TETRACYCLINES .10. TOTAL SYNTHESIS AND STRUCTURAL ASPECTS OF RACEMIC 8-OXYGENATED TETRACYCLINES

A stereoselective total synthesis of the first 8-oxygenated tetracycline derivatives 43 and 4 is described. Key steps for the construction of the tetracycline skeleton are the condensation of the tetralone aldehyde (obtained from 3,5-dimethoxybenzoic acid via 12 steps in 25% yield) with the thiazolone 32 followed by condensations of its product with methyl 3-oxoglutaramate 35. These steps furnished the 4 possible diastereomeric 12a-deoxytetracycline derivatives 38a-d, which were isolated pure and stereochemically characterized by UV and 1H NMR. The 4-epi derivative 38b was highly stereo- and regioselectively oxidized to the corresponding 12a-hydroxy derivative. A number of functional group modifications led to the 8-methoxy- and 8-hydroxytetracycline derivatives 43 and 4, respectively, which with respect to their relative stereochemistry belong to the natural tetracycline series. The yield of 4 over 19 steps was 3.6%. A versatile acetalization method and simplified and improved preparations for the reagents 32 and 35 are also described. A crystal structure determination for racemic 43 was carried out. The crystal displays space group symmetry P.hivin.1 and lattice parameters a = 8.547 (2) .ANG., b = 13.571 (3) .ANG., c = 13.845 (3) .ANG., .alpha. = 103.51 (2).degree., .beta. = 111.58 (2).degree., .gamma. = 92.45 (2).degree.. The structure was refined with 9994 reflections to an R value of 4.7%. Crystalline 43 displays the enolic free structure and associated conformation previously observed in the solid state only for 5-oxygenated tetracycline free bases. The H atom of the enolic A-ring chromophore was localized on the amide O atom.