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New key carbohydrate intermediate, 1-chloroacetyl-1-dehydroxy-2,3,5-tri-O-benzoyl-β-D-ribofuranose (1a), has been synthesized. The application of this key intermediate would be very wide. We have very conveniently synthesized several C-nucleosides including monocyclic and 5,5-membered bicyclic compounds from this intermediate.

Facile and general preparative method of C-nucleosides has been achieved via 4 steps starting from 2-deoxy-D-ribose. The essential step in this method is the use of radical coupling reaction of 2-deoxy-D-ribofuranosyl radical derivative and some heteroaromatic bases.

The various synthetic approaches to 2′-deoxyribo-C-nucleosides are summarized. These approaches are divided into four groups. Emphasis is placed on the techniques used in determination of anomeric configuration in the products.

D-Glucosamine 1 can be easily converted into 2,5-anhydro-6-O-benzoyl-3,4-dideoxygluconic acid 6 which can be taken on to both 2′,3′-dideoxynucleosides such as dideoxyuridine (ddU) 4 and 2′,3′-dideoxy C-nucleosides such as dideoxyformycin B 5 and dideoxyshowdomycin 20.

A new stereoselective synthesis of C-nucleosides is described. The fused NH,NH-dihydro pyrazole derivative 1 was transformed with carbohydrates into chiral azomethine imines 2 – 4 . The 1,3-dipolar cycloaddition of these to methyl acrylate affords the nucleosides 5 – 7 . The compound 8 was prepared from 1 , unprotected D-ribose and methyl acrylate in a one-pot procedure. The synthesis is highly stereoselective to give products in >62;95% ee, except for 5 .

Novel syntheses of 4′-modified cyclopentenyl pyrimidine C-nucleosides were performed via C-C bond formation using SN2 alkylation via the key intermediate mesylates 6 and 16, which were prepared from acyclic ketone derivatives. When antiviral evaluation of synthesized compound was performed against various viruses such as HIV-1, HSV-1 and HSV-2, isocytidine analogue 20 showed moderate anti-HIV activity in CEM cell line (EC50 = 13.1 μmol).7

Two series of aldose N-(3-substituted-4-oxo-3,4-dihydroquinazolin-2-yl)hydrazones were prepared by the reaction of each of the aldoses with the appropriate 2-hydrazino-3-substituted-quinazolin-4(3H)-ones. Oxidative cyclisation of these aldose hydrazones with ferric chloride in ethanol yielded the title acyclo C-nucleosides.

The Hantzsch reaction of C-glycosyl aldehyde/enamino ester/beta-ketoester systems under l-proline catalysis to give dihydropyridine C-glycoconjugates is reported. Asymmetric cyclocondensations of differentially substituted enamine and beta-dicarbonyl components with formyl alpha-L-C-threofuranoside and with the alpha-D-isomer were also carried out. Each reaction occurred with high yet opposite stereoselectivity (de95%) so that the pair of alpha-threofuranose C-nucleoside enantiomers was prepared.

Structure and biological activity of thirty-six new nucleoside antibiotics which appeared after the 1988 review are described. New synthetic analogs of neplanocin and oxetanocin are also described with special emphasis on their antiviral activities. New biosynthetic findings on nikkomycins, blasticidin S, and griseolic acid are also reviewed.

The first synthesis of an imidazole C-nucleoside linked through C-4, 2-carbamoyl-4-(2′-deoxy-β-d-ribofuranosyl)imidazole was achieved by way of a nine-step sequence starting from 2-deoxy-3,5-di-O-p-toluoyl-d-erythro-pentofuranosyl chloride.

Many kinds of heteroaromatic bases were easily alkylated by the reaction of carboxylic acids with [bis(trifluoroacetoxy)iodo]benzene or [bis(trifluoroacetoxy)iodo]pentafluorobenzene via radical decarboxylative pathways. This system was further applied to the reaction with tetrahydrofurylcarboxylic acid, 1-(2,3,5-tri-O-benyl)-D-ribofuranosylacetic acid, and 1-(2,3,5-tri-O-benzyl)-D-ribofuranosylcarboxylic acid for the model synthesis of C-nucleosides.

The synthesis of 3-aryl-5-(1,2- O -isopropylidene-α- d - xylo -tetrofuranos-4-yl)-2-isoxazoline ( 3 ) from arylnitrile oxides and 5,6-dideoxy-1,2- O -isopropylidene-α- d - xylo -hex-5-enofuranose ( 1 ) is described. The 1,3-dipolar cycloaddition reactions give mainly anti-adducts (⩾95% π-facial stereoselectivity).

An approach to the synthesis of acyclo-1-deazathymidine nucleosides is described. Diels-Alder reaction of 3,5-dichloro-6-methyl-2 H -1,4-oxazin-2-one with acetylenic compounds 4 and 5 yielded the 3-[(tetrahydropyran-2-yl)oxy]-methyl- and 3-bromomethyl-5-methyl-2,6-dichloropyridine intermediates 7 and 8 . The bromomethyl group of compound 8 underwent easy substitution with the appropriate nucleophiles, permitting the introduction of acycLo sugar moieties. The resulting 3-substituted 2,6-dichloro-5-methyl pyridines 9a,b - precursors for some acyclo pyridine-C-nucleosides - were treated with sodium phenylmethoride to afford 2,6-dibenzyloxypyridines 10 a,b. Debenzylation using a palladium-strontium carbonate catalyst gave the unstable C-nucleosides 2a,b of the 6-hydroxy-1 H -pyridin-2-one type. A stable 6-hydroxy-1 H -pyridin-2-one 2c, exempt from benzylic oxygen, was obtained via cycloaddition of THP-protected 6-hydroxy-1-hexyne.

2′-Deoxy-5-methylisocytidine is widely used in assays to personalize the care of patients infected with HIV, hepatitis C, and other infectious agents. However, oligonucleotides that incorporate 2′-deoxy-5-methylisocytidine are expensive, because of its intrinsic chemical instability. We report here a C-glycoside analog that is more stable and, in oligonucleotides, pairs with 2′-deoxyisoguanosine, contributing to duplex stability about as much as a standard 2′-deoxycytidine and 2′-deoxyguanosine pair.

Canonical recognition of gene sequences would allow precise means for specific genetic intervention. Unfortunately, specific recognition of two of the four possible base pairs by triplex-forming oligonucleotide (TFO) as X x T-A and Y x C-G within a triplex currently remains elusive. A series of C1-ethenyl nucleosides have been devised and evaluated extensively for stability and specificity by molecular dynamics simulation. A synthesis via olefin metathesis of the unprotected heterocycle and a conveniently prepared anomerically pure C1-vinyl 2-deoxyribofuranose is presented as a significant improvement over a previously reported strategy.

The synthesis of pyrimidine- and pyrazole-based acyclo-C-nucleosides as carbohybrids was optimized and developed. The synthesis of acyclic polyol-fused pyrimidines was achieved in good to excellent yield with high purity by the cyclocondensation of 2- C -formyl glycals and various amidines using K 2 CO 3 as inorganic base in co-solvent system. In comparison, the syntheses of pyrazole-based acyclo-C-nucleosides were accomplished simply by the cyclocondensation of 2- C -formyl glycals with hydrazine hydrate at room temperature and with phenyl hydrazine at refluxing temperature in ethanol.

A novel expeditious synthetic protocol for 1,3-benzoxazine-2-thione C-nucleosides via Cu(OTf)2-mediated dehydrazinative beta-glycosylation of 4-hydrazino-2H-benz[e]-1,3-oxazine-2-thiones with unprotected D-ribose is reported.

Microwave-assisted synthesis of novel acyclic C-nucleosides of 6-alkyl/aryl-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (5–12) and the 6-aryl-thiomethyl analogues 25–27 has been described. Deblocking of 5–12 and 25–27 afforded the free acyclic C-nucleosides 13–20, and 28–30, respectively. All of the synthesized compounds showed no inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 6-(3,4-dichlorophenyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (6) is a potent inhibitor, in vitro, of the replication of HIV-2. These results suggest that compound 6 should be considered as a new lead in the development of antiviral agent.

Cyclotrimerization of β- or α-ethynyl-3,5-di- O -toluoyl-2-deoxy- d -ribofuranose with α,ω-diynes proceeded smoothly under Rh-catalysis to afford the corresponding β- or α-benzene C -nucleoside derivatives. Analogous co-cyclotrimerization of α- or β-propynyl- and -phenylethynyl-3,5-di- O -toluoyl-2-deoxy- d -ribofuranose with α,ω-diynes gave the corresponding arene derivatives only under microwave irradiation in the presence of a Rh-catalyst in moderate yields. Attempted homocyclotrimerization of β- or α-ethynyl-3,5-di- O -toluoyl-2-deoxy- d -ribofuranose under Rh-catalysis led only to enynes while the use of Ru-catalyst gave the desired 1,2,4- and 1,3,5-tri-(2-deoxyribofuranose-1-yl)benzene.

A new series of acyclic C-nucleosides 1′,2′-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4] triazolo[3,4-b][1,3,4]thiadiazoles bearing arylsulfonamide (5–8) and arylcarboxamide (9–12) residues have been synthesized under microwave irradiation. Thiadiazines 13–15 have been analogously prepared, and upon acid hydrolysis, afforded the free nucleosides 16–18. The new synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compound 7 was also screened against a panel of tumor cell lines consisting of CD4 human T-cells.

We describe a new class of DNA-like oligomers made exclusively of nonnatural, stable C-nucleosides. The nucleosides comprise four types of nonnatural bases attached to a deoxyribose through an acetylene bond with the beta-configuration. The artificial DNA forms right-handed duplexes and triplexes with the complementary artificial DNA. The hybridization occurs spontaneously and sequence-selectively, and the resulting duplexes have thermal stabilities very close to those of natural duplexes. The artificial DNA might be applied to a future extracellular genetic system with information storage and amplifiable abilities.

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

A new method for the synthesis of mono- and bis-C-glycosylated 2,3,4-trisubstituted 1 H-pyrroles, a type of cyclo- and -acyclo- C-nucleoside analogues, is described. The reaction of readily available sensitive 2 H-azirines derived from carbohydrates with 1,3-dicarbonyl compounds is catalysed by tris(triphenylsilyl)vanadate under mild conditions. The reaction of 2 H-azirines with vanadium enolates has not been described previously. This methodology may be suitable for the synthesis of combinatorial libraries with the trisubstituted 1 H-pyrrole skeleton as a molecular scaffold.

Dye-sensitized photooxygenation of 2-methyl 5-(2,3,5-tri- O -acetyl-β- d -ribofuranosyl)furoate leads to (1 S ,4 R )- endo -peroxide, highlighting a high facial diastereoselectivity. This endo -peroxide rearranges into syn -(1 R ,2 R :3 S ,4 R )-diepoxide C-nucleoside, while by Et 2 S-reduction followed by NEt 3 catalysis affords a spirocyclic C-nucleoside.

Metallation-ribosylation of 2-bromothiophene 1 when conducted at room temperature afforded the original glycosylated dibromothiophene 3b following a regiocontrolled halogen transfer-based halogen-dance process. Then, stereocontrolled reduction-cyclization of hemiacetals 3a-c allowed straightforward access to the halogenated thiophenyl-C-nucleosides 6a-c. (C) 2008 Elsevier Ltd. All rights reserved.

Synthese de 3-[per-O-acetyl-L-galacto-(ou D-gluco-) pentitolyl]-6-phenyl-(ou 6-benzyl) 1,2,4-Triazolo [3,4-a] phtalazine et de 3-[per-O-acetyl-D-glycero-D-gulohexitolyl] 1,2,4-Triazolo [3,4-a] phtalazine a partir de la reaction d'1-hydrazino (ou 1-chloro) phtalazine (pouvant etre benzyle ou phenyle) avec soit les chlorures, hydrazides ou lactones d'acides aldoniques

Synthese de 5-[hexopyranosyl] (ou 5-[β-D-glucopyranosyluronate] barbiturates a partir de D-glucose, D-galactose, D-mannose ou d'acide D-glucuronique et d'acide barbiturique

Note: Univ lausanne,inst chim organ,ch-1005 lausanne,switzerland. Reference LGSA-ARTICLE-1990-004doi:10.1021/jo00295a039 Record created on 2005-11-09, modified on 2017-05-12

A rule to establish the structure of alpha and beta isomers of C-nucleosides, based on 1H-1H coupling constants is proposed and checked.

The preparation of 2,3:5,6-di-O-isopropylidene-α,β-D-mannofuranosyl-pyrimidine and 2,3-O-isopropylidene-5-O-trityl-α,β-D-ribofuranosyl-pyrimidine and triazole homo-C-nucleosides 3, 4, 6, 10–17 by different synthetic approaches is discussed and their anomeric configurational assigments are made based upon 1H- and 13C-NMR data.

An extension of the Vorbruggen method of nucleotide synthesis for the synthesis of C-glucopyranosides, as intermediates for C-nucleosides, is described. It could be shown that the diastereoselectivity of the reaction can be tuned by a simple change of protecting groups.

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

5 pages, 1 table, 3 schemes., A new method for the synthesis of mono- and bis-C-glycosylated 2,3,4-trisubstituted 1H-pyrroles, a type of cyclo- and ­acyclo-C-nucleoside analogues, is described. The reaction of readily available sensitive 2H-azirines derived from carbohydrates with 1,3-dicarbonyl compounds is catalysed by tris(triphenylsilyl)vanadate under mild conditions. The reaction of 2H-azirines with vanadium enolates has not been described previously. This methodology may be suitable for the synthesis of combinatorial libraries with the trisubstituted 1H-pyrrole skeleton as a molecular scaffold., This work was supported by the Investigation programs No. CTQ2004-06381/BQU and CTQ2004-02367/BQU of the Ministerio de Educación y Ciencia, Spain, cofinanced with the Fondo Europeo de Desarrollo Regional (FEDER). C.R.A. thanks the I3P-CSIC program for a fellowship.

An expeditious mineral-catalyzed cycloisomerization of salicylaldehyde 4-arylsemicarbazones under solvent-free microwave irradiation yields 4-hydrazino-2 H-benz[ E]-1,3-oxazin-2-ones, which conveniently undergo dehydrazinative β-glycosylation -directly with unprotected D-ribose in aqueous media to afford high yields of 4-β- D-ribofuranosyl-2 H-benz[ E]-1,3-oxazin-2-ones in a one-pot procedure.

A series of 1,3-diaryl-5-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1H-1,2,4-triazole nucleosides (3a-f) were synthesized via the intermolecular cyclization of hydrazonyl chlorides with peracylated ribofuranosyl cyanide catalyzed by Yb(OTf)3 or AgNO3, respectively. Similarly, the 1,2,4-triazole of glucopyranosyl C-nucleosides 5a,b were prepared from the hydrazonyl chlorides and the nitrile 4. Alternatively, the 1,2,4-triazole N-nucleoside 8 was obtained from cyclization of the unsymmetrical bis[alpha-(4-methoxyphenyl)aminobenzylidene]-hydrazine with peracylated 1-amino-D-manno-pentitol.

The cis opening of glycal epoxides with arylaluminum reagents provides strict stereocontrol in C-glycosylation. beta-Aryl-C-2-deoxynucleosides are obtained from known glycals by an epoxidation-glycosylation-deoxygenation sequence.

Synthetic approaches to new 4‐(furanos‐4‐C‐yl)‐1H‐pyrazole and 3‐(furanos‐4‐C‐yl)‐1H‐pyrazole derivatives are described, including its pyrazole‐5‐carboxylate derivative, which is a pyrazofurin analogue. Preparation of related 5‐acetoxy‐1‐acetyl‐1H‐pyrazole, 5‐acetoxy‐1H‐pyrazole‐1‐carboxylate, and 4,5‐dihydro‐1‐phenyl‐1H‐pyrazol‐5‐one derivatives is also reported. The formation of the pyrazole rings was accomplished either by reaction of enones and of 1,3‐diketones with N‐nucleophiles or by ring closure of a diazoketone.

The first synthesis of a 4'-branched carbocyclic C-nucleoside 11 was achieved via the key intermediate 6, which was prepared using Knovenagel type condensation from ketone derivative 4.

An efficient diastereo- and enantioselective synthesis of 4'-quaternary 2'-deoxy-3'-epi-β-C-nucleosides is described employing the RAMP-hydrazone methodology to establish the first stereocentre. Further key steps include diastereoselective nucleophilic 1,2-additions with Grignard and organocerium reagents.