as in their less complicated model systems, but still delivered the product stereospecifically. Perhaps some of the newer cyclopropanation reagents (rhodium carbenoids, newer organozincs) could give better yields.

*For a half-page review of stereoselectivity in the reductive alkylation of bicyclic enones, see this half-page review I made back in my grad school days.

Original article: Dauben, W. G.; Ashcraft, A. C J. Am. Chem. Soc. 1963, 85, 3673. http://dx.doi.org/10.1021/ja00905a032