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Organic Chemistry Highlights

Total Synthesis

Monday, November 7, 2005
Douglass Taber
University of Delaware

Total Synthesis of the Tetracyclines

Although the tetracycline antibiotics have been mainstays of antibacterial chemotherapy for decades, they had eluded efficient total synthesis. In a landmark accomplishment, Andrew G. Myers of Harvard University recently reported (Science 2005, 308, 395, DOI: 10.1126/science.1109755; J. Am. Chem. Soc. 2005, 127, 8292, DOI: 10.1021/ja052151d.) the first such syntheses.

In the Science paper, which was published first, total syntheses of the clinically-important 6-deoxytetracyclines, including doxycycline (9), are described. The starting point for the synthesis was the enantiomerically-pure ester 2, prepared by fermentation of benzoic acid (1) to the 1,2-dihydrodiol, followed by epoxidation, rearrangement and silylation. Acylation of 3 with 2 gave the ketone 4, which on exposure to LiOTf underwent a very interesting, and diastereoselective, carbon-carbon bond forming reaction to give, after selective desilylation with TFA, the alcohol 5. The authors speculate that this reaction is proceeding by initial SN2Žepoxide opening by the N, followed by ylide formation and 2,3-rearrangement.

The alcohol 5 was the common intermediate for both syntheses. For the deoxy series, 5 was carried on to the enone 6. Conjugate addition of the anion 7 proceeded with remarkable diastereoselectivity, to give, after intramolecular acylation and deprotection, doxycycline (9).

The JACS paper describes the total synthesis of the more highly oxygenated (-)-tetracycline (16). To this end, the alcohol 5 was carried on to the enone 10. Opening of the cyclobutane 11 to the o-quinone methide followed by Diels-Alder cycloaddition to 10 delivered the endo adduct 12.

Deprotection and oxidation of 12 gave 13, which was further oxidized to the sulfoxide. Elimination of the sulfoxide gave the naphthalene derivative 14, which underwent spontaneous oxidation to 15. Reductive deprotection then gave tetracycline (16). The diastereoselectivity of the air and light-mediated oxidation is remarkable.

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