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Totally Synthetic by Paul H. Docherty, 20 September 2009

Total Synthesis of Lupeol


K. Surendra, E. J. Corey, J. Am. Chem. Soc. 2009, 131, 13928-13929.

DOI: 10.1021/ja906335u

Corey he has been working in the area of steroid and terpenoid chemistry for years. And lupeol has been a pretty popular target too - look to Stork for his classic 1971 synthesis, with countless others working past lupeol en route to other terpenoids.

Examination of Corey’s starting point reveals a cuperate addition to a farnesyl acetate derivative, with the other fragment a tetra substituted benzyl Grignard. This reaction leads to an epoxy diene, which is ready for a Lewis acid induced zipper reaction, completing three rings, installing five stereocenters and dearomatising the catechol.

Some reductions under drastic conditions fully reducted the catechol and provided a further trio of stereocenters, the final installed by alkylation to provide the handle for another cyclisation.

Removal of the TBS ether completes the initial target, lupeol. Further reaction of lupeol in the presence of a small amount of triflic acid gave a mixture of six different terpenoids. Now, the yields might be useless - but the products are very interesting! The group measured the rate of rearrangement to the six product by comparison of crude material to authentic samples of each of the terpenoids, and found that five are formed at roughly the same rate.

This chemical result is quite different to that found in vivo. Indeed, the triterpene synthase enzymes can target one terpenoid only, which Corey attributes to a combination of protein and substrate conformation. He also concludes that this mechanism must be mostly aprotic, as an acid catalysed biosynthesis should result in the same diverse mixture found in his reaction mixture.