Fluoroadenosines

Deoxy-5 -fluoroadenosine (911) and the analogs 910, 912, 913 were prepared by coupling of 5-deoxy-5-fluoro-D-ribofuranose and 6-chloro-purine. 2, 5 -Dideoxy-5 -fluoroadenosine (914) was prepared through a displacement reaction of the corresponding 5 -0-tosyl precursor with fluoride (BU4NF in DMF). The carbocyclic nucleosides 915 and 916 have been prepared and their antiviral activities evaluated. 

Figure 13.18 Biosynthesis of fluorinated metabolites via 5 -deoxy-5 -fluoroadenosine...

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]. 

The reported examples of halogen exchange have been carried out on heterocycles activated by the presence of heteroatoms in the ring and by benzo-fusion, e.g., the preparation of 8-fluoroadenosine (137) by Kobayashi et al.212 from 8-bromoadenosine (136) and KF in acetonitrile. 

Regarding the 1,3-oxazocines, it was reported that the isolation of 5, 8-anhydro-adenosine in an attempt of obtaining 8-fluoroadenosine <2007T3782>, a decaline-fused 1,3-oxazocine, which was unexpectedly obtained in the contest of an attempted synthesis of axinyssamine <2007T1544>, an efficient synthesis and X-ray crystal structure analysis of [ 1 ]bcnzopyrano[4,3-r/]l,3-benzoxazocin-13-onc and its derivatives and 5,6-dihydro-2,4-... 

The same conditions led to decomposition in an attempt to prepare 2 -deoxy-2-fluoroadenosine from 2 -deoxyadenosin-2-amine. The reaction was successful when applied to 3, 5 -di-0-acetyl-2 -deoxyadenosin-2-amine giving the 2-fluoro derivative 2. ... 

When 2, 3, 5 -tri-0-acetyladenosin-8-amine is diazotized with sodium nitrite in 40% fluoro-boric acid at 20 °C, 2, 3, 5 -tri-0-acetyl-8-fluoroadenosine (3) is obtained in approximately 10% yield. 8-Fluoroinosine and adenin-8-ol are also obtained as byproducts. 

Synthesis of 2 -Deoxy-2 -a-fluoroadenosine Using a Protection Strategy with 3and 5 -Hydroxyl Groups... 

FddA from 2 -Deoxy-2 -a-fluoroadenosine Until recently, the introduction of a fluoro group to the P-side of C-2 has been quite difficult, as described earlier. Accordingly, a novel strategy that involves the inversion of C-2 of 2 -deoxy-2 -a-fluororiboside to its 2 -p-fluoro epimer was developed by Marquez and co-workers (see Scheme 7.12). In their synthesis, A -benzoyl-2 -deoxy-2 -a-fluoroadenosine (43a) was converted to 3 -0-... 

Maruyama, T., Utzumi, K., Sato, Y. and Richman, D. D. (1994) Synthesis and anti-HIV activity of 2-substituted 2 -deoxy-2 -fluoroadenosines. Nucleosides Nucleotides, 13, 1219-1230. 

The majority of newly reported nucleoside 5 -monophosphates have been prepared using phosphorus oxychloride in trialkyl phosphate solution. These include the monophosphates of 2-fluoroadenosine, 2-amino-6-chloro-9-(/S-D-ribofuranosyl)-purine, bredinin (6), cordycepin 2 -azido-2 -deoxyadenosine, 2 -fluoro-... 

Cyclic Nucleotides.—New analogues of cAMP and cGMP that have been reported include 2-fluoroadenosine 3, 5 -monophosphate, 9-/ -D-xylofuranosylguanine 3, 5 -monophosphate, 8-carbamoyl- and 8-carboxy-adenosine 3, 5 -monophosphates (prepared from 8-bromo-cAMP, using standard transformations), and a series of 2-substituted-l,A -ethenoadenosine 3, 5 -monophosphates, prepared by ring reclosure of (30), which is the product of alkaline hydrolysis of 1, N -etheno-cAMP. The last-named have useful fluorescent properties, like the parent compound. So, also, have 8-azido-l,N -ethenoadenosine 3, 5 -monophosphate (also prepared... 

Nitration of 6-substituted purines at C-2, using a mixture of tetra-n-butylammonium nitrate and trifluo-roacetic anhydride, is an exceptionally useful functionalisation of the purine ring system. The reaction works for both electron-rich (adenosine), 6-alkoxypurines and electron-poor (6-chloropurine) substrates, but full protection of all OH and NH groups is required. This is not a simple electrophihc substitution - the mechanism has been shown, using 6-chloro-9-Boc purine, to involve sequential nitration of N-7, addition of trifluoroacetoxy at C-8 and then migration of the nitro group to C-2. The final, re-aromatisation, step involves elimination of trifluoroacetic acid. Displacement of a 2-nitro group, thus introduced, by fluoride as nucleophile (see 27.5 for nucleophilic substitutions) can be made the means to synthesise 2-fluoroadenosine. ... 

Since 1976 a number of 2 -substituted 2 -deoxynucleoside 5 -diphosphates have been shown to be mechanism-based inactivators of the ribonucleotide reductases from a variety of sources (Table I). This work was extended by Stubbe and Kozarich 50, 51), who studied the reaction of several 2 -halo-substituted 2 -deoxynucleoside 5 -diphosphates with RDPR. Incubation of RDPR with CIUDP, 2 -deoxy-2 -fluoroadenosine 5 -diphosphate (FADP), or 2 -deoxy-2 -fluorocytidine 5 -diphosphate (FCDP) resulted in time-dependent enzyme inactivation, concomitant and stoichiometric loss of all substituents from the ribose moiety, increase in the UV-Vis absorbance of the protein near 320 nm, and... 

Routes to 8-fluoropurines had been limited until recently. However, an efficient one-step synthesis was reported in 1996 that has made available these compounds for a variety of studies. Thus, reaction of a series of protected oxopurines and protected adenosine with 1% F2 in He gave the corresponding 8-fluoro derivatives in 25-30% yields (Fig. 3.60). 2, 3, 5 -Tri-0-acetyl-8-fluoroadenosine so prepared was found to undergo defluorination under normal conditions of deprotection. A thermal labile hydrolase was subsequently used to effect this deprotection to produce, for the first time, free 8-fluoroadenosine. More detailed studies on the mechanism of defluorination of 8-fluoropurines indicated that acidic conditions are incompatible with 8-fluoroguanine and 8-fluoroadenosine while basic conditions are also incompatible... 

Butora, G. Schmitt, C. Levorse, D.A. Streckfuss, E. Doss, G.A. MacCoss, M. The elusive 8-fluoroadenosine a simple non-enz3unatic synthesis and characterization. 

Fluoriuation (5, 153 154). The very unstable and reactive 2, 3, 5 -tris-0- cetyl-8-fluoroadenosine (2) has been prepared for the first time by reaction of (1) with KF in the presence of 18-crown-6 with acetonitrile as solvent yield 257.. The product is of interest since 5-fluoropyrimidine nucleosides have nti-tumor activity. 

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