Formycin pyrimidine

Formycins pyrimidine antibiotics (see Nucleoside antibiotics) synthesized by Nocardia interforma. For-mycin itself is 3-P-D-ribofuranosyl-7-amino-pyrazolo-(4,3-d) pyrimidine. The biogenetic precursor is adenosine. F. is converted to formycin 5 -triphosphate, which acts as an ATP analog. Mycobacterium and Xantho-monas oryzae are particularly sensitive to formycin. 

Aminopyrazolo[4,3-d]pyrimidine moiety (47) is present in several nucleosides of both biological and synthetic origins. Among them, formycin (47, R = 3/3-D-ribofuranozyl) is of particular interest as a C-nucleoside analog of adenosine. 

Several analogues of adenine or adenosine are reported to be incorporated into nucleic acids 2-fluoroadenosine [342], tubercidin [190, 192, 342a], toyacamycin [193,342a], sangivatnycin [342a, b], cordycepin [168,343,344], 4-aminopyrazolo[3, 4-d] pyrimidine [119], formycin [344a], and 9- -D-arabinofuranosyladenine [152, 154], The evidence for the incorporation of 9-(3-D-arabinofuranosyladenine has been questioned [345]. 

Isolation and characterization of the nucleoside antibiotic formaycin as 3-j8-ribofuranosylpyrazolo[4,3-[Pg.346]

The tautomeric equilibrium between IH- and 2//-formycin (7-amino-3)8-D-ribofuranosyl-l//-pyrazolo[4,3-d]pyrimidine) has a constant ratio N(2)H/N(1)H = 0.2 and an enthalpy difference estimated at 1 kcal mol". The tautomeric interconversion is catalyzed by (3 x 10 Msec" ) and by OH" (5 X 10 M" sec" ). No other catalytic pathway such as water catalysis or tautomerization via tautomeric cations contributes significantly to the interconversion. Protonation on the pyrazole ring of formycin does not occur significantly (80JA3897). 

Very interesting additional data come from studies on poly 3-iso-adenylic acid (nonsubstrate) 440) and the unusual purines related to formycin (substrates), F, 441, 443). The activity of the enzyme on these compounds is much higher than that toward the normal purines and is comparable to that toward the pyrimidines. Ikehara et al. 441) have reported the action of RNase on poly (F-C), poly (F-U), and poly (F-G) FpUp, FpCp, and GpFp were obtained. With more enzyme the first two yielded F > p and eventually 3 -FMP. Under the digestion conditions used poly (A-G) was not attacked at all. 

The mass spectrum of formycin (54a) showed M+ and MH+ ions due to the protonated base moiety of the molecule <78MI 712-01). The mass spectra of 5-substituted oxazolo[4,5-d]pyrimidines (78) proceeds via loss of the C-5 substituent <82KGS1255>. The main fragmentations of substituted imidazo[4,5-/>]pyrazines (79) <89KGS532> and oxazolo[5,4- have been determined. 

Formycin A was initially isolated from rice mold <65JAN259> and identified <66JHC110, 66TL597) as 3-ribofuranosylpyrazolo[4,3-G ]pyrimidine-7-amine (54a). The reported synthesis utilizes the pyra-zole derivative (522) as starting material which is converted in situ on treatment with zinc dust in methanol in the presence of ammonium chloride into the amine (523) which is then reacted with formamidine to yield formycin A after deprotection (Scheme 53) <78CCC1431>. 

Formamidine acetate is a useful reagent because it can provide a C—N unit to synthesize a pyrimidine ring, e.g. as in Scheme 69 (74JOC2023). Another important example is seen in a synthesis of the antibiotic formycin (223 Scheme 70) (80CJC2624). 

The first synthesis of formycin (386) was reported in 1971 using the nucleoside-nucleoside transformation approach [71JCS(C)2443]. Formycin B (387) was O-acetylated and transformed to the 6-chloropyrazolo[4,3-r/]pyrimidin-3-yl derivative 396. Amination of 396 with liquid ammonia gave formycin (386) (Scheme 112). 

Oxoformycin B (388), the catabolite of formycin and formycin B, was synthesized before the parent nucleosides in 1970 from the 2,5-anhydro-l-ureido-D-allitol derivative 416. Compound 416 was used to build the 4,5-dimethoxycarbonylpyrazol-3-yl C-nucleoside 419, followed by construction of the fused pyrimidine ring as shown in Scheme 117. Selective amidation of the ester function at C5, rather than that at C4, is a key step during this... 

Formycin and formycin B with modified sugar subunits have also been prepared using, mostly, the nucleoside-nucleoside approach. In one instance, however, 2 -deoxyformycin B (458) was prepared by regio- and stereospecific palladium-mediated C—C bond formation between the fu-ranoid glycal 454 and protected 3-iodopyrazolo[4,3-d]pyrimidine. The C-nucleoside 455 having an unsaturated sugar moiety was subsequently elaborated to 458 (92JOC4690) (Scheme 125). 

Formycin has been prepared by constructing the pyrimidine ring from a 4-nitro-pyrazole-C-nucleoside precursor. Diels-Alder reactions have been used in a synthesis of DL-showdomycin (21) via the adduct (22) outlined in Scheme... 

Formycin Nocardia interforma 7-Aminopyrazolo- pyrimidine Ribose Adenosine... 

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