Fluoronucleosides, isothiocyanato C-nucleosides, and thioureylene di-C-nucleosides via cyclic sulfates

Cyclic sulfates of N- and C-nucleosides (D-ribo and D-erythro configurations, respectively) are used to prepare 3'-fluoro and 3'-azido D-xylo N-nucleosides and L-threo C-nucleosides. The reduction of the 3'-azido C-nucleosides (furan, imidazoline-2-thione, and pyrrole derivatives) gives 3'-amino C-nucleosides, which, by reaction with thiocarbonyldiimidazole, are transformed into 3'-isothiocyanato C-nucleosides. Reaction of the 3'-amino with the 3'-isothiocyanato C-nucleosides gives thioureylene di-C-nucleosides, a type of nucleotide analogue with a nonionic bridge isosteric of the phosphate group.     

Novel pyrrole C-nucleosides by nitrogen extrusion from pyridazine C-nucleosides

Pyridazine C-nucleosides have been synthesized by [4+2] cycloaddition of alkynyl C-nucleosides with substituted tetrazines. These pyridazines on extrusion of a nitrogen atom afforded novel pyrrole C-nucleosides with good yields. The results of electrochemical and chemical reduction are compared.     

Stereoselective Conversion of Sugar Derivatives into C-nucleosides

A two-step process for the transformation of readily available carbohydrate derivatives into acyclic C-nucleosides is described. The carbohydrate undergoes a scission process that is followed by the addition of aryl ketone derivatives, allowing the introduction of a variety of aryl rings. The resulting acyclic C-nucleosides are transformed into 2-deoxy cyclic pyranosides in good yield and excellent stereoselectivity.     

Modular synthesis of 5-substituted thiophen-2-yl C-2'-deoxyribonucleosides

A new modular methodology of preparation of 5-substituted thiophene-2-yl C-nucleosides was developed. A Friedel-Crafts-type of C-glycosidation of 2-bromothiophene with toluoyl-protected methylglycoside 2 gave the desired protected 1beta-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose 4a in 60%. The key intermediate 4a was then subjected to a series of palladium-catalyzed cross-coupling reactions. The cross-coupling reactions with alkyl organometallics gave beta-(5-alkylthiophen-2-yl)-2-deoxyribonucleosides 4 and 7 in moderate yields accompanied by side-products of reduction. On the other hand, cross-couplings with arylstannanes proceeded smoothly to give a series of beta-(5-arylthiophen-2-yl)-2-deoxyribonucleosides 4 in good yields. Deprotection of toluoylated nucleosides by NaOMe in MeOH and silylated nucleosides by Et 3N.3HF gave a series of free C-nucleosides 6. Alternatively, other types of 5-arylthiophene C-nucleosides 6 were prepared in one step by the aqueous-phase cross-coupling reactions of unprotected 1beta-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose with boronic acids. Title 5-arylthiophene C-nucleosides 6 exhibit interesting fluorescent properties with emission maxima varying from 339 to 396 nm depending on the aryl group attached.     

Dimetalation of pyrazines. a one-pot synthesis of multisubstituted pyrazine C-nucleosides.

As a part of our efforts to pursue direct, convergent, and concise methodologies for the synthesis of pyrazine C-nucleosides, we have successfully established a sequential dilithiation-addition method, which allows one to introduce two different functional groups to a pyrazine ring in a one-pot fashion. 2,6-Dichloropyrazine was dilithiated at -100 degrees C and then allowed to react with an electrophile, such as bromine, iodine, or disulfides, followed by a reaction with a protected ribonolactone to afford C-nucleosides. After reduction and deprotection, tetrasubstituted pyrazine C-nucleosides, including 2,6-dichloro-3-iodo-5-(beta-D-ribofuranosyl)pyrazine and 2-bromo-3,5-dichloro-6-(beta-D-ribofuranosyl)pyrazine, were obtained. A tandem reaction sequence occurred when disulfides were used, resulting in the formation of 5,6-bis-methylthio-2-chloro-3-(beta-D-ribofuranosyl)pyrazine and 6-(beta-D-ribofuranosyl)-2,3,5-tris-phenylthiopyrazine.     

Preparation of stilbene-tethered nonnatural nucleosides for use with blue-fluorescent antibodies

The synthesis of the first examples of stilbene-tethered hydrophobic C-nucleosides is described. Compounds of this type are targeted for use with our recently reported "blue-fluorescent antibodies" with the aim of probing native and nonnatural DNA. The nucleophilic addition of aryl Grignard reagents to either a protected 2'-deoxy-1'-chloro-ribofuranose or a protected 2'-deoxy-ribonolactone was the key synthetic step and afforded C-nucleosides in good yields. Both routes resulted in a final product that was >/=90% of the beta-anomer. Amide- and ether-based linkers for attachment of trans-stilbene to the nucleobase were assessed for utility during synthesis and in binding of the ligands to a blue-fluorescent monoclonal antibody. X-ray structures of each complex were obtained and serve as a guideline for second-generation stilbene-tethered C-nucleosides. The development of these hydrophobic nucleosides will be useful in current native and nonnatural DNA studies and invaluable for investigations regarding novel, nonnatural genomes in the future.     

Concise synthesis of aryl-C-nucleosides by Friedel-Crafts alkylation

A fast and simplified synthesis of 1',2'-dideoxy-1'-pyrenyl-riboside and several other C-nucleosides is shown. Shelf-stable 1-O-methyl-3,5-di-O-toluoyl-2-deoxyribose is demonstrated to serve as a versatile glycosyl donor in Lewis acid promoted Friedel-Crafts alkylations of unsubstituted pyrene and other inexpensive arenes such as fluorene and methylnaphthalene. The reaction conditions favour the formation of beta-configurated C-nucleosides which renders additional epimerisation steps unnecessary. As a result, protected beta-aryl-C-nucleosides are available directly from non-substituted arenes in three steps overall.     

Studies on the generation of unnatural C-nucleosides with 1-alkynyl-2-deoxy-D-riboses

1-alkynyl-2-deoxy-D-riboses 7 and 8 were independently synthesized and subsequently used to generate several novel C-nucleosides.     

Synthesis and Anti-H5N1 Activity of Substituted Pyridine Glycosides and (Oxadiazolyl)oxymethylpyridine Acyclic C-Nucleoside Analogues

Russian Journal of General Chemistry - New aryl- and heteroaryl-substituted pyridinyl sugar hydrazones and their derivatives, 1,3,4-oxadiazole acyclic C-nucleosides, were synthesized. Novel...     

Synthèse de C-nucléosides dérivés de l'hydroxy-8 (1,2,4)triazolo[1,5-c] et [4,3-c]pyrimidines

Ether and ester derivatives corresponding to the novel C-nucleosides 2-β-D-ribofuranosyl-8-hydroxy[1,2,4]triazolo[1,5-c]pyrimidine and 2-(2-hydroxyethoxymethyl)-8-hydroxy[1,2,4]TRIAZOLO[1,5-C]Pyrimidine were obtained by condensation of 5-benzyloxy-4-hydrazinopyrimidine respectively with thiobenzy1-2-(2-benzoyloxyethoxy)acetimidate hydrochloride. Cleavage of the easter group by ammonia in methanol followed by hydrogenolysis of the benzylic ether afforded the above C-nucleosides derived from heterocyclic phenols. Unambiguous structural assignment were made by UV AND ¹H and ¹³C nmr studies.     

Carbocyclic 4′-epi-formycin

Formycin is a naturally occurring biologically responsive C-nucleoside. In pursuing the design and syntheses of novel C-nucleosides, convenient access to carbocyclic C-nucleosides based on the formycin framework was a goal. One such target was carbocyclic 4′-epi-formycin (4). This compound is reported via a procedure based on an asymmetric aldol/ring closure metathesis strategy. To provide a preliminary glimpse into the biological characterization of 4 an antiviral assay was conducted. Target 4 was found to be inactive and to lack cytotoxicity to the host cells.     

Modular and practical synthesis of 6-substituted pyridin-3-yl C-nucleosides

A novel modular and practical methodology for preparation of 6-substituted pyridin-3-yl C-nucleosides was developed. The Heck reaction of 2-chloro-5-iodopyridine with a 3'-TBDMS-protected glycal gave a 6-chloropyridin-3-yl nucleoside analogue, which was then desilylated, selectively reduced, and reprotected to give the TBDMS-protected 6-chloropyridin-3-yl C-2'-deoxyribonucleoside as a pure beta-anomer in a total yield of 39% over four steps. This key intermediate was then subjected to a series of palladium-catalyzed cross-coupling reactions, aminations, and alkoxylations to give a series of protected 1beta-(6-alkyl-, 6-aryl-, 6-hetaryl, 6-amino-, and 6-tert-butoxypyridin-3-yl)-2'-deoxyribonucleosides. 6-Unsubstituted pyridin-3-yl C-nucleoside was prepared by catalytic hydrogenation of the chloro derivative and 6-oxopyridine C-nucleoside by treatment of the 6-tert-butoxy derivative with TFA. Deprotection of all the silylated nucleosides by Et3N.3HF gave a series of free C-nucleosides (10 examples).     

Recent advances in the chemistry of nucleosides and their analogs (review)

Methods for the preparation of nucleosides and their analogs, C-nucleosides, and cyclonucleosides, and their properties are reviewed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 723–738, June, 1978.     

Alkynyl-2-deoxy-d-riboses, a cornucopia for the generation of families of C-nucleosides

This study focuses on the preparation of some 1-alkynyl-2-deoxy-d-riboses and their application to the generation of C-nucleosides analogues. Examples are provided in which the alkyne functionality took part in alkylation or cycloaddition reactions. A discussion of the protecting group used is provided.     

1,3-Dipolar cycloaddition approach to pyrrolidine analogues of C-nucleosides related to pseudouridine

Pyrrolidine analogues of C-nucleosides related to pseudouridine have been synthesized by 1,3-dipolar cycloaddition reactions of uracil-5 and 2,4-dimethoxypyrimidine-5 nitrones with allyl alcohol and methyl acrylate, and subsequent reductive cleavage of the isoxazolidine cycloadducts. The dimethoxy derivatives have been easily deprotected to the corresponding uracils bearing the pyrrolidine ring instead of a sugar moiety. The regio and stereoselectivity of the reactions are discussed.     

Mannich-type C-nucleosidations in the 5,8-diaza-7,9-dicarba-purine family

[structure: see text] C-Nucleosidation with cyclic iminium salts occurring under mild reaction conditions and affording C-nucleosides that are isosteric with N-nucleosides of natural purines is shown to be a consistent property of the entire family of 2,6-(oxo or amino)-disubstituted 5,8-diaza-7,9-dicarba-purines.     

Synthesis of C-nucleosides via coupling of ribosyl fluoride with typical aromatic heterocycles bearing a TMS group

The direct coupling reaction of D -ribosyl fluoride with typical π-excessive aromatic heterocycles such as furan, thiophene, pyrrole, benzofuran, benzothiophene, and indole and their trimethylsilyl derivatives was performed in the presence of boron trifluoride to afford the corresponding C-nucleosides in moderate to good yields.     

Practical synthesis of 1′-substituted Tubercidin C-nucleoside analogs

Several 1′-substituted analogs of Tubercidin C-nucleosides were prepared using a highly convergent synthesis. Good to high diastereoselectivity was achieved using a variety of nucleophiles targeting the 1′-position. The source for this stereoselectivity is herein proposed. It is thought to be attributed to a temperature-dependent chelation of the incoming nucleophile to either the 2′- or 3′-benzyloxy ether of the ribose core.     

New modular and efficient approach to 6-substituted pyridin-2-yl C-nucleosides

A novel modular, efficient, and practical methodology of preparation of 6-substituted pyridin-2-yl C-nucleosides was developed. An addition of 2-lithio-6-bromopyridine 2b to TBDMS-protected 2-deoxyribonolactone 5 gave aduct 7 as an equilibrium mixture of anomeric hemiketals 1-(6-bromopyridin-2-yl)-1-hydroxynucleosides 7a,b and its open form 7c. Reduction of the adduct 7 with Et3SiH and BF3 x Et2O afforded the desired 6-bromonucleoside 8a as pure beta-anomer in a total yield of 32% over two steps from 5. Intermediate 8a was then subjected to a series of palladium catalyzed cross-coupling reactions and aminations to give a series of protected 1beta-(6-alkyl-, 6-aryl-, and 6-aminopyridin-2-yl)-2-deoxyribonucleosides 9. Catalytic hydrogenation of 8a gave an unsubstituted pyridine C-nucleoside, and diazotative oxodeamination of 6-aminopyridine nucleoside 9f by isopentyl nitrite in acetic acid gave 6-oxopyridine nucleoside 10i. Deprotection of silylated nucleosides 9 by Et3N.3HF gave a series of free C-nucleosides 10.     

Isoxazolidine analogues of pseudouridine: a new class of modified nucleosides

A new class of modified C-nucleosides has been synthesized according to the 1,3-dipolar cycloaddition methodology. The obtained compounds are structurally related to natural pseudouridine, where the sugar moiety is replaced by an isoxazolidine ring. Different experimental conditions, and the effect of additives on the cycloaddition process, have been examined; the best results were obtained when the cycloaddition reaction was performed under microwave irradiation