286009-93-6Relevant articles and documents
Mechanistic studies of the reduction of daunomycin with sodium borohydride. Formation and reaction of borate esters
Schweitzer, Barbara Ann,Egholm, Michael,Koch, Tad H.
, p. 242 - 248 (2007/10/02)
Reduction of daunomycin with excess sodium borohydride in methanol degassed with prepurified nitrogen yielded 89% daunomycinol and 11% recovered daunomycin. Monitoring of the reaction by UV-vis spectroscopy revealed the formation of an intermediate with absorptions at 336 and 430 nm, which was assigned the borate ester structure 5 on the basis of the UV-vis absorption bands together with high-field 1H NMR, FTIR, and mass spectral data. Similar results were obtained upon reduction without nitrogen degassing. In contrast, sodium borohydride reduction under strictly anaerobic conditions, achieved with freeze-thaw degassing, predominantly yielded the products of glycosidic cleavage, 7-deoxydaunomycinol (6, 58%) along with daunomycinol (4, 17%). The sequential formation of two intermediates was observed: first, borate ester 5 and second, a longer lived intermediate with absorptions at 360 and 580 nm. The second intermediate is proposed to be 7-deoxydaunomycinol quinone methide borate ester (9) on the basis of the absorption bands, lifetime, and product structures compared with those observed upon reduction with the one-electron reducing agent, bi(3,5,5-trimethyl-2-oxomorpholin-3-yl) (TM-3 dimer). Reduction of 7-deoxydaunomycinone with excess sodium borohydride in nitrogen-degassed methanol yielded 42% 7-deoxydaunomycinol (6), 31% 5,7-dideoxydaunomycinol tautomer (1,2,3,4-tetrahydro-2,11-dihydroxy-2-(1-hydroxyethyl)-7-methoxy-5,12- naphthacenedione, 11), and 27% 7,12-dideoxydaunomycinol tautomer (1,2,3,4-tetrahydro-2,6-dihydroxy-2-(1-hydroxyethyl)-7-methoxy-5,12- naphthacenedione, 12). Again an intermediate with absorptions at 336 and 430 nm was observed, in this case, assigned to regioisomeric borate esters 13 and 14 on the basis of formation of regioisomeric dideoxydaunomycinol tautomers 11 and 12. The intermediacy of long-lived borate esters is relevant to the interpretation of studies employing sodium borohydride for the reductive activation of anthracyclines.
