Experiments Directed Towards the Synthesis of Anthracyclinones. XXIX. Fluoro-Substituted Tetracycles

Diastereoselective formation of 9-fluoro-9-methylanthracyclinones has been achieved by treating ortho-methallyl-substituted anthraquinonyl homochiral dioxans with boron trifluoride etherate . The demethoxy anthraquinonyl dioxan (16) underwent slow reaction to give exclusively the (7S,9R) fluoro tetracycle (21) in 58% yield. The dimethoxy anthraquinonyl dioxan (15) was less reactive, allowing other reactions to compete, but boron trifluoride -acetic acid complex effected rapid cyclization of (15) with high diastereoselectivity. Short reaction times with this reagent circumvented the formation of the alkenes (25) and the naphthacenedione (9). Boron trifluoride-nitromethane gave the (7S,9R) fluoro tetracycle (19) in 36% yield. Although the yields of the fluoro tetracycles were modest, they compare favourably with a 4% yield reported for the fluorination of daunomycinone. The 6-demethoxy tetracycle (21) has been shown to exist in the expected half-chair conformation, with the bulky C7 side chain in a pseudo-equatorial position. In contrast, the 6,11-dimethoxy fluoro tetracycle (19) exists in a significantly perturbed half-chair conformation with a pseudo-axial side chain.