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.

     

An Improved Synthesis of 2′-Hydroxy-3′,4′,6′-trimethoxyacylophenones

A wide variety of 2′-hydroxypolymethoxyacetophenones and propiophenones, e.g. 1a and 1b are used in the synthesis of flavone and ehromone natural products.¹ Repeated attempts to prepare 1a and 1b by reacting 1,2,3,5-tetramethoxybenzene 2 with acetyl or propionyl chlorides and AlCl₃ in ether² gave products which were difficult to purify.³ We traced the problem to ring-ethoxy contaminants which were isolated and tentatively identified as 3a and 3b.     

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 Steroidal Spiro-1′,2′,4′-triazolidine-3′-thiones

Steroidal ketone thiosemicarbazones (4–6), obtained from the corresponding ketones(1–3), on oxidative cyclization with H₂O₂ at 0°C provide title compounds (7–9), respectively. The structures of these compounds have been established on the basis of their elemental analytical and spectral data.     

Synthesis and antiviral evaluation of 2′,2′,3′,3′-tetrafluoro nucleoside analogs

Herein, we report the synthesis of novel 2′,2′,3′,3′-tetrafluorinated nucleoside analogs along with their phosphoramidate prodrugs. A tetrafluoro ribose moiety was coupled with different Boc/benzoyl-protected nucleobases under Mitsunobu conditions. After deprotection, tetrafluorinated nucleosides 13b, 14b, 20b-22b were reacted with phenyl-(isopropoxy-l-alaninyl)-phosphorochloridate to afford corresponding monophosphate prodrugs 24b–28b. All synthesized compounds were evaluated against several DNA and RNA viruses including HIV, HBV, HCV, Ebola and Zika viruses.     

MASS SPECTROMETERY OF THE ISOMERIC OCTAHYDROBENZOPYRIMIDINE-2′-THIONE-4′,1-SPIROCYCLOHEXANE AND 2′-AMINOOCTAHYDROBENZO-3′,1′-THIAZINE-4′,1-SPIROCYCLOHEXANE

Abstract

Some authors have shown that tetrahydropyrimidine-2-thiones are hydrated in acidic solution and then isomerise to the 2-imino-or 2-enamino-1,3-thiazine.     

Structure of Ethanol Coordinated 1,8,15,22-Tetra-（2′,2′,4′-trimethyl-3′-pentoxy）phthalocyaninatocobalt

Crystal structure of ethanol coordinated 1,8,15,22-tetra(2′,2′,4′-trimethyl-3-pentoxy) phthalocyaninatocobalt (C64H80N8O4Co·2C2H5OH, Mr = 1176.43) was determined by X-ray diffrac- tion methods. The crystal is of monoclinic, space group P21/c with a = 16.4294(4), b = 8.0560(2), c = 24.3654(7)(A。), β = 98.3680(8)°, Z = 2, V = 3190.6(1) (A。)3, Dc = 1.225 g/cm3, F(000) = 1262, μ(MoKα) = 0.326 mm-1, the final R = 0.0865 and wR = 0.2737 for 4787 observed reflections with I ≥ 2σ(I). The bulky branched alkyloxy substituents lead to a one structural isomer and space the phthalocyanine molecules where two ethanol molecules coordinate to the cobalt atom from two sides of each molecule.     

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.     

1,1′,2,2′,6,6′-Hexaphenyl-4,4′-bipyridinium cation radical

Aniline reacts with 2,2,6,6-tetraphenyl-4,4-bipyrilium perchlorate to form 1,1,2,2,6,6-hexaphenyl-4,4-bipyridine perchlorate. A relatively stable cation radical is formed in the first stage of electrochemical reduction of this compound, which has been examined by ESR, where there are splittings from two nitrogen nuclei and the four protons in the 3,3,5,5 positions: a_N=0.38; a_H=0.14 mT.Translated from Teoreticheskaya i Éksperimental'naya Khimiya, No. 1, pp. 61–64, January–February 1992.     

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 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.     

Copper(II) complexing with 2′,2′-diethylheptanohydrazide

Acid-base properties of 2′,2′-diethylheptanohydrazide (DEHH) and its complex formation with copper(II) ions in water-isopropanol solutions were studied. Cationic complexes with [Cu²⁺] : [DEHH] ratios of 1 : 1 and 1 : 2 were found to be formed in weak acid media, and an uncharged complex with a [Cu²⁺] : [DEHH] ratio of 1 : 2 was found to be formed in a basic medium. log K _st values were determined. The data obtained were compared with the stability constants of copper(II) 2′,2′-diethylbenzohydrazide complexes.     

Synthesis and mesomorphic properties of 4-methoxyphenyl 4′- n -alkoxy-2′,3′,5′,6′-tetrafluorobiphenyl-1-carboxylates

A novel type of 4-methoxyphenyl 4′-n-alkoxy-2′,3′,5′,6′-tetrafluorobiphenyl-1-carboxylates have been synthesized. Textural observations by polarizing microscopy and DSC measurements of the phase transitions show that all of these compounds are thermotropic liquid crystals with only a nematic mesophase. The relationship between the properties and chemical structures of these compounds is discussed.     

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.     

Crystal structure of 1,1′-biphenyl-2,2′,3,3′-tetracarboxylic and 1,1′-biphenyl-2,2′,3,3′,5,5′,6,6′-octacarboxylic acids: solid-state chiralization and dissociation

X-ray diffraction analysis revealed unexpected stereochemical features accompanying crystal self-assembly of the two title oligocarboxylic acids.     

Synthesis of Novel 1-Arylsulfonyl-4-(1′-N-2′, 3′, 4′, 6′-tetra-O-acetyl-β-D-glucopyranosyl)thiosemicarbazides

Some 1-arylsulfonylthiosemicarbazides have been reported as fungicides1 and bacterio-static agents2. Recently, it is well documented that thiosemicarbazide is a novel class ofnon-peptide antagonists for bradykinin B2 , which is beneficial in the symptomat…     

Synthesis of 2′-deoxy-2′-fluororibo- and 2′-deoxy-2′,2′-difluororibonucleosides derived from 6-(het)aryl-7-deazapurines

A series of novel sugar-modified derivatives of cytostatic 6-hetaryl-7-deazapurine ribonucleosides (2′-deoxy-2′-fluororibo- and 2′-deoxy-2′,2-difluororibonucleosides) bearing an aryl or hetaryl group in position 6, was prepared and screened for biological activity. The fluororibo derivatives were prepared by aqueous palladium catalyzed cross-coupling reactions of the corresponding 6-chloro-7-deazapurine 2′-deoxy-2′-fluororibonucleoside 11 with (het)arylboronic acids. The key intermediate 11 was prepared by a six-step sequence from the corresponding arabinonucleoside by selective protection of 3′- and 5′-hydroxyls by acid-labile groups followed by stereoselective S_N2 fluorination and deprotection. The difluororibo-series was prepared by non-stereoselective glycosidation of 6-chloro-7-deazapurine with benzoyl-protected 2-deoxy-2,2-difluoro-d-erythro-pentofuranosyl-1-mesylate followed by cross-couplings, separation of anomers and deprotection. The title nucleosides did not show considerable cytostatic or antiviral activity.     

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.     

Complexation of copper(II) with 2′,2′-dialkyl-para-tert-butylbenzohydrazides

The complexation of copper(II) with 2′,2′-dimethyl-, 2′,2′-dibutyl-, and 2′,2′-diisobutyl-para-tert-butylbenzohydrazide in water-ethanol media was studied. The reagents (HL) formed [Cu(HL)]²⁺ and [Cu(HL)₂]²⁺ cationic complexes in a weakly acidic medium and uncharged CuL₂ complexes in an alkaline medium. logK _st was calculated for these complexes. The effect of 2′,2′-alkyl radicals on the stability of the complexes was considered. The obtained results were compared with data on the complexation of copper(II) ions with 2′,2′-dialkylbenzohydrazides.     

Synthesis of 2′,3′-dideoxynucleosides from 5-alkoxymethyluracils

Summary A modified synthesis of protected 2,3-dideoxyribose5 starting fromL-glutamic acid (1) is described. Reaction of5 with silylated 5-hydroxymethyluracil7 a and 5-alkoxymethyluracils7 b–e in the presence of trimethylsilyl triflate afforded an anomeric mixture of 2,3-dideoxyuridine derivatives8 a–e and9 a–e. Deprotection with methanolic ammonia and separation by chromatography gave the corresponding nucleosides10 a–e and11 a–e. Treatment of9 b–e with tri(1H-1,2,4-triazol-1-yl)phosphine oxide and subsequent reaction of12 b–e with ammonia in dioxane afforded the cytosine derivatives13 b–e which on treatment with methanolic ammonia gave the corresponding 2,3-dideoxycytidine derivatives14 b–e and15 b–e. In contrast with the parent compounds, these alkoxymethyl derivatives had no appreciable activity against human immunodeficiency virus (HIV-1).

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Synthese von 2,3-Dideoxynucleosiden aus 5-Alkoxymethyluracilen

Zusammenfassung Ausgehend vonL-Glutaminsäure (1) wird eine modifizierte Synthese von geschützter 2,3-Dideoxyribose (5) beschrieben. Reaktion von5 mit silyliertem 5-Alkoxymethyluracilen7 b–e in Gegenwart von Trimethylsilyltriflat ergab anomere Mischungen der 2,3-Dideoxyuridinderivate8 a–e und9 a–e. Abspaltung der Schutzgruppe mit methanolischen Ammoniak und chromatographische Trennung ergab die entsprechenden Nucleoside10 a–e und11 a–e. Behandlung von9 b–e mit Tri(1H-1,2,4-triazol-1-yl)phosphinoxid und nachfolgende Reaktion von12 b–e mit Ammoniak in Dioxan ergab die Cytosinderivate13 b–e, welche nach Behandlung mit methanolischem Ammoniak die entsprechenden 2,3-Dideoxycytidinderivate14 b–e und15 b–e ergaben. Im Gegensatz zur Stammverbindung hatten diese Alkoxymethylderivate keine nennenswerte Wirksamkeit gegen den menschlichen Immunschwächevirus (HIV-1).