Trapping of the Quinone Methide from Reductive Cleavage of Menogaril with the Nitrogen Nucleophile Imidazole

Article abstract of DOI:10.1021/jo00282a024

Anaerobic reduction of menogaril, 7-con-O-methylnogarol (1), a semisynthetic antitumor drug in clinical trials, with 10 mol percent of meso-bi(3,5,5-trimethyl-2-oxomorpholin-3-yl) (meso-TM-3 dimer, 4) in methanol at ambient temperature in the presence of a large excess of imidazole yielded 58percent of a mixture of con- and dis-7-imidazoyl-7-deoxynogarol (8) and 13percent 7-deoxynogarol (7).Similar reduction of 1 with 30 mol percent of a mixture of the diastereoisomers of bi(3,5-dimethyl-5-(hydroxymethyl)-2-oxomorpholin-3-yl) (DHM-3 dimers, 9) in water yielded 54percent 8 and 33percent 7.The reaction isproposed to occur by the Fisher chain mechanism with reductive activation to the quinone methide state 2 followed by nucleophilic addition of imidazole and subsequent oxidation of adduct hydroquinone 14 by starting menogaril.These experiments represent the first trapping of an anthracycline quinone methide state with a nitrogen nucleophile.