Time-resolved resonance Raman investigation of the 2-fluorenylnitrenium ion reactions with C8 guanosine derivatives

A nanosecond time-resolved resonance Raman (ns-TR3) spectroscopic study of the reactions of the 2-fluorenylnitrenium ion with several C8-substituted guanosine derivatives is reported. The TR3 spectra show that the 2-fluorenylnitrenium ion reacts with the C8-substituted guanosine derivatives (C8-methylguanosine and C8-bromoguanosine) to produce C8 intermediates with the methyl and bromine moieties still attached to the intermediate species at the C8 position. The C8-bromoguanosine species was observed to be less reactive toward the 2-fluorenylnitrenium ion compared to the guanosine and C8-methylguanosine species. Comparison of the TR3 spectra to the results obtained from density functional theory calculations was used to characterize the C8 intermediates observed to learn more about their structure and properties. The implications of these results for the chemical reactivity of arylnitrenium ions toward substituted guanosine derivatives are briefly discussed.     

An Unusual Reductive Debromination of 8-Bromoguanosine by Tri-n-Butylphosphine

A reaction of 8-bromoguanosine with benzyl disulfide in the presence of tri-n-butylphosphine in aprotic or protic solvent afforded guanosine instead of 8-bromo-5′-benzylthio-5′-deoxyguanosine through an unexpected reductive debromination.     

Oligonucleotide duplexes containing N8-glycosylated 8-aza-7-deazaguanine and self-assembly of 8-aza-7-deazapurines on the nucleoside and the oligomeric level

The 8-aza-7-deazaguanine N8-(2'-deoxy-beta-D-ribofuranoside) (1) was synthesized, converted into the phosphoramidite 4 and incorporated into oligonucleotides. Nucleoside 1 forms stable base pairs with 2'-deoxy-5-methylisocytidine in DNA with antiparallel chain orientation (aps) and with 2'-deoxycytidine in duplexes with parallel chains (ps). According to the CD spectra self-complementary oligonucleotides d(1-m5isoC)3 and d(1-C), form autonomous DNA-structures. Neither the nucleoside 1 nor the regularly linked 8-aza-7-deaza-2'-deoxyguanosine form G-like tetrads while the regularly linked 8-aza-7-deaza-2'-deoxyisoguanosine gives higher molecular assemblies which are destroyed by bulky 7-bromo substituents. This was verified on monomeric nucleosides by ESI-MS spectrometry and on oligonucleotides by HPLC analysis.     

Microwave-Assisted One-Pot Synthesis of 3-Amino-1-aryl-8-bromo-2,4-dicyano-9H-fluorenes in Water

A series of novel 3-amino-1-aryl-8-bromo -2,4-dicyano-9H-fluorenes derivatives were prepared using arylaldehyde, 4-bromo-indanone, malononitrile, and sodium hydroxide as the reactants in water via one-pot synthesis under microwave irradiation. A green and efficient method was successfully developed via microwave irradiation. The method possesses several advantages, such as environmental friendliness, shorter reaction time, and simple workup procedure.      

Nitrone—XI Isoxazolidin-verbindungen—VIII : N-substituierte 5-isoxazolidinone durch reformatzky-reaktion mit nitronen

The two step procedure of the Reformatzky reaction with nitrones enables the synthesis of 2-alkyl 3-aryl 5-isoxazolidinones from α-bromo esters and such nitrones, which are too basic for the one step procedure, Diethyl α-bromo methylmalonate is especially suited for the Reformatzky reaction with nitrones, yielding the E-isomer of the corresponding isoxazolidinone. Reaction of ethyl α-bromo butyrate yields chiefly the Z-isomer, from which result conclusions are drawn concerning the transition state of the primary addition step.     

A Convenient Procedure for the Conversion of Carboxylic Acids to α-Bromo Thiolesters

Carboxylic acids can be conveniently transformed to the corresponding α-bromo thiolesters by a one-pot procedure involving Hell-Volhard-Zelinsky reaction and trapping the α-bromo acyl bromide intermediate with mercaptans.     

Restricting the conformational heterogeneity of RNA by specific incorporation of 8-bromoguanosine

In an effort to reduce the conformational heterogeneity of RNA, the modified nucleobase 8-bromoguanosine (8BrG) was introduced into oligonucleotides having the hairpin tetraloop motif YNMG (Y = U or C and M = C or A). Purine nucleobases with bromine at position eight are known to preferentially adopt the syn conformation as nucleosides. The hairpin tetraloop motif YNMG was chosen as a model system because it has a syn guanosine at position four of the loop that is essential for thermodynamic stability. Thermodynamic and structural characterization of modified oligonucleotides with the hairpin sequences UUCG, CGCG, and CGAG by UV-melting and NMR spectroscopy revealed that 8BrG substitution has a small effect upon the hairpin conformation, while the duplex conformation is strongly destabilized (DeltaDeltaG degrees 37 approximately +4.7 kcal mol-1), thus inhibiting dimerization. These results support a model in which 8BrG substitution shifts the hairpin-duplex equilibrium constant toward the hairpin conformation by destabilizing the duplex. This methodology should be useful for limiting conformational heterogeneity in large RNAs, with potential applications in structural biology and enzymology.     

Prostanoids: LXXXIV. Synthons for New Halochlorvulones II from 6,7-Dichloro-1,4-dioxaspiro[4.4]non-6-en-8-one

By reaction of 6,7-dichloro-1,4-dioxaspiro[4.4]non-6-en-8-one with NaI and LiBr in boiling acetylacetone or methyl butyl ketone the corresponding 3-iodo and 3-bromo derivatives of cyclopentenone were prepared.     

C6-substituted analogues of 8-azanebularine: probes of an RNA-editing enzyme active site

[reaction: see text] We describe the synthesis of derivatives of 8-azanebularine, a known inhibitor of adenosine deaminases including the RNA-editing enzyme ADAR2. 6-Methyl, 6-hydroxymethyl, 6-cyano, and 6-mercapto derivatives were obtained from 6-bromo precursors using different cross-coupling or substitution reactions. The C6-methyl derivative was incorporated into an RNA substrate for ADAR2 via the phosphoramidite. Quantitative gel mobility shift experiments with the resulting RNA indicate that methylation at C6 dramatically reduces the affinity of 8-azanebularine for ADAR2.     

Coprecipitation study of As(III), Cu(II) and Cd(II) from aqueous solution using 5-bromo and 2-methylthioquinoline-8-thiol

Oxidation products of 5-bromo and 2-methylthio-quinoline-8-thiol are used for the quantitative coprecipitation of As(III), Cu(II) and Cd(II) from water solutions in a wide range of acidity. The recovery is >95%.     

Acetylation of 8-Bromo-5-hydroxy-6,7,4′-trimethoxyflavone

5-Hydroxy-6,7,4′-trimethoxyflavone was isolated from Centaurea pseudomaculosa Dobrocz., and its bromo derivative was obtained. The reaction of 8-bromo-5-hydroxy-6,7,4′-trimethoxyflavone with acetic anhydride in the presence of a catalytic amount of p-toluenesulfonic acid gave of a 73% 5-acetoxy-8-bromo derivative whose structure was established by X-ray diffraction.__________Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 6, 2005, pp. 999–1001.Original Russian Text Copyright © 2005 by Donbaeva, Yamovoi, Tuleuvov, Turdybekov, Gatilov, Adekenov.     

DBU induced formation of 8-bromoguanosine dimer with three hydrogen bonds between the GG− base pairs

Upon hemideprotonation of 8-bromoguanosine (8-BrG) at the N1 position, induced by DBU, the adduct [8-BrG][8-BrG]^?[DBU–H]⁺ was formed. Slow evaporation of the 8-BrG methanol solution, in the presence of 0.5 equiv of DBU, yielded two polymorphic structures (1 and 2), where a neutral [8-BrG] (A) and N1 deprotonated, anionic 8-bromoguanosine [8-BrG]^? (B) were joined together through three intermolecular hydrogen bonds involving O6, N1 and C2–NH₂ sites. Such pairing gave planar GG^? dimers as the basic motif of crystal packing in both polymorphs. Both neutral and deprotonated guanosine molecules in the structure of 1 had the ribose units in a syn conformation. In the structure of polymorph 2, the N1 deprotonated guanosine molecule (B) retained the syn glycosidic conformation, while the non-deprotonated guanosine molecule (A) adopted the natural anti conformation of the ribose unit with respect to the nucleobase. Ribose rings revealed different puckering; only those of deprotonated molecules 1B and 2B possessed the usual C2′-endo envelope conformation. Crystal packing in both structures was guided by the highly complex H-bonded pattern. The CSD was searched for related structures, which are discussed with reference to polymorphs 1 and 2. ¹H and ¹³C NMR spectroscopic evidence is provided showing that the three H-bonded adduct [8-BrG][8-BrG]^?[DBU–H]⁺ was also formed in the highly H-bond competitive DMSO solution.     

Stereoselective preparation of (RP)-8-hetaryladenosine-3',5'-cyclic phosphorothioic acids

Cyclic adenosine monophosphate (cAMP) has been converted into its 8-bromo derivative and 2'O-TBDMS protected before activation of the phosphoric acid moiety with a reagent generated in situ from oxalyl chloride and DMF. Further reactions with primary amines furnished corresponding phosphoramidates with high stereoselectivity at the phosphorus atom. Cross-coupling reactions with the 8-bromopurine yielded 8-hetaryl derivatives. X-Ray analyses showed the amidates to possess the (S(P))-configuration. Carbon disulfide effected thiylation under strongly basic conditions stereospecifically provided the (R(P))-phosphorothioic acids.     

Synthesis, photochemistry and application of (7-methoxycoumarin-4-yl)methyl-caged 8-bromoadenosine cyclic 3',5'-monophosphate and 8-bromoguanosine cyclic 3',5'-monophosphate photolyzed in the nanosecond time region

New caged derivatives of hydrolysis-resistant 8-bromoadenosine cyclic 3',5'-monophosphate (8-Br-cAMP) and 8-bromoguanosine cyclic 3',5'-monophosphate (8-Br-cGMP) are described. The compounds are the axial and equatorial isomers of the (7-methoxycoumarin-4-yl)methyl (MCM) esters of cyclic nucleotides. Synthesis is accomplished by treatment of 4-bromomethyl-7-methoxycoumarin with the tetra-n-butylammonium salts of the 8-bromo-substituted cyclic nucleotides or with the free acids of 8-Br-cAMP and 8-Br-cGMP in the presence of silver(I) oxide. MCM-caged 8-Br-cAMP and MCM-caged 8-Br-cGMP liberate 8-Br-cAMP and 8-Br-cGMP during irradiation with ultraviolet light within a few nanoseconds. They show favorable absorption properties and quantum yields and are resistant to hydrolysis in aqueous buffer solutions. The moderate fluorescence properties of the caged compounds in comparison with the strongly fluorescent 4-hydroxymethyl-7-methoxycoumarin (MCM-OH) photoproduct allow the indirect estimation of the amount of photolytically released cyclic nucleotides in aqueous buffer solutions using fluorescence measurements. Their usefulness for physiological studies has been examined in a mammalian cell line expressing the cyclic nucleotide-gated ion channel of bovine olfactory sensory neurons using the patch-clamp technique and confocal laser scanning microscopy. The caged compounds serve as efficient and rapid intracellular sources of 8-Br-cAMP and 8-Br-cGMP. However, at least in HEK 293 cells, fluorescence signals cannot be used to monitor the photolysis of MCM-caged 8-Br-cAMP and 8-Br-cGMP, due to quenching of the fluorescence of MCM-OH.     

One-electron attachment reaction of B- and Z-DNA modified by 8-bromo-2'-deoxyguanosine

The one-electron attachment reaction of 8-bromo-2'-deoxyguanosine ((Br)G) in DNA was studied by comparing that in B- and Z-DNA. Oligodeoxynucleotides (ODNs) modified by (Br)G were synthesized as Z-DNA in which the syn-conformation deoxyguanosine is stabilized by steric interference between the 8-bromo group of (Br)G and the sugar moiety. Debromination from the (Br)G-modified ODNs occurred from the one-electron attachment during the gamma-radiolysis. The structural dependence of B- and Z-DNA was observed for the one-electron attachment reaction. The conversion of (Br)G was higher in Z-DNA than in B-DNA. Because the solvent-accessible surface of the purine base in Z-DNA is greater than that in B-DNA, it is demonstrated that the reactivity of purine base C8 is enhanced in Z-DNA compared to that in B-DNA.     

An efficient synthesis of cyclic IDP- and cyclic 8-bromo-IDP-carbocyclic-riboses using a modified Hata condensation method to form an intramolecular pyrophosphate linkage as a key step. An entry to a general method for the chemical synthesis of cyclic ADP-ribose analogues

An efficient synthesis of cyclic IDP-carbocyclic-ribose (3) and its 8-bromo derivative 6, as stable mimics of cyclic ADP-ribose, was achieved, and a condensation reaction with phenylthiophosphate-type substrate 15 or 16 to form an intramolecular pyrophosphate linkage was a key step. N-1-Carbocyclic-ribosylinosine derivative 28 and the corresponding 8-bromo congener 24 were prepared via condensation between N-1-(2,4-dinitrophenyl)inosine derivative 17 and a known optically active carbocyclic amine 18. Compounds 24 and 28 were then converted to the corresponding 5"-phosphoryl-5'-phenylthiophosphate derivatives 15 and 16, respectively, which were substrates for the condensation reaction to form an intramolecular pyrophosphate linkage. Treatment of 8-bromo substrate 15 with I2 or AgNO3 in the presence of molecular sieves 3A (MS 3A) in pyridine at room temperature gave the desired cyclic product 12 quantitatively, while the yield was quite low without MS. The similar reaction of 8-unsubstituted substrate 16 gave the corresponding cyclized product 32 in 81% yield. Acidic treatment of these cyclic pyrophosphates 12 and 32 readily gave the targets 6 and 3, respectively. This result suggests that the construction of N-1-substituted hypoxanthine nucleoside structures from N-1-(2,4-dinitrophenyl)inosine derivatives and the intramolecular condensation by activation of the phenylthiophosphate group with I2 or AgNO3/MS 3A combine to provide a very efficient route for the synthesis of analogues of cyclic ADP-ribose such as 3 and 6. Thus, this may be an entry to a general method for synthesizing biologically important cyclic nucleotides of this type.     

On the synthesis and animation of 5-chloro-and 5-bromo-1,7-naphthyridine

A new synthesis of 5-chloro- and 5-bromo-1,7-naphthyridine, using 8-amino-1,7-naphthyridine as starting material is described. On amination with potassium amide in liquid ammonia, the 5-bromo compound undergoes a tele-amination into 8-amino- and 2-amino-1,7-naphthyridine and a Chichibabin reaction yielding 8-amino-5-bromo-1,7-naphthyridine. The reaction with the 5-chloro compound occurs at a much lower rate than the 5-bromo compound and only gives 8-amino-5-chloro-1,7-naphthyridine in a small yield. Convincing ¹H-nmr evidence is presented, showing that the 5-bromo- and 5-chloro-1,7-naphthyridine give addition of the amide ion at position 8 and that the 5-chloro compound also gives addition at position 2.     

Synthesis of 1-(2-oxopropyl)adamantane from 1-bromo(chloro)adamantanes and isopropenyl acetate in the presence of iron and manganese compounds

An efficient procedure has been developed for the synthesis of 1-(2-oxopropyl)adamantane by reaction of 1-bromo(chloro)adamantanes with isopropenyl acetate in the presence of manganese and iron compounds.     

New Synthesis of 8-Alkoxycarbonylangelicins

A new procedure was developed for the synthesis of 8-alkoxycarbonylangelicins by base-catalyzed cyclization of ortho-acyl(hydroxy)coumarins with haloacetic acid esters. The procedure was successfully applied to prepare a series of new 8-alkoxycarbonyl- and 8-acylangelicins.     

Synthesis of 9-Bromo-2-fluoro-6,7-dihydro-5H-benzocycloheptene-8-carboxaldehyde

Cinnamaldehye is an antioxidant shown to induce apoptotic cell death in a number of human cancer cells. This article reports a synthesis of 9-bromo, 2-fluoro substituted, and Z-ring locked (by a trimethylene bridge at C-8 and C-11) crystalline fluorine-substituted derivative of cinnamaldehyde. The synthon, 8-fluoro-1-benzosuberone was treated with PBr₃, dimethylformamide (DMF), and CHCl₃ as a solvent to obtain 9-bromo-2-fluoro-6,7-dihydro-5H-benzocycloheptene-8-carboxaldehyde. The one-step trifunctionalization process converts a bicyclic ring–fused ketone into a β-bromo-α,β-unsaturated aldehyde in a chemoselective and regioselective manner. The process also creates a new carbon–carbon bond between C-8 and C-12. The structure of the previously unreported product has been obtained by x-ray crystallographic analysis. It has been characterized spectroscopically by infrared (IR), ¹H NMR, ¹³C NMR, gas chromatography–mass spectrometry (GC-MS), and elemental analysis. It is a structural element found in sterically hindered retinoids and is a useful advanced intermediate in the total synthesis of these naturally occuring bioactive polyenes.