SYNTHESIS AND CONFORMATIONAL PREFERENCE OF NOVEL 8-FLUOROANTHRACYCLINES

Analogues of daunorubicin possessing a fluorine atom at position C(8) of ring A have been synthesized with the aim of comparing their DNA-dr ug interaction and antitumour properties with those of the clinically useful anthracyclines doxorubicin and idarubicin. The synthesis of (8S )-8-fluoro-4-demethoxydaunorubicin, 1, is reported and molecular mecha nics and NMR studies which guided towards the synthesis of the epimeri c (8R)-8-fluoro-4-demethoxydaunorubicin, 2, are discussed. Both compou nds were prepared by divergent routes starting from the common interme diate, 6, obtained via the Diels-Alder cyclisation between quinizarin diquinone, 3, and 2-(1-hydroxyethyl)-1,3-butadiene, 4. The synthesis o f the (8S)-fluoroepimer proceeded via epoxidation of the C(8)-C(9) ole finic bond of 6, oxidation, oxirane cleavage by BF3 . Et(2)O to give t he fluorohydroxyketone, 9, followed by the introduction of the hydroxy l moiety at C(7) and glycosylation. Conversely, the synthesis of the ( 8R)-fluoroepimer involved the fluorobromination of the C(8)-C(9) olefi nic bond of 6, formation of the C(9)-C(13) epoxide, 20 which, after re gioselective hydrolysis and oxidation of the resulting fluorodiol to t he epimeric fluorohydroxyketone, 21, similarly gave the desired fluoro aglycone, 25 and, hence, the corresponding glycoside, 2. The cytotoxic properties of the two 8-fluoroanthracycline analogues, 1 and 2, were markedly affected by the stereochemistry of the fluorine substituent.