One-pot synthesis of N-alkyl purine and pyrimidine derivatives from alcohols using TsIm: a rapid entry into carboacyclic nucleoside synthesis

A convenient and efficient one-pot N-alkylation of nucleobases from alcohols using N-(p-toluenesulfonyl)imidazole (TsIm) is described. In this method, treatment of alcohols with a mixture of purine or pyrimidine nucleobase, TsIm, K₂CO₃, and triethylamine in refluxing DMF regioselectively furnishes the corresponding N-alkyl nucleobases in good yields. This methodology is highly efficient for various structurally diverse primary alcohols.     

Hydrolytic deamination reactions of amidine and nucleobase derivatives

Amidines share the same NC─N building framework with many essential biochemical substances. In this work, we present a comparative mechanistic study on the deamination reactions of 19 amidine and nucleobase derivatives by the use of density functional theory. All the computations are performed at the B3LYP/6-31G(d,p) level in the gas phase and with the polarizable continuum model (PCM). Mechanisms of 2- and 3-step pathways including six- or eight-membered ring transition states were explored. Our results show that the overall activation energies for the deamination of amidine derivatives are close to those of nucleobase derivatives of the saturated C5─C6 bond, and lower than those of nucleobase derivatives of the unsaturated C5─C6 bond, while purine derivatives have the highest activation energies among all the derivatives studied. The 3-step mechanism gives results that are more consistent with the available experimental data than the 2-step mechanism. Based on the results of our current and previous work, we believe that the 3-step mechanism is the most likely mechanism for the hydrolytic deamination reactions of amidine and nucleobase derivatives.     

Studies on 2'-alpha-C-carboxyalkyl nucleosides and their application to a stereocontrolled nucleobase exchange process

The ability of 2'-alpha-C-carboxyalkyl nucleosides to undergo an unusual two-step stereocontrolled nucleobase exchange process has been investigated. Upon silylation a protected 2'-deoxy-2'-alpha-C-(carboxymethyl)uridine derivative can undergo intramolecular displacement of the uracil base, by the 2'-carboxylic acid group, to form a pentofuranosyl gamma-lactone. Under identical conditions the homologous 2'-deoxy-2'-alpha-C-(carboxyethyl)uridine derivative does not yield the corresponding delta-lactone, but undergoes elimination of uracil to give the corresponding glycal. The pentofuranosyl gamma-lactone is a good substrate for nucleoside synthesis by the Vorbrüggen procedures and undergoes completely stereoselective ring opening with either pyrimidine or purine silylated nucleobases to give novel 2'-C-carboxymethyl beta-nucleosides in moderate to high yield.     

Macrochelation, cyclometallation and G-quartet formation: N3- and C8-bound PdII complexes of adenine and guanine

The reactions of Pd(II) ions with a series of chelate-tethered derivatives of adenine and guanine have been studied and reveal a difference in the reactivity of the purine bases. Reactions of [PdCl2(MeCN)2] and A-alkyl-enH x Cl (alkyl = propyl or ethyl, A adenine, en = ethylenediamine) yield the monocationic species [PdCl(A-N3-Et-en)]+ (1) and [PdCl(A-N3-Pr-en)]+ (2). Both involve co-ordination at the minor groove site N3 of the nucleobase as confirmed by single-crystal X-ray analysis. Reactions with the analogous G-alkyl-enH x Cl derivatives (G=guanine, alkyl = ethyl or propyl) were more complex with a mixture of species being observed. For G-Et-en HCI a product was isolated which was identified as [PdCl(G-C8-Et-en)]+ (3). This compound contains a biomolecular metal-carbon bond involving C8 of the purine base. Crystallography of a product obtained from reaction of G-Pr-enH x Cl and [Pd(MeCN)4][NO3]2 reveals an octacationic tetrameric complex (4), in which each ligand acts to bridge two metal ions through a combination of a tridentate binding mode involving the diamine and N3 and monodentate coordination at N7.     

L-ProT catalyzed highly regioselective N-alkoxyalkylation of purine rings with vinyl ethers

An efficient and regioselective synthesis of N-9 alkoxyalkylated purine nucleoside derivatives was achieved via the N-alkoxyalkylation of purine rings with vinyl ethers catalyzed by L-ProT.The advantages of this protocol include good to excellent yield,mild reaction condition,and simple manipulation.A plausible mechanism for the transformation was given.     

Simple synthesis of some pentafluoropropenyl derivatives of pyrimidine and purine based on addition-elimination reaction

Various pentafluoropropenyl derivatives of pyrimidine and purine bases have been obtained in good to high yield. The procedure involves the reaction of appropriate lithium derivatives prepared from both electron-rich and electron-poor pyrimidines, with the hexafluoropropene at a low temperature, via an addition-elimination process. Organolithiums of pyrimidine and purine bases give addition-elimination products as E/Z mixtures, whereas the products of the reaction of lithium amide of protected inosine with hexafluoropropene contain traces of an addition product as well as the stable perfluoroenamine. The methodology proposed allows a series of perfluorovinyl nucleobases to be obtained quickly and conveniently.     

Azetidines-Containing Fluorescent Purine Analogs: Synthesis and Photophysical Properties

Analogues of N,N-dimethyladenine exploiting both thieno-and isothiazolo-pyrimidine cores were modified with 3-subsituted azetidines to yield visibly emissive and responsive fluorophores. The emission quantum yields, among the highest seen for purine analogues (0.64 and 0.77 in water and dioxane respectively), correlated with the Hammett inductive constants of the substituents on the azetidine ring. Ribosylation of the difluoroazetidino-modified nucleobase yielded an emissive nucleoside that displayed a substantially lower emission quantum yield in water, compared to the precursor nucleobase. Importantly, high emission quantum yield was restored in deuterium oxide, which highlights the potential impact of the sugar moiety on the photophysical features of fluorescent nucleosides, a functionality usually considered non-chromophoric and photophysically benign.     

The synthesis of piperidine nucleoside analogs—a comparison of several methods to access the introduction of nucleobases

This work deals with the synthesis of piperidine and hydroxypiperidine analogs of nucleosides. Starting from commercially available 3-hydroxypiperidine, proline or 4-hydroxyproline, a series of piperidine derivatives of both purine and pyrimidine nucleobases was prepared. Various methods of nucleobase attachment were evaluated. The prepared compounds were tested for cytostatic, antibacterial, and antiviral properties but no significant activity was found.     

Mitsunobu Reactions for the Synthesis of Carbocyclic Analogues of Nucleosides: Examination of the Regioselectivity1

In order to provide a general synthetic method for carbocyclic nucleosides, regioselectivities in Mitsunobu reaction of purine, pyrimidin-2-one and their substituted derivatives with a variety of alcohols were examined and found to depend upon both substituents of the bases and kind of the alcohols.     

Application of capillary electrophoresis in the analysis of novel synthetic dideoxynucleoside analogues with potential anti-HIV activity.

The aim of this study was the development of a capillary electrophoretic method for the analysis of a series of novel synthetic dideoxynucleoside analogues with potential anti-HIV activity. These analogues consist of a tetrahydrofuranyl or a tetrahydropyranyl ring as the pseudosugar part and bear a hydroxyethyl side-chain and a nucleobase of the pyrimidine (eg thymine or uracil) or the purine (adenine) type with cis or trans configuration. Analysis of these derivatives was performed by capillary zone electrophoresis using 25 mM phosphate pH 3.00 and 4.00 as operating buffers for pyrimidine and purine analogues, respectively, and detection of separated species at 254 nm.     

β-Hydroxyamide derivatives of salicylic acid as organocatalysts for enantioselective reductions of prochiral ketones

In order to find the most effective catalyst for the enantioselective reduction of a prochiral ketone, a series of novel β-hydroxyamide derivatives of salicylic acid and chiral amino alcohols were synthesized. Different substituted prochiral ketones have been reduced in high yield (up to 99%) and the corresponding secondary alcohols are formed with good enantiomeric excess (up to 86%). The mechanism of this type of catalyst can be explained by considering the reaction mechanism for the CBS catalyst.     

Efficient access to fluorinated homoallylic alcohols through an indium promoted fluoroallylation reaction

Herein, an efficient access to fluorinated homoallylic alcohol is reported. The fluorinated alcohols were obtained in good to excellent yield using indium and halo-fluorinated allylic derivatives. The developed methodology using γ-substituted halo-fluorinated allylic derivatives gave the corresponding α-substituted fluorinated homoallylic alcohol in good yields and good diastereoselectivities up to 86:14.     

A simple and mild derivatization method for hydroxyl compounds using condensation agent carbazole-9-N-(2-methyl)-acetyl-benzene-disulfonate and its application for the determination of volatile alcohols from plasma by HPLC with fluorescence detection

A simple and sensitive HPLC method for the determination of hydroxyl compounds including volatile alcohols from spiked plasma, using a fluorescent condensation agent, namely carbazole-9-N-(2-methyl)-acetyl-benzene-disulfonate (CMABS), has been developed. A mixture of alcohols and pyridine in dichloromethane was treated with CMABS to give a quantitative yield of esters. The maximum fluorescence emissions for the derivatized alcohols are at 365 nm (λ_ex 335 nm). Studies on derivatization conditions indicate that alcohols react very fast with CMABS in presence of pyridine in dichloromethane to give the corresponding fluorescent derivatives. The method, in conjunction with a multi-step gradient, offers a baseline resolution of the common alcohol derivatives on a reversed-phase C₁₈ column, which is more convenient and more efficient than previous methods which require the prior conversion of the carboxylic acids to the acyl chlorides. The application of this method to the analysis of volatile alcohols in plasma was also investigated. The LC separation shows good selectivity and reproducibility for alcohol derivatives. The relative standard deviations ?(n = 5) for 100 pmol of each alcohol are < 4%. The detection limits are at the fmol level for C₁–C₃ alcohols and pmol level for C₄–C₉ alcohols. Received: 9 November 1998 / Revised: 3 May 1999 / Accepted: 6 May 1999     

A simple and mild derivatization method for hydroxyl compounds using condensation agent carbazole-9-N-(2-methyl)-acetyl-benzene-disulfonate and its application for the determination of volatile alcohols from plasma by HPLC with fluorescence detection

A simple and sensitive HPLC method for the determination of hydroxyl compounds including volatile alcohols from spiked plasma, using a fluorescent condensation agent, namely carbazole-9-N-(2-methyl)-acetyl-benzene-disulfonate (CMABS), has been developed. A mixture of alcohols and pyridine in dichloromethane was treated with CMABS to give a quantitative yield of esters. The maximum fluorescence emissions for the derivatized alcohols are at 365 nm (λ_ex 335 nm). Studies on derivatization conditions indicate that alcohols react very fast with CMABS in presence of pyridine in dichloromethane to give the corresponding fluorescent derivatives. The method, in conjunction with a multi-step gradient, offers a baseline resolution of the common alcohol derivatives on a reversed-phase C₁₈ column, which is more convenient and more efficient than previous methods which require the prior conversion of the carboxylic acids to the acyl chlorides. The application of this method to the analysis of volatile alcohols in plasma was also investigated. The LC separation shows good selectivity and reproducibility for alcohol derivatives. The relative standard deviations ¶(n = 5) for 100 pmol of each alcohol are < 4%. The detection limits are at the fmol level for C₁–C₃ alcohols and pmol level for C₄–C₉ alcohols.     

PHOTOALKYLATION OF PURINES IN DNA

Abstract— Ultraviolet light irradiation of DNA in the presence of alcohols such as 2-propanol leads to hydroxyalkylation of the purine bases. The purine photoproducts were identified as C-8 hydroxyalkyl derivatives of adenine and guanine by chromatographic mobility, co-crystallization with authentic samples, and by photoreversal to the original purines. Experiments are reported which demonstrate that the photoalkylation reaction is dependent upon secondary structural alterations in DNA. It is suggested that the photoalkylation of purines proceeds through free-radical intermediates.
The presence of alcohols during irradiation considerably decreases pyrimidine-dimer formation.     

Conformational properties of shape modified nucleosides--fleximers

A detailed (1)H NMR conformational study complemented with ab initio computations was performed in solution on fleximer nucleosides 1, 3, and 5 in relation to their natural counterparts. The substitution of the purine nucleobase found in the natural nucleosides with a more flexible two-ring heterocyclic system strongly increased the population of anti conformation around the glycosidic bond. This was accompanied by a large shift toward a north-type sugar conformation, which was explained by the interplay of anomeric, gauche, and steric effects. The formal separation of the bicyclic purine base into its imidazole and pyrimidine moieties allows for formation of a hydrogen bond between the NH(2) and 2'-OH groups and facilitates favorable conjugation between the two heterocyclic rings. Our results show that the interplay of stereoelectronic effects, combined with the flexibility of the nucleobase and possible conjugation effects within the nucleobase, plays a crucial role in the search for shape-mimic nucleosides that will interact with flexible binding sites.     

Click fleximers: a modular approach to purine base-expanded ribonucleoside analogues

The synthesis of nucleoside analogues incorporating 4-(5-pyrimidinyl)-1,2,3-triazole aglycons as expanded purine nucleobase mimics were accessed using the copper-catalyzed azide-alkyne Huisgen cycloaddition between a ribosyl azide and 5-alkynylpyrimidines. Depending on the nature of the alkyne employed, other nucleoside analogues that possess fluorescence or potential metal-binding properties were prepared. Computational studies were undertaken on the purine analogues and indicate that the heterocycles of the unfused nucleobase prefer a coplanar arrangement and the anti-glycosidic conformer is favoured in most instances.     

Glucose–Nucleobase Pseudo Base Pairs: Biomolecular Interactions within DNA

Noncovalent forces rule the interactions between biomolecules. Inspired by a biomolecular interaction found in aminoglycoside–RNA recognition, glucose‐nucleobase pairs have been examined. Deoxyoligonucleotides with a 6‐deoxyglucose insertion are able to hybridize with their complementary strand, thus exhibiting a preference for purine nucleobases. Although the resulting double helices are less stable than natural ones, they present only minor local distortions. 6‐Deoxyglucose stays fully integrated in the double helix and its OH groups form two hydrogen bonds with the opposing guanine. This 6‐deoxyglucose‐guanine pair closely resembles a purine‐pyrimidine geometry. Quantum chemical calculations indicate that glucose‐purine pairs are as stable as a natural T‐A pair.     

Double Functionalization of Carbon Nanotubes with Purine and Pyrimidine Derivatives

Herein, we have developed a synthetic strategy for the covalent double functionalization of single‐walled carbon nanotubes (SWCNTs) with a combination of purine–pyrimidine and purine–purine nucleobase systems. The nucleobases were introduced on the sidewall of oxidized SWCNTs through 1,3‐dipolar cycloaddition and by amidation of the carboxylic acids located at the tips and defect sites of the nanotubes. The new nanohybrids were characterized by transmission electron microscopy, thermogravimetric analysis, FTIR and Raman spectroscopy, magic‐angle spinning NMR spectroscopy, and Kaiser test. The nucleobase/SWCNT conjugates can be envisaged for the modulation of the interactions with nucleic acids by means of base pairing, thereby opening new possibilities in the development of DNA/CNT nanobioconjugates.