Synthesis of Purine Nucleosides

8-dichloro-9-D-glucopyranosyl-9H-adenine (36), now known to have the /3 configuration at the glycosyl center. By appropriate reactions, this nucleoside was converted to 9-/3-n-glucopyranosyladenine (37) and 9-/3-D-glucopyranosylguanine (38). 

Almost thirty years passed before Todd and coworkers applied the Fischer-Helferich procedure to the synthesis of the natural purine nucleosides, adenosine (l)i and guanosine (2). Condensation of tri-O-acetyl-D-ribofuranosyl chloride, prepared from 5-0-benzyl-D-ribose by way of tetra-0-acetyl-D-ribofuranose,i 2 with the silver salt of 2,8-dichloroadenine 

The stereochemistry underlying the trans rule—that is, control of the entry of the purine moiety by the 2-acyloxy group of the sugar—discussed in detail by Baker, has been reviewed comprehensively in this Series by Fox. Reviews of the mechanisms of glycoside syntheses from poly-0-acylglycosyl halides have also appeared. -  

Although Baker and coworkers have found exceptions to the C-l-C-2-trans rule that have been related to iV -benzoyladenine and to particular sugars, such as 2,3-di-0-acetyl-5-deoxy-D-ribofuranosyl chloride, it should be emphasized that anomers having the C-l-C-2-cfs configuration are not often observed and, when they are observed, they occur in only minor proportion. Khorana and coworkers, by applying the converse 

7- and 9-isomers. This same work also established that, contrary to then-existing opinion, the nature of the glycosyl halide can also determine the position into which it enters, since tetra-O-acetyl-D-gluco-pyranosyl bromide and the chloromercuri derivative of JV ,iV -dimethyl-adenine (44a) gave only the iV -nucleoside (45a) whereas tri-O-acetyl- 

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Davoll, J., Lythgoe, B., Todd, A.R. (1948) Experiments on the Synthesis of Purine Nucleosides. Part XIX. A Synthesis of Adenosine. Journal of the Chemical Society, 967-969. 

The value of some nucleosides for use as flavor enhancers,1348 and the possible antiviral or antitumor activity of certain nucleosides,135 have led to the synthesis of purine nucleosides containing analogs of D-apiose in which the ring-oxygen atom of the furanose forms has been replaced.136 Monomolar p-toluenesulfonylation of 3-C-(hydroxy-methyl)-l,2-0-isopropylidene-/3-L-threofuranose (50) yielded 3-C-(hydroxymethyl)-l,2-0-isopropylidene-31-0-p-tolylsulfonyl-/3-L-thre-ofuranose (51) which, through a series of steps, was converted into either methyl 2,3-O-isopropylidene- [3-C-(hydroxymethyl)-4-thio-/3-D-... 

Almost all recorded purine syntheses from imidazoles involve the cyclization of 5(4)-aminoimidazole-4(5)-carboxylic acid derivatives especially the carboxamides, thiocar-boxamides, carboxamidines, carboxamidoximes, nitriles and esters. The intermediates used for completion of the purine ring are much the same as have been used for Traube cyclization of diaminopyrimidines (Section 4.09.7.3), especially formic and carbonic acid derivatives, and cyclization generally occurs-under much milder conditions. This feature has been of special value in the synthesis of purine nucleosides from imidazole nucleoside precursors. The resultant purine will have variable substituents at C-2 and C-6 and it is convenient to discuss and classify the various preparations largely in terms of the introduced 2-substituents. The C-6 substituents largely reflect the type of carboxylic acid moiety used and do not vary very much between amino, oxo and thioxo. 

VII. Solid-state synthesis of purine nucleosides. J. Mol. Evol. 90. 1972 1 249-257. 

In contrast to the synthesis of purines, the synthesis of purine nucleosides from glycosylated pyrimidinediamines is less common than from glycosylated imidazoles. The synthesis protocol follows that of simple purines. A one-carbon unit is introduced into a 4-(glycosylamino)-pyrimidin-5-amine by selective thioformylalion of the 5-amino group with subsequent cycliza-tion of the 5-thioformamido compound under basic conditions, e.g. the sequence 4 5 -> 6. ... 

The transglycosylation method for the introduction of a sugar in a purine base is unique and often useful, especially for the synthesis of purine nucleosides of functionalized sugars that are difficult to prepare by conventional procedures, e.g. formation of 19. The transfer of the ribosyl moiety of acylated pyrimidine nucleosides to purines has been accomplished in the presence of a Lewis acid catalyst. ... 

Wolfrom and Conigliaro4 found that S-ethyl trifluorothioacetate selectively acylates the amino group of 2-amino-2-desoxy-D-glucose (methanolic sodium methoxide, 24 hours, room temperature, 73% yield). They used this protective group in the synthesis of purine nucleosides. The group was removed by means of methanolic ammonia. (Note that purine nucleosides are unstable to acid.)... 

This method for the synthesis of purine nucleosides, developed by Todd and coworkers, was valuable in that it unequivocally established that the point of attachment of the sugar moiety of the nucleic acid nucleosides is at N-9. In this synthesis, a sugar is condensed with a 4,6-diaminopyrim-idine (132) in alcohol solution in the presence of acid, and the resultant 4-amino-6-(glycosylamino)pyrimidine (133) is coupled with an aromatic diazonium salt. The (phenylazo)pyrimidine (134) is reduced to the amino compound (135), and cyclization to the purine nucleoside (137) is accomplished by way of the 5-thioformamide compound (136). 

Trifluoroacetyl as an N-Protective Group in the Synthesis of Purine Nucleosides of 2-Amino-2-deoxy Saccharides, M. L. Wolfrom and P. J. Conigliaro, Carbohyd. Res., 11, 63-76 (1969). 

J. Davoll, B. Lythgoe, and A. R. Todd, Synthesis of purine nucleosides. XII. The configuration at the glycosidic center in natural and synthetic pyrimidine and purine nucleosides, J. Chem. Soc., (1946) 833-838. 

A comparison between three standard methods of synthesis of purine nucleosides, namely fusion, condensation of acetylated glycosyl chlorides, and from 1-acetates in the presence of titanium(iv) chloride has been made. Thus when the glucosaminyl acetate (1) was fused with theophylline in the presence of p-toluenesulphonic acid and p-nitrophenol, a 45 % yield of the nucleoside (2) was obtained. In contrast to the findings of Ishido et al. Carbohydrate Res., 1975, 44, 215), lower yields were obtained when the activating agents were omitted. The nucleoside (3) synthesized in 32 % yield from the glucosyl acetate... 

Since pentoses and phosphates were not included in the HCN-NH4OH mixtures one could not expect the formation of nucleosides or nucleoside phosphates in such mixtures, as in the biochemical de novo synthesis of purine nucleotides, even though an adenine derivative of possible nucleosidic nature was detected in one of our early experiments. Alternate biochemical routes also exist (salvage pathways) for the synthesis of nucleosides from the preformed bases. The latter general approach has been followed in the prebiotic synthesis of purine nucleosides, and the former has been used in the synthesis of pyrimidine nucleosides and nucleotides. 

The synthesis of purine nucleosides is easier. Thus, when purine bases are heated with ribose and the salts from sea water (which contain magnesium chloride, a catalyst for this reaction) small yields of the different nucleosides are obtained, approximately 3% of /S-guanosine, 2% of /3-adenosine and comparable yields of the a-nucleosides. ... 

Fuller, W. D., Sanchez R. A. and Orgel L. E. (1972) Studies in prebiotic synthesis. Solid-state synthesis of purine nucleosides. J. Molec. Evolution 1, 249-257. 

Furukawa, Y andHonjo, M (1968) A novel method for the synthesis of purine nucleosides using Friedels-Crafts catalysts Chem Pharm Bull 16,1076-1080... 

Since the discussion livened up again about the formation of nucleotides for DNA-replication and DNA-repair by the contested theory of Werner (1971) it seems important to study the problems of nucleotide formation during repair processes. Our own studies performed with the radiosensitive organism Byssochlamys fulva and the radioresistant Pullularia pullulans led us to suppose that the synthesis of purine nucleoside monophosphates via purinephosphoribosyltransferase (purine-PRT) is not as sensitive to radiation as the de novo synthesis. Therefore a relation between the salvage pathway and nucleotide formation during repair processes does not seem impossible. 

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