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Organic Chemistry Highlights

Total Synthesis

Monday, April 5, 2010
Douglass F. Taber
University of Delaware

The Corey Synthesis of (+)-Lupeol

The total synthesis of lupeol was one of the crowning achievements of the Robinson annulation/reductive alkylation approach to stereocontrolled polycarbocyclic construction developed by Gilbert Stork (J. Am. Chem. Soc. 1971, 93, 4945. DOI: 10.1021/ja00748a068). It is a measure of the progress of organic synthesis since that time that E. J. Corey of Harvard University could devise (J. Am. Chem. Soc. 2009, 131, 13928. DOI: 10.1021/ja906335u) an enantioselective synthesis of (+)-lupeol (3) that could be carried out by a single co-worker. The key step in the synthesis was the Lewis acid-mediated cyclization of 1 to 2.

The preparation of 1 began with the enantioselective epoxidation of farnesol acetate (4). To this end, asymmetric dihydroxylation delivered the diol 5. Selective mesylation followed by exposure to dilute methoxide effected ring closure to the epoxide, but also removed the acetate, so this had to be reapplied.

The synthesis of the aromatic portion of 1 started with the phenol 7. Protection as the very bulky triisopropylsilyl ether was important for the success of the subsequent cyclization, perhaps because it discouraged complexation of the Lewis acid with the aryl ether. Metalation followed by formylation delivered the aldehyde 8, that was reduced and carried on to the bromide 9. The derived Grignard reagent coupled smoothly with 6 under Li2CuCl4 catalysis.

The cyclization of 1 to 2 proceeded with remarkable efficiency (43%!), for a reaction in which three new carbon-carbon bonds, four rings and five new stereogenic centers were established. It is particularly noteworthy that the cyclization cleanly set the trans, anti, trans, anti tetracyclic backbone of (+)-lupeol (3).

To complete the synthesis of 3, the less substituted alkene of 2 was selectively hydrogenated, then CH3Li was added to give 10. Hydrolysis and dehydration yielded 11, that was reduced and equilibrated to 12. On brief exposure to MsCl/Et3N, 13 cyclized to (+)-lupeol (3).

It is a measure of the remarkable efficiency of this synthesis of (+)-lupeol (3) that it provided sufficient material to enable studies of the rearrangement of 3 under acidic conditions to other pentacyclic triterpenes, including, inter alia, germanicol, α-amyrin, β-amyrin and taraxasterol (14).

D. F. Taber, Org. Chem. Highlights 2010, April 5.