6-Bromopurine Nucleosides as Reagents for Nucleoside Analogue Synthesis

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...

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Bibliographic Details
Published in:Journal of organic chemistry 2001-12, Vol.66 (25), p.8592-8598
Main Authors: Véliz, Eduardo A, Beal, Peter A
Format: Article
Language:English
Subjects:
Amines - chemistry
Catalysis
Indicators and Reagents
Metals
Nucleosides - chemical synthesis
Oxygen - chemistry
Purines - chemical synthesis
Sulfur - chemistry
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Summary: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 SNAr 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 SNAr 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.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo016078v