REDUCTION OF DAUNOMYCIN AND 11-DEOXYDAUNOMYCIN WITH SODIUM DITHIONITE IN DMSO - FORMATION OF QUINONE METHIDE SULFITE ADDUCTS AND THE 1ST NMR CHARACTERIZATION OF AN ANTHRACYCLINE QUINONE METHIDE

Daunomycin (1) yields 7-deoxydaunomycinon-7-yl sulfonates (6 and 7) upon anaerobic reaction with 6 mol equiv of dithionite in 5% H2O-95% DMSO followed by oxidation with molecular oxygen. The reaction is proposed to occur via reductive glycosidic cleavage to 7-deoxydaunomycinone quinone methide (4) followed by reversible dithionite addition to form adduct hydroquinone 17 and subsequent molecular oxygen oxidation at the hydroquinone and at the sulfur functional groups to yield 6 and 7. Byproducts 7-deoxydaunomycinone (2) and bi(7-deoxydaunomycinon-7-yl) (3), epidaunomycinone (8), 7-deoxy-7-ketodaunomycinone (9), 7-deoxy-7,13-epidioxydaunomycinol (10), and daunomycinone (11) result from protonation of 4 and molecular oxygen oxidation of 4, respectively. Sulfonate adducts 6 and 7 are relatively stable even in semiquinone and hydroquinone redox states. 11-Deoxydaunomycin (12) yields 7,11-dideoxydaunomycinon-7-yl sulfonates (14 and 15) upon similar reduction with even 1 mol equiv of dithionite. Sulfonates 14 and 15 are proposed to form by both dithionite and hydrogen sulfite addition to intermediate 7,11-dideoxydaunomycinone quinone methide (16), with hydrogen sulfite being a byproduct of quinone reduction by dithionite. With these reaction conditions, quinone methide 16 is long-lived and is characterized by H-1 NMR spectroscopy; the spectrum suggests a B-ring quinone methide structure.