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Organic Chemistry Highlights

Total Synthesis

Monday, September 6, 2004
Douglass Taber
University of Delaware

Synthesis of (-)-Podophyllotoxin

(-)-Podophyllotoxin 1 and its derivative etoposide 2, derived from natural sources, are in current clinical use. Michael Sherburn of Australian National University reports (J. Am. Chem. Soc. 2003, 125, 12108. DOI: 10.1021/ja0376588) complementary total syntheses of 1 and of its enantiomer. The key step in each of these syntheses is a spectacular intramolecular alkene arylation, exemplified by the conversion of 4 to 5.

The absolute configuration of 1 was set by conjugate addition to the oxazoline 3 followed by trapping of the product anion, following the precedent of Meyers. Reduction of the oxazoline to the alcohol followed by thionocarbonate formation then set the stage for the key aryl transfer reaction.

The aryl transfer is thought to be initiated by addition of the silyl radical to the thiocarbonyl. The radical so formed adds to the alkene to generate the benzylic radical 7. This radical adds to the arene to give 8, which fragments to 5.

Oxidation of the silyl group of 5 to the ketone followed by Pd-mediated decarboxylation led to the ketone 9. The conversion of 9 to podophyllotoxin 1 followed the literature precedent.

D. F. Taber, Org. Chem. Highlights 2004, September 6.