Direct synthesis of pyrrole nucleosides by the stereospecific sodium salt glycosylation procedure

A stereospecific high-yield glycosylation of preformed fully aromatic pyrroles has been accomplished for the first time. Reaction of the sodium salt of pyrrole-2-carbonitrile ( 1a ) and pyrrole-2,4-dicarbonitrile ( 1b ) with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose ( 2 ) gave exclusively the corresponding blocked nucleosides with β-anomeric configuration 3a and 3b , which on deprotection gave 1-(2-deoxy-β-D-erythro-pentofuranosyl) derivatives of 1a ( 3c ) and 1b ( 3d ). Functional group transformation of 3c and 3d provided a number of 2-monosubstituted 4a-c and 2,4-disubstituted 4d-f derivatives of 1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrole. Similar glycosylation of the sodium salt of 1a and 1b with 1-chloro-2,3,5-tri-O-benzyl-α-D-arabinofuranose ( 5 ) and further functional group transformation of the intermediate blocked nucleosides 6a and 6b provided 1-β-D-arabinofuranosyl derivatives of pyrrole-2-carboxamide ( 7b ) and pyrrole-2,4-dicarboxamide ( 7d ). The synthetic utility of this glycosylation procedure for the preparation of 1-β-D-ribofuranosylpyrrole-2-carbonitrile ( 12 ) has also been demonstrated by reacting the sodium salt of 1a with 1-chloro-2,3-O-isopropylidene-5-O-(t-butyl)dimethylsilyl-α-D-ribofuranose ( 10 ) and subsequent deprotection of the blocked intermediate 11 . This study provided a convenient route to the preparation of aromatic pyrrole nucleosides.     

A facile and improved synthesis of tubercidin and certain related pyrrolo[2,3-d]pyrimidine nucleosides by the stereospecific sodium salt glycosylation procedure

A simple synthesis of tubercidin ( 1 ), 7-deazaguanosine ( 2 ) and 2′-deoxy-7-deazaguanosine ( 14 ) has been accomplished using the sodium salt glycosylation procedure. Reaction of the sodium salt of 4-chloro- and 2-amino-4-chloro-pyrrolo[2,3-d]pyrimidine, 3 and 4 , respectively, with 1-chloro-2,3-0-isopropylidene-5-0-(t-butyl)dimethylsilyl-α-D-ribofuranose ( 5 ) gave the corresponding protected nucleosides 6n and 7 with β-anomeric configuration. Deprotection of 6 provided 8 , which on heating with methanolic ammonia gave tubercidin ( 1 ) in excellent yield. Functional group transformation of 7 , followed by deisopropylidenation gave 2-aminotubercidin ( 10 ) and 2-amino-7-β-D-ribofuranosylpyrrolo[2,3-d]pyrimidine-4(3H)-thione ( 11 ). Treatment of 7 with 1N sodium methoxide followed by exposure to aqueous trifluoroacetic acid, and ether cleavage furnished 7-deazaguanosine ( 2 ). 2′-Deoxy-7-deazaguanosine ( 14 ) and 2′-deoxy-7-deaza-6-thioguano-sine ( 18 ) were also prepared by using similar sequence of reactions employing 4 and 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose ( 15 ).     

A convenient one-step synthesis of 6-selenoxo-9-(β-D-ribofuranosyl)purine 3′,5′-cyclic phosphate and related compounds

A useful, facile procedure for preparing seleno-heterocyclic compounds is reported. Treatment of cAMP, AMP, adenosine, 2-aminoadenosine, adenine arabinoside and formycin with hydrogen selenide in aqueous pyridine at 65° for 1.5-5 days gave the corresponding seleno compounds in good yield, while these compounds were relatively inert to hydrogen sulfide. A reaction mechanism is proposed.     

Total synthesis of N-malayamycin A and related bicyclic purine and pyrimidine nucleosides

Methods are described for the total synthesis of bicyclic perhydrofuropyran nucleosides as N-analogues of the naturally occurring malayamycin A. Formation of the N-nucleosides relied on the activation of thioglycosides, proceeding via sulfonium intermediates. Ring closure metathesis was used in two approaches to build the bicyclic dioxa heterocycle. Another approach relied on the use of a sugar precursor and cyclization to the bicyclic thioglycoside.     

Ab initio calculations on the barrier to pseudorotation of model 2′-deoxyfuranose and 2′-deoxy-2′-fluorofuranose rings

Model ring systems 2′-deoxy-2′-fluororibofuranose and deoxyribofuranose have been investigated using ab initio calculations with the 3–21G basis set. The energy barrier to pseudorotation between the N and S states has been evaluated for the three preferred orientations of the (3′)-OH group. Positions of the energy minima and the transition state have been optimized with respect to the (3′)-OH orientation. The barrier to pseudorotation of 2′-deoxy-2′-fluorofuranose is high and asymmetrical (ΔE_N→S ≈ 20, ΔE_N←S ≈ 8 kJ/mol), whereas the barrier of 2′-deoxyfuranose is lower and almost symmetrical (ΔE ≈ 11–12 kJ/mol). The results obtained show that the preferred configuration of the 2′-deoxy-2′-fluororibo-furanose (N state) is stabilized by an internal O(3′)-H…?F interaction in accord with the crystallo-graphic data.     

A new synthesis of 2′,3′-dideoxycytidine

A new synthesis of 2′,3′-dideoxycytidine is described and the utility of this synthesis to prepare larger quantities of said nucleoside is shown.     

Synthesis and In Vivo antitumor and antiviral activities of 2′-deoxyribofuranosyl and arabinofuranosyl nucleosides of certain purine-6-sulfenamides,sulfinamides and sulfonamides

2′-Deoxyribofuranosyl and arabinofuranosyl nucleosides of certain purine-6-sulfenamides, sulfinamides and sulfonamides have been prepared by sequential amination and controlled oxidation of the corresponding 6-thiopurine nucleosides, and evaluated for antiviral and antitumor activities in mice. Amination of 2′-deoxy-6-thioinosine ( 4a ) and 9-β-D-arabinofuranosyl-6-thiopurine ( 4c ) with chloramine solution gave the corresponding 6-sulfenamides 5a and 5c , respectively, which on selective oxidation with 3-chloroperoxybenzoic acid (MCPBA) gave diastereomeric 9-(2-deoxy-β-D-erythro-pentofuranosyl)purine-6-sulfinamide ( 6a ) and 9-β-D-arabinofuranosylpurine-6-sulfinamide ( 6c ), respectively. However, oxidation of 5a and 5c with excess of MCPBA gave the corresponding 6-sulfonamide derivatives 7a and 7c , respectively. Similar amination of 2′-deoxy-6-thioguanosine ( 4b ), ara-6-thioguanine ( 4d ) and α-2′-deoxy-6-thioguanosine ( 8 ) gave the respective 6-sulfenamide derivatives 5b, 5d and 9 . Controlled oxidation of 5b, 5d and 9 gave (R,S)-2-amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)purine-6-sulfinamide ( 6b ), (R,S)-2-amino-9-β-D-arabinofuranosylpurine-6-sulfinamide ( 6d ) and the α-anomer of ( 6b) (10 ), respectively. The diastereomeric mixture of (R,S )-10 was partially resolved and the structure of S -10 was assigned by single-crystal X-ray diffraction analysis. Oxidation of 5b, 5d and 9 with excess of MCPBA afforded the respective 6-sulfonamide derivatives 7b, 7d and 11 . Nucleosides 5c and 7c were significantly active against Friend leukemia virus in mice, whereas 6c was somewhat less active. Of the 20 nucleosides evaluated, 12 exhibited biologically significant anti-L1210 activity in mice. Nucleosides 6b and 7a at 173 mg/kg/day × 1 showed a T/C of 153, whereas 7d at 800 mg/kg/day × 1 showed a T/C of 153 against L1210 leukemia. The α-nucleoside 9 at 480 mg/kg/day × 1 gave a T/C of 172. A single treatment with 6b, 7a, 7d and 9 reduced the body burdens of viable L1210 cells by more than 99.2%. The antileukemic activity of these novel nucleosides tended to parallel solubility.     

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.     

Synthesis of 2′-deoxyribofuranosyl indole nucleosides related to the antibiotics SF-2140 and neosidomycin

The 2′-deoxyribofuranose analog of the naturally occurring antibiotics SF-2140 and neosidomycin were prepared by the direct glycosylation of the sodium salts of the appropriate indole derivatives, with 1-chloro-2- deoxy-3,5-di-O-p-toluoyl-α-D-erythropentofuranose ( 5 ). Thus, treatment of the sodium salt of 4-methoxy-1H- indol-3-ylacetonitrile ( 4a ) with 5 provided the blocked nucleoside, 4-methoxy-1-(2-deoxy-3,5-di-O-p-toluoyl-β- D-erythropentofuranosyl)-1H-indol-3-ylacetonitrile ( 6a ), which was treated with sodium methoxide to yield the SF-2140 analog, 4-methoxy-1-(2-deoxy-β-D-erythropentofuranosyl)-1H-indol-3- ylacetonitrile ( 7a ). The neosidomycin analog ( 8 ) was prepared by treatment of the sodium salt of 1H-indol-3-ylacetonitrile ( 4b ) with 5 to obtain the blocked intermediate 1-(2-deoxy-3,5-di-O-p-toluoyl-β-D-erythropentofuranosyl) ?1H-indol-3-ylace-tonitrile ( 6b ) followed by sodium methoxide treatment to give 1-(2-deoxy-β-D-erythropentofuranosyl)-1H- indol-3-ylacetonitrile ( 7b ) and finally conversion of the nitrile function of 7b to provide 1-(2-deoxy-β-D- erythropentofuranosyl)-1H-indol-3-ylacetamide ( 8 ). In a similar manner, indole ( 9a ) and several other substituted indoles including 1H-indole-4-carbonitrile ( 9b ), 4-nitro-1H-indole ( 9c ), 4-chloro-1H-indole-2-carboxamide ( 9d ) and 4-chloro-1H-indole-2-carbonitrile ( 9e ) were each glycosylated and deprotected to provide 1-(2-deoxy-β-D-erythropentofuranosyl)-1H-indole ( 11a ), 1-(2-deoxy-β-D-erythropentofuranosyl)-1H-indole-4- carbonitrile ( 11b ), 4-nitro-1-(2-deoxy-β-D-erythropentofuranosyl)-1H-indole ( 11c ), 4-chloro-1-(2-deoxy-β-D- erythropentofuranosyl)-1H-indole-2-carboxamide ( 11d ) and 4-chloro-1-(2-deoxy-β-D-erythropentofuranosyl)- 1H-indole-2-carbonitrile ( 11e ), respectively. The 2′-deoxyadenosine analog in the indole ring system was prepared for the first time by reduction of the nitro group of 11c using palladium on carbon thus providing 4-amino-1-(2-deoxy-β-D-erythropentofuranosyl)- 1H-indole ( 16 , 1,3,7-trideaza-2′-deoxyadenosine).     

Synthesis of 5′-halo-2′,3′-lyxo-epoxy and 2′,3′-unsaturated thieno[3,2-d]pyrimidine nucleosides

A series of thieno[3,2-d]pyrimidine-2,4-dione nucleosides modified in the carbohydrate moiety has been synthesized. In the first part, synthetic routes are described for the replacement of 5′-hydroxyl group in preformed 1-(β-D-ribofuranosyl)thieno[3,2-d]pyrimidine-2,4-dione I by fluoro, iodo or chloro atoms. Reduction of the 5′-iodo substituent of VI was then carried out catalytically using palladium on carbon as catalyst to give the expected 5′-deoxy derivative VIII. The lyxo-epoxide derivative XII was then synthesized by sequential treatment of the 5′-deoxy-5′-chloro derivative X with methanesulfonyl chloride and with sodium hydroxide. In the second part, most of attention has been devoted to apply different methods reported in the literature that allow access to 2′,3′-olefinic derivatives from the corresponding 2′,3′-dihydroxy precursor. The 5′-O-silyl protected bisxanthate XIV either on reduction with tri-n-butyltin hydride or by reductive elimination of the haloacetate XVI afforded the free 2′,3′-olefin nucleoside after removal of the 5′-protecting group. However none of the compounds in this series exhibited significant antiviral activity against HIV at the doses tested.     

Nucleotides part XXX Chemical synthesis of adenylyl-(2′ → 5′)-adenylyl-(2′ → 5′)-8-azidoadenosine,and activation and photoaffinity labelling of RNase L by [32P]p5′A2′p5′A2′p5′N38A

The chemical synthesis of adenylyl-(2′–5′)-adenylyl-(2′–5′)-8-azidoadenosine ( 15 ) was performed by the phosphotriester approach. Enzymatic phosphorylation of 15 by [γ-³²P]ATP led to the corresponding labelled 5′-monophosphate 16 . Photoinsertion of 16 took place on UV irradiation by covalent cross linking to a protein of M_r 80 K known to be RNase L. Radiobinding and core-cellulose assays as well as photoaffinity labelling experiments with 16 are described.     

A convenient synthesis of 2‐mercapto and 2‐chlorobenzothiazoles

A convenient synthesis of 2‐mercapto and 2‐chlorobenzothiazoles is described. The key feature of the synthesis is an exclusive ortho‐selective nucleophilic aromatic substitution reaction of ortho‐haloanilines with potassium/sodium O‐ethyl dithiocarbonate under mild conditions. Subsequent intra‐molecular cycliza‐tion affords 2‐mercaptobenzothiazoles in high yields. The 2‐mercaptobenzothiazoles are readily converted to corresponding 2‐chlorobenzothiazoles upon treatment with sulfuryl chloride.     

Synthesis of Carotenoids in the Gliding Bacteria Taxeobacter: (all-E,2′R)-3-deoxy-2′-hydroxyflexixanthin

The c₄₀-carotenoid (all-E, 2′R)-deoxy-2′-hydroxyflexixanthin (=1′,2′-dihydroxy-3′,4′-didehydro-1′,2′-dihydro-β,ψ-caroten-4-one;(2′R)- 2 ) was synthesized according to a C₁₅ + C₁₀ + C₁₀ = C₄₀ strategy. The chiral centre was introduced into the C₁₀-end group by the enantioselective Sharpless dihydroxylation. The four building blocks were coupled by applying four consecutive Witting reactions. By comparison of the CD spectra of the synthetic (2′R)- 2 with those of 2 isolated from the gliding bacteria Taxeobacter, the configuration of natural 2 was determined as (2′R).     

Regio‐ and stereospecific assembly of dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidines] from simple precursors using a one‐pot procedure: synthesis,spectroscopic and structural characterization,and a proposed mechanism of formation

The synthesis and characterization of three new dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine] compounds are reported, together with the crystal structures of two of them. (3RS,1′SR,2′SR,7a′SR)‐2′‐(4‐Chlorophenyl)‐1‐hexyl‐2′′‐sulfanylidene‐5′,6′,7′,7a′‐tetrahydro‐2′H‐dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine]‐2,4′′‐dione, C₂₈H₃₀ClN₃O₂S₂, (I), (3RS,1′SR,2′SR,7a′SR)‐2′‐(4‐chlorophenyl)‐1‐benzyl‐5‐methyl‐2′′‐sulfanylidene‐5′,6′,7′,7a′‐tetrahydro‐2′H‐dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine]‐2,4′′‐dione, C₃₀H₂₆ClN₃O₂S₂, (II), and (3RS,1′SR,2′SR,7a′SR)‐2′‐(4‐chlorophenyl)‐5‐fluoro‐2′′‐sulfanylidene‐5′,6′,7′,7a′‐tetrahydro‐2′H‐dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine]‐2,4′′‐dione, C₂₂H₁₇ClFN₃O₂S₂, (III), were each isolated as a single regioisomer using a one‐pot reaction involving l ‐proline, a substituted isatin and (Z)‐5‐(4‐chlorobenzylidene)‐2‐sulfanylidenethiazolidin‐4‐one [5‐(4‐chlorobenzylidene)rhodanine]. The compositions of (I)–(III) were established by elemental analysis, complemented by high‐resolution mass spectrometry in the case of (I); their constitutions, including the definition of the regiochemistry, were established using NMR spectroscopy, and the relative configurations at the four stereogenic centres were established using single‐crystal X‐ray structure analysis. A possible reaction mechanism for the formation of (I)–(III) is proposed, based on the detailed stereochemistry. The molecules of (I) are linked into simple chains by a single N—H…N hydrogen bond, those of (II) are linked into a chain of rings by a combination of N—H…O and C—H…S=C hydrogen bonds, and those of (III) are linked into sheets by a combination of N—H…N and N—H…S=C hydrogen bonds.     

A second triclinic modification of 2′,6′‐di­methoxy­flavone

Crystals of a second triclinic modification of the title compound, 2‐(2,6‐di­methoxy­phenyl)‐4H‐1‐benzo­pyran‐4‐one, C₁₇H₁₄O₄, were grown from a hot cyclo­hexane solution. In the mol­ecule, the O—C—C—C torsion angle at the junction between the benzo­pyran and phenyl rings is 67.6 (3)°.