Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, February 6, 2012
Douglass F. Taber
University of Delaware

The Theodorakis Synthesis of (-)-Jiadifenolide

There has recently been a great deal of interest in the synthesis of natural products that promote neurite outgrowth. Emmanuel A. Theodorakis of the University of California, San Diego described (Angew. Chem. Int. Ed. 2011, 50, 3672. DOI: 10.1002/anie.201100313) the preparation of one of the most potent (10 nM) of these, (-)-Jiadifenolide (3). Fittingly, a key transformation en route to this highly-oxygenated seco-prezizaane was the oxidative rearrangement of 1 to 2.

The starting point for the synthesis was the commercially-available diketone 4. Allylation followed by addition to 5 gave the prochiral triketone 6. Enantioselective aldol condensation following the Tu/Zhang protocol then delivered the bicyclic enone 7. Alkylation to give 8 proceeded with high diastereoselectivity, perhaps controlled by the steric bulk of the silyloxy group.

Exposure of the protected ketone to the McMurry reagent PhNTf2 gave the enol triflate 9, that smoothly carbonylated to the lactone 10. Epoxidation with alkaline hydrogen peroxide followed by oxidation gave the carboxylic acid, that spontaneously opened the epoxide, leading to the bis lactone 1.

With 1 in hand, the stage was set for the key oxidative rearrangement to 2. It was envisioned that epoxidation would generate the cis-fused 11, that on oxidation would undergo acid-catalyzed elimination to give 12. The newly-freed OH would then be in position to engage the lactone carbonyl, leading to 2. In the event, oxidation of the epoxide with the Dess-Martin reagent required sonication for two hours. The rearranged lactone, even though it was susceptible to further oxidation, was secured in 38% overall yield from 1.

After hydrogenation and protection, preparation of the enol triflate 13 from the congested cyclopentanone necessitated the use of the more reactive Comins reagent. Hydrogenation of the trisubstituted alkene from coupling with Me3Al then required 90 atmospheres of H2 overpressure. Hydroxylation of the lactone 14 with the Davis oxaziridine followed by further oxidation to the ketone with Jones reagent and deprotection then completed the synthesis of (-)-Jiadifenolide (3).

D. F. Taber, Org. Chem. Highlights 2012, February 6.