Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, March 1, 2010
Douglass F. Taber
University of Delaware

The Trost Synthesis of (-)-Pseudolaric Acid B

(-)-Pseudolaric Acid B (3), isolated from the bark of the golden larch Pseudolarix kaempferi, shows potent antifungal activity. A key step in the total synthesis of 3 described (J. Am. Chem. Soc. 2008, 130, 16424. DOI: 10.1021/ja806724x) by Barry M. Trost of Stanford University was the free radical cyclization of 1 that established the angular ester and the trans ring fusion of 2 and thus of 3.

To prepare the bicyclic skeleton of 1, the authors envisioned the Rh-mediated intramolecular addition of the alkyne of 11 to the alkenyl cyclopropane. The acyclic centers of 11 were established by Noyori hydrogenation of (equilibrating) racemic 4. One enantiomer reduced much more quickly than did the other, leading to 5. The absolute configuration of the cyclopropane was set by Charette cyclopropanation of the monosilyl ether of the inexpensive diol 8. The two components were then coupled using a Corey-Schlosser protocol. Alkylation of the ylide 10 with 7 gave a new phosphonium salt, that in situ was deprotonated and condensed with the aldehyde 9. The resulting betaine was deprotonated and quenched, then exposed again to base to give the trans alkene 11. It is important in this procedure to use PhLi as the base, since the alkyl lithium can displace the alkyl group on phosphorus.

The product from Ru-catalyzed cyclization was the expected 1,4-diene 12. Fortunately, it was found that TBAF desilylation led to concomitant alkene migration, to give the more stable conjugated diene 13. Selective epoxidation of the more electron-rich alkene followed by exposure to strong base then delivered 14, with the requisite angular oxygenation established.

Pseudolaric Acid B (3) would be derived from cyclization of the selenocarbonate of a tertiary alcohol. In fact, however, attempted cyclization of such selenocarbonates led only to decarboxyation and reduction. Even with the selenocarbonate 1 prepared from the secondary alcohol, the cyclization to 2 required careful optimization, including using not AIBN, but azobis(dicyclohexylcarbonitrile) as the radical initiator.

Acetylide addition to the ketone 15 could be effected with high diastereocontrol, but lactone construction proved elusive. Alkaline conditions led quickly to addition of the angular hydroxyl to the activated alkene in the seven-membered ring. Eventually it was found that the ester exchange catalyst 16 developed by Otera delivered 17, that could be carried on to (-)-Pseudolaric Acid B (3).

D. F. Taber, Org. Chem. Highlights 2010, March 1.