Novel 2′-Deoxy Pyrazine C-Nucleosides Synthesized VIA Palladium-Catalyzed Cross-Couplings

Abstract

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-ß-D-ribofuranosyl)-3,5-diaminopyrazine (4a) and methyl 3-amino-6-(2-deoxy-ß-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.     

Synthesis and Evaluation of 2′,3′-Dideoxy-9-Deazaadenoslne and Some Related Derivatives

Abstract

In this paper we report the synthesis of 2′,3′-dideoxy-9-dearaadenosine (2) and the corresponding 2′,3′-unsaturated- and 3′-deoxy- analogs, 6 and 8. These C-nucleosides are very stable towards acid and thus overcome one of the main drawbacks of 2′,3′-dideoxy-purine-nucleosides, such as the antiviral agent 2′,3′-dideoxyadenosine (ddA). However, evaluation of these compounds and some related 2′-deoxy derivatives (10-14) in the antiviral assay for the human immunodeficiency virus has revealed no significant activity.     

Ethyl[2-Deoxy-5-O-(4,4′-dimethoxytrityl)-α- and β-D-erythro-Pentofuranosyl] Acetates as Versatile Intermediates in Nucleic Acid Chemistry

Abstract

The title compounds (1a,b) were synthesized in three steps from 2-deoxy-D-ribose, and used in the preparation of oligonucleotide conjugates, branched oligonucleotides as well as homo-N-nucleosides.     

Conformational Properties of Purine-Like C-Nucleosides

Abstract

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.

     

Studies in the Synthesis and Biosynthesis of C-Nucleosides

Abstract

The naturally occurring C-nucleosides show marked antiturnour and antiviral properties. We have developed, over a period of years, a general synthetic route to C-nucleosides by way of acetylenic intermediates. Tri-O-benzyl-D-ribofuranose (1) reacts with acetylenic Grignard reagents to give mixtures of D-allo and D-altro diols. The latter, on ring closure by means of toluene-p-sulphonyl chloride in pyridine, gives derivatives, (2) or (3), of β-D-ribofuranosylethyne in ～50% yield from (1).     

An Efficient Multigram Synthesis of Monomers for the Preparation of Novel Oligonucleotides Containing Isosteric Non-Phosphorous Backbones

Abstract

The facile preparation of two novel classes of nucleoside analogs for the inclusion as dimeric non-phosphorous containing subunits in chimeric backbones has been accomplished. The concise preparation of 3′-formylnucleosides and 5′-O-(N-methylhydroxylamino)-nucleosides is reported.     

Synthesis and Anti-Hiv Activity of 4′-Modified Cyclopentenyl Pyrimidine C-Nucleosides

Novel syntheses of 4′-modified cyclopentenyl pyrimidine C-nucleosides were performed via C-C bond formation using S_N2 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     

2,2′-Anhydro-4′-Thionucleosides: Precursors for 2′-Azido- and 2′-Chloro-4′-thionucleosides and for a Novel Thiolane to Thietane Rearrangement

Abstract

2,2′-Anhydro-4′-thio-β-and α-nucleosides 9 and 10 have been prepared by an in situ 4-thio-1,2-glycal addition route. They undergo ring-opening by azide or chloride ion to give, after deprotection, the 2′-substituted-4′-thionucleosides 13 and 14, whereas reactions with cyanide or fluoride sources lead to the unsaturated nucleosides 17 or 18, depending upon conditions. An unexpected and clean rearrangement to the thietane 23 occurs on treatment of uracil derivative 20 with DAST.     

NEW GLYCOSYL-(CARBOXAMIDE)-1,2,3-TRIAZOLE-N-NUCLEOSIDES: SYNTHESIS AND ANTITUMOR ACTIVITY

ABSTRACT

A series of potential bioactive compounds, 1-glucopyranosyl-1,2,3-triazole-4,5-dimethylcarboxylate, 1-glucopyranosyl-1,2,3-triazole-4,5-N-dicarboxamide,-dialkyl-dicarboxamide-N-nucleosides and 6-amino-4H-1-(β-D-glucopyranosyl)-8-hydroxy-1,2,3-triazolo[4,5-e][1,3]-diazepin-4-one, were synthesized. Primary activity screening of the novel nucleosides showed poor or no anticancer activity against breast, lung and CNS tumors.     

SYNTHESES OF 2′,3′-DIDEOXY-D-C-NUCLEOSIDES FROM γ-LACTONE

Abstract

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.     

Design,Synthesis, and Antiviral Evaluation of Some Polyhalogenated Indole C-nucleosides

2,5,6-Trichloro-1-(β-D-ribofuranosyl)benzimidazole (TCRB), 2-bromo-5,6-dichloro-1-(β-D-ribofuranosyl)benzimidazole (BDCRB) and 2-benzylthio-5,6-dichloro-1-(β-D-ribofuranosyl)benzimidazole (BTDCRB) are benzimidazole nucleosides that exhibit strong and selective anti-HCMV activity. Polyhalogenated indole C-nucleosides were prepared as 1-deaza analogs of the benzimidazole nucleosides TCRB and BDCRB. A mild Knoevenagel coupling reaction between an indol-2-thione and a ribofuranose derivative was developed for the synthesis of 2-benzylthio-5,6-dichloro-3-(β-D-ribofuranosyl)indole (12). 3-(β-D-ribofuranosyl)-2,5,6-trichloroindole (16) was prepared from 12 in 4 steps. A Lewis acid-mediated glycosylation method was then developed to prepare the targeted 2-haloindole C-nucleoside 16 stereoselectively in four steps from the corresponding 2-haloindole aglycons. Only 12 was active against HCMV but it also was somewhat cytotoxic.     

Domino Reaction Involving (Diacetoxyiodo)Benzene- Promoted Oxidative Rearrangement: A Novel Multicomponent and Efficient Strategy for the Synthesis of Thiadiazole N-Nucleosides

An efficient one-pot three-component synthesis of thiadiazole N-nucleosides with high atom economy from β-D-ribosylhydrazine, aryl thiamide, and aromatic aldehyde promoted by (diacetoxyiodo)benzene under microwave irradiation is reported. The strategy involves formation of thiourea derivatives by microwave-assisted addition of an arylisothiocyanate formed in situ by (diacetoxyiodo)benzene-promoted oxidative rearrangement of an aryl thiamide with Schiff bases of β-D-ribosylhydrazine and a substituted/unsubstituted aromatic aldehyde. The thiourea intermediate on intramolecular heterocyclization yielded thiadiazole N-nucleosides, 2-(arylimino)-3-(β-D-ribosyl)-5-aryl-1,3,4-thiadiazoles. The whole reaction sequence proceeded with quantitative transformation of reactants into thiadiazole N-nucleosides at an ambient temperature. The reaction sequence is supported by isolation of Schiff bases and their quantitative conversion into final product by reaction with arylisothiocyanate under the same reaction conditions.     

Oligonucleotides With Purine Nitrogen-7 as Glycosylation Site

Abstract

The synthesis of phosphoramidites (2 and 3) derived from hypoxanthine and isoguanine N⁷-2¹-deoxyribonucleosides is described. Solid-phase synthesis furnishes oligonucleotides containing N⁷-glycosylated purines. New base pairs between purine N⁷- and N9-nucleosides are proposed.     

A comparison of enzymatic phosphorylation and phosphatidylation of β-l- and β-d-nucleosides

Enzymatic 5′-monophosphorylation and 5′-phosphatidylation of a number of β-l- and β-d-nucleosides was investigated. The first reaction, catalyzed by nucleoside phosphotransferase (NPT) from Erwinia herbicola, consisted of the transfer of the phosphate residue from p-nitrophenylphosphate (p-NPP) to the 5′-hydroxyl group of nucleoside; the second was the phospholipase d (PLD)-catalyzed transphosphatidylation of l-α-lecithin with a series of β-l- and β-d-nucleosides as the phosphatidyl acceptor resulted in the formation of the respective phospholipid-nucleoside conjugates. Some β-l-nucleosides displayed similar or even higher substrate activity compared to the β-d-enantiomers.     

An Expeditious Synthesis of Benzoxazine-2-Thione c-Nucleosides Via Cu(OTf)2-Mediated Dehydrazinative β-Glycosylation

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

Synthesis of 2′-Deoxypyrimidine Nucleosides via Copper (I) Iodide Catalysis

Abstract

The coupling of various 5-substituted-2,4- disilyl pyrimidines with ã–2-deoxy-3,5-di-p-toluyl ribofuransyl chloride in the presence of copper (I) iodide in chloroform yields predominantly β-nucleosides (>15/1 β/α selectivity in some cases) in >90% overall yields.     

Chemical-Enzymatic Synthesis of 3′-Amino-2′, 3′-dideoxy-β-D-ribofuranosides of Natural Heterocyclic Bases and Their 5′-Monophosphates

Abstract

Treatment of O², 3′-anhydro-5′-O-trityl derivatives of thymidine (1) and 2′-deoxyuridine (2) with lithium azide in dimethylformamide at 150 °C resulted in the formation of the corresponding isomeric 3′-azido-2′, 3′-dideoxy-5′-O-trityl-β-D-ribofuranosyl N¹- (the major products) and N³-nucleosides (3/4 and 5/6). 3′-Amino-2′, 3′-dideoxy-β-D-ribofuranosides of thymidine [Thd(3′NH₂)], uridine [dUrd(3′NH₂)], and cytidine [dCyd(3′NH₂)] were synthesized from the corresponding 3′-azido derivatives. The Thd(3′NH₂) and dUrd(3′NH₂) were used as donors of carbohydrate moiety in the reaction of enzymatic transglycosylation of adenine and guanine to afford dAdo(3′NH₂) and dGuo(3′NH₂). The substrate activity of dN(3′NH₂) vs. nucleoside phosphotransferase of the whole cells of Erwinia herbicola was studied.     

Enzymatic Regioselective Alkoxycarbonylation of Nucleosides and Its Utility in Nucleoside Derivative Synthesis

The regioselective enzymatic alkoxycarbonylation of nucleosides is described for α-, xylo-, anhydro-, and arabino-nucleosides to obtain Cbz-derivatives. The utility of these compounds and of the related vinyl carbonates of 2‘-deoxynucleosides is shown by the synthesis of 3‘-O-acetates of α-and xylo-thymidine and the synthesis of some nucleoside carbamates, respectively.     

NOVEL SYNTHESIS OF seco TYPE OF ACYCLO C-NUCLEOSIDES OF 1,2,4-TRIAZOLE AND 1,2,4-TRIAZOLO[3,4-b][1,3,4]THIADIAZINE

The seco C-nucleosides 3-(1,2,3,4,5-penta-O-acetyl-D-gluco- and D- galacto-pentitol-1-yl)-1H-1,2,4-triazoles (8 and 9) were obtained in a one pot by deamination and dethiolation of 4-amino-3-(D-gluco- and D-galacto-pentitol-1-yl)-5-mercapto-1,2,4-triazoles (1 and 2), respectively, using sodium nitrite in orthophosphoric acid and subsequent acetylation. Condensation of 1, 2, and 4-amino-3-(D-glycero-D-gulo-hexitol-1-yl)-5-mercapto-1,2,4-triazole (12) with phenacylbromide (11) afforded the corresponding 3-(D-gluco-, D-galacto-pentitol-1-yl) and 3-(D-glycero-D-gulo-hexitol-1-yl)-6-phenyl-7H-1,2,4- triazolo[3,4-b][1,3,4] thiadiazines (15, 16, and 17). Acetylation of 15–17 gave the penta- and hexa-O-acetyl derivatives 18–20, respectively. The structures were confirmed by using ¹H, ¹³C, and 2D NMR spectra, DQFCOSY, HMQC, and HMBC experiments. The favored conformational structures were deduced from the vicinal coupling constants of the protons.