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Organic Chemistry Highlights

Total Synthesis

Monday, February 7, 2005
Douglass Taber
University of Delaware

Synthesis of the Dendrobatid Alkaloid 251F

The Dendrobatid “poison arrow” frogs of Central and South America exude a potent mixture of alkaloids from their skins. It was originally thought that the frogs biosynthesized these alkaloids, but it has since been shown that they are of dietary origin. The skin exudate of the Colombian frog Minyobates bombetes causes severe locomotor difficulties, muscle spasms and convulsions upon injection in mice. The major component of the alkaloid mixture is 251F 3. Jeff Aubé of the University of Kansas recently described (J. Am. Chem. Soc. 2004, 126, 5475. DOI: 10.1021/ja0320018) the enantioselective total synthesis of 3. The key step in the synthesis was the cyclization of the keto azide 2.

The ketone 1, with four ternary stereogenic centers in one cyclopentane ring, was a significant challenge for synthesis. A clever solution flowed from the idea of coupling a chiral Diels-Alder reaction with alkene metathesis. The relative and absolute configuration of 1 were set by the Diels-Alder cycloaddition of the acyl oxazolidine 4 to cyclopentadiene, to give 5. Homologation of 5 to the enone 6 set the stage for alkene metathesis, mediated by the Grubbs catalyst 7, to give 1.

Conjugate addition to 1 proceeded across the open face of the bicyclic system to give an enolate, condensation of which with the enantiomerically-pure aldehyde 8 gave the enone 9. Conjugate reduction of the enone also removed the benzyl ether, to give the alcohol. Conversion of the alcohol to the azide gave 10. Ozonolysis followed by selective reduction then gave 2.

The acid-mediated intramolecular addition of the azide to the ketone proceeds by way of addition followed by a pinacol-type rearrangement, to give the amide 12. The regioselectivity of the bond migration is remarkable. Reduction of the amide then gave 3.

D. F. Taber, Org. Chem. Highlights 2005, February 7.