| The tetracycline antibiotics have been used extensively in medicine, animal health, and agriculture for therapy and prophylactic control of bacterial infections for over 50 years. Regulatory approval of (-)-minocycline (15) in 1972 was the last for any tetracycline antibiotic; however, a number of new C- and D-ring modified tetracyclines with exciting activity profiles have been characterized recently. A convergent and enantioselective synthetic route to the tetracyclines was developed that allows for the late-stage introduction of the C- and D-rings, as demonstrated by syntheses of (-)-tetracycline (3) and (-)-doxycycline (14). The route enables the preparation of new tetracycline derivatives, many of which are otherwise inaccessible.; The C12a hydroxyl group was introduced in the first step of the synthetic route by the microbial (Alcaligenes eutrophus strain B9) dihydroxylation of benzoic acid, which provided the diol 76 (>95% ee, 79%, 90-g batch). The diol 76 was transformed in a three-step sequence to the epoxide 112, the B-ring precursor to the tetracyclines. Acylation of the vinyl anion derived from the isoxazole 135 (prepared on the mole scale in four steps from glyoxylic acid) with the epoxide 112 provided the ketone 138. Intramolecular cyclization of the ketone 138 provided the tricycle 141 in a reaction that is reminiscent of a Stevens rearrangement. The tricycle 141 contains the A,B-ring system of the tetracyclines with a fully functionalized A-ring in protected form, and provides a common intermediate from which many structurally diverse tetracyclines and tetracycline derivatives are accessible.; Application of the synthetic route to (-)-tetracycline ( 3) itself provided the antibiotic in 17 steps (1.1% yield) from benzoic acid. Elaboration of the tricycle 141 into the vinyl sulfide 187 was accomplished in a six-step sequence that featured the reductive transposition of an allylic alcohol group. Construction of the C- and D-rings of (-)-tetracycline (3) was achieved by a late-stage Diels-Alder reaction of the o-quinone dimethide generated from the benzocyclobutenol 176 with the vinyl sulfide 187. Oxidative transformations and protective group manipulations were used to prepare (-)-tetracycline (3) from the resulting cycloadduct.; Application of the synthetic route to (-)-doxycycline (14 ) provided the antibiotic in 18 steps (8.2% yield) from benzoic acid. A series of steps, including bromination, alkylation, oxidation, rearrangement, and protection led to the cyclohexenone 156 from the tricycle 141. Construction of the C- and D-rings of (-)-doxycycline ( 14) was accomplished by a late-stage Michael-Dieckmann reaction sequence of the anion derived from the phenyl ester 201 with the cyclohexenone 156. Deprotection of the Michael-Dieckmann addition product provided (-)-doxycycline (14).*; *Please refer to dissertation for diagrams. |
