Convenient synthesis of 2-halo-2'-deoxyadenosines

Wright, George E.; Hildebrand, Catherine; Freese, Stephen; Dudycz, Lech; Kazimierczuk, Zygmunt

doi:10.1021/jo00229a037

Cited by 17 publications

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“…A search of the literature found that N 2 -aryl-2-aminopurine derivatives had been synthesized by the reaction of 2-bromopurines with the appropriate aromatic amine in alcohol at reflux. , This result indicated that direct displacement of bromide from the purine C2 could be accomplished with weak nucleophiles, such as aromatic amines. In addition, it was found that 2-halo-6-bromopurine derivatives underwent substitution at the C6 position under mild conditions (25 °C), − whereas, the subsequent reaction at the C2 position required more forcing conditions (120 °C) . Little was known, however, regarding the efficiency of direct displacement of bromide from the 6-position of 6-bromopurine nucleosides.…”

Section: Resultsmentioning

confidence: 99%

6-Bromopurine Nucleosides as Reagents for Nucleoside Analogue Synthesis

Véliz

Beal

2001

J. Org. Chem.

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Surprisingly facile direct substitution reactions with acetyl-protected 6-bromopurine nucleosides are described. Included in the series of bromonucleosides studied is the guanosine derivative N(2)-2',3',5'-tetraacetyl-6-bromopurine ribonucleoside, the synthesis of which is reported here for the first time. Brominated nucleosides had not previously been considered optimal substrates for S(N)Ar reactions given the general reactivity trend for halogenated aromatic systems (i.e. F > Cl > Br > I). However, even weakly nucleophilic aromatic amines give high yields of the substitution products in polar solvents with these 6-bromopurine nucleosides. For primary aromatic amines, secondary aliphatic amines, and imidazole, reaction takes place only at C6, with no effect on the acetyl-protected ribose. In addition, we report the first synthesis of 3',5'-di-O-acetyl-6-bromopurine-2'-deoxyribonucleoside and its reaction with an arylamine in MeOH in the absence of added metal catalyst. Thus, C6-arylamine derivatives of both adenosine and 2'-deoxyadenosine can be prepared via simple S(N)Ar reactions with the corresponding 6-bromo precursor. We also describe high yielding and C6-selective substitution reactions with 6-bromonucleosides using alcohol and thiol nucleophiles in the presence of added base (DBU). Finally, C6-bromonucleosides are shown to be readily hydrogenated to give purine or 2-aminopurine products in good yield. This work increases the arsenal of reactions and strategies available for the synthesis of nucleoside analogues as potential biochemical tools or new therapeutics.

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Section: Resultsmentioning

confidence: 99%

6-Bromopurine Nucleosides as Reagents for Nucleoside Analogue Synthesis

Véliz

Beal

2001

J. Org. Chem.

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“…More recently, l a was prepared from 2-iodoadenosine photochemically [ 191. We observed that the very potent antileucemic drug [20] 2-chloro-2'-deoxyadenosine (9a) prepared from dichloro compound 8a [21[ [22] as well as its bromo analogue 10 [23] also underwent photochemical transformation. As we considered the syntheses of the base-modified 2'-deoxyisoguanosine analogues 3 and 4, we tested the applicability of this reaction on compounds 9b [24], and pyrazolo[3,4-d]pyrimidine derivative 9c was obtained from 8c [25] by selective displacement of the 4-chloro substituent with methanolic ammonia under simultaneous deprotection of the toluoyl groups (Scheme 2).…”

Section: Aa)mentioning

confidence: 99%

2′‐Deoxyisoguanosine and Base‐Modified Analogues: Chemical and Photochemical Synthesis

Kazimierczuk

Mertens

Kawczynski

et al. 1991

Helvetica Chimica Acta

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The synthesis of 2'-dcoxyisoguanosine (2), and the pyrrolo[2,3-d]pyrimidine and pyrazolo [3,4-d]pyrimidine 2'-deoxyribonucleosides 3 and 4 is described. Condensation of the imidazole precursor 5 with benzoyl isocyanate followed by reaction with ammonia gave 2. Its N(7) regioisomer was obtained from 6. Compound 2 was also prepared by the photochemically induced conversion of 2-chloro-and 2-bromopurine 2'-deoxyribofuranosides 9a and 10, respectively, in aqueous solution. The photo reaction was further used for the synthesis of the compounds 3 and 4 starting with the amino-chloro-2'-deoxynucleosides 9b and 9c, respectively.

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“…The efficient chemical method for the synthesis of cladribine consists in the stereospecific glycosylation of sodium salt of 2,6-dichloropurine with 2-deoxy-3,5-di-O-p-toluoyl-a-d-ribofuranosyl chloride leading to the formation of the corresponding N 9 -b-d-nucleoside as the main product (58%), along with the N 9 -a-d-isomer (13%) [31] [32]. Treatment of the former with NH 3 afforded cladribine (71%) [31] [32].…”

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confidence: 99%

“…Treatment of the former with NH 3 afforded cladribine (71%) [31] [32]. Two enzymatic approaches have been used for the preparation of cladribine.…”

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A Universal Biocatalyst for the Preparation of Base- and Sugar-Modified Nucleosides via an Enzymatic Transglycosylation

Barai

Zinchenko

Eroshevskaya

et al. 2002

HCA

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Dedicated to Prof. Dr. Wolfgang Pfleiderer on the occasion of his 75th birthdayThe E. coli BMT-4D/1A cells have been selected according to Munch-Petersen et al. They carry two regulatory mutations (cytR and deoR) and are able to synthesize constitutively nucleoside-catabolizing enzymes, e.g., cells that possess high UPase and PNPase activities. The cells have been cross-linked by glutaraldehyde to afford a biocatalyst that retained high UPase and PNPase activities and was comfortable for repeated use. An incubation of 2'-deoxyguanosine (1) and 2-chloroadenine (2) (molar ratio 3 : 1) in Kphosphate buffer (10 mm ; pH 7.0) in the presence of the biocatalyst at 658 for 7 h resulted in quantitative transformation of 2 into 2-chloro-2'-deoxyadenosine (4; cladribine) that was isolated in 81% yield (Scheme 1). Similarly, the reaction of guanosine (5) and 1,2,4-triazole-3-carboxamide (6) (molar ratio 1 : 1) in K-phosphate buffer (10 mm ; pH 7.0) in the presence of the biocatalyst at 608 for 30 h led to the formation of 1-(b-dribofuranosyl)-1,2,4-triazole-3-carboxamide (8; ribavirin) in 90 ± 92% yield (67 ± 70% isolated yield) (Scheme 2).Introduction. ± Nucleoside analogues are a mainstream in the treatment of many viral infections and play a significant role in the chemotherapy of different malignancies [1 ± 4]. Most of them are produced by chemical methods employing the natural nucleosides as starting compounds, or by a convergent approach via the condensation of the carbohydrate precursor and heterocyclic base. The latter strategy suffers from many drawbacks, most serious of which are the low stereospecificity of the glycosidic-bond formation and ambiguous regiospecificity, especially in the case of purine bases. As a result, chemical schemes of nucleoside-analogue preparation are rather complicated and accompanied by a tedious isolation of the individual desired compounds [5].Considerable progress in the preparation of nucleoside analogues under consideration was achieved by combination of chemical methods and biochemical transformations (for reviews, see [6]). The enzymatic equilibrium-transfer reaction of the sugar moiety of one nucleoside to the heterocyclic base was discovered by Krenitsky in the 60×s [7] [8]. It was established that this equilibrium reaction is catalyzed by purine nucleoside phosphorylase (PNPase) in the case of purine nucleosides and purine bases, and by uridine (thymidine) phosphorylases (UPase or TPase) in the case of pyrimidine nucleosides and pyrimidines. More than a decade later, it was shown that this reaction can be used for the preparation of base-and sugar-modified nucleosides [9 ± 13].

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Convenient synthesis of 2-halo-2'-deoxyadenosines

Cited by 17 publications

References 0 publications

6-Bromopurine Nucleosides as Reagents for Nucleoside Analogue Synthesis

6-Bromopurine Nucleosides as Reagents for Nucleoside Analogue Synthesis

2′‐Deoxyisoguanosine and Base‐Modified Analogues: Chemical and Photochemical Synthesis

A Universal Biocatalyst for the Preparation of Base- and Sugar-Modified Nucleosides via an Enzymatic Transglycosylation

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