Synthesis of 2′,3′-Dideoxy-2′-Fluorokanamycin A

2′,3′-Dideoxy-2′-fluorokanamycin A (23) was prepared by condensation of 6-azido-4-0-benzoyl-2,3,6-trideoxy-2-fluoro-α-D-ribo-hexopyranosyl bromide (13) and a protected disaccharide (19). Methyl 4,6-0-benzylidene-3-deoxy-β-D-arabino-hexopyranoside (5) prepared from methyl 4,6-0-benzylidene-3-chloro-3-deoxy-β-D-allo-hexopyranoside (1) by oxidation with pyridinium chlorochromate followed by reduction with Na₂ S₂O₄ was fluorinated with the DAST reagent to give methyl 4,6-O-benzylidene-2,3-dideoxy-2-fluoro-β-D-ribo-hexopyranoside (7). Successive treatment of 7 with NBS, NaN₃ and SOBr₂ gave 13. The structure of the final product (23) was determined by the ¹H and ¹⁹F and shift-correlated 2D NMR spectra.     

Synthesis of β-L-2′,3′-Dideoxy-2′-fluoro-3′-hydroxymethylarabinofuranosyl Pyrimidine Nucleosides

β-2′,3′-Dideoxy-2′-fluoro-3′-hydroxymethylarabinofuranosylthymine 10 and cytosine 12 were synthesized from L-xylose and were found to be inactive against HIV-1 in acutely infected lymphocytes.     

Synthesis of 2-O-ethyl analogues of 3′-azido- and 3′-fluoro-2′,3′-dideoxyuridines and evaluation of their biological activity against HIV

Summary 2-O-Ethyluracil and 2-O-ethylthymine were silylated with 1,1,1,3,3,3-hexamethyldisilazane and condensed in the presence ofTMS triflate with 2,3-dideoxy-3-fluoro-D-erythro-pentofuranoside, 3-azido-2,3-dideoxy-D-erythro-pentofuranoside, and 2,3-dideoxy-3-phthalimido--D-erythro-pentofuranose derivatives to give the corresponding 2-O-ethyl nucleosides. Deprotection with saturated methanolic ammonia afforded the 2,3-dideoxy-3-fluoro-2-O-ethyluridines, whereas 3-azido-2,3-dideoxy-3-O-ethyluridine was obtained by deprotection with tetrabutylammonium fluoride in tetrahydrofuran. 3-Amino-2,3-dideoxy-3-O-ethyluridine could be obtained only by treatment of the corresponding 3-azido nucleoside with triphenylphosphine in pyridine. 3-Deoxy-2-O-ethyl-3-fluorothymidine (6b) showed moderate activity against HIV-1.

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Synthese von 2-O-Ethyl-Analogen von 3-Azido- und 3-Fluor-23-dideoxyuridinen und Bestimmung ihrer biologischen Aktivität gegenüber HIV

Zusammenfassung 2-O-Ethyluracil und 2-O-Ethylthymin wurden mit 1,1,1,3,3,3-Hexamethyldisilazan silyliert und in Gegenwart vonTMS-triflat mit 2,3-Dideoxy-3-fluoro-D-erythro-pentofuranosid, 3-Azido-2,3-dideoxy-D-erythro-pentofuranosid und 2,3-Dideoxy-3-phthalimido--D-erythro-pentofuranosederivaten zu den entsprechenden 2-O-Ethyl-Nucleosiden umgesetzt. Entfernung der Schutzgruppe mit gesättigter methanolischer Ammoniaklösung lieferte 2,3-Dideoxy-3-fluor-2-O-ethyluridin; 3-Azido-2,3-dideoxy-3-O-ethyl-uridin wurde durch Entschützung mit Tetrabutylammoniumfluorid in Tetrahydrofuran erhalten. 3-Amino-2,3-dideoxy-3-O-ethyl-uridin konnte nur durch Behandeln des entsprechenden 3-Azido-Nucleosids mit Triphenylphosphin in Pyridin hergestellt werden. 3-Deoxy-2-O-ethyl-3-fluor-thymidin (6b) zeigt geringe Aktivität gegenüber HIV-1.

     

New route for the synthesis of 2-thiouracil analogues of 3′-azido-2′,3′-dideoxy nucleosides

Summary Reaction of 3-azido-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-D-erythro-pentofuranoside (5) with silylated 2-thiouracil and 5-alkoxy-2-thiouracils in the presence of trimethylsilyl trifluoromethanesulfonate afforded an anomeric mixture of the corresponding 3-azido-2,3-dideoxy-2-thiouridine derivatives with the -anomer as the main product. Deprotected nucleosides were obtained by treatment with tetrabutylammonium fluoride.

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Ein neuer Weg zur Synthese von 2-Thiouracil-Analogen von 3-Azido-2,3-dideoxy-Nucleosiden

Zusammenfassung Die Reaktion von 3-Azido-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-D-erythro-pentofuranosid (5) mit silyliertem 2-Thiouracil und 5-Alkoxy-2-thiouracil in Gegenwart von Trimethylsilyltrifluormethansulfonat ergab eine anomere Mischung der entsprechenden 3-Azido-2,3-dideoxy-2-thiouridin-Derivate, wobei das -Anomer das Hauptprodukt darstellte. Die ungeschützten Nucleoside wurden mittels Behandlung mit Tetrabutylammoniumfluorid erhalten.

     

Photolysis of adamantane-2-spiru-3′-diazirine

The spectral characteristics and photochemical transformations of adamantane-2-spiro-3-diazirine and its 5-hydroxy derivative were studied. The transformations of the photoexcited molecules of adamantane-2-spiro-3-diazirine in individual solvents and their mixtures and with various sources of UV radiation were studied by gas-liquid chromatography. The main process in saturated hydrocarbons is the formation of diazoadamantane, which is then converted into adamantanone azine. The addition of small amounts of formic or acetic acid leads to the formation of significant amounts of alkyladamantanes, which are the products from transformations of the intermediately formed carbene adamantylidene. Concurrent transformation paths are also observed in cyclohexene. It is suggested that the adamantylidene is preceded by the formation of an exciplex of diazirine with the polar solvent molecule. The ambiphilic nature of adamantylidene in the photolysis of diazirines was demonstrated by concurrent carbenylation.Kiev Polytechnical Institute, L. V. Pisarzhevskii Institute of Physical Chemistry, Academy of Sciences of the Ukrainian SSR, Kiev. Higher Chemical Technology School, Prague. Translated from Teoreticheskaya i Ésperimental'naya Khimiya, Vol. 27, No. 2, pp. 211–220, March–April, 1991. Original article submitted July 11, 1989.     

Synthesis of 2′-5′,3′-5′ linked triadenylates

2′-5′,3′-5′ Linked triadenylates have been synthesized by direct bisadenylylation of adenosine 2′ and 3′ hydroxyls with an adenosine 5′-phosphorochloridite followed by oxidation.     

Synthesis of 2′,3′-didehydro-3′-deoxythymidine and its activity against HIV

2,3-Didehydro-3-deoxythymidine has been obtained with an overall yield of 10% by the condensation of 1,2-di-O-acetyl-3,5-di-O-benzoyl-D-xylofuranose with bis-(dimethylsilyl)thymine and a series of subsequent transformations. The anti-HIV activity of the compound obtained was studied on the model of MT-4 lymphoid cells primarily infected with HIV-1. It was found that the substance effectively inhibits the reproduction of HIV-1 in a cell culture.Institute of Organic Chemistry, Ural Branch, Russian Academy of Sciences, Ufa. Vector Scientific-Production Association, Kil'tsovo, Novosibirsk Province. Institute of the Chemistry of Plant Substances, Uzbek SSR Academy of Sciences, Tashkent. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 133–136, January–February, 1993.     

Diastereoselective and enantioselective synthesis of 4′-aza analogues of 2′,3′-dideoxynucleosides

A diastereo- and enantioselective synthesis of 4′-aza analogues of 2′,3′-dideoxynucleosides has been designed by the strategy of the 1,3-dipolar cycloaddition reaction of a Vasella-type nitrone. The reaction leads to (1′R)- and (1′S)-4′-aza analogues of 2′,3′-dideoxythimidine and fluorouridine, in enantiomerically pure forms.     

Syntheses of Novel 3-Substituted-2′-deoxy-3-deazauridine Nucleosides

Syntheses of novel 3-ethynyl (8), 3-vinyl (10) and 3-acetoxy (13)-2′-deoxy-3-deazauridine analogs starting from the protected 2′-deoxy-3-deazauridine derivative 4 are described.     

Synthesis of 5-substituted-3-[(2′S,3′S)-3′-hydroxy-2′-hydroxymethyltetrahydrofuran-3′-yl]-1,2,4-oxadiazoles and their epimers

5-Phenyl-3-[(2′R,3′S)-3′-hydroxy-2′-dimethoxymethyltetrahydrofuran-3′-yl]-1,2,4-oxadiazole 10a and its epimer 11a, 5-methyl-3-[(2′R,3′S)-3′-hydroxy-2′-dimethoxymethyltetrahydrofuran-3′-yl]-1,2,4-oxadiazole 10b and its epimer 11b were synthesized from cyanohydrin benzoates 8a, 9a and cyanohydrin acetates 8b, 9b, respectively, by treatment with hydroxylamine in methanol via intramolecular transacylation and subsequent cyclization of the corresponding amidoximes. Hydrolysis and reduction of the dimethoxymethyl groups in the above compounds gave the desired compounds 12a, 13a, 12b and 13b.     

Synthesis of 3-(3′-Acetyl-5′-aroyl-1′,3′,4′-oxadiazolyl-2′)-chromones

A general method has been proposed for synthesizing 3-(3-acetyl-5-aroyl-1,3,4-oxadiazolyl-2)-chromones that has been based on conversion of 3-formylchromones to acylhydrazones and of theacylhydrazones into the heterocyclic chromones.     

Thermal analysis of 5′-deoxy-5′-iodo-2′,3′-O-isopropylidene-5-fluorouridine

The melting temperature, melting enthalpy, and specific heat capacities (C _p) of 5′-deoxy-5′-iodo-2′,3′-O-isopropylidene-5-fluorouridine (DIOIPF) were measured using DSC-60 Differential Scanning Calorimetry. The melting temperature and melting enthalpy were obtained to be 453.80 K and 33.22 J g^?1, respectively. The relationship between the specific heat capacity and temperature was obtained to be C _p/J g^?1 K^?1 = 2.0261 – 0.0096T + 2 × 10^?5 T ² at the temperature range from 320.15 to 430.15 K. The thermal decomposition process was studied by the TG–DTA analyzer. The results showed that the thermal decomposition temperature of DIOIPF was above 487.84 K, and the decomposition process can be divided into three stages: the first stage is the decomposition of impurities, the mass loss in the second stage may be the sublimation of iodine and thermal decomposition process of the side-group C₄H₂O₂N₂F, and the third stage may be the thermal decomposition process of both the groups –CH₃ and –CH₂OCH₂–. The obtained thermodynamic basic data are helpful for exploiting new synthetic method, engineering design, and commercial process of DIOIPF.     

Microwave promoted one-pot synthesis of 3-(2′-amino-3′-cyano-4′-arylpyrid-6′-yl)coumarins

A facile procedure for the synthesis of 3-(2′-amino-3′-cyano-4′-arylpyrid-6′-yl)coumarins are being reported starting from 3- acetylcoumarin,aromatic aldehydes and malononitrile.The reactions were carded out on microwave irradiation in good yield with short time and easy work-up.The structures of all the compounds have been confirmed on the basis of their analytical,IR,~1H NMR, and mass spectral data.     

Convergent synthesis of 2′,3′-dideoxy-3′-mercapto nucleosides — Potential anti-HIV agents

Summary Methyl 3-benzoylthio-5-O-tert-butyldiphenylsilyl-2,3-dideoxy--D-erythro-pentofuranoside (4) and its corresponding anomer5 were synthesized in four steps from 2-deoxy-D-ribose and used as substrates for the synthesis of nucleosides by condensation with silylated thymidine and N⁶-isobutyryladenine. The nucleosides were deprotected by treatment with Bu₄NF inTHF followed by reaction with MeONa in MeOH to give 3-deoxy-3-mercaptothymidine (8), 2,3-dideoxy-3-mercaptoadenosine (15) and its corresponding anomer16. In the latter reactions it was important to use degassed solvents to minimize formation of the corresponding disulfides of purine nucleosides. Using Bu₄NF, without subsequent reaction with MeONa in the deprotection reaction, resulted in intermolecular transesterification reactions.On leave from Chemistry Department, Faculties of Science and Education, Tanta University, Tanta, Egypt     

An Efficient Procedure for the Preparation of 3′-Acetyl-2′,3′-dihydrobenzothiazoles by Ring Contraction of 2′,3′-Dihydro-1,5-Benzothiazepines Under Acetylating Conditions

Reaction of 2-benzoyl-6-hydroxy-3-methyl-5-(2′-substituted-2′,3′-dihydro-1,5-benzothiazein-4′-yl) benzofurans (4a-f) with a mixture of acetic anhydride and pyridine afforded 6-acetoxy-2-benzoyl-3-methyl-5-(3′-acetyl-2′-substitutedstyryl-2′,3′-dihydrobenzothiazole-2′-yl) benzofurans (5a-f) as sole products in good yields. A reaction mechanism for the ring contraction is proposed. All the compounds (5a-f) were screened for their antifeedant activity by the “Non-Choice test method” using 6 h prestarved fourth instar larvae of Spodoptera litura F. Compounds 5a, 5c and 5d exhibited highest antifeedant activity.     

Synthesis of 2-fluoro-substituted and 2,6-modified purine 2′,3′-dideoxy-2′,3′-difluoro-d-arabinofuranosyl nucleosides from d-xylose

A series of novel purine-modified 2′,3′-dideoxy-2′,3′-difluro-D-arabinonucleosides, including fluorinated analogs of fludarabine and nelarabine, have been prepared via anion glycosylation reactions of salts of 2-fluoropurine derivatives with the glycosyl bromide. A short and efficient synthetic route to the carbohydrate precursor 5-O-benzoyl-2,3-difluoro-α-d-arabinofuranosyl bromide was developed in five steps from d-xylose. Improved synthesis of methyl 5-O-benzoyl-2,3-difluoro-α-d-arabinofuranoside based upon the study of diethylaminosulfur trifluoride (DAST)-reactions with 5-O-protected methyl D-xylosides was explored using mild reaction conditions on the key step. New peculiarities for selective fluorinations of 5-O-benzoylated α- and β-D-pentofuranosides with DAST leading to the formation of mono and difluoro-furanoside derivatives are reported.     

Darstellung von 2′,3′-Dideoxy-2′-hydroxymethyl-nucleosiden

Zusammenfassung Die Synthese von geschützten 2,3-Dideoxy-2-hydroxymethyl-nucleosiden wird beschrieben. Die durch ein Mehrstufenverfahren aus Isopropylidenglycerol erhaltenen Nucleoside können als Bausteine zur Darstellung von Oligonucleotiden verwendet werden, deren 2- und 5-Positionen über eine Etherbrücke verbunden sind.

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Synthesis of 2,3-dideoxy-2-hydroxymethyl nucleosides

Summary The synthesis of protected 2,3-dideoxy-2-hydroxymethyl nucleosides is presented. The nucleosides, obtained in a multi-step procedure starting from isopropylideneglycerol, may be used as building blocks for the synthesis of 2,5-ether linked oligonucleotides.

     

2′-Fluoro-3-deazaaristeromycin

The carbocyclic nucleoside 3-deazaaristeromycin has shown biological promise but a library of its derivatives upon which to expand this property is lacking. To address this situation, the synthesis of the two diastereomers of 2′-fluoro-3-deazaaristeromycin is described in a multistep convergent process that calls upon d-ribose for construction of the cyclopentyl fluoro units.     

Calorimetric characterization of 2′,3′-dideoxyinosine water solution

A study of 2′,3′-dideoxyinosine (ddI) stability and its interaction with human serum albumin (HSA) was carried out by differential scanning microcalorimetry DSC. Scan rate dependent and irreversible endothermic thermal degradation of ddI was analyzed with use of kinetic approach. Observed process could be interpreted in terms of simple first-order one step kinetic model. Moreover it was shown that ddI bound weakly to the human serum albumin and stabilized this protein.