Folate analogues. 22. Synthesis and biological evaluation of two analogues of dihydrofolic acid possessing a...

Two analogues of dihydrofolic acid possessing a 7,8-dihydro-8-oxapterin ring system have been synthesized and evaluated for their antifolate activities. These compounds, N-[(2-amino-4-hydroxy-7,8-dihydro-8-oxa-6-pteridinyl)benzoyl]-L-glutamic acid (3) and N-[[(2-amino-4-hydroxy-7,8-dihydro-8-oxa-6-pteridinyl) methyl]benzoyl]-L-glutamic acid (4), were synthesized by reacting the appropriately substituted alpha-halo ketones with 2,5-diamino-4,6-dihydroxypyrimidine (2). Elaboration of p-carbomethoxybenzaldehyde (5) to p-carbomethoxyphenacyl bromide (7) was accomplished by its oxidation with Jones reagent and the successive treatment of the oxidation product with SOCl2, CH2N2, and HBr. Commercially available p-vinylbenzoic acid (11) was converted to its glutamate conjugate 12 and was further converted to the bromo ketone, diethyl N-[p-(1-bromo-2-oxopropyl)benzoyl]-L-glutamate (17), by a series of reactions involving epoxidation, oxirane ring opening with HBr, Jones oxidation, Zn/HOAc reduction, and successive treatment of the reduction product 16 with SOCl2, CH2N2, and HBr. These bromo ketones, 7 and 17, upon reaction with pyrimidine 2, gave the diethyl esters of the target compounds, which were hydrolyzed to 3 and 4 with NaOH. Compound 4 underwent an interesting acid-catalyzed isomerization where the double bond of 4 was shifted from the 5,6-position to the 6,9-position to give the isomer 19. Both compounds 3 and 4 were inactive against Lactobacillus casei (ATCC 7469) and did not serve as synthetic substrates of L. casei dihydrofolate reductase. Compound 4 showed activity against Streptococcus faecium (ATCC 8043), but 3 was inactive against this organism.