First synthesis of 2',3'-epimino-carbocyclic nucleosides

The preparation of 2',3'-epimino-carbocyclic analogues of adenosine is reported. The reaction of p-tosyl azide with N-substituted 2-azabicyclo[2.2.1]hept-5-en-3-one (ABH) (1a) provided aziridine-fused ABH (2), which was converted to 2',3'-epimino-carbocyclic nucleosides (11).     

Non-glycosidic analogues of nucleotides: 2′(R),3′(S),5′-trihydroxypentyl derivatives of adenine and cytosine

Chiral 2′,3′,5′-trihydroxypentyl derivatives of adenine and cytosine in which configurations at C-2′ and C-3′ are opposite to those of the natural nucleosides have been synthesized. The nucleoside analogues were converted into 3′-phosphates and dinucleoside phosphate analogues with 3′–5′ phosphodiester linkages. PMR, UV and CD spectra of the compounds are presented.     

Synthetic utility of an isolable nucleoside phosphonium salt

The reaction of O6-benzyl-3',5'-bis- O-( tert-butyldimethylsilyl)-2'-deoxyxanthosine with 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) yielded the nucleoside C-2 tris(dimethylamino)phosphonium hexafluorophosphate salt as a stable, isolable species. This is in contrast to reactions of inosine nucleosides with BOP, where the in situ formed phosphonium salts undergo subsequent reaction to yield O6-(benzotriazol-1-yl)inosine derivatives. The phosphonium salt obtained from the 2'-deoxyxanthosine derivative can be effectively used to synthesize N2-modified 2'-deoxyguanosine analogues. Using this salt, a new synthesis of an acrolein-2'-deoxyguanosine adduct has also been accomplished.     

Multinuclear magnetic resonance study of the structure and tautomerism of azide and iminophosphorane derivatives of chloropyridazines

Some azido‐ and iminophosphorane derivatives of 3,6‐dichloro‐ and 3,4,5,6‐tetrachloropyridazine were synthesized and studied by means of NMR measurements. Based on multinuclear data (chemical shifts, coupling constants) for compounds containing the azide group, no potentially possible tetrazole–azide equilibrium can be observed, even under acidic conditions. An unusual substitution of a chlorine atom (in position 4) of tetrachloropyridazine in the reaction with hydrazine was demonstrated by NMR measurements of two newly synthesized compounds containing azido‐ and iminophosphorane groups. Using multinuclear magnetic resonance data, the sites of ethylation and protonation of azido‐ and iminophosphorane derivatives of chloropyridazines were established. In the case of the tetrazolopyridazines, ethylation occurs at the N1′ and N2′ atoms, whereas for monocyclic compounds it takes place at the N1 and/or N2 atoms of the pyridazine ring. Preferred sites of protonation are the N1′ atom of the tetrazole ring and the N1 atom of the pyridazine ring. Moreover, the structures of potassium salts of 6‐(3‐cyano‐1‐triazeno)tetrazolo[1,5‐b] pyridazine and its amido derivative were established using NMR data, especially ¹⁵N NMR chemical shifts. Copyright © 2002 John Wiley & Sons, Ltd.     

原位反应合成四唑金属配位聚合物：结构与磁性

使用Demko-Sharpless方法,在溶剂热条件下可以安全、有效地获得含四唑基团的配体。基于此反应,引入叠氮短桥共配,获得了2个结构新颖的配位聚合物Co₃(3-ptz)₄(N₃)₂(H₂O)₂·4H₂O (1)与Mn₃(3-ptz)₂(N₃)₄(H<     

Synthesis and Anti-Hepatitis B Virus Activity of Glucosylated 2-O-Ethyluracils

Summary.  2-O-Ethyluracils were silylated with HMDS and condensed in the presence of TMS-triflate with β-D-glucose pentaacetate to give the corresponding β-nucleosides. Alternatively, these could be synthesized by nucleoside coupling of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide with the sodium salts of 2-O-ethyluracils, which were deprotected with saturated ammonia in methanol. 6′-O-Tosylate nucleoside derivatives were prepared by treating of the latter with tosyl chloride in anhydrous pyridine. The compounds thus obtained were treated with sodium azide in anhydrous DMF to afford the corresponding 6′-azido nucleoside derivatives, which can also be prepared by treatment with sodium azide in the presence of carbon tetrabromide and triphenylphosphine in anhydrous DMF. Nucleophilic displacement of the 6′-tosyloxy group by morpholine gave 6′-deoxy-6′-morpholino nucleosides. The reduction of the azido group of the 6′-azido nucleosides using triphenylphosphine in pyridine afforded the 6′-amino analogues. Glucosylated 2-O-ethyluracils showed moderate activity against HBV. E-mail: adelnassar63@hotmail.com Received September 16, 2002; accepted (revised) October 15, 2002 Published online April 24, 2003     

Unusual deoxygenation and reactivity studies related to O6-(benzotriazol-1-yl)inosine derivatives

New and unusual developments related to the chemistry of O6-(benzotriazol-1-yl)inosine derivatives are reported. First, a simple, scalable method for their syntheses via the use of PPh3/I2/HOBt has been developed and has been mechanistically investigated by 31P(1H) NMR. Studies were then conducted into a unique oxygen transfer reaction between O6-(benzotriazol-1-yl)inosine nucleosides and bis(pinacolato)diboron (pinB-Bpin) leading to the formation of C-6 (benzotriazol-1-yl)purine nucleoside derivatives and pinB-O-Bpin. This reaction has been investigated by 11B(1H) NMR and compared to pinB-O-Bpin obtained by oxidation of pinB-Bpin. The structures of the C-6 (benzotriazol-1-yl)purine nucleosides have been unequivocally established via Pd-mediated C-N bond formation between bromo purine nucleosides and 1H-benzotriazole. Finally, short and extremely simple synthesis of 1,N6-ethano- and 1,N6-propano-2'-deoxyadenosine are reported in order to demonstrate the synthetic versatility of the O6-(benzotriazol-1-yl)inosine nucleoside derivatives for the assembly of relatively complex compounds.     

Electron impact mass spectrometry of some 6-substituted tetrazolo[1,5-c]pyrimidin-5(6H)-ones

The electron impact mass spectra of 6-methyltetrazolo[1,5-c]pyrimidin-5(6H)-one, its 7- and 8-methyl derivatives, three 8-halo derivatives and two related nucleosides are reported. On the basis of the high-resolution data and detected metastable ions, the fragmentation routes of their molecular ions are proposed. Coexistence of the tautomeric forms of the title compounds of cyclic (tetrazole) or linear (azide) structure can be suggested owing to the fragmentation pathways identified for the bases. Decomposition of the related nucleosides lies in the breaking of nucleoside bonds to produce the appropriate base and sugar fragments.     

Bromination at C-5 of Pyrimidine and C-8 of Purine Nucleosides with 1,3-Dibromo-5,5-dimethylhydantoin

Treatment of the protected and unprotected nucleosides with 1,3-dibromo-5,5- dimethylhydantoin in aprotic solvents such as CH(2)Cl(2), CH(3)CN, or DMF effected smooth bromination of uridine and cytidine derivatives at C-5 of pyrimidine rings as well as adenosine and guanosine derivatives at C-8 of purine rings. Addition of Lewis acids such as trimethylsilyl trifluoromethanesulfonate enhanced efficiency of bromination.     

A novel polymer supported approach to nucleoside modification

Polymer-supported O(6)-(benzotriazol-1-yl)inosine derivatives (Pol-I and Pol-dI) have been synthesized reasonably effectively via reaction of nucleoside phosphonium salts with polymer-linked HOBt (Pol-HOBt). In constast to solution chemistry, use of polymer-supported BOP (Pol-BOP) did not lead to efficient nucleoside loading. Presence of the nucleosides on the support could be readily detected by MAS NMR. Exposure of the polymer-supported nucleosides, Pol-I and Pol-dI, to alcohol, phenol, thiol and amine nucleophiles caused cleavage from the support leading directly to the C-6 modified nucleoside analogues. To our knowledge, these are the first examples of the application of such technology for nucleoside modification. Where possible, results of reactions with the polymer-supported nucleosides are compared to those from solution chemistry, providing insight into the differences between the two techniques. These new polymer-supported nucleosides can be conveniently utilized for diversity-oriented synthesis.     

Synthesis, modeling and evaluation of 3'-(1-aryl-1H-tetrazol-5-ylamino)-substituted 3'-deoxythymidine derivatives as potent and selective human mitochondrial thymidine kinase inhibitors

Based on the presumed binding mode of an earlier identified inhibitor, we herein report new 3'-modified nucleosides as potent and selective inhibitors of mitochondrial thymidine kinase (TK2). A series of thirteen 3'-amino-, 3'-guanidino- and 3'-tetrazole-containing nucleosides were synthesized and evaluated for their TK2 inhibitory activity. Within the tetrazole series, compounds with nanomolar inhibitory activity were identified. A homology model of TK2 allowed to elucidate the observed activities. Introduction of a 2-bromovinyl group on C-5 of the pyrimidine base of the most promising 3'-derivative further improved the inhibitory activity, and caused a significant increase in the selectivity for TK2 versus TK1. Interestingly, for the current series of analogues, a strong correlation was observed between TK2 and Drosophila melanogaster dNK inhibition, further substantiating the phylogenetic relationship between these two nucleoside kinases.     

Acyclic analogues of purine and imidazole nucleosides

Hydroxyl-protected derivatives of 1- and 3-(2-hydroxyethoxymethyl)imidazoles ( 4,5,7-10 ) have been prepared from 5-amino-4-carbamoylimidazoles ( 2 ). The protected derivatives were converted to acyclic analogues of imidazole nucleosides ( 6 ) or subjected to various cyclisation reactions leading to 9-(2-hydroxy-ethoxymethyl)-substituted 2-methyl-, 2-phenyl- and 2-azahypoxanthines ( 18,13 and 20 , respectively) and 1-methylguanine ( 28 ). For assignment of structures to isomeric imidazole and purine derivatives, ¹³C chemical shifts have been used.     

Diazo-, azo- et azidoazoles. III. Tautoméric azido/tétrazole dans des nouveaux azidoazoles

Some derivatives of 2-azidoimidazole and 3(5)azido-s-triazole were prepared to investigate the possibility of an azido/tetrazole equilibrium in these compounds. An explanation for observed differences in azido/tetrazole equilibrium between azole series and azine or thiazole series is suggested.     

Microwave-assisted synthesis and transformations of sterically hindered 3-(5-tetrazolyl)pyridines

Sterically hindered 2,4-disubstituted 3-(5-tetrazolyl)pyridines were synthesized from corresponding nicotinonitriles using microwave technology. 2-Methylnicotinonitriles were converted into the 2-azidomethyl-3-cyanopyridines via 2-hydroxymethyl and 2-chloromethyl derivatives. Intramolecular [3+2] cycloaddition of an heteroaromatic cyano group to side azido group was carried out to form a novel heterocyclic system containing a (tetrazolo)azaisoindole unit. Condensation of the 2-methylnicotinonitriles and aldehydes gave rise to the corresponding 2-vinyl derivatives, which were then transformed into novel heterocyclic system (5,6-dihydrotetrazolo[5,1-f]-1,6-naphthyridine) by intramolecular N-alkylation reaction of tetrazole ring with olefinic fragment. The 3-(5-tetrazolyl)pyridines obtained were alkylated to give the various N- and C-benzyl derivatives as well as acylated to afford the 3-(1,3,4-oxadiazol-2-yl)pyridines in good yields. A majority of above-mentioned reactions was carried out under microwave irradiation.     

Synthesis of Novel Nucleic Acid Mimics via the Stereoselective Intermolecular Radical Coupling of 3'-Iodo Nucleosides and Formaldoximes(1)

A highly convergent free radical coupling of alkyl iodides and oximes, mediated by bis(trimethylstannyl) benzopinacolate (8), has been utilized to prepare a series of dimeric nucleosides as mimics of natural nucleic acids. The systematic optimization of the reaction conditions allowed for the single-step conversion of the appropriate iodides and oximes into the 2'-deoxy dimers 9 in moderate to excellent yields. For example, the reaction of 3'-deoxy-3'-iodo-5'-(triphenylmethyl)thymidine (6a) with 3'-O-(tert-butyldiphenylsilyl)-5'-O-(methyleneimino)thymidine (7a) in the presence of 8 in degassed benzene gave an 81% yield of 3'-de(oxyphosphinico)-3'-(methyleneimino)-5'-O-(triphenylmethyl)thymidylyl-(3'-->5')-3'-O-(tert-butyldiphenylsilyl)thymidine (9a). Similarly prepared were dimers containing both pyrimidine (thymine, 5-methylcytosine) and purine (adenine, guanine) bases. The reaction was highly stereoselective, giving only a single dimeric species having the ribo-configuration of the newly introduced C-3'-branched methylene moiety. Also prepared were dimers 16, incorporating 2'-O-methyl ribonucleosides in both halves of the dimer. This required the synthesis of 3'-deoxy-3'-iodo-2'-O-methyl nucleosides 12 as well as 2'-O-methyl-5'-O-methyleneimino nucleosides 15. For example, 5'-O-(tert-butyldiphenylsilyl)-3'-deoxy-3'-iodo-2'-O-methyl-5-methyluridine (12e) was prepared in 80% yield by displacement of the corresponding triflate with Bu(4)NI. Also prepared were the suitably protected 3'-deoxy-3'-iodo adenosine and guanosine derivatives. Compounds 15 were prepared in high yield by a regioselective Mitsunobu reaction to give the corresponding 5'-O-phthalimido nucleosides 13, which were subsequently converted to the requisite oximes 15. In the 2'-O-methyl series, the pinacolate coupling reaction proceeded with efficiency equal to that observed for the 2'-deoxy series 9, but with slightly less stereoselectivity, giving predominantly the C-3'ribo products 16, contaminated with 5-25% of the epimeric material. Mixed base dimers containing both pyrimidine and purine bases at all possible positions, including purine-purine dimers were prepared. The hydroxylamine or methyleneimino (MI) backbone of several representative dimers so prepared was converted via methylation to give the corresponding methylenemethylimino (MMI)-linked compounds, which are novel phosphate surrogates for use in antisense oligonucleotides.     

Conversion of spirostane and solanidane into pregnane (1)introduction of oxygen function into C-23

A spirosolane derivative possessing a hydroxyl group at C-23, esculeogenin A, a sapogenol of tomato saponin, was found to be easily converted into the corresponding pregnane derivative by refluxing with aqueous pyridine. Therefore, introduction of a hydroxyl group into the C-23 of diosgenin (as representative of spirostane derivatives) and solasodine (as representative of spirosolane derivatives) was attempted by the reaction of NaNO(2)-BF(3)?·?Et(2)O. In diosgenin, the objective compound was obtained by the reaction in AcOH. However, in solasodine, we obtained a 23-nitroso derivative by the reaction in AcOH and 23,24-bisnorcholanic acid 22-16 lactone, or vespertilin, in AcOH and CHCl(3).     

从配位聚合物到单分子化合物的转化：Demko-Sharpless四唑合成法制备两个新颖的Co(II)配合物

The reaction of CoCl₂·6H₂O with 4-cyanopyridine N-oxide in the present of NaN₃ affords two novel complexes, {[(POTZ)(H₂O)₂N₃]Co(H₂O)} (1) and Co(POTZ)₂(H₂O)₄ (2) (POTZ=4-tetrazolyl pyridine N-oxide), which are two different phases yielded at different stages of a single Demko-Sharpless′ tetrazole synthesis reaction. Surprisingly the 1D chain coordination polymer 1 is almost completely converted into monomeric complex 2 in this reaction, and, in a separate test, 2 also can be converted into 1. CCDC: 641222, 1; 641223, 2.     

Structure of C-1 substituted glycopyranosyl azides: new insights based on CD measurements

CD spectra have been recorded for a series of peracetylated d-glycopyranosyl azides (d-gluco, d-galacto, d-xylo, d-arabino configuration) substituted at the anomeric position by various groups: amido, azido, cyano, ethoxy, methoxy. Application of the azide octant rule for the interpretation of the sign for the long-wavelength azide band allowed conformation of the azido group in each mono azido derivative investigated to be established. In each 1-cyano derivative, the azido group was in a gauche-like arrangement with respect to the C-1–O^ring bond, which is considered as a manifestation of the exo-anomeric effect of the azido group. For the 1-alkoxy derivatives, an antiparallel orientation of the azido group with respect to the C-1–O^ring bond was found in solution by CD measurement analysis, as already observed for methoxyazide 5 in the solid state. For azidoamide derivatives, intramolecularly (N–H–N^x_azide) H-bonded conformers are believed to prevail in methanol, in contrast to the situation in DMSO.     

Preparation of 4′-Spirocyclobutyl Nucleoside Analogues as Novel and Versatile Adenosine Scaffolds

Despite the large variety of modified nucleosides that have been reported, the preparation of constrained 4′-spirocyclic adenosine analogues has received very little attention. We discovered that the [2+2]-cycloaddition of dichloroketene on readily available 4′-exo-methylene furanose sugars efficiently results in the diastereoselective formation of novel 4′-spirocyclobutanones. The reaction mechanism was investigated via density functional theory (DFT) and found to proceed either via a non-synchronous or stepwise reaction sequence, controlled by the stereochemistry at the 3′-position of the sugar substrate. The obtained dichlorocyclobutanones were converted into nucleoside analogues, providing access to a novel class of chiral 4′-spirocyclobutyl adenosine mimetics in eight steps from commercially available sugars. Assessment of the biological activity of designed 4′-spirocyclic adenosine analogues identified potent inhibitors for protein methyltransferase target PRMT5.