Synthesis Of Nucleoside Analogues Research Articles

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 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.

Chiral Synthons from the Iridoid Glucoside Antirrhinoside − Synthesis of a Carbocyclic Homonucleoside Analogue

The synthetic modification of the natural cyclopentanoid monoterpene glucoside antirrhinoside is reported. Some stereoselective modifications have been performed on the bicyclic iridoidic ring, resulting in opening of the dihydropyran ring. A series of chiral synthons having a highly oxygenated cyclopentanoid ring has been prepared, which could be used in the synthesis of nucleoside analogues. We describe herein the synthesis of an acyclovir derivative (DA-146) as an example.

Synthesis of nucleoside analogs and new Tat protein inhibitors

Two studies, concerning the synthesis of original nucleoside analogs regarded as an application of heterochemistry on thiaazaheterocycle systems from thiaazabutadienes are discussed. The preparation of new N- and C-nucleosides is presented. In the second part, the discovery of aromatic polycyclic derivatives as inhibitors of Tat protein is exposed. The work presented takes into account the participation of African partners in further synthetic research programs carried out in collaboration with the laboratory of Nantes.

The Cohalogenation of 1-N-Vinylpyrimidinediones: A New Approach to Nucleoside Analogs

A new approach to the synthesis of nucleoside analogs has been developed, which involves initial chemo- and regioselective cohalogenation of 1-N-vinylpyrimidinediones 10a,b using N-bromosuccinimide in the presence of variously substituted propargylic alcohols. Radical carbocyclization of the resulting β-bromo propargylic ethers 17-22 then leads to 3-methylenetetrahydrofurans 23-26. In such cyclizations, different reactivities have been observed for diastereomers 22a,b obtained by cohalogenation with (R)-1-benzyloxybut-3-yn-2-ol; although the expected anti 3-methylenetetrahydrofurans 27a,b were obtained, the syn diastereomers 28a,b were only the minor constituents of a mixture in which bicyclonucleosides 29a,b were the major components. The formation of 29a,b results from a 1,6-hydrogen transfer followed by cyclization, which might be favored by a CH-π interaction in radical intermediate synII.

Stereoselective synthesis of nucleoside analogues of chiral imidazolidines from sugar isothiocyanates

The syntheses of the disaccharide 5 and the trisaccharide 6 glycosyl isothiocyanates starting from di- or monosaccharide N-dialkoxycarbonylvinylglycosylamines 1 and 2 are described. Compounds 5, 6, α- d -ribopyranosyl) and β-( d -glucopyranosyl, d -ribopyranosyl) isothiocyanates and 1,3,4,6-tetra- O-acetyl-2-deoxy-2-isothiocyanato-β- d -glucopyranose are used in the diastereoselective synthesis of the nucleoside analogues of (5 R)- and (5 S)-5-hydroxyimidazolidine-2-thiones 7, 11, 14, 16, 17, 18a, and 18b. The 5 R:5 S ratio depends on the anomeric configuration (configuration of C-2′ for 18a, 18b) of the sugar isothiocyanate. β-Glycosyl isothiocyanates give mostly the (5 R)-epimer, whereas when a α-glycosyl isothiocyanate is used, there is practically no stereoselectivity.

Nitrogen Glycosylation Reactions Involving Pyrimidine and Purine Nucleoside Bases with Furanoside Sugars

Different approaches for the synthesis of nucleoside analogs (potential HIV inhibitors) are described. Starting from a suitably substituted furanose ring, it is demonstrated that a high facial stereocontrol of the glycosylation reaction can be effected. Different reaction conditions including Lewis acid promoted, SN2 displacement and some enzymatic methodologies for the stereoselective synthesis of these compounds are reviewed.

Synthesis of Nucleoside Analogues Using Immobilised N-Deoxyribosyltransferases

Crude N-deoxyribosyltransferase from Lactobacillus leichmannii was immobilised by hydrophobic interaction on octyl-Sepharose or by covalent attachment to poly(acrylamide-co-N-acryl-oxysuccinimide) (PAN). Little enzyme activity was retained by entrapment in K-carrageenan. N-deoxyribosyltransferase immobilised on PAN was used to prepare 2′-deoxy-2-thiouridine.

Synthesis of nucleoside analogues with a 1,5-anhydrohexitol moiety

Glucose after conversion to a 3-deoxy-1,5-anhydro-D-glucitol moiety, was coupled at its 2-position to heterocyclic bases either by nucleophilic displacement or under Mitsunobu reaction conditions to afford new nucleoside analogues with a 1,5-anhydrohexitol moiety.

ChemInform Abstract: A New Strategy for the Synthesis of Nucleoside Analogues Based on Enzyme‐Catalyzed Aldol Reactions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of Nucleoside Analogues Containing an Oxetane Ring Fused to the Furan Ring

Abstract The photo-adduct obtained from benzoyloxyacetaldehyde and furan was epoxidized, and the tricyclic compound was converted by reaction of persilylated thymine and cytosine in the presence of zinc chloride to thymidine and cytidine analogues containing a fused dioxabicyclo[3.2.0]heptane „sugar“ portion, which were converted to furanosides of well defined stereochemistry.

A new strategy for the synthesis of nucleoside analogs based on enzyme-catalyzed aldol reactions

A new synthetic approach to nucleoside analogs based on enzyme-catalyzed aldol condensations has been demonstrated in the synthesis of 6-adenyl-6-deoxy-D-fructose and 6-adenyl-6-deoxy-L-sorbose

Organometallic Intermediates in the Synthesis of Nucleoside Analogs

Abstract The common nucleosides, modified or derivatized in some way at the heterocyclic ring carbons, include examples of structures which a r e useful as biological probes and chemotherapeutic agents. Like previous authors, we will use the term “nucleoside analog” for structures related to one of the common naturally occurring nucleosides. Nucleosicle analogs can be derivatives which differ by such minor modification as replacement of hydrogen by a single atom or derivatives which are grossly modified at both the carbohydrate and the base. Examples of the former include 5-fluoro-2′-deoxyuridine, an inhibitor of thymidylate synthetase as its 5′-phosphate, and 5′-iodo-2′-deoxyuridine, a clinically useful antiviral agent. Larger groups have frequently been linked to nucleoside as probes for enzymatic processes. Side chains in “nonrestricted positions” may be used to carry spectroscopic or chemically reactive probes, or provide the means to attach a molecule to an affinity column. Ultimately with positions of bulk tolerance defined, it may be possible to design “active site directed irreversible enzyme inhibitors” as defined by B.R. Baker. Nucleoside structures in which a side chain is attached at a pyrimidine or purine carbon will undoubtedly, in some instances be the most appropriate structure. Yet, these have typically been more difficult to synthesize than analogs with side chains attached to heteroatoms.

Synthesis of nucleoside analogs by addition-cyclization reaction of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate

Reactions of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate (I) with various hydrazides gave 4-substituted 1-acylthiosemicarbazides. Their cyclization, by treatment with sodium methoxide, gave analogs of nucleosides. The reaction of (I with thioglycolic acid to give substituted 1,3-thiadiazolidine has also been studied.

A general, stereocontrolled entry to pyrimidine homo- [formula omitted]-nucleosides

A simple synthesis of nucleoside analogues with a methylene group between the ribose and 5-position of pyrimidine appendages is outlined.

Synthesis of nucleoside analogs from hydrazine derivatives

Synthesis of nucleoside analogs from hydrazine derivatives

ChemInform Abstract: SYNTHESIS OF NUCLEOSIDE ANALOGS OF 1,4‐OXATHIANE, 1,4‐DITHIANE, AND 1,4‐DIOXANE

Abstract1,4‐Oxathian (I) liefert das Sulfoxid (II), das nach Pummerer zu (III) acetyliert wird.

Synthesis of nucleoside analogs of 1,4‐oxathiane, 1,4‐dithiane, and 1,4‐dioxane

AbstractThe two regioisomers 6‐chloro‐9‐(1, 4‐oxathian‐3‐yl)‐9H‐purine (5) and 6‐chloro‐9‐(1,4‐oxathian‐2‐yl)‐9H‐purine (6) were obtained when 3‐acetoxy‐1,4‐oxathiane (3) was subjected to the acid‐catalyzed fusion procedure; compound 3 was prepared by a Pummerer reaction with 1,4‐oxathiane 4‐oxide (2). The nucleoside analog 6 could he converted into the adenine derivative 7 and 9‐(1,4‐oxathian‐2‐yl)‐9H‐purine‐6(1H)thione (8). The following nucleoside analogs have also been synthesized: 6‐chloro‐9‐(1,4‐dithian‐2‐yl)‐9H‐purine (13), 9‐(1,4‐dithian‐2‐yl)adenine (14), 9‐(1,4‐dithian‐2‐yl)‐9H‐purine‐6(1H)thione (15), and 6‐chloro‐9‐(1,4‐dioxan‐2‐yl)‐9H‐purine (18).