Nucleosides. Part L.. Structure of lumazine N1-(2′-deoxy-D-ribonucleosides) ( = 1-(2′-deoxy-D-ribofuranosyl)pteridine-2,4(1H,3H)-diones): A revision of the anomeric configuration

The anomeric configuration of the glycosidic bond in lumazine N¹-(2′-deoxy-D -ribonucleosides) 1–6 was investigated by NOE difference spectroscopy. The former configurational assignment of the α - and β -D -anomers 1 and 2, 3 and 4 , and 5 and 6 , respectively, has to be reversed to be in agreement with the physical data. Additional proof is presented by X-ray analysis of 3 and 6 . Chemical interconversions of 1-(2′-deoxy-β-D -ribofuranosyl)-6,7-diphenyllumazine ( 6 ) into 2,3′ -anhydrolumazine 2′-deoxyribonucleosides 16 and 17 are also in agreement with the revised anomeric configuration.     

Nucleotide. IX. Synthese und Eigenschaften von 1-(2′-Desoxy-D-ribofuranosyl)-lumazin-3′-monophosphaten

Nucleotides. IX. Synthesis and properties of 1-(2′-deoxy-D -ribofuranosyl)-lumazin-3′-monophosphates The synthesis of various 1-(2′-deoxy-α-[and β-]D -ribofuranosyl)-lumazine-3′-monophosphates 25--30 starting from the corresponding pteridine nucleosides 1--6 is described. Monomethoxytritylation in 5′-position to 7--12 , phosphorylation by cyanoethylphosphate to 13--18 , and deprotection by acid and base treatment afforded the lumazine nucleotides 25--30 in good overall yield. The various reaction products have been characterized by physical means, such as UV. spectra, pK-values and their chromatographical and electrophoretical behaviour. Enzymatic dephosphorylations by alkaline phosphatase led to the starting material 1--6 with a 3--4 times slower hydrolysis rate in comparison to Tp.     

Synthesis of New Nucleosides by coupling of chloropurines with 2- and 3-deoxy derivatives of N-methyl-D-ribofuranuronamide

The synthesis of new deoxyribose nucleosides by coupling chloropurines with modified D -ribose derivatives is reported. The methyl 2-deoxy-N-methyl-3-O-(p-toluoyl)-α-D -ribofuranosiduronamide (α-D - 8 ) and the corresponding anomer β-D - 8 were synthesized starting from the commercially available 2-deoxy-D -ribose ( 1 ) (Scheme 1). Reaction of α-D - 8 with the silylated derivative of 2,6-dichloro-9H-purine ( 9 ) afforded regioselectively the N⁹-(2′-deoxyribonucleoside) 10 as anomeric mixture (Scheme 2), whereas β-D - 8 did not react. Glycosylation of 9 or of 6-chloro-9H-purine ( 17 ) with 1,2-di-O-acetyl-3-deoxy-N-methyl-β-D -ribofuranuronamide ( 13 ) yielded only the protected β-D -anomers 14 and 18 , respectively (Scheme 3). Subsequent deacetylation and dechlorination afforded the desired nucleosides β-D - 11 , β-D - 12,15 , and 16 . The 3′-deoxy-2-chloroadenosine derivative 15 showed the highest affinity and selectivity for adenotin binding site vs. A₁ and A_2A adenosine receptor subtypes.     

Nucleoside und Nucleotide. Teil 16. Verhalten von 1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)-pyrimidinon-5′-triphosphat, 1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)pyridinon-5′-triphosphat und 4-Amino-1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)-pyridinon-5′-triphosphat gegenüber DNA-Polymerase

Nucleosides and Nucleotides. Part 16. The Behaviour of 1-(2′-Deoxy-β-D -ribofuranosyl)-2(1H)-pyrimidinone-5′-triphosphate, 1-(2′-Deoxy-β-D -ribofuranosyl-2(1H))-pyridinone-5′-triphosphate and 4-Amino-1-(2′-desoxy-β-D -ribofuranosyl)-2(1H)-pyridinone-5′-triphosphate towards DNA Polymerase The behaviour of nucleotide base analogs in the DNA synthesis in vitro was studied. The investigated nucleoside-5′-triphosphates 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyrimidinone-5′-triphosphate (pppM_d), 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone-5′-triphosphate (pppII_d) and 4-amino-1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone-5′-triphosphate (pppZ_d) can be considered to be analogs of 2′-deoxy-cytidine-5′-triphosphate. However, their ability to undergo base pairing to the complementary guanine is decreased. When pppM_d, pppII_d or pppZ_d are substituted for pppC_d in the enzymatic synthesis of DNA by DNA polymerase no incorporation of these analogs is observed. They exhibit only a weak inhibition of the DNA synthesis. The mode of the inhibition is uncompetitive which shows that these nucleotide analogs cannot serve as substrates for the DNA polymerase.     

Nucleosides and nucleotides. Part 25.. Synthesis of a protected 1-(2′-deoxy-β-D-ribofuranosyl)-1 H-benzimidazole 3′-phosphate

1-(2′-Deoxy-5′-O-dimethoxytrityl-′-D -ribofuranosyl)-1 H-benzimidazole 3′-[(p-chlorophenyl)(2-cyanoethyl) phosphate] ( 6 ) has been synthesized from 1-(β-D -ribofuranosyl)-1H-benzimidazole ( 3b ) using regiospecific 2′-deoxygenation. The latter compound was obtained by glycosylation of benzimidazole with the D -ribose derivative 2 leading exclusively of the β-D -anomer.     

Nucleotides. Part LIV. Synthesis of condensed N1-(2′-deoxy-β-D-ribofuranosyl)lumazines,New fluorescent building blocks in oligonucleotide synthesis

Various condensed areno[g]lumazine derivatives 2 , 3 , and 5 – 7 were synthesized as new fluorescent aglycones for glycosylation reactions with 2-deoxy-3, 5-di-O-(p-toluoyl)-α/β-D -erythro-pentofuranosyl chloride ( 10 ) to form, in a Hilbert-Johnson-Birkofer reaction, the corresponding N¹-(2′-deoxyribonucleosides) 15 – 21 . The β-D -anomers 15 , 17 , 19 , and 21 were deblocked to 24 – 27 and, together with N¹-(2′-deoxy-β-D -ribofuranosyl)lumazine ( 22 ) and its 6, 7-diphenyl derivative 23 , dimethoxytritylated in 5′-position to 28–33. These intermediates were then converted into the 3′-(2-cyanoethyI diisopropylphosphoramidites) 34 – 39 which function as monomeric building block in oligonucleotide syntheses as well as into the 3′-(hydrogen succinates) 40 – 45 which can be used for coupling with the solid-support material. A series of lumazine-modified oligonucleotides were synthesized and the influence of the new nucleobases on the stability of duplex formation studied by measuring the T_m values in comparison to model sequences. A substantial increase in the T_m is observed on introduction of areno[g]lumazine moieties in the oligonucleotide chain stabilizing obviously the helical structures by improved stacking effects. Stabilization is strongly dependent on the site of the modified nucleobase in the chain.     

Nucleoside und Nucleotide. Teil 10. Synthese von Thymidylyl-(3′-5′) -thymidylyl-(3′-5′)-1-(2′-desoxy-β-D-ribofuranosyl)-2(1 H)-pyridon

Nucleosides and Nucleotides. Part 10. Synthesis of Thymidylyl-(3′-5′)-thymidylyl-(3′-5′)-1-(2′-deoxy-β-D - ribofuranosyl)-2(1 H)-pyridone The synthesis of 5′-O-monomethoxytritylthymidylyl-(3′-5′)-thymidylyl-(3′-5′)-1-(2′-deoxy-β-D -ribofuranosyl)-2(1H)-pyridone ((MeOTr)T_dpT_dp∏_d, 5 ) and of thymidylyl-(3′-5′)-thymidylyl-(3′-5′)-1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridone (T_dpT_dp∏_d, 11 ) by condensing (MeOTr) T_dpT_d ( 3 ) and p∏_d(Ac) ( 4 ) in the presence of DCC in abs. pyridine is described. Condensation of (MeOTr) T_dpT_dp ( 6 ) with Π_d(Ac) ( 7 ) did not yield the desired product 5 because compound 6 formed the 3′-pyrophosphate. The removal of the acetyl- and p-methoxytrityl protecting group was effected by treatment with conc. ammonia solution at room temperature, and acetic acid/pyridine 7 : 3 at 100°, respectively. Enzymatic degradation of the trinucleoside diphosphate 11 with phosphodiesterase I and II yielded T_d, pT_d and p∏_d, T_dp and Π_d, respectively, in correct ratios.     

Nucleoside und Nucleotide. Teil 15. Synthese von Desoxyribonucleosid-monophosphaten und -triphosphaten mit 2(1H)-Pyrimidinon, 2(1H)-Pyridinon und 4-Amino-2(1H)-pyridinon als Basen

Nucleosides and Nucleotide. Part 15. Synthesis of Deoxyribonucleoside Monophosphates and Triphosphates with 2(1H)-Pyrimidinone, 2(1H)-Pyridinone and 4-Amino-2(1H)-pyridinone as the Bases The phosphorylation of the modified nucleosides 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyrimidinone (M_d, 4 ), 4-amino-1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone (Z_d, 6 ) and the synthesis of 1–2′-deoxy-β-D -ribofuranosyl-2(1 H)-pyrimidinone-5′-O-triphosphate (pppM_d, 1 ), 1-(2′-deoxy-β-D ribofuranosyl)-2(1 H)-pyridinone-5′-O-triphosphate (pppII_d, 2 ), and 4-amino-1-(2′-deoxy-βD -ribofuranosyl)-2(1 H)-pyridinone-5′-O-triphosphate (pppZ_d, 3 ) are described. The nucleoside-5′-monophosphates pM_d (5) and pZ_d (7) were obtained by selective phosphorylation of M_d (4) and Z_d (6) , respectively, using phosphorylchloride in triethyl phosphate or in acetonitril. The reaction of pM_d (5) pII _d (8) or pZ_d (7) with morpholine in the presence of DCC led to the phosphoric amides 9, 10 and 11 , respectively, which were converted with tributylammonium pyrophosphate in dried dimethylsulfoxide to the nucleoside-5′triphosphates 1, 2 and 3 , respectively.     

N-(2,2,2-Trichloroethylidene)- and N-(1-Hydroxy-2,2,2-trichloroethyl)amides in C-Amidoalkylation Reaction of Functionally-substituted Aromatic Compounds

A reaction with phenol and pyrocatechol of N-(2,2,2-trichloroethylidene)arenesulfonyl-, ethoxycarbonylamides and 1-hydroxy-substituted N-(2,2,2-trichloroethyl)amides of arenesulfonic, carbamic, and acetic acids in the presence of oleum or in sulfuric acid provided the corresponding (1-amido-2,2,2-trichloroethyl)-substituted phenols. N-(2,2,2-Trichloroethylidene)-4-chlorobenzenesulfonamide reacted with salicylamide in the presence of oleum to afford 3-aminocarbonyl-4-[2,2,2-trichloro-1-(4-chlorobenzenesulfonamido)ethyl]benzene whereas the 1-hydroxy-2,2,2-trichloroethylamides of the acetic, carbamic, and arenesulfonic acids did not enter into such reactions.     

Synthesis and Properties of N-(2,2,2-Trichloroethyl)-2-thiophenesulfonamides

Chlorination of 2-thiophenesulfonamide gave unstable N,N-dichloro-2-thiophenesulfonamide which was brought into reactions with 1,2-polyhaloethenes. The condensation of 2-thiophenesulfonamide with trichloroacetaldehyde afforded N-(2,2,2-trichloro-1-hydroxyethyl)-2-thiophenesulfonamide which reacted with benzene, toluene, 2-chlorothiophene, and phenol to form the corresponding N-(1-aryl-2,2,2-trichloroethyl)-2-thiophenesulfonamides. Under more severe conditions, the latter were converted into 1,1-diaryl-2,2,2-trichloroethanes. The reaction of N-(2,2,2-trichloro-1-hydroxyethyl)-2-thiophenesulfonamide with substituted arenes, including phenol, was regioselective: only the corresponding para-substituted products were obtained. Hydrolysis of N-[2,2,2-trichloro-1-(4-tolyl)ethyl]-2-thiophenesulfonamide yielded N-(2-thienylsulfonyl)-2-(4-tolyl)glycine.     

Alkylation of Phenols with N-(2,2,2-Trichloroethylidene)- and N-(2,2,2-Trichloroethyl)arenesulfonamides

N-(2,2,2-Trichloroethylidene)- and N-(2,2,2-trichloroethyl)arenesulfonamides react with phenol, 2-chlorophenol, and 2-methylphenol in the presence of oleum or sulfuric acid to give the corresponding 4-(2,2,2-trichloro-1-arylsulfonylaminoethyl)phenols in good yields.     

A convenient synthesis of certain 1-(β-D-ribofuranosyl)benzotriazoles

The synthesis of 5,6-dichloro-1-(β-D -ribofuranosyl)benzotriazole ( 4a ), 5,6-dimethyl-1-(β-D -ribofuranosyl)benzotriazole ( 4b ) and 1-(β-D -ribofuranosyl)benzotriazole ( 4c ) in good yield has been accomplished by the condensation of the appropriate 1-trimethylsilylbenzotriazole ( 1a, 1b , and 1c ) with 2,3,5-tri-O-acetyl-D -ribofuranosyl bromide (2) followed by subsequent deacetylation of the reaction products. The assignment of anomeric configuration and site of glycosidation for all nucleosides reported is discussed.     

Nucleoside und Nucleotide,Teil 12. Synthese von Dinucleosidmonophosphaten mit 1-(2′-Desoxy-β-D-ribofuranosyl)-2(1H)-pyrimidon als Baustein

Nucleosides and Nucleotides. Part 12. Synthesis of Dinucleoside Monophosphates Containing 1-(2′-Deoxy-β-D -ribofuranosyl)-2(1H)-pyrimidone The connexion of the modified nucleoside 1-(2′-deoxy-β-D -ribofuranosyl)-2(1H)-pyrimidone (M_d, 2 ) with the natural nucleotides pT_d and pG_d is described. The protected dinucleoside monophosphates (MeOTr)M_dpT_d ( 6 ) and (MeOTr)M_dpG ( 9 ) were prepared by the standard phosphodiester method using DCC as condensing agent. M_dpT_d ( 7 ) was obtained by treatment of 6 with formic acid/methanol 7 : 3 at 0° 9 was converted to the free dinucleoside monophosphate M_dpG_d ( 11 ) by removing the N-isobutyryl- and p-methoxytrityl protecting group on consecutive treatment with 0.04N CH₃ONa in CH₃OH and HCOOH/CH₃OH 7:3 at 0° respectively. Enzymatic degradation of the free dinucleoside of the free dinucleoside monophosphates 7 and 11 yielded the corresponding nucleosides and nucleotides in the correct ratios.     

Nucleosides and Nucleotides. Part 13. Synthesis and spectral properties of 1- (3′-O-Phosphoryl-2′-deoxy-β -D-ribofuranosyl)-2(1H)-pyridone-(3′-5′)-1-(2′-deoxy-β-D-ribofuranosyl)-2 (1H)-pyridone

The dinucleoside phosphate Π_dpΠ_d ( 4 ) was synthesized from the monomers 1-(5′-O-monomethoxytrityl - 2′ - deoxy - β - D - ribofuranosyl) - 2 (1 H) - pyridone ((MeOTr) Π_d, 2 ) and 1-(5′-O-phosphoryl-3′-O-acetyl-2′-deoxy-β-D -ribofuranosyl)-(1H)-pyridone (pΠ_d(Ac), 3 ). Its 6.4% hyperchromicity and an analysis of the ¹H-NMR. spectra indicate that the conformation and the base-base interactions in 4 are similar to those in natural pyrimidine dinucleoside phosphates.     

Synthesis and Biological Evaluation of 2-(2-Deoxy-β-D-ribofuranosyl)pyridine-4-carboxamide

A new protected 2-deoxy-D -ribose derivative, 5-O-[(tert-butyl)diphenylsilyl]-2-deoxy-3,4-O- isopropylidene-aldehydo-D -ribose ( 5 ), was synthesized starting from 2-deoxy-D -ribose. This compound was coupled with 2-lithio-4-(4,5-dihydro-4,4-dimethyloxazol-2-yl)pyridine giving a D /L -glycero-mixture 7 of 5-O-[(tert-butyl)diphenylsilyl]-2-deoxy-1-C-[4-(4,5 -dihydro-4,4-dimethyloxazol-2-yl)pyridin-2-yl]-3,4-O-isopropylidene- D -erythro-pentitol. The mixture 7 was 1-O-mesylated with methanesulfonyl chloride and subsequently treated with CF₃COOH/H₂O and ammonia to afford the α/β-D -anomers 10 of 2-(2-deoxy-D -ribofuranosyl)pyridine-4-carboxamide. Both anomers were purified and separated by HPLC and identified by NMR and DCI-MS. Anomer β-D - 10 was evaluated against a series of tumor-cell lines and a variety of viral strains. No antitumor or antiviral activity was observed.     

The synthesis of 3-(β-D-ribofuranosyl)imidazo[4,5-c] pyridazines

7-Chloro-3-(β- D -2,3,5-tri-O-benzoylribofuranosyl)imidazo[4,5-c] pyridazine ( 3 ), obtained from the condensation of 7-chloro-3-trimethylsilylimidazo[4,5-c] pyridazine ( 1 ) with 2,3,5-tri-O-benzoyl- D -ribofuranosyl bromide ( 2 ), served as the percursor of 7-chloro- ( 4 ), 7-amino- ( 8 ), and 7-mercapto-3-(β- D -ribofuranosyl)imidazo[4,5-c] pyridazine ( 9 ). 3-(β- D -ribofuranosyl)imidazo[4,5-c] pyridazine ( 7 ) was obtained from 3-(β- D -2,3,5-tri-O-benzoylribofuranosyl)imidazo-[4,5-c]pyridazine ( 6 ). The site of ribosidation is based upon uv spectral comparisons with model methyl compounds. The assignment of the anomeric configuration is derived from pmr spectral data.     

4-Oxa(thia)-9-oxa-2-azabicyclo[4.2.1]nonane-3-on(thion) derivatives

The synthesis of 7,8-dihydroxy-2-(2-methoxycarbonylethyl)-4,9-dioxa-2-azabicyclo[4.2.1]nonane- 3-thione ( 16 ) and of its parents 9-oxa-4-thia-3-thione 17 , and 9-oxa-4-thia-3-one 18 is described. The conversion of 5′-deoxy-5′-iodo-2′,3′-O, O-isopropylidene-5,6-dihydrouridin ( 1 ) into the 2-O-methyl-5,6-dihydrouridine 5 , the 5′-O-acetyl-5,6-dihydrouridine 4 , and into the N-(5-O-acetyl-2,3-O, O-isopropylidene-β-D -ribofuranosyl)-N-(2-methoxycarbonyl thyl)-urea ( 6 ) invoked 2′,3′-O, O-isopropylidene-2,5′-anhydro-5,6-dihydrouridine ( 2 ) as the common intermediate.     

Synthesis and properties of esters and amido esters of 1-(2-thienyl)-2,2,2-trichloroethylphosphorous acid

Conclusions The esterification of amido- and ester-amidophosphites with 1-(2-thienyl)-2,2,2-trichloroethanol gave the l-(2-thienyl)-2,2,2-trichloroethyl dialkyl- and 1-(2-thienyl)-2,2,2-trichloroethyl alkylamidophosphites, which easily add sulfur or are oxidized to the corresponding thiophosphates and phosphates.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, pp. 182–187, January, 1981.     

Stereoselective synthesis of pyrrolo[2,3-d]pyrimidine α- and β-D-ribonucleosides from anomerically pure D-ribofuranosyl chlorides: Solid-Liquid Phase-Transfer Glycosylation and 15N-NMR Spectra

Solid-liquid phase-transfer glycosylation (KOH, tris[2-(2-methoxyethoxy)ethye]amine ( = TDA-1), MeCN) of pyrrolo[2,3-d]pyrimidines such as 3a and 3b with an equimolar amount of 5-O-[(1,1 -dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-α-D -ribofuranosyl chloride (1) [6] gave the protected β-D -nucleosides 4a and 4b , respectively, stereoselectively (Scheme). The β-D -anomer 2 [6] yielded the corresponding α-D -nucleosides 5a and 5b with traces of the β-D -compounds. The 6-substituted 7-deazapurine nucleosides 6a , 7a , and 8 were converted into tubercidin (10) or its α-D -anomer (11) . Spin-lattice relaxation measurements of anomeric ribonucleosides revealed that T₁ values of H? C(8) in the α-D -series are significantly increased compared to H? C(8) in the β-D -series while the opposite is true for T₁ of H? C(1′). ¹⁵N-NMR data of 6-substituted 7-deazapurine D -ribofuranosides were assigned and compared with those of 2′-deoxy compounds. Furthermore, it was shown that 7-deaza-2′deoxyadenosine ( = 2′-deoxytubercidin; 12 ) is protonated at N(1), whereas the protonation site of 7-deaza-2′-deoxyguanosine ( 20 ) is N(3).     

Variants of Solid-State and Solution Structures of (η3-Allyl)- {2-[2′-(diphenylphosphino)phenyl]-4,5-dihydrooxazole-P,N}palladium(II) hexafluorophosphates and tetraphenylborates

Crystal and solution structures of the enantiomerically pure and the racemic pairs of (η³-allyl) {2-[2′-(diphenylphosphino)phenyl]-4,5-dihydro-4-phenyloxazole}palladium(II) hexafluorophosphates ( 1 , and rac- 1 , resp.) and tetraphenylborates ( 2 , and rac- 2 , resp.) as well as (η³-allyl){2-[2′-(diphenylphosphino)phenyl]-4,5-dihydro-4-isopropyloxazole}palladium(II) tetraphenylborate ( 3 ) were characterized by X-ray crystallography and ¹H-NMR spectroscopy. In the solid state, rac- 1 and rac- 2 proved to be disordered with both diastereoisomeric complexes in the crystal. The complexes 2 and 3 exist only in the ‘exo’ form. The X-ray structures show that the [Pd^II(η³-allyl)] moiety may adopt different configurations between a nearly symmetrical three-electron Pd^II(π³-allyl) system and an asymmetrical allyl group with a η¹- and a η²-bonding to the metal center. The [Pd^II(η³-allyl)] system of rac- 1 and of ‘endo’ rac- 2 is closer to the former, and that of 2 , ‘exo’-rac- 2 , and 3 closer to the later geometry. The ¹H-NMR spectra of the hexafluorophosphates 1 and rac- 1 show two sets of signals of the allylic protons in an ‘exo’/‘endo’ ratio of 2:3. The tetraphenylborates 2, rac- 2 , and 3 give only one set of broad signals of the allylic protons.