Spectroscopic and Kinetic Evidence for the Tautomer of 7-deoxyalklavinone as an Intermediate in the Reductive Coupling of Aclacinomycin A

Article abstract of DOI:10.1021/ja00316a049

Reduction of aclacinomycin A (7) with an excess of dl-bi(3,5,5-trimethyl-2-oxomorpholin-3-yl) (11) in Trizma-buffered methanol solvent in the absence of oxygen gave 7-deoxyalkavinone (8), bi(7-deoxyalkavinon-7-yl) (9), 5,6-dihydro-3,5,5-trimethyl-1,4-oxazin-2-one (12), and 3,5,5-trimethyl-2-oxomorpholine (13).The reducing agent was 3,5,5-trimethyl-2-oxomorpholin-3-yl (5) resulting from bond homolysis of 11.The relative yields of 8 and 9 were a function of the initial concentrations of 7 and 11 and the reaction time.The semiquinone 15 of 7 was observed as anintermediate by EPR spectroscopy.Uv-visible spectroscopic monitoring revealed the formation of the tautomer 14 of 7-deoxyalklavinone as a second intermediate in the formation of both 8 and 9.The tautomer showed absorption at 350 and 548 nm.Reaction of 9 with 11 resulted in reductive cleavage of 9 to 8 and disproportionation of 11 to 12 and 13.The mechanism proposed for the reduction of 7 is shown in Scheme III and includes protonation of 14 to give 8 and coupling of 14 followed by oxidation with 12 to give 9.The decay of the tautomer absorption followed mixed kinetics, first and second order in 14.Nonlinear least-squares analysis of the decay gave a pseudo-first-order rate constant for protonation equal to 3.36x10^-3s^-1 and a second-order rate constant for coupling equal to approximately 180 M^-1s^-1.The tautomer 14 of 7-deoxyalklavinone is protonated in buffered methanol 15 times slower than the tautomer 6 of 7-deoxydaunomycinone, thus allowing the coupling reaction to take place.The difference in reactivity of the tautomers may be relevant to the tumorresponse and toxicity of the two anthracyclines.