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The novel imido esters of 2-deoxy-α- and -β-D-ribose 8 and 9 have been synthesized and successfully transformed to the protected 1,2,4-triazine-C -nucleosides 11 and 12 using an inverse type Diels-Alder reaction with the 1,2,4,5-tetrazine 10. The electron deficient diazadiene system of both C -nucleosides 11 and 12 proved to be highly reactive in a consecutive [4 + 2] cycloaddition with inverse electron demand towards several electron rich dienophiles yielding after successful deprotection the novel pyridine-, pyrindine- and isoquinoline-C-nucleosides 15, 18 and 21 of 2 -deoxy-α-D-ribose and 23, 25 and 27 of 2-deoxy-β-D-ribose.

A synthesis of the C-nucleoside, 2-amino-7-(2-deoxy-beta-D-erythro- pentofuranosyl)-3H,5H-pyrrolo[3,2-d]pyrimidin-4-one (9-deaza-2'-deoxyguanosine) was achieved starting from 2-amino-6-methyl-3H-pyrimidin-4-one (5) and methyl 2-deoxy-3,5-di-O-(p-nitrobenzoyl)-D-erythro-pento-furanoside (11). The anomeric configuration of the C-nucleoside was established by 1H NMR, NOEDS and ROESY. This C-nucleoside did not inhibit the growth of T-cell lymphoma cells.

Treatment of α,α′-dichloroazo compounds 1 with SbCl5 afforded the 1-(chloroalkyl)-1-aza-2-azoniaallene salts (2) which reacted in a 1,3-dipolar cycloaddition with the acetoxy nitriles 3 and 4 to the 1,2,4-triazolium salts 5 and 6, respectively. 5 and 6 rearranged spontaneously to the protonated 1,2,4 triazoles 7 and 8, respectively. The salts 7 were in situ hydrolyzed to the acyclic 1,2,4-triazole C-nucleosides 9 which gave the free nucleosides 11a,b, and f after deblocking. Treatment of 8 with NaOMe resulted in the de-acetylation along with the hydrolysis of the salts to the free homonucleosides 13a-f.

Photochemistry of cyclobutanones in the presence of HCN or malononitrile give photoadducts derived from oxacarbene insertion into C–H. These intermediates are useful for the preparation of C -nucleosides by structural elaboration of the CN groups.

Reaction of d -glucono- ( 1 ) or d -galactono- ( 2 ) 1,5-lactones and d - glycero - d -guloheptonic-1,4-lactone ( 11 ) with thiocarbohydrazide ( 3 ) afforded the seco C-nucleosides 4-amino-3-( d -gluco- ( 4 ) or d - galacto - ( 5 ) pentitol-1-yl)-5-mercapto-1,2,4-triazoles and 4-amino-3-( d - glycero - d - gulo -hexitol-1-yl)-5-mercapto-1,2,4-triazole ( 12 ). Their conversions to the 3-(1,2,3,4,5-penta- O -acyl- d - gluco - ( 7 and 9 ) or the d - galacto ( 8 and 10 ) pentitol-1-yl)-6-substituted 1,2,4-triazolo[3,4-b]1,3,4-thiadiazole and 3-(1,2,3,4,5,6-hexa- O -acetyl- d - glycero - d - gulo hexitol-1-yl)-6-methyl-1,2,4-triazolo[3,4- b ]1,3,4-thiadiazole ( 13 ) were achieved under acylative conditions. Reaction of diethyl galactrate ( 17 ) with 3 gave 1,4-bis (4-amino-5-mercapto-1,2,4-triazol-3-yl)- galacto -tetritol ( 18 ), which upon reaction with acetic anhydride gave 1,4-bis(6-methyl-1,2,4-triazolo[3,4- b ]1,3,4-thiadiazol-3-yl)-1,2,3,4-tetra- O -acetyl- galacto -tetritol ( 19 ). When the tetra- O -acetylgalactaric acid ( 15 ) was used instead of 17 , the attack of 3 had taken place on the ester group rather than the carboxylic group, whereby 16 was obtained rather than the tetra- O -acetyl derivative of 18 . The structures were confirmed by using 1 H, 13 C and 2D NMR spectra (DQFCOSY and HMQC) experiments. The vicinal coupling constants were used to deduce the favored conformations.

Isoxazoline rings have been successfully connected to imidazo[1,2-a]pyridine derivatives via carboncarbon bonds for the synthesis of new C -nucleoside analogs 7 and 8 . These two isomers, possessing altered positions of nitrogen and oxygen atoms, can be formed through dipolar cycloaddition reactions of the appropriate olefins and nitrile oxides.

Condensative cyclization of aldehydo-sugar S-methylhydrazonecarbodithioates and S-benzylhydrazonecarbodithioates with acetic anhydride in the presence of pyridine gave the corresponding 3-acetyl-2-(poly-O-acetyl-alditol-1-yl)-5-alkylthio-1,3,4-thiadiazolines. De-O-acetylation of the latter compounds gave the title acyclo C-nucleosides. The compounds prepared were found antimicrobially inactive against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and Candida albicans.

We herein present our results showing that a simple mononucleotide block actually acts as a wire. This is evidenced by the fact that any change of the electronic character of the nucleobase is transmitted to drive the sugar conformation, which in turn dictates cooperatively the preferred orientation of the phosphate backbone.

Cyclodehydrogenation of the ethylidene derivative of (5-methyl-1,2,4-triazino[5,6-b]indol-3-yl)hydrazine (1) gave the angular isomer, 1,10-dimethyl-1,2,4-triazolo[3′,4′:3,4][1,2,4]triazino[5,6-b]indole (4). The linear isomer, 3,10-dimethyl-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indole (7) could be prepared regioselectively by the cyclodehydration of the acetyl derivative of 1. The cyclodehydrogenation was extended to the monosaccharide derivatives of 1. The role of the N-methyl group on the site of annellation has been discussed.

A new route to the synthesis of pyrazole and pyrimidine C-nucleosides, involving as the key step a metal catalysed reaction of β-D-ribofuranosyl ketoesters with alkyl cyanoformates, is described, 2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl cyanide (1) reacts with α-bromoesters, in the presence of zinc dust, to give β-D-ribofuranosyl-enaminoesters 2 which are easily hydrolised to β-ketoesters 3. The reactions of compounds 3 with alkyl cyanoformates, in the presence of catalytic amounts of [Cu(acac)2], afford C-glycosyl enaminoketosters 4. These compounds react with benzylhydrazine and acetamidine to give pyrazole and pyrimidine C-nucleosides 5 and 6 respectively.

A variable temperature 600 MHz 1H NMR conformational analysis of 3JHH coupling constants in pyrazolo[4,3-c]pyridine carbaribo-C-nucleoside 1 in D2O has shown that the carbocyclic nucleoside analogu...

The metabolic instability of the glycosidic linkage in 2,5,6-trichloro-1-(β-d-ribofuranosyl)benzimidazole prompted us to synthesize the structurally related C-nucleoside 2,6,7-trichloro-3-(β-d-ribofuranosyl)imidazo[1,2-a]pyridine. Synthesis of this first C3-ribofuranosylimidazo[1,2-a]pyridine was accomplished by developing a modification of existing iodocyclization methodology for obtaining a 1‘,4‘-syn furanosyl precursor, without an extensive protection scheme. This 1‘,4‘-syn precursor was elaborated into the desired ribofuranosyl C-nucleoside. X-ray crystallography was used to unambiguously determine structure and absolute stereochemistry of this C-nucleoside.

The 2(3)-formyl-glycals 2, 4, 6 react with hydrazine hydrate to furnish the C-(1H-pyrazol-3-yl)alditoles 7, 8, 9. Treatment of 2, 4, 6 with cyanoacetamide provides the 2(3)-(2-aminocarbonyl-2-cyano-vinyl)-1,5(2,6)-anhydro-2(3)-deoxy-hex-enitols 10, 13, 15, which are converted into the polyhydroxyalkyl 2-amino-nicotinamides 11, 14, 16 and pyridinecarbonitriles 12, respectively.

Chiral 2-formyl and 2-(1-oxoalkyl)-1,3-dioxolanes have been prepared by ozonolysis of the corresponding alkenes and by oxidation of 2-(1-hydroxyalkyl)-1,3-dioxolanes, which are readily available from 2-(tributylstannyl)dioxolanes, and taken through to αβ-unsaturated esters by condensation with stabilized ylids. The (4′S,5′S)-1-benzyl-5-[4,5-bis(ethoxycarbonyl)-1,3-dioxolan-2-yl]-2-pyridone 47 was prepared as an analogue of a C -nucleoside, but was found to be unstable.

Two nucleoside derivatives of the pyrimidine bases T and m 5ox C have been prepared with flexible acyclic carbohydrate linkers. A new procedure, beginning with ( R )-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol permits the preparation of the stereochemically pure acyclic derivatives of both protected nucleoside analogues without contamination by a problematic rearrangement product. By simply increasing the flexibility of the carbohydrate portion of the am 5ox C nucleoside derivative, 15-mer triplexes containing five contiguous G-C base pairs exhibit a 7–8°C increase in T m value.

1,3-Dipolar cycloaddition of dipolarophiles (1) and (2) with endocyclic heterocyclic azomethine ylides (4), (14) and (24), prepared in situ, leads to the protected β-and α-C-nucleo-sides (7), (8), (17), (18), (27) and (28), respectively. These, on subsequent hydrolysis, provide the corresponding C-nucleosides. The structures of all the synthesized com pounds are con­ firmed through analytical and spectral data. The assignment of configuration at C -1′ position of the C-nucleosides could be done by a comparative study of the properties of the corre­sponding α and β anomers with a reasonable degree of certainity.

The palladium-catalyzed cross-couplings of 2-chloro-3,5-diamino-6-iodopyrazine (1a) and methyl 3-amino-6-iodopyrazine-2-carboxylate (1b) with 1,4-anhydro-3,5-O-bis[(tert-butyl)dimethylsilyl]-2-deoxy-D-erythro-pent-1-enitol (2) followed by desilylation and stereospecific reduction of the 2′-deoxy-3′-keto adduct leads to the formation of 2-chloro-6-(2-deoxy-s-D-ribofuranosyl)-3,5-diaminopyrazine (4a) and methyl 3-amino-6-(2-deoxy-s-D-ribofuranosyl)pyrazine-2-carboxylate (4b) in 58% yield and 21% yield, respectively. These are the first syntheses of the heretofore unknown 2′-deoxy pyrazine C-nucleosides and demonstrate the utility of a convergent approach for the synthesis of pyrazine C-nucleosides.

A pairwise comparison of the free-energy of the two-state N (North, C2′-exo-C3′-endo, 0° -2′,3′-dideoxynucleosides (ddNs) 2, 4, 5, 7 and 9 with their α- -counterparts 1, 3, 6 and 8 shows that the conformation of the pentofuranose moiety is efficiently driven towards the N-type sugars in the β- - series and to the S-type conformation in the α- - anomers. The extent of the free-energy of stabilization of the N-type sugars in β- -ddNs is however 2–3 times greater than the corresponding S-type sugar stabilization in α- -ddNs. The estimation of ΔH° contribution to the free-energy shows that the intrinsic flexibility of the sugar moiety in β- -ddNs is 2–4 times larger than in α- -ddNs as a result of change of either temperature or pD of the medium. This enhanced modulation of conformation by the change of temperature or pD of the solution in β- -ddNs compared to α- -ddNs is the result of the more efficient transmission of the anomeric effect [ n(O 4′)→σ C1′N ∗ orbital interactions between O4′ lonepair of sugar with the σ ∗ of C1′N bond] to drive the sugar conformation in the former compared to the latter. An important implication of this finding is that the evolutionary forces of Nature have opted for molecules that can adopt multiple conformations owing to the unique internal flexibility as a result of interaction with various ligands.

Tetra- O -acetyl- d -ribose, penta- O -acetyl- d -glucose, 2,3;5,6-di- O -isopropylidene- d -mannofuranose, 2,3,5-tri- O -benzyl- d -arabinofuranose and 2,3,5,6-tetra- O -benzyl- d -glucose react with pyrrole and indole, in presence of Lewis acids, to afford C-glycosylpyrroles and indoles in position 2 and 3 respectively (acyclic C-nucleosides, 1–7 ). The crystal structure of 4 was determined by X-ray crystallography.

C-Nucleosides, 4-amino-8-(β- l -ribofuranosyl)pyrazolo[1,5-a]-1,3,5-triazine ( 12 ) and 4-amino-7-(β- l -ribofuranosyl)-5H-pyrrolo[3,2-d]pyrimidine ( l -9-deazaadenosine, 22 ), were synthesized from the key intermediate, 3-dimethylamino-2-(2,3-O-isopropylidene-5-O-trityl- l -ribofuranosyl)acrylonitrile ( 8 ), which was prepared from l -xylose in 11 steps.

1-Acyclo C-nucleosides of 7-methyl-10H-1,2,4-triazolo[3’,4’:3,4][1,2,4]triazino[5,6-b]indoles (9) have been prepared by cyclodehydrogenation of the sugar derivatives of 3-hydrazino-8-methyl-5H-1,2,4-triazino[5,6-b]indole (1). The respective linear isomer as 4 has been prepared by a dehydrative cyclization of the amides of 1. Acetylation of the sugar hydrazones and their cyclized products gave the per-N,O-acetyl derivatives. The molecular connectivity of the products was established by 1H, 13C, and 2D H ,H Cosy spectra.

Several new polychlorinated imidazo[1,2-a]pyridine C-nucleosides have been prepared. Lithiated imidazo[1,2-a]pyridines were condensed with protected ribonolactones, trapped as 1‘-acetoxy derivatives, and these 1‘-acetoxy derivatives were reductively deacetoxylated and deprotected to give C-nucleosides. Long-range proton−carbon decoupling experiments were used to determine the actual site of ribosylation and established that the ribose moiety was unexpectedly attached to the C5 position of the imidazo[1,2-a]pyridines. This method has provided C-nucleosides, such as 2,6-dichloro-5-(β-d-ribofuranosyl)imidazo[1,2-a]pyridine and 2,6,7-trichloro-5-(β-d-ribofuranosyl)imidazo[1,2-a]pyridine and the corresponding α-products.

We here report for the first time the ionization constant of 9-deazaadenosine ( 1 ) (pK a 6.0) as well as the third ionization constant for Formycin B ( 2 ) (pK a of 1.3) in addition to its two known pK a s of 8.8 and 10.4.

Apioshowdomycin (3-(D-apio-β-D-furanosyl)-1H-pyrrole-2,5-dione,2) has been prepared as an analogue of the C-nucleoside showdomycin (1) in eight steps and with 5% overall yield, starting from 2,3-O-isopropylidene-D-apio-β-D-furanose (3).

Anomeric 2-(α- and β- d -erythrofuranosyl)benzimidazole C-nucleoside analogues 2 and 3 , were prepared from the corresponding epimeric 2-( d - arabino , and d - ribo -tetritol-1-yl)benzimidazole analogues 1 and 4 , respectively. Similarly, 2-(β- l -erythrofuranosyl)benzimidazole 13 was obtained from the precursor 2-( l - arabino -tetritol-1-yl)benzimidazole 12 . The structure and anomeric configuration of the C-nucleoside analogues 2 , 3 , and 13 were determined by acylation, 1 H and 13 C NMR spectroscopy, and mass spectrometry.

Apioshowdomycin (3-(D-apio-β-D-furanosyl)-1H-pyrrole-2,5-dione,2) has been prepared as an analogue of the C-nucleoside showdomycin (1) in seven steps, starting from 2,3-O-isopropylidene-D-apio-D-furanose (8). The key step is the addition of a radical generated from apiosyl bromide5b to (E)-methyl 3-cyanoacrylate (4).

The dye-sensitized photooxygenation of furanosyl furans easily affords C- or O-glycosides with cis-alpha,beta-unsaturated 1,4-dioxo aglycones. The reaction, performed on a ribofuranosyl furan, provides a useful new entry to a novel pyridazine C-nucleoside that can be achieved through a simple one-pot procedure.

The 3-(D-alditol-1-yl)-4-amino-5-mercapto-1,2,4-triazoles 4 and 5 can be successfully prepared using microwave irradiation. Condensation of 4 and 5 with p-nitrobenzaldehyde afforded Schiff bases 6 and 7, respectively. Reaction 4 and 5 with ethylchloroacetate gave the corresponding alkylated products 10 and 11. Better yields and much less time were the characteristic features of using the microwave heating over the conventional one. The structure of the prepared compounds was confirmed by 1H-NMR, 2D-NMR and mass spectra.

Standard Pd-catalyzed cross-coupling reactions proceed chemoselectively at the position of the bromine, whereas nucleophilic substitutions are unselective.

D-Mannitol 1 is a convenient starting material for organic synthesis because of the homotopic relation between the upper and the lower part of the molecule. For this reason dehydration of 1 via 2-5 hydroxyl groups yields one product only, i.e. 2,5,anhydro-D-glucitol 2. Our interest in 2 and its derivative 5 stems from a possibility of application of the latter for C-nucleoside synthesis. Acid catalyzed dehydration of 1 was performed followed by some manipulations, and permitted isolation of the 2,5anhydro-4,6-di-O-benzyl-D-glucitol 5, together with 2,6-anhydro-1,3-di-O-benzyl-D-mannitol 7 (or 1,5anhydro-4,6-di-O-benzyl-D-mannitol due to a symmetry of 1). A structure of 7 was confirmed by xray analysis.

A novel and stereoselective synthetic route towards carba-C-nucleosides was investigated applying an enantiodivergent biooxidation strategy by two different Baeyer–Villiger monooxygenases. Within only three chemo-enzymatic steps it was possible to introduce four chiral centers starting from commercially available non-chiral starting material. Fil: Bianchi, Dario Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina Fil: Moran Ramallal, Roberto. Vienna University of Technology; Austria Fil: Iqbal, Naseem. Vienna University of Technology; Austria Fil: Rudroff, Florian. Vienna University of Technology; Austria Fil: Mihovilovic, Marko D.. Vienna University of Technology; Austria

Abstract: 2′,3′-Dideoxy-D-C-nucleosides, 2,4-diamino-5-(2,3-dideoxy-D-glycero-pentofuranosyl)pyrimidine.s (11 and 12), 4-amino-8-(2,3-dideoxy-D-glyceropentofuranosyl)pyrazolo[1,5-a]-1,3,5-triazines (17 and 18), 4-amino-7-(2,3-dideoxy-D-glyceropentofuranosyl)-5H-pyrrolo[3,2-d]pyrimidines (2 and 25), 7-(2,3-dideoxy-D-glyceropentofuranosyl)-4-oxo-3H,5H-pyrrolo[3,2-d]pyrimidines (30 and 31) have been synthesized from γ-lactone 4. These 2′, 3′-dideoxy-nucleosides were evaluated against HBV and HIV. No significant antiviral activities were found up to 100 μM.

Palladium was used for a cross coupling of 2,6-dichloro-3-iodoimidazo[1,2-a]pyridine (2) to 2,3-dihydrofuran (3). Optimization of the coupling conditions have given exclusively (+/−)-2,6-dichloro-3-(2′,5′-dihydrofuran-2′-yl)imidazo[1,2-a]pyridine (4) in high yield. Compound 4 was dihydroxylated using a catalytic amount of osmium tetroxide to give the erythrofuranosyl C-nucleoside derivatives 6 and 7. This is the first report of a C-nucleoside derivative containing a sugar moiety attached to the C3 position of an imidazo[1,2-a]pyridine heterocycle.

A series of new carbocyclic C-nucleosides with a cis-4′-(hydroxymethyl)cyclopent-2′-enyl sugar moiety and unnatural pyrimidine bases (2–6) were synthesized in racemic form in two steps starting from the easily accessible cyclic carbonate 1.

A novel ribosylated imidazo[1,2-a]pyridine C-nucleoside was synthesized by condensing a lithiated 2,6-dichloroimidazo[1,2-a]pyridine ( 1 ) with a protected ribonolactone ( 2 ), followed by acetylation to give the intermediate nucleoside 4 . This intermediate was reductively deacetoxylated and deprotected to give what was determined to be the novel and unexpected 2,6-dichloro-5-(β-D-ribofuranosyl)imidazo[1,2-a]pyridine ( 7 ) and the corresponding α-product ( 8 ). The site of ribosylation was established with long range proton-carbon decoupling experiments. This ribosylation at C5 was entirely unexpected in view of previously reported condensations with lithiated imidazo[1,2-a]pyridines which occurred only at the C3 position.

The multiplicities and chemical shifts of the 5′-hydroxyl resonances in the NMR spectra of a series of purine-like C-nucleosides reflect the presence of a hydrogen bond to N(1), and hence afford a method for assessing solution syn/anti conformational preferences. This paper is dedicated to Dr. Yoshihisa Mizuno on the occasion of his 75th birthday.

The determination of the energetics of the temperature-dependent two-state N reversible arrow S pseudorotational equilibrium through (3)J(HH) analysis in 36 nucleos(t)ides and 3 abasic sugars has a ...

Asymmetric synthesis of four novel C-nucleosides, (2′R,5′R)-, (2′S,5′R)-, (2′S,5′S)- and (2′R,5′S)-2-[2-hydroxymelhy])-1,3-dioxolan-5-yl]-1 ,3-thiazole-4-carboxamide has been accomplished by the condensation of key intermediates, 2-(1R- and 1S-glycol-1-yl)-4-ethoxycarbonyl-1,3-thiazole with 2-benzoyloxy acetaldehyde dimethyl acetal.

Novel C-nucleosides (2′R,4′S)-and (2′S,4′R)-2-[4-(hydroxymethyl)-1,3-dioxolan-2-yl]-1,3-thiazole-4-carboxamide have been synthesized from stereoselectively induced condensation of optically active triols (S or R) with a 1,3-thiazole-4-carboxamide derivative.

Reaction of diarylcadmium or diarylzinc reagents with 1,2-dideoxy-3,5-di-O-p-toluoyl-1-chloro-α-D-ribofuranose affords 3,5-di-O-protected aromatic C-nucleosides in good yields.

C-Nucleosides of the pyrazolo[1, 5-a]-1, 3, 5-triazine aglycon system have been prepared by palladium-mediated coupling of 8-iodopyrazolo[1, 5-a]-1, 3, 5-triazines. 4-(N, N-Diisobutyloxycarbonyl)amino-8-iodopyrazolo[1, 5-a]-1, 3, 5-triazine and the furanoid glycal 1, 4-anhydro-2-deoxy-3-O[(1, 1 dimethylethyl)diphenylsilyl]-D-erythro-pent-1-enitol coupled in the presence of catalytic palladium(0) to yield, after desilylation of the intermediate silyl enol ether, a C-glycoside analog of adenosine.