Synthesis of 3′-deoxy-3′-iminodiacetic acid and 3′-deoxy-3′-aminodiethanol thymidine analogues and NMR study of their complexation with boronic acids

The iminodiacetic acid and aminodiethanol moieties are known for their ability to generate with boronic acids bicyclic structures having a strong intramolecular NB coordination. We describe here the convergent synthesis of 3′-deoxy-3′-iminodiacetic acid and 3′-deoxy-3′-aminodiethanol thymidine analogues. The abilities of these compounds to form boronate complexes with aliphatic or aromatic boronic acids were established by 1D and 2D ¹H and ¹³C NMR. Moreover, conformational analysis of the newly synthesized compounds revealed a marked preference for an N-type sugar puckering.     

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.

     

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.     

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 and Crystal Structure of 3′-Ethyl 5′-Methyl 1-Benzyl-4′-methyl-2-oxo-3′,4′-dihydrospiro-[indoline-3,2′-pyrrole]-3′,5′-dicarboxylate

The crystal structure of the title compound(C24H24N2O5, Mr = 420.45) has been determined by single-crystal X-ray diffraction. The crystal is of triclinic, space group P1 with a = 8.991(1), b = 11.166(1), c = 11.169(1) , α = 91.413(2), β = 105.887(2), γ = 90.992(2)°, V = 1077.8(2) 3, Z = 2, Dc = 1.296 g/cm3, F(000) = 444, μ(MoKα) = 0.091 mm-1, the final R = 0.0466 and wR = 0.1507 for 4185 observed reflections(I 2σ(I)). The single-crystal X-ray diffraction data indicated intermolecular C(17)–H(17)O(4), C(5)–H(5)… O(4) hydrogen bonds and C–H…π interaction in the structure.     

Differentiation of 2′-O- and 3′-O-methylated Ribonucleosides by tandem mass spectrometry

Recent studies revealed that the 3'-terminal nucleotides in plant microRNAs were methylated on the ribose at the 2' or 3' hydroxyl groups. Here we examined the fragmentation of the electrospray-produced [M + H]+ and [M - H]- ions of 2'- and 3'-O-methylated ribonucleosides. It turned out that the predominant fragmentation pathway for the [M + H]+ ions of ribose-methylated nucleosides was the neutral loss of the methylated ribose, which made it impossible to distinguish 2'-O-methylation from 3'-O-methylation by positive-ion MS/MS. However, characteristic fragment ions, resulting from the cleavage through the ribose rings, were produced for the [M - H]- ions of each pair of ribose-methylated nucleosides. In this respect, the neutral loss of a 90-Da fragment (C3H6O3) was observed for 2'-O-methylated cytidine, guanosine and adenosine, but not for their 3'-O-methylated counterparts. On the other hand, the neutral loss of a 60-Da fragment (C2H4O2) was found for 3'-O-methyluridine, but not for 2'-O-methyluridine.     

Concise Synthesis and Cellular Evaluation of 3′-Formyl-4′,6′-dihydroxy-2′-methoxy-5′-methylchalcone (FMC) and Its Analogues

3′-Formyl-4′,6′-dihydroxy-2′-methoxy-5′-methylchalcone (FMC) was a natural product isolated from Cleistocalyx operculatus. A four-step synthetic strategy toward FMC and its four analogues (1b–1e) was first developed. All compounds were synthesized from commercially available 2,4,6-trihydroxyacetophenone; formylation at 3′ position under Vilsmeier–Haack conditions was followed by the introduction of a methyl group at 5′ position. The key step of selective methylation at 2′ position was achieved by trimethylsilyldiazomethane (TMSCHN₂). Then substituted aromatic aldehydes were condensed through Claisen–Schmidt reaction in the presence of potassium hydroxide. All structures were confirmed by ¹H NMR, ¹³C NMR, and high-resolution mass spectra. FMC and analogues were screened for their antiproliferative activity.     

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.     

Nucleophilic Substitution on 5-Nitrobenzofurazan-3-Oxide: A New Synthetic Route for Novel Benzofurazan-5, 5′-Oxybis 3, 3′-Dioxide and Benzofurazan-5, 5′-Thiobis-3, 3′-Dioxide

The nucleophilic substitution of the nitro group in 5-nitrobenzofurazan-3-oxide is studied undder soild-liquid phase-transfer catalysis (PTC) conditions.     

4-Methoxy-3′-alkylsulfinyl-3,4′-diquinolinyl Sulfides--Synthesis and the Reaction with Sodium Methoxide #

Reaction of 4-methoxy-3'-alkylthio-3,4'-diquinolinyl sulfides 1a-d with a nitrating mixture led to the title sulfoxides 2a-d , but the same treatment of isopropylthio derivative 1e resulted in S-dealkylation and oxidation with formation of 3,3'-diquinolinyl disulfide 3 . 3'-Alkylsulfinyl group promotes nucleophilic methoxy-desulfidation of 4'-quinolinyl sulfur bond in sulfoxides 2 , as compared to that in sulfides 1 , in which case it leads to 3-quinolinyl sulfoxides 6 and 3-quinolinethiolate 4-A .     

Characterization and crystal structures of solvated N′-(4-hydroxy-3-nitrobenzylidene)-3-methylbenzohydrazide and N′-(4-dimethyl-aminobenzylidene)-3-methylbenzohydrazide

Two new solvated benzohydrazone derivatives N′-(4-hydroxy-3-nitrobenzylidene)-3-methylbenzohydrazide-methanol-water (2/1/1) 2(C₁₅H₁₃N₃O₄)·CH₃OH·H₂O (1) and N′-(4-dimethylamino-benzylidene)-3-methylbenzohydrazide methanol monosolvate C₁₇H₁₉N₃O·CH₃OH (2) are prepared and characterized by elemental analysis, ¹H and ¹³C NMR, and single crystal X-ray diffraction. Compound 1 crystallizes in the monoclinic space group P2₁/c with unit cell dimensions a = 17.084(2) Å, b = 12.706(1) Å, c = 15.412(1) Å, β = 113.207(1)°, V = 3074.1(4) ų, Z = 4, R ₁ = 0.0567, and wR ₂ = 0.1209. Compound 2 crystallizes in the monoclinic space group P2₁/n with unit cell dimensions a = 15.058(1) Å, b = 6.658(1) Å, c = 17.211(2) Å, β = 94.189(2)°, V = 1720.8(3) ų, Z = 4, R ₁ = 0.0611, and wR ₂ = 0.1594. X-ray diffraction indicates that the asymmetric unit of 1 contains two independent benzohydrazone molecules, one methanol and one water molecules. The asymmetric unit of 2 contains one benzohydrazone molecule and one methanol molecule. Benzohydrazone molecules of the compounds display trans configurations with respect to the C=N double bonds. The crystal structures of the compounds are stabilized by hydrogen bonds and weak π...π interactions.     

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.     

Structure and stability of molecular and ionic complexes of AlCl3 with pyrazine and 4,4′-bipyridyl

Structural and thermodynamic characteristics of molecular and ionic complexes of aluminum trichloride with pyrazine (pyz) and 4,4′-bipyridyl (bipy) are calculated at the RI-BP86/def2-SVP level. It is found that for molecular 2AlCl₃·3L and 4AlCl₃·3L complexes an energy difference between isomers does not exceed 4 kJ/mol, and the rotation barrier of the AlCl₃ moiety relative to the N-Al-N bond does not exceed 24 kJ/mol. A comparison of the stability of molecular and ionic complexes of aluminum in the gas phase shows that the maximum energy difference is ～60 kJ/mol. For L = pyz the molecular complex is more stable whereas for L = bipy it is the ionic one.     

Die indikatoreigenschaften des vicinalen m-Xylenolphthaleins (3′ ,5′ ,3′' ,5′'-Tetramethylphenolphthalein)

Ohne ZusammenfassungMit 1 Abbildung