REDUCTION OF DAUNOMYCIN IN DIMETHYL-SULFOXIDE - LONG-LIVED SEMIQUINONES AND QUINONE METHIDE AND FORMATION OF AN ENOLATE AT THE 14-POSITION VIA THE QUINONE METHIDE

Anaerobic reduction of daunomycin (1, daunorubicin) in 5%/95% H2O/DMSO (DMSO = dimethyl sulfoxide) or in DMSO with sodium dithionite or bi(3,5,5-trimethyl-2-oxomorpholin-3-yl) (TM-3 dimer), respectively, yields 7-deoxydaunomycinone (7) and a mixture of the diastereomers of bi(7-deoxydaunomycinon-7-yl) (8). A precursor to both 7 and 8 is 7-deoxydaunomycinone quinone methide (4) formed from glycosidic cleavage of daunomycin hydroquinone (3). The hydroquinone 3 is established as a precursor to the quinone methide 4 from relative rates. In 5%/95% H2O/DMSO or DMSO, daunomycin senliquinone (2) and quinone methide (4) have much longer lifetimes than in 100% protic solvents such as H2O or methanol. The quinone methide reacts to form the side chain enolate most likely by intramolecular proton transfer from the methyl group at the 14-position to the 7-position.