Cytosines 5-fluoro

Because synthesis of l-(2-deoxy-2-fluoro-)S-D-arabinofuranosyl)cytosine (744, FAC), an elementary arabino type of nucleoside having a growth-inhibitory effect against L 1210 leukemia in mice, through direct introduction of a fluorine atom in the 2 - up (arabino) position was difficult, compound 744 was prepared by condensation of trimethylsilylated A -acetylcytosine with 3-0-acetyl-5-(7-benzoyl-2-deoxy-2-fluoro-D-arabin-ofuranosyl bromide (742), which had been prepared by periodate oxidation of 6-0-benzoyl-3-deoxy-3-fluoro-D-glucofuranose (741). Similar condensa-... 

Deoxy-3-fluoro- -D-xylofuranosyl)cytosine (821) was prepared by condensation of 2,5-di-0-benzoyl-3-deoxy-3-fluoro-D-xylofuranosyl bromide with bis(trimethylsilyl)cytosine (773). It was proposed that 1 -(3 1eoxy-3-fluoro-)S-D-arabinofuranosyl)uracil (823), prepared from l-(2,3-anhy-dro-)S-D-lyxofuranosyl)uracil (822) with anhydrous HF ( 8% in 1,4-dioxane 116 °, 41 h, 3% yield), has a twist conformation of the furanose ring(°r, acetone- 4-D20 . Jn-vf 13.5, Hz). Reexamination ... 

Schinazi RF, McMillan A, Cannon D, Mathis R, Lloyd RM, Peck A, Sommadossi J-P, St Clair M, Wilson J, Furman PA, Painter G, Choi W-B, Liotta DC. Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-l-[2-(hydroxymethyl)-l,3-ox-athiolan-5-yl]cytosine. Antimicrob Agents Chemother 1992 36 2423-2431. 

Fluorine addition with trifluoromethyl hypofluoritc to various uracil and cytosine bases and nucleosides has been extensively studied. Vicinal fluoro trifluoromethoxy or fluoro methoxy adducts, formed mainly by syn addition, are usually hydrolyzed thus resulting in fluoro-sub-stituted derivatives,42 48 e.g. formation of 24 and 25. 

Direct 5-fluorination can be effected on activated pyrimidines for example, F2 in HOAc or anhydrous HF have been used for the preparation of 5-fluoro-2(lH)-pyrimidinones (77CCC2694), and for 5,5-difluorination of 6-O-cyclouridines (83TL1055). Uracil and cytosine are 5-fluorinated by the same procedure (80TL4605,82CPB887). 

Table VII contains the results of the CNDO/2 calculation158 on the energy of cytosine tautomers 2, 3 or 6 and of some derivatives. It can be seen that the calculated energy shifts are in agreement with the effect of substitution on the tautomeric equilibrium of cytosine discussed in Section II, B. Thus, a 5-fluoro substituent causes a small tautomeric shift toward forms 3 (dB i3F Cyt - di ,3t = 2.98 kcal/mole) or 6 (JB l8F Cyt — = 4.87 kcal/mole), while a 6-fluoro substituent...

Dominating tautomers 2 and 3 for 5-fluoro and 6-fluorocytosine, respectively. d From ref. 3. For cytosine itself the value was calculated3 to be equal to — 15... 

The fluorine chemical shifts for fluoropyrimidines, 2-fluoropyrazine, 2-fluoro quinoxaline, 4-fluoroquinazaline, 5-fluorouracil, 5-fluoro-cytosine, and cyanuric fluoride are provided in Scheme 3.82. The fluorine of 2-fluoropyrimidine is considerably deshielded relative to... 

In 5-fluoro cytosine monohydrate [BIRMEU] (Fig. 15.15), there are two symmetry-independent molecules which have almost identical hydrogen bonding. The... 

BIRMEU. 5-Fluoro-cytosine monohydrate (C4H4FN30, H20). Louis T, Low JN, Ibllin P (1982) Cryst Struct Commun 11 1059... 

Preparation of l-(2,3-dideoxy-3-fluoro-(l-i.-glycero-pent-2-eno-furanosyl) cytosine... 

In an earlier investigation by the author (2), cis- and trans-2-benzoyloxymethyl-5-(N-acetyl-5 -fluoro-cytosin-E-yl)-1,3-oxathiolane were prepared then hydrolyzed into the corresponding alcohols. 

The Step 9 analogue, l-(2-deoxy-2-fluoro-4-thio-/3-D-arabinofuranosyl)-cytosine, (III), has been prepared and is described (4). 

Koch, S. A. M. and Sloan, K. B., N-Mannich base dcrivates of 5-fluoro-cytosine a pro-drug approach to improve topical delivery, Inl. J. Pham, 35, 243, 1987 Chem. Absir., 106.219506, 1987. 

Figure 4 Catalytic activation of cytosine for C5-methylation by nucleophilic addition of a thiolate at the C6 position, (a) The chemical mechanism of enzymatic DNA cytosine-S methylation. Mechanism-based inhibition of DMA MTases by cytidine analogs 5-fluoro-2 -deoxycytidine (b), 5-aza-2 -deoxy-cytidine (c), and 2-pyrimidinone-l-p-D-(2 -deoxyriboside) (d).

Fluoro-2, 5 -dideoxyuridine-5 -5-thiosulfate (37) was synthesised from 5-fluoro-5 -0-tosylo-2 -deoxyuridine and sodium thiosulfate pentahydrate in ethanol at reflux. This compound is a member of a larger family of analogues of dUMP, dTMP and 5-fluoro-dUMP which have been used to probe interactions with thymidylate synthase. Ethyl chloroformate was shown to be an effective promoter as an alternative to DCC in the preparation of l-[((5)-2-hydroxy-2-oxo-l,4,2-dioxaphosphorinan-5-yl)methyl] cytosine (cyclic HPMPC) from HMPC in large scale quantities and in high isolated yield as well as purity. " ... 

Cook reported the syntheses of phosphonamidite and H-phosphonates derivatives of 3 -C-methylene modified thymidines (77a-e), 3 -C-methylene 5-methyl-iV-pyrrolidine-modified cytosine (78) and 3 -C-methylene 5-methyl modified uridine (79) having methoxy, fluoro, hydrogen and methoxyethoxy substituents at the 2 -positions. The H-phosphonates were synthesised from the corresponding key intermediate 3 -C-iodomethyl nucleosides through an... 

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