Electrochemical deglycosidation of anthracyclines: stereoelectronic requirements

The redox behavior of daunombicin and its analogues has been studied by differential pulse polarography (DPP) in phosphate-buffered (pH 7. I) solutions at 37.S"'. 'The reductive deglycosidation reaction has been found to be under stereoelectronic control as the conformation of the alicyclic ring strongly affects the kinetics of the sugar moiety detachment. The substitution pattern of the anthraquinone system and/or the cyclohexene ring may determine the shape of the latter and in turn the stability of the glycosidic bond. We observe that while daunorubicin, 4-demethoxy-l I-deoxydaunorubicin, and 10(R)methoxydaunorubicin easily eliminate L-daunosamine upon polarographic reduction yielding the corresponding 7-deoxyaglycones, 4-demethoxy-6-deoxydaunombicin and 10(S)-methoxydaunorubicin are stable towards deglycosidation. There is a pronounced stereoelectronic effect which results in a faster cleavage of those glycosidic bonds which have a relatively small dihedral angle with respect to the T-type orbital(s) of the anthraquinone system. Among the aglycones, the 10(S)-acetoxy and 10(R)-azidodaunomycinones are reductively converted to daunomycinone whereas the 10(R)-and 10(S)-methoxydaunomycinones do not undergo splitting of either the benzylic CIO-OCH, or the C 7 4 H bond.