INTRAMOLECULAR TRAPPING OF THE QUINONE METHIDE FROM REDUCTIVE CLEAVAGE OF DAUNOMYCIN WITH OXYGEN AND NITROGEN NUCLEOPHILES

Intramolecular trapping with oxygen and nitrogen nucleophilic sites of the quinone methide from reductive cleavage of daunomycin (1a) is described. The oxygen and nitrogen nucleophilic sites were located at the 13-position of daunomycin in oxime, semicarbazone, and benzoylhydrazone derivatives. Reduction of daunomycin oxime (2a) and semicarbazone (2b) in methanol and water with the one-electron reducing agents bi(3,5,5-trimethyl-2-oxomorpholin-3-yl) (TM-3 dimer, 3a) and bi[3,5-dimethyl-5-(hydroxymethyl)-2-oxomorpholin-3-yl] (DHM-3 dimer, 3b) yielded cyclooxime 8a and cyclosemicarbazone 8b as well as 7-deoxydaunomycinone oxime (6a) and 7-deoxydaunomycinone semicarbazone (6b), respectively. Product ratios were pH dependent. Cyclooxime but not cyclosemicarbazone was reductively cleaved to the respective 7-deoxy aglycon. Reduction of daunomycin benzoylhydrazone (2c) yielded only 7-deoxydaunomycinone benzoylhydrazone (6c). Quinone methide intermediates, 5b and 5c, were observed by UV-visible spectroscopy. Cyclomer formation is discussed in terms of intramolecular nucleophilic attack at the 7-position of the quinone methide. The lack of cyclomer formation during the reduction of 2c resulted from the configuration of the benzoylhydrazone functionality, syn to the methyl at the 14-position. © 1990, American Chemical Society. All rights reserved.