2,2 -Anhydro-1 - uracils

It is claimed that this reaction proceeds via a 2, 3 -thionocarbonate or a thiocarbamate derivative. If the 5 -OH group of uridine was not protected, the yield of the 2,2 -anhydro-l-(j -D-arabinofuranosyl)uracil was low. 

A glycosylamine analog in the D series (59), a derivative of uracil, has been prepared78 by the action of sodium benzyloxide on l-[2,3-anhydro-5-0-(methylsulfonyl)-/3-D-lyxofuranosyl]uracil (58). 

The action of sodium methoxide on l-[5-0-(methylsulfonyl)-/3-D-lyxofuranosyl Juracil (60) leads78 to l-(2,5-anhydro-/3-D-lyxofuranosyl)-uracil (61) the 3,5-oxetane ring that might equally well have been... 

Another example of based-catalyzed elimination in the 2-deoxy sugar series is that of l-[2-deoxy-3-0-(methylsulfonyl)-5-0-trityl-/3-D-eryMro-pentofuranosyl]uracil and 2, 3-anhydro-l-(2-deoxy-5- 0-trityl-/3-D-<. reo-pentofuranosyl) uracil, which, when treated with potassium ferf-butoxide in methyl sulfoxide, give a 70% yield of a 2,3-unsaturated nucleoside.28... 

The studies of Levene and LaForge60 on the nitration of uridine have since been re-investigated. It had been reported, several decades ago, that treatment of uridine with nitric acid produced a Nitro-Uridin-Carbon-saure which was stated to be a dimer containing an anhydro typeof linkage (positions unspecified) between two nucleoside residues.60 According to an abstract,269 this compound has now been identified as the monomeric 5-ni-tro-l-(/8-D-ribosyluronic acid)uracil (CXXII) this was converted to the isopropyl ester and the 2,3-O-isopropylidene acetal thereof. Nitration of the pyrimidine moiety of uridine without oxidation of the 4-(hydroxy-... 

AFUTHU. 2,2 -Anhydro-l-/ -D-arabinofuranosyl-2-thio-uracil (C9H10N2O4S). Yamagata Y, Yoshimura J, Fujii S, Fujiwara T, Ibmita K-I, Ueda T (1980) Acta Crystallogr, Sect B 36 343 AGALAM01. N-Acetyl-a-D-galactosamine (CgH NOg). Gilardi RD, Flippen JL (1974) Acta Crystallogr, Sect B 30 2931... 

Pankiewicz, K. W. and Watanabe, K. A. (1987) Nucleosides. CXLIII. Synthesis of 5 -deoxy-5 -substituted-2,2 -anhydro-l-(P-D-arabinofuranosyl)uracils. Anew 2,5 - to 2,2 -anhydronucle-oside transformation. Studies directed toward the synthesis of 2 -deoxy-2 -substituted arabino nucleosides. (4). Chem. Pharm. Bull., 35, 4494 1497. 

The first preparation of a secondary deoxyfluoro sugar, other than by total synthesis, involved the cleavage of 2,2 -anhydro-3-( 8-D-arabino-furanosyl) uracil (3) to give 3-(2-deoxy-2-fluoro-/3-D-ribosyl) uracil. This reaction, which can be extended to cleavage by hydrogen bromide or chloride, is at pr ent the only route to 2-deoxy-2-fluoro-D-ribose deriva-... 

Indeed, in the acid hydrolysis of uridine 3 5 -cyclic phosphate (175), reported by Khorana and coworkers, the 67% yield of uracil observed may represent the minimum amount of anhydronucleotide intermediates (176) and (180) which had formed, as uridine 5 -phosphate is, under these conditions, completely stable. In addition to cleavage to uracil, it would be expected that some of the anhydronucleotide (180) would also give rise to uridine 3 (2 )-phosphate. Furthermore, intermediate (176) may also generate l- 3-D-xylofuranosyluracil 5 -phosphate (177) and its arabino isomer (181), as well as uracil. Such a reaction has been observed by Yung and Fox in the acid hydrolysis of 2,3 -anhydro-l- 3-D-xylofuranosyl-uracil (182), which yielded the xylo- (183) and arabwo-nucleosides (184) and uracil. The formation of the arabino nucleoside (184) would arise by conversion of some of (182) into a 2, 3 -epoxide, which would be directly hydrolyzed to (183) and (184), or by conversion of this 2, 3 -epoxide into a 2,2 -anhydronucleoside, which would be hydrolyzed by acid to (184). Such mechanisms, applied to the anhydronucleotide (176), could give rise to (177) and (181). 

Sodium ferf-butoxide in N,N-dimethylformamide at KXP was found to be very effective in promoting intramolecular displacements408 and 2,5 -anhydrothymidine was obtained directly from 5 -0-(methyl-sulfonyl)thymidine with these reagents. The same conditions have also been used to synthesize the anhydronucleosides 121 and 122 from a pseudouridine derivative408 and from a D-ribosyl derivative of 2,4-quinazolinedione.410 The same reagents with 3 -0-p-tolylsulfonyl-uridine gave mainly 1 -(2,3 -anhydro-y3-D-xylofuranosyl)uracil.408... 

The favored, intramolecular displacement at C-3 in the presence of a 5 -methylsulfonyloxy group, observed402 with 3, 5 -di-0-(methyl-sulfonyl)thymidine (115), was also evident in the formation,3 from l-[2,3,5-tri-0-(methylsulfonyl)-/3-D-arabinofuranosyl]uracil (144), of 2,3 - anhydro -1 - [2,5 - di - O (methylsulfonyl) -/3-D-lyxofuranosyl]uracil (145). 

Dimethyl-1-a-D-ribofuranosylbenzimidazole 5-Acetyl-l-(3,5-0-isopropylidene-) -D-xylofuranosyl)uracil 2,3 -Didehydro-[5-methyl-2//-l,2,6-thiadiazin-3yl 4,6-di-O-acetyl-2,3-dideoxy-a-L-eryt/iro-hexopyranoside] 1,1 -di-S-oxide 3,1 -anhydro-[2-(4,6-di-0-acetyl-2,3-dideoxy-a-L-eryt/iro-hexopyranose-3-yl)-3-hydroxy-5-methyl-2if-l,2,6-thiadiazine] 1,1-dioxide ... 

Also lying in the spongonucleoside field was Dr. Baker s novel synthesis of the yS-D-arabinofuranosylpyrimidines utilizing 2-0-acetyl-5-0-methoxycarbonyl-3-O-p-tolylsulfonyl-D-xylofuranosyl chloride, the halide that had been used in the synthesis of 2 -deoxyadenosine. When this halide was condensed with mercury derivatives of thymine and 5-fluoro-uracil and the products deacylated with base, l-yS-n-arabinofuranosyl-thymine and -5-fluorouracil were obtained directly, in reactions that proceeded by way of the 2,3-anhydro-n-ribofuranosides and the 2,2 -anhydronucleosides. These studies were later expanded by others, in synthetic work that has provided alternative paths to purine deoxy-nucleosides and /2-D-arabinosyIpurines, and they anticipated many of the syntheses of arabinosylcytosine (an important antitumor agent) that proceed by way of 2,2 -anhydronucleosides. 

C-cyano-3 -deoxy-P-D-ffcr o and erythro nucleosides 47 (63%) and 31 (25%). Related openings of 2, 3 -anhydro-P-D-lyxofuranosyl nucleosides with sodium cyanide [84] and with diethylaluminium cyanide [85] to afford 3 -C-cyano-3 -deoxy-P-D-arabinofuranosyl derivatives of adenine, uracil, thymine and isocytosine have been described. 

Compounds of the type 65 have been prepared by opening of the epoxide ring of l-(2,3-anhydro-5-0-trityl-P-D-lyxofuranosyl)uracil with a variety of carbon nucleophiles such as ethynyl lithium, vinylmagnesium bromide/cuprous iodide and l,3-dithian-2-yl lithium. These reactions afforded regioselectively 3 -C-substituted-3 -deoxy-P-D-arabinofuranosyl nucleosides 69-71 in 10-68% yield [84, 87] (Fig. 12). These intermediates have been transformed into a variety of other 3 -C-substituted-3 -deoxy-arabinofuranosyl uridines 72-77 [84]. 9-(3-Deoxy-3-C-methyl-P-D-xylofuranosyl)adenine has been prepared by glycosidation reaction of a 3-deoxy-3-C-methyl-P-D-xy/ofuranosyl chloride with adenine [90]. 

Numerous syntheses have also been reported for arabinofuranosyl nucleoside analogues, prepared either conventionally from arabinofuranosyl derivatives or via 2,2-anhydro-nucleosides obtained from appropriate ribonucleosides. 5-Aza-cytosine-D-arabinoside has been synthesized and found to show similar antiviral activity to Ara-C(arabinosyl-cytosine). 7-a-, 7-<3-, 9-0 -, and 9- 3-arabino-furanosyl derivatives of 3-deazaguanine have also been prepared, but none showed any anti-tumour activity. 9-(o -D-Arabinofuranosyl)-8-aza[2- C]-adenine, 7-(/3-D-arabinofuranosyl)-pyrrolo[2,3-d]pyrimidine-4(3//)-one (15)," l-(a-D-arabinofuranosyl)- and l-(/3-D-xylofuranosyl)-4-nitropyrazole, and Ot-arabino-nucleosides of 5-fluoro-cytosine and -uracil derivatives have also been prepared. An improved synthesis of 9-(/3-D-arabinofuranosyl)-2-fluoro-adenine has been reported. The ratio of o to 3 anomers obtained by phase-transfer reaction of 2,3,5-tri-O-benzyl-D-arabinofuranosyl bromide with 6-chloro-2-thiomethyl-7-deazapurine varied with the quaternary ammonium salt used as a catalyst, although the jU-anomer predominated in every case. 2,2-Anhydro-nucleosides have been used to prepare l-j3-D-arabinofiiranosyl derivatives of 5-alkylthio-uracils, 5-ethyl-cytosine, and 5-ethyl-uracil, 8-alkylamino-purines, and 2-aralkylamino-l,4-dihydro-4-imino-pyrimidine hydrochlorides (16). ... 

Anhydro-adenosine has been isomerized to 2, 3-anhydro-jS-D-lyxo-furanosyl-adenine in 42% overall yield by the sequence outlined in Scheme 8. Deamination of l-(3-amino-3-deoxy-j3-D-xylofuranosyl)-uracil with nitrous acid did not yield any 2, 3 -anhydro-uridine or products derived from this anhydro-sugar derivative, uracil being the major product. ... 

Addition of the anion derived from uracil to l,5 2,3-dianhydro-4,6-0-benzyli-dene-D-allohexitol, followed by inversion of configuration of the resulting 3-OH group by displace,ment of its mesylate derivative with sodium hydroxide, afforded 12. Compound 12 was a useful intermediate for making l,5-anhydro-2-deoxy-D-mannitol-containing pyrimidine nucleoside analogues. ... 

Anhydro-l-(3 -0-tosyl- -D-arabinofuranosyl)uracil heated 5 hrs. at 100 with dry NaNg in dimethylformamide -> 2,2 -anhydro-l-(3 -azido-3 -deoxy-j -D-arabino-furanosyl)uracil. Y 52%. F. e. s. M. Hirata, Chem. Pharm. Bull. 16, 291 (1968). 

A soln. of 2,2 -anhydro-l-(3,5-di-0-acetyi-i -D-arabinofuranosyl)uracil in dimethyl-formamide treated with Na-ethylmercaptide, allowed to stand 15 hrs. at 37°, evaporated to dryness in vacuo, treated with water and acetic acid to pH 7, passed through a column of activated charcoal, and eluted with aq.-alc. NHg l-(3-ethylthio-3-deoxy-/ -D-xylofuranosyl)uracil. Y 90%. Y. Furakawa et al., Chem. Pharm. Bull. 18, 554 (1970). 

Uracil and cytosine derivatives of 4-thio-DL-erythrofuranose and adenine and guanine nucleoside analogues of 4-thio-D-ribofuranose, 4-thio-D-xylofuranose, and 5-thio-D-xylopyranose have been reported. Treatment of 2,2 -anhydro-cytosine with phosphorus pentasulphide gave the cyclic thiophosphate derivatives (49), which was used to prepare other 2 -thio-cytidine derivatives. The... 

Nucleosides, Nucleotides, Derivatives, and Related Compounds. — 5-Substituted uracils were examined for conformational dependence on the substituents, uridine 5 -phosphate disodium salt, 2 -deoxyuridine 5 -phosphate disodium salt, " 6-methyl-2 -deoxyuridine, 5-C-acetyl-2 -deoxyuridine, dihydrouridine 3 -phosphate potassium salt, 5-hydroxymethyl-2 -deoxyuridine, 4-thio--uridine, 2,5 -anhydro-2, 3 -0-isopropylidene-2-thiouracil, 2,2 -an-hydro-1 - 3-D-arabinofuranosyl-2-thiouracil. ... 

Uridine 2, 3 -episulphide and an analogous D-/yxo 2, 3 -episulphide have been prepared from l-(2,3-anhydro-5-0-benzoyl-p-D-lyxofuranosyl)uracil and 2,2 -S-anhydro-l-p-D-arabinofuranosyl-2-mercaptouracil, respectively, by conventional procedures. Treatment of 2, 3 -anhydroinosine with dilute sodium hydroxide solution at 80°C gave the 3, 5-cyclonucleoside-4-carboxamide (604). ... 

A convenient synthesis of 5 -deoxy-2-fluoroadenosine from guanosine has been reported. Ring-opening of l-(2,3-anhydro-P-D-lyxofuranosyl)-cytosine and -uracil with ammonium bromide, iodide, azide, and thiocyanate in refluxing ethanol has been used to prepare l-(3-deoxy-3-halogeno-P-D-arabinofuranosyl)-... 

A mixture of 2,2 -anhydro-l-(5 -0-benzoyl-3 -0-mesyl-)5-D-arabinofuranosyl)-uracil and water refluxed 4-5 brs. l-(5 -0-benzoyl- -D-lyxofuranosyl) uracil. Y 83%.—Tbis reaction is unusual from several viewpoints it involves removal under mild conditions of a sec. mesyloxy group tbis mesyloxy group is replaced with net inversion by a bydroxyl group in an acid medium tbe reaction proceeds stereospecifically to a 2, 3 -cis-configuration. F. e., also from tbe 3, 5 -di-0-mesyl analog with partial 0-demesylation, s. R. Fecber, J. F. Codington, and J. J. Fox, Am. Soc. 83, 1889 (1961). 

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