Fervenulin, 2 -methyl

To prepare fervenulin 4-oxides 12 or toxoflavine 4-oxides 146, it is convenient to use the reaction of l,3-dimethyl-2,4-dioxopyrimidin-6-yl hydrazone 147 or N-(3-methyl-2,4-dioxopyiimidin-6-yl) iV-methylhydrazone 148 with potassium nitrate in acetic acid [75CPB1885,76CPB338,76JCS(CC)658,82JHC1309,93CPB362]. Diethyl azodicarboxylate can be used instead of potassium nitrate [76JCS(P1 )713]. 

The synthesis of the /m-benzo-separated analogue 380 of the broad spectrum antibiotic fervenulin was reported (81JOC1699) in five steps from 7-chloro-2,4(l//,3//)quinazolinedione 374. Nitration of 374 gave 375, whose methylation gave 376. Pursuant to the synthesis of 380, 376 was converted into 377 with hydrazine and then formylated with formic acid to give 378 or converted to the ethoxymethylene derivative 379. Catalytic hydrogenation of 378 or preferably 379 gave 380. 

Reumycin and xanthothricin were isolated from Actinomyces rectus bruneus and are useful as antitumor antibiotics. Methylation of reumycin resulted in the formation of the antibiotics, fervenulin, toxoflavine, and 7-methoxyreumycin. A review on their effects on an electron transport mechanism in animal and yeast cells was published in 1975 by Russian authors (75MI1, 75MI2). 

The dealkylation-alkylation of toxoflavin 7 with methyl iodide in DMF at reflux furnishes fervenulin 8, as shown in Scheme 6. Interestingly, heating toxoflavin 7 at reflux in DMF results in demethylation to give the 1-demethyl-ated species, reumycin 57, which can be methylated to give fervenulin 8 <1997H(45)643>. 

It is of interest that the methyl alcohol 81 underwent oxidation with chromic acid to afford 3-acetylfervenulin 83 in good yield, whereas the same conditions resulted in the conversion of alcohol 79 into fervenulin 8. The desired product of this latter transformation, that is, fervenulin-3-carboxaldehyde 82, could, however, be obtained, albeit in low yield, by the oxidation of alcohol 79 with manganese dioxide. Fervenulin-3-carboxaldehyde 82 could be obtained in much better yield from the treatment of 3-styrylfervenulin 68 with periodate in the presence of osmium tetroxide, or by ozonolysis of the same substrate. 

Demethylation of toxoflavins (941) to reumycin (942) is effected by dimethylformamide or diethylamine and also proceeds via radical-anions (87JHC1373). On treatment with DMF and methyl iodide, (941, R=H) undergoes a concomitant demethylation and methylation to give the fervenulin (943) (74JHC271, 75BCJ2884). 

N-Methyl derivatives of pyrimido[5,4e][l,2,4]triazine-5,7-dione are the naturally occurring antibiotics fervenulin (planomycin 815), toxoflavin (xanthothricin 816) and reumycin (817). The related antibiotic MSD-92 is 2,6,8-trimethylpyrimido[5,4-e]-[l,2,4]triazine-3,5,7-trione (818) (78HC(33)189, p. 808). 

---