Prolinol-based nucleoside phosphonic acids: new isosteric conformationally flexible nucleotide analogues

trans-4-Hydroxy-l-proline has been used as a starting material for the synthesis of prolinol-based nucleotide analogues with an N-phosphonomethyl moiety attached to the prolinol ring nitrogen atom. The synthetic methodology based on the inversion of configuration at both 1- and 4-position led to all diastereoisomeric O-protected 4-mesyloxyprolinol-N-phosphonates. Alkylation of nucleobases using the synthons in the l-series afforded the nucleotide analogues corresponding to α-l- and β-l-nucleotide. The NMR-based conformational study of these compounds in aqueous solution performed at two different pH values, showing either N-fully protonated or deprotonated forms, revealed the occurrence of the same mostly populated conformer in both cases. All final l-prolinol-based nucleoside phosphonic acids were tested for cytotoxic and antiviral properties, but no significant activity was found.     

2'-deoxyribonucleoside 3'-aryl phosphoranilidates: Key intermediates in the stereospecific synthesis of 2'-deoxyribonucleoside cyclic 3',5'-phosphorothioates and dinucleoside(3'→5')-phosphoranilidates

Phosphorylation of the 5'-O-monomethoxytrityl-2'-deoxyribonucleosides by means of aryl phosphoranilidochloridates gives the diastereoisomers of 5'-O-monomethoxytrityl-2'-deoxyribonucleoside 3'-aryl phosphoranilidates. Their separation can be performed by means of chromatographic techniques. They can be further converted to the 2'-deoxyribonucleoside cyclic 3'-5' phosphoranilidates, which are intermediates in the stereospecific synthesis of 2'-deoxyribonucleoside cyclic (3'-5')phosphorothioates of known absolute configuration at phosphorus.     

1H-NMR-spektroskopische konformationsanalyse von halogenierten thymidinabkömmlingen: I. konformation von thymidin, 3',5'-didesoxy-3'-chlor-5'-fluor-thymidin und 3', 5'-didesoxy-3',5'-difluor-thymidin

An improved method is given for determining the conformation of furanoid nucleosides by ¹H-NMR-spectra analysis using halogen-substituted thymidines as examples. The state of the three equilibria - ring-puckering, rotation about the C₄-C₅- bond and about the glycosidic bond - are influenced by the halogen substituents. Compared with thymidine the 3'-chlorine substituent shifts the furanose conformation to conformers, where the 3'-chlorine substituent is equatorial. The 5'-fluorine substituent increases the contribution of the G-G-rotamer and the ratio of syn-conformation. The relationships between the conformers in the pseudo-rotatory cycle and the population of the C_4'-C_5' rotamers are discussed.     

Microbiological transformations—XII: Microbiological reduction of racemic 1-(2',2',3'-trimethyl-cyclopent-3'-en-1'-yl)propan-2-one and 1-(2',2',3'-trimethyl-cyclopent-3'-en-1'-yl)butan-2-one by rhodotorula mucilaginosa

The microbiological reduction of (±)-l-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-propan-2-one (4) and (±)-1-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-butan-2-one (5) by Rhodotorula mucilaginosa was investigated. Both enantiomers of 4 are reduced stereospecifically to corresponding alcohols; (+)-(2S, l'R)-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-propan-2-ol (6) and (-)-(2S,l'S)-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-propan-2-ol (7). p ]The substrate selectivity in the reduction of 5 was observed: R enantiomer of 5 yields stereospecifically (+)-(2S,1'R)-(2',2',3'-trimethylcyclopent-3'-en-l'-yl)-butan-2-ol (8) while S(-)5 remains unchanged.     

Efficient synthesis of phosphorus-containing dendrimers capped with isosteric functions of amino-bismethylene phosphonic acids

An efficient synthetic strategy to synthesize phosphorus-containing dendrimers capped with isosteric acid functions derived from tyramine is described. The method is demonstrated on a first generation dendrimer that can be easily capped with 12 amino(bismethylene) sulfonic acids and amino(bismethylene) carboxylic acids that are strict analogs of the corresponding amino(bismethylene) phosphonic acids.     

Heterocyclic N-glycosyl derivatives—XIX : Glycal nucleosides. their relationship with 2',3'-unsaturated nucleosides and their utilization in the synthesis of 1',3'-two base nucleosides

The acid catalized reaction of tri-0-acetyl-D-glucal with benzotriazole or 6-methylthiopurine in acetonitrile gave a mixture of 1',2'- and 2',3'-unsaturated nucleosides, the former predominating. The relationship between these unsaturated nucleosides is studied and an allylic carbonium ion is proposed as an intermediate for these isomerizations. The acid catalized reaction of 1',2'-unsaturated nucleosides with more benzotriazole or 6-methylthiopurine gave 1',3'-two base nucleosides. The conformation and anomeric configuration of the N-glycosyl compounds obtained were assigned by NMR spectroscopy.     

An efficient synthesis of certain 5-substituted-2'-deoxyuridine 3',5'-cyclic monophosphate p-o-alkyl(aralkyl) esters. The crystal and molecular structure of 5-IODO-2'-deoxyuridine 3',5'-cyclic monophosphate p-o-methyl ester with axial methoxy group

Some 5-alkyl- and 5-halogeno-2'-deoxyuridine 3',5'-cyclic mono- phosphate P-O-alkyl(aralkyl) esters have been prepared from the silver salts of the parent cyclic monophosphates and alkyl(aralkyl) iodides. The diastereomeric phosphotriesters have been characterized by spectroscopic methods. The crystal and molecular structure of 5-iodo-2'-deoxyuridine 3',5'-cyclic monophosphate P-O-methyl ester with axial methoxy group has been determined. We failed to obtain the desired triesters from the reactions of the cAMP silver salt with alkyl iodides, contrary to previous claims in the literature.     

Second-generation synthesis of protected phosphonothiodifluoromethylene analogues of nucleoside-3′-phosphates

A practical, eight-step synthesis of the key intermediate 14 in 19% overall yield from α-d-xylose is described. The preparation can be carried out on multi-gram scale and involves the use of the organomagnesium reagent 2d. The capability of derivative 14 to be transformed into the title compounds is examplified by the preparation of 15. Additionally, X-ray crystallography of intermediate 12 provided the first structural data on difluorophosphonothioates.     

Design,synthesis, and anti-TMV bioactivities of nucleobase phosphonate analogs

A series of novel nucleobase derivatives and their analogues possessing diethoxyphosphoryl scaffolds were synthesized through four-step reactions and screened for their antiviral activity toward tobacco mosaic virus (TMV). Preliminary bioassays suggested that some of these simple structures displayed appreciable anti-TMV activity in vivo. Among them, compound (diethoxyphosphoryl)methyl 4-[2-(1H-benzo[d][1,2,3]triazol-1-yl)acetamido]-benzoate (a-3) exerted the strongest chemotherapeutic and protective effects against TMV with the rates of 52.8 and 72.2% at the dosage of 500 µg/mL, respectively, which were comparable with those of the commercial agricultural antiviral agent ningnanmycin (54.2 and 70.2%). Molecular docking with TMV helicases revealed that compound a-3 had strong interactions with receptor amino acid residues. Given the facile synthetic route and significant chemotherapeutic and protective potentials, compound a-3 could be further studied and exploited as a promising antiviral candidate.     

Polypyrazolic macrocycles—I : A study of the polycondensation of 3-chloromethyl-3'(5'),5-dimethyl-5'(3)-pyrazolyl-1-pyrazole

The polycondensation of 3 - chloromethyl - 3'(5'),5 - dimethyl - 5'(3') - pyrazolyl - 1 - pyrazole under neutral or basic conditions yields new macrocyclic compounds. With suitable choice of base it is possible to direct the reaction towards the formation of a species possessing six pyrazole groups.     

One step synthesis of imidazole and benzimidazole acycloaromatic nucleoside analogs

A facile and rapid method for the synthesis of novel imidazole and benzimidazole aromatic acyclic nucleosides is described. Synchronous N-alkylation of imidazole or benzimidazole and potassium aryloxide with methylene iodide in the presence of triethylamine and a catalytic amount of tetrabutylammonium bromide (TBAB) in dry acetonitrile or acetone gave moderate yields of the acycloaromatic nucleoside analogs.     

一种吲哚螺吡咯多取代杂环化合物的合成及其晶体结构

利用多组分1,3偶极环加成反应方法,合成了一种新的螺环结构1'-甲基-3'-吡啶甲酰基-4'-(2-噻吩基)螺[吲哚啉-3,2'-吡咯啉]-2-酮化合物,并对该化合物进行了红外光谱、核磁共振谱及X-射线单晶衍射表征.单晶衍射结果表明:该晶体属于三斜晶系,空间群为P-1,晶体参数为a=0.899 9(1)nm,b=0.914 4(1)nm,c=1.271 1(2)nm,α=92.852(1)°,β=107.305(2)°,γ=101.580(1)°.在分子晶体结构中,吡咯啉环采用了信封式构象,通过螺碳原子与吲哚啉环相连,形成刚性螺环结构,2个环接近垂直构型,其二面角为84.15(2)°.     

A direct method for the synthesis of nucleoside 5′-methylenebis(phosphonate)s from nucleosides

An efficient method for the preparation of nucleoside 5′-methylenebis(phosphonate)s has been developed. Unprotected nucleosides are phosphonylated directly with methylenebis(phosphonic dichloride). Reaction conditions were optimized to prevent side product formation.     

新型螺双二氢茚二酚衍生物的合成

螺双二氢茚二酚(SPINOL)与N-溴代丁二酰亚胺经溴代反应制得6,6'-二溴-螺双二氢茚二酚(1);1与叔丁基二甲基硅基三氟甲磺酸(TBSOTf)经醚化反应得6,6'-二溴-7-羟基-7'-叔丁基二甲硅氧基-1,1'-螺二氢茚(2);SPINOL经羟基保护后与碘甲烷经双甲基化反应制得6,6'-二甲基-7,7'-双(1-甲氧甲氧基)-1,1'-螺二氢茚(4);4经脱保护后再与TBSOTf经醚化反应合成了6,6'-二甲基-7-羟基-7'-叔丁基二甲硅氧基-1,1'-螺二氢茚(6)。2和6为新化合物,其结构经1H NMR,13C NMR和HR-ESI-MS表征。     

Structure of cyclic nucleoside phosphonate ester prodrugs: an inquiry

The configuration at phosphorus in cyclic (S)-HPMPC (1, cidofovir) and (S)-HPMPA (2) phenyl ester (5 and 6, respectively) diastereomers ((R(p))-5, (R(p))-6, (S(p))-6) was determined by X-ray crystallography and correlated to their (1)H and (31)P NMR spectra in solution. (R(p))-5 and (R(p))-6 have chair conformations with the nucleobase substituent equatorial and the P-OPh axial. Perhaps surprisingly, (S(p))-6 is (a, a) in the crystal and exists largely as an equilibrium of (a, a)/(e, e) conformers in chloroform or acetonitrile.