Comprehensive structural studies of 2',3'-difluorinated nucleosides: comparison of theory, solution, and solid state

The conformations of three 2',3'-difluoro uridine nucleosides were studied by X-ray crystallography, NMR spectroscopy, and ab initio calculations in an attempt to define the roles that the two vicinal fluorine atoms play in the puckering preferences of the furanose ring. Two of the compounds examined contained fluorine atoms in either the arabino or xylo dispositions at C2' and C3' of a 2',3'-dideoxyuridine system. The third compound also incorporated fluorine atoms in the xylo configuration on the furanose ring but was substituted with a 6-azauracil base in place of uracil. A battery of NMR experiments in D 2O solution was used to identify conformational preferences primarily from coupling constant and NOE data. Both (1)H and (19)F NMR data were used to ascertain the preferred sugar pucker of the furanose ring through the use of the program PSEUROT. Compound-dependent parameters used in the PSEUROT calculations were newly derived from complete sets of conformations calculated from high-level ab initio methods. The solution and theoretical data were compared to the conformations of each molecule in the solid state. It was shown that both gauche and antiperiplanar effects may be operative to maintain a pseudodiaxial arrangement of the C2' and C3' vicinal fluorine atoms. These data, along with previously reported data by us and others concerning monofluorinated nucleoside conformations, were used to propose a model of how fluorine influences different aspects of nucleoside conformations.     

Synthesis and Conformational Analysis of 1′‐ and 3′‐Substituted 2‐Deoxy‐2‐fluoro‐D‐ribofuranosyl Nucleosides

Convergent syntheses of the 9‐(3‐X‐2,3‐dideoxy‐2‐fluoro‐β‐D ‐ribofuranosyl)adenines 5 (X=N₃) and 7 (X=NH₂), as well as of their respective α‐anomers 6 and 8 , are described, using methyl 2‐azido‐5‐O‐benzoyl‐2,3‐dideoxy‐2‐fluoro‐β‐D ‐ribofuranoside ( 4 ) as glycosylating agent. Methyl 5‐O‐benzoyl‐2,3‐dideoxy‐2,3‐difluoro‐β‐D ‐ribofuranoside ( 12 ) was prepared starting from two precursors, and coupled with silylated N⁶‐benzoyladenine to afford, after deprotection, 2′,3′‐dideoxy‐2′,3′‐difluoroadenosine ( 13 ). Condensation of 1‐O‐acetyl‐3,5‐di‐O‐benzoyl‐2‐deoxy‐2‐fluoro‐β‐D ‐ribofuranose ( 14 ) with silylated N²‐palmitoylguanine gave, after chromatographic separation and deacylation, the N⁷‐β‐anomer 17 as the main product, along with 2′‐deoxy‐2′‐fluoroguanosine ( 15 ) and its N⁹‐α‐anomer 16 in a ratio of ca. 42 : 24 : 10. An in‐depth conformational analysis of a number of 2,3‐dideoxy‐2‐fluoro‐3‐X‐D ‐ribofuranosides (X=F, N₃, NH₂, H) as well as of purine and pyrimidine 2‐deoxy‐2‐fluoro‐D ‐ribofuranosyl nucleosides was performed using the PSEUROT (version 6.3) software in combination with NMR studies.     

13C nuclear magnetic resonance spectroscopy of selected adenine nucleosides: Structural correlation and conformation about the glycosidic bond

Structural correlations have been carried out from ¹³C chemical shifts (δ) and by analysis of ¹J(CH) coupling constants, and the conformation about the glycosidic bond has been studied by means of the ³J(CH) vicinal coupling constants between C-8 and H-1′ of some adenine nucleosides such as adenosine (Ado), N(7)-β-D-ribofuranosyladenine (N(7)-Ado), N(9)- and N(7)-β-D-xylofuranosyladenine (N(9)-xylAde and N(7)-xylAde), N(9)-(3-chloro-3-deoxy-β-D-xylofuranosyl)adenine (3′-Cl-xylAde) and N(9)-(2-chloro-2-deoxy-β-D-arabinofuranosyl)adenine (2′-Cl-araAde). The analysis of the influence on δ¹³C of the nature and configuration of the substituent in the carbohydrate fragment of the molecule has revealed two types of effects, namely, 1,2-cis and 1,2-trans. This approach, as well as the ³J(CH) values and the analysis of the C-3′-endo?C-2′-endo equilibrium of the carbohydrate fragment of nucleosides, and circular dichroism (CD) data, provides important information on the conformation about the glycosidic bond. The magnitudes of ³J(C-4, H) are indicative of the position of attachment of the carbohydrate fragment to the heterocyclic base.     

Some features of the reaction of β-dicarbonyl compounds with urea in oleum

Conclusions The reaction of urea with-alkyl--formylcarboxylate esters and oxalacetic ester in oleum gives 5-alkyluracils and orotic acid, respectively.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 918–920, April, 1968.     

High precision delta(17)O isotope measurements of oxygen from silicates and other oxides: method and applications

The use of infrared laser-assisted fluorination to release oxygen from milligram quantities of silicates or other oxide mineral grains is a well-established technique. However, relatively few studies have reported the optimisation of this procedure for oxygen-17 isotope measurements. We describe here details of an analytical system using infrared (10 μm) laser-assisted fluorination, in conjunction with a dual inlet mass spectrometer of high resolving power ( approximately 250) to provide (17)O and (18)O oxygen isotope measurements from 0.5-2 mg of silicates or other oxide mineral grains. Respective precisions (1) of typically 0.08 and 0.04 per thousand are obtained for the complete analytical procedure. Departures from the mass-dependent oxygen isotope fractionation line are quantified by Delta(17)O; our precision (1) of such measurements on individual samples is shown to be +/-0.024 per thousand. In turn, this permits the offset between parallel, mass-dependent fractionation lines to be characterised to substantially greater precision than has been possible hitherto. Application of this system to investigate the (17)O versus (18)O relationship for numerous terrestrial whole-rock and mineral samples, of diverse geological origins and age, indicates that the complete data set may be described by a single, mass-dependent fractionation line of slope 0.5244+/- 0.00038 (standard error). Copyright 1999 John Wiley & Sons, Ltd.     

2'-chloro-2',3'-dideoxy-3'-fluoro-d-ribonucleosides: synthesis,stereospecificity, some chemical transformations,and conformational analysis

The synthesis of methyl 5-O-benzoyl-2-chloro-2,3-dideoxy-3-fluoro-beta-d-ribofuranoside (5) and its use as a glycosylating agent for persilylated thymine, N(6)-benzoyladenine, and N(4)-benzoylcytosine are described (Scheme 1). The 2'-chloro-2',3'-dideoxy-3'-fluoro-d-ribonucleosides 10-12 synthesized were transformed to 2',3'-dideoxy-3'-fluoro-alpha- and -beta-d-erythro-pentofuranoside nucleosides of thymine (13a,b), adenine (14a,b), and cytidine (15a,b) by treatment with tributyltin hydride in the presence of alpha,alpha'-azobisisobutyronitrile (Scheme 2). Treatment of 2'-chloro-2',3'-dideoxy-3'-fluoro-d-ribonucleosides with 1 M MeONa/MeOH under reflux for 1-5 h afforded 2',3'-didehydro-2',3'-dideoxy-2'-chloro-d-pentofuranosyl nucleosides as the principal products (47-81%) of the reaction, along with recovered starting nucleoside (11-33%) (Scheme 3). Easy HF elimination was also observed in the case of the 2'-azido-2',3'-dideoxy-3'-fluoro-beta-d-ribofuranosides of thymine (17) and adenine (20) (Scheme 3). The role of conformational peculiarities of 2'-chloro-2',3'-dideoxy-3'-fluoro-d-ribonucleosides as well as of 17 and 20 in the observed exclusive elimination of HF is discussed. The conformational analysis of a rather broad palette of 2,3-dideoxy-3-fluoro-2-(X-substituted)-d-ribofuranosides was performed with the aid of the PSEUROT (version 6.3) program, using (i) the recently reparametrized Karplus-type relation (Chattopadhyaya and co-workers. J. Org. Chem. 1998, 63, 4967) and (ii) empirical bond angle correction terms suggested by us. The predictive power of the Brunck and Weinhold model (J. Am. Chem. Soc. 1979, 101, 1700) of the gauche effect between atoms and groups as a conformational driving force acting upon the pentofuranose ring is explored. Their model invokes maximum antiperiplanar sigma <--> sigma stabilization when the donating bond is the least polar one and the acceptor orbital is at the most polarized bond and is found at least as satisfactory, and in various specific cases more so than, as rationalizations on the basis of the preference of the gauche vs the trans conformation of two vicinal electronegative substituents (Wolfe. Acc. Chem. Res. 1972, 5, 102).     

Interaction of molecules of the neonicotinoid imidacloprid and its structural analogs with human serum albumin

We have used fluorescence spectroscopy methods to show that imidacloprid and its structural analogs form complexes with human serum albumin (HSA). The nature of the spectral changes in the ligand×protein systems and the calculated complexation parameters suggest that these low molecular weight compounds mainly bind to a specific section of the protein molecule, near the tryptophan residue in the 214 position of the polypeptide chain. We have found that the association constants are on the order of 10⁴ M⁻¹, and the affinity of the ligands for HSA varies in the series 6-chloronicotinic acid > 6-methoxynicotinic acid = imidacloprid > the keto analog of imidacloprid. The major contribution to the complexation energy probably comes from hydrophobic interaction forces with participation of the aromatic pyridine ring of the ligands, while additional enhancement of ligand-protein affinity can be provided by the nitroimine group of imidacloprid. Translated from Zhurnal Prikladnoi Spektroskopii, Vol. 75, No. 6, pp. 859–866, November–December, 2008.