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Spectroscopic and kinetic evidence for the tautomer of 7 deoxy alkavinone as an intermediate in the reductive coupling of aclacinomycin a


Journal of the American Chemical Society 106(4): 1105-1109
Spectroscopic and kinetic evidence for the tautomer of 7 deoxy alkavinone as an intermediate in the reductive coupling of aclacinomycin a
Reduction of aclacinomycin A (7) [clinical antitumor drug] with an excess of dl-bi(3,5,5-trimethyl-2-oxomorpholin-3-yl) (11) in Trizma-buffered methanol solvent in the absence of O2 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 an intermediate by EPR spectroscopy. UV-visible spectroscopic monitoring revealed the formation of the tautomer 14 of 7-deoxyalkavinone as a 2nd intermediate in the formation of 8 and 9. The tautomer showed absorption at 350 and 548 nm. Reaction of 9 and 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 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, 1st- and 2nd-order in 14. Nonlinear least-squares analysis of the decay gave a pseudo-1st-order rate constant for protonation equal to 3.36 .times. 10-3 s-1 and a 2nd-order rate constant for coupling equal to .apprx. 180 M-1 s-1. The tautomer 14 of 7-deoxyalkavinone 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 tumor response and toxicity of the 2 anthracyclines.


Accession: 006460870



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