Synthesis of indazole C-nueleosides and analogues

1-Deoxy-1-diazo-3,6-anhydro-4,5,7-tri-O-benzoyl-D-allo-heptulosc (III) has been prepared from 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allonic acid. 1,3-Dipolar cycloaddition of III to benzyne afforded the indazole C-nucleoside analog V. Cycloaddition of methyl 6-deoxy-6-diazo-2,3-O-isopropylidene-β-D-ribohexofuranosid-5-ulose (IV) to the benzyne generated from 5-methyl-anthranilic acid gave a mixture of the β-isomeric C-glycosylindazoles VI and VII along with traces of the corresponding α-anomers VIa and VIIa. Finally, a multistep transformation of the acyclic carbohydrate moiety of 2,3,4,5-tetra-O-acetyl-1-(indazol-3-yl)-keto-D-ribopentulose (I, R = H, n = 3 , D-ribo) led to the C-nucleoside indazole, 3-(2,3-O-isopropylidene-β-D-ribofuranosyl)-indazol (X), as the major product.     

Synthesis of 5-Methyluridine and Its 5′-Mercapto-, 2-Amino-, and 4′,5′-Unsaturated Analogues

The stereospecific cis-hydroxylation of 1-(2,3-dideoxy-β-D -glyceropent-2-enofuranosyl)thymine (1) into 1-β-D -ribofuranosylthymine (2) by osmium tetroxide is described. Treatment of 2′,3′-O, O-isopropylidene-5-methyl-2,5′-anhydrouridine (8) with hydrogen sulfide or methanolic ammonia afforded 5′-deoxy-2′,3′-O, O-isopropylidene-5′-mercapto-5-methyluridine (9) and 2′,3′-O, O-isopropylidene-5-methyl-isocytidine (10) , respectively. The action of ethanolic potassium hydroxide on 5′-deoxy-5′-iodo-2′,3′-O, O-isopropylidene-5-methyluridine (7) gave rise to the corresponding 1-(5-deoxy-β-D -erythropent-4-enofuranosyl)5-methyluracil (13) and 2-O-ethyl-5-methyluridine (14) . The hydrogenation of 2 and its 2′,3′-O, O-isopropylidene derivative 4 over 5% Rh/Al₂O₃ as catalyst generated diastereoisomers of the corresponding 5-methyl-5,6-dihydrouridine ( 17 and 18 ).     

Total Asymmetric Synthesis of 5-Deoxy-5-thio-l-allose

Abstract

The optically pure Diels-Alder adduct of furan to 1-cyanovinyl (1R)-camphanate was converted to methyl(methyl 5-bromo-5-deoxy-2,3-O-isopropylidene-β-l-allo-hexo-furanosid)uronate. Ester reduction, followed by HBr elimination afforded (+)-methyl 5,6-anhydro-2,3-O-isopropylidene-d-β-talo-hexofuranoside. Applying the method of Adley and Owen, (+)-methyl 5,6-dideoxy-5,6-epithio-2,3-O-isopropylidene-l-β-allo-hexofuranoside was obtained and acetolysed to give, after deprotection, (-)-5-deoxy-5-thio-l-allose.     

Syntheses of 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one,an isostere of oxanosine,and the guanosine analog 6-amino-1-(β-d-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one via ring closure of pyrazole-5-thioureido intermediates

6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 4 ), an isostere of the nucleoside antibiotic oxanosine has been synthesized from ethyl 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxylate ( 6 ). Treatment of 6 with ethoxycarbonyl isothiocyanate in acetone gave the 5-thioureido derivative 7 , which on methylation with methyl iodide afforded ethyl 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-ethoxycarbonyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxylate ( 8 ). Ring closure of 8 under alkaline media furnished 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 10 ), which on deisopropylidenation afforded 4 in good yield. 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 5 ) has also been synthesized from the AICA riboside congener 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxamide ( 12 ). Treatment of 12 with benzoyl isothiocyanate, and subsequent methylation of the reaction product with methyl iodide gave 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-benzoyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxamide ( 15 ). Base mediated cyclization of 15 gave 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 14 ). Deisopropylidenation of 14 with aqueous trifluoroacetic acid afforded 5 in good yield. Compound 4 was devoid of any significant antiviral or antitumor activity in culture.     

A New Total Synthesis of D-threo-L-talo-Octose

A new approach to the total, asymmetric synthesis of D -threo-L -talo-octose ((?)- 1 ) and its derivatives is presented. It is based on the chemoselective Wittig-Horner monoolefination of a 5-deoxy-D -ribo-hexodialdose derivative 4 obtained by selective reduction of (?)-5-deoxy-2.3-O-isopropylidene-/β-D -ribo-hexofuranurono-6,1-lactone ((?)- 3 ). Allylic bromination of the resulting methyl (E)-oct-6-enofuranuronate (+)- 5 followed by intramolecular nucleophilic displacement of the so-obtained bromides gave a 13.3:1 mixture of (?)-methyl (E)-l,4-anhydro-6,7-dideoxy-2,3-O-isopropylidene-β-L -talo-oct-6-enopyranuronate ((?)- 8 ) and methyl (E)-l,4-anhydro-6,7-dideoxy-2,3-O-isopropylidene-α-D -allo-oct-6-enopyranuronate ( 9 ). The double hydroxylation of the enoate (?)- 8 followed Kishi's rule and gave the corresponding D -threo-β-L -talo-octopyranuronate derivative (?)- 11 with a good diastereoselectivity. Reduction of ester (?)- 11 and deprotection led to pure (?)- 1 .     

Synthesis of Some Quaternary N-(1,4-anhydro-5-deoxy-D,L-ribitol-5-yl)ammonium Salts

The successful removal of the isopropylidene-protecting group from 1,4-anhydro-2,3-O-isopropylidene-5-O-tosyl-D,L-ribitol and from quaternary N-(1,4-anhydro-5-deoxy-2,3-O-isopropylidene-D,L-ribitol-5-yl)ammonium salts is reported. The structures of all isolates were determined by spectral analysis, including extensive 2-D NMR analyses. Single-crystal x-ray diffractions of 1,4-anhydro-5-O-tosyl-D,L-ribitol and its 2,3-O-isopropylidene derivatives are reported.     

Displacement of Sugar Triflates with C-Nucleophiles: D-Glucopyranose and D-Ribofuranose Chain Extension and Functionalization

Treatment of methyl 4-O-benzyl-2,3-di-O-methoxymethyl-6-O-1-6-O-trifluoromethanesulfonyl-α -D-glucopyranoside 1 or 3-O-benzyl-1,2-O-isopropylidene-5-O-trifluoromethenesulfonyl-α-D-ribofuranoside 2 with a variety of functionalized C-nucleophiles in THF/HMPA leads to the corresponding chain-extended sugars in very good to excellent yields.     

Synthesis of the Antibiotic 1,5-dideoxy-1,5-imino-d-mannitol

Abstract

Easily accessible benzyl 2,3-O-isopropylidene-α-D-mannofuranoside (1) was converted in six steps into benzyl 2,3-O-isopropylidene-5-N-benzyl-5-deoxy-6-O-benzyl-α-D-mannofuranoside or benzyl 2,3-O-isopropylidene-5-azido-5-deoxy-6-O-benzyl-α-D-mannofuranoside. Both compounds afforded, after hydrogenolysis and acidolysis, 1-deoxymannojirimycin in an overall yield of 38% based on 1.     

Enzymic Hydrolysis of Methyl 2,3-O-Acetyl-5-Deoxy-α and β-D-Xylofuranosides - An Active-Site Model of Pig Liver Esterase

Abstract

The regioselective enzymic hydrolysis of methyl 2,3-di-O-acetyl-5-deoxy-α-D-xylofuranoside (1) and methyl 2,3-di-O-acetyl-5-deoxy-β-D-xylofuranoside (2) in the presence of pig liver esterase (PLE) was studied by GLC. Diacetate 2 gave exclusively methyl 3-O-acetyl-5-deoxy-β-D-xylofuranoside (6) while diacetate 1 produced both methyl 2-O-acetyl-5-deoxy-α-D-xylofuranoside (3) and methyl 3-O-acetyl-5-deoxy-α-D- xylofuranoside (4) in low yield. At high conversion, methyl 5-deoxy-α-D-xylofuranoside (7) was the only product. The first-order rate constants, Michaelis constants, and maximal velocities were determined for 1, 2, and the monoacetates 3 - 6. The results were interpreted on the basis of a recent active-site model for PLE.     

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.     

Cyclophosphamides from aminosugars and aminonucleosides

Condensation of bis-(2-chloroethyl)phosphoramidic dichloride with 3′-amino-3′-deoxy-N,N-dimethyladenosine afforded the 2′,3′-cyclicphosphorodiamidate (III). By an improved synthesis, methyl 3-amino-3-deoxy-β-D-ribofuranoside was obtained as a model compound for conversion to the analogous 2,3-cyclicphosphorodiamidate (XII). Existence of the latter as two diastereomers due to phosphorus asymmetry was shown by nmr analysis, using comparison with the 5-(O-p-nitrobenzoate) (XIII) as a basis for assignments.     

Synthesis and biological evaluation of 5-substituted-4-nitroimidazole ribonucleosides

The imidazole nucleosides, 4(5)-bromo-5(4)-nitro-1-β-D-ribofuranosylimidazoles, have been prepared via glycosylation of the trimethylsilylated aglycone, 4(5)-bromo-5(4)-nitroimidazole, with tetra-O-acetyl-β-D-ribo-furanose followed by removal of the acetyl protecting groups. The 5-bromo-4-nitro-1-β-D-ribofuranosylimidazole nucleoside was acetonated to produce 5-bromo-4-nitro-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-imidazole which was cyclized to provide the corresponding anhydronucleoside 5,5′-anhydro-4-nitro-5-oxo-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole. Sodium hydrosulfide treatment of 5-bromo-4-nitroimidazole nucleoside provided 5-mercapto-4-nitro-1-β-D-ribofuranosylimidazole 5-sodium salt which was alkylated with E-1,5-diiodopent-1-ene to yield 5-(E-1-iodo-1-penten-5-yl)thio-4-nitro-1-β-D-ribofuranosylimidazole. The corresponding iodine-125-labeled compound was prepared similarly using radiolabeled diiodopentene. The 5-bromo-4-nitroimidazole, 5-mercapto-4-nitroimidazole, and 5-iodopentenylthio-4-nitroimidazole nucleosides were cytotoxic to Molt-3 cells in vitro at concentrations higher than 10 μg/mL. The radiolabeled 5-iodopentenylthio-4-nitroimidazole nucleoside showed 2-fold higher uptake in a rapidly growing tumor as compared to uptake in a relatively slower growing tumor in mice.     

Strukturelle Abwandlungen an partiell silylierten Kohlenhydraten mittels Triphenylphosphin/Azodicarbonsäure-diäthylester. 3. Mitteilung [1]

Structural Modification on Partially Silylated Carbohydrates by Means of Triphenylphosphine/Diethyl Azodicarboxylate Reaction of methyl 2, 6-bis-O-(t-butyldimethylsilyl)-β-D -glucopyranoside ( 1a ) with triphenylphosphine (TPP)/diethyl azodicarboxylate (DEAD) and Ph₃P · HBr or methyl iodide yields methyl 3-bromo-2, 6-bis-O-(t-butyldimethylsilyl)-3-deoxy-β-D -allopyranoside ( 3a ) and the corresponding 3-deoxy-3-iodo-alloside 3c (Scheme 1). By a similar way methyl 2, 6-bis-O-(t-butyldimethylsilyl)-α-D -glucopyranoside ( 2a ) can be converted to the 4-bromo-4-deoxy-galactoside 4a and the 4-deoxy-4-iodo-galactoside 4b . In the absence of an external nucleophile the sugar derivatives 1a and 2a react with TPP/DEAD to form the 3,4-anhydro-α- or -β-D -galactosides 5 and 6a , respectively, while methyl 4, 6-bis-O-(t-butyldimethylsilyl)-β-D -glucopyranoside ( 1b ) yields methyl 2,3-anhydro-4, 6-bis-O-(t-butyldimethylsilyl)-β-D -allopyranoside ( 7a , s. Scheme 2). Even the monosilylated sugar methyl 6-O-(t-butyldimethylsilyl)-α-D -glucopyranoside ( 2b ) can be transformed to methyl 2,3-anhydro-6-O-(t-butyldimethylsilyl)-β-D -allopyranoside ( 8 ; 56%) and 3,4-anhydro-α-D -alloside 9 (23%, s. Scheme 3). Reaction of 1c with TPP/DEAD/HN₃ leads to methyl 3-azido-6-O-(t-butyldimethylsilyl)-3-deoxy-β-D -allopyranoside ( 10 ). The epoxides 7 and 8 were converted with NaN₃/NH₄Cl to the 2-azido-2-deoxy-altrosides 11 and 13 , respectively, and the 3-azido-3-deoxy-glucosides 12 and 14 , respectively (Scheme 4 and 5). Reaction of 7 and 8 with TPP/DEAD/HN₃ or p-nitrobenzoic acid afforded methyl 2,3-anhydro-4-azido-6-O-(t-butyldimethylsilyl)-4-deoxy-α- and -β-D -gulopyranoside ( 15 and 17 ), respectively, or methyl 2,3-anhydro-6-O-(t-butyldimethylsilyl)-4-O-(p-nitrobenzoyl)-α- and -β-D -gulopyranoside ( 16 and 18 ), respectively, without any opening of the oxirane ring (s. Scheme 6). - The 2-acetamido-2-deoxy-glucosides 19a and 20a react with TPP/DEAD alone to form the corresponding methyl 2-acetamido-3,4-anhydro-6-O-(t-butyldimethylsilyl)-2-deoxy-galactopyranosides ( 21 and 22 ) in a yield of 80 and 85%, respectively (Scheme 7). With TPP/DEAD/HN₃ 20a is transformed to methyl 2-acetamido-3-azido-6-O-(t-butyldimethylsilyl)-2,3-didesoxy-β-D -allopyranoside ( 25 , Scheme 8). By this way methyl 2-acetamido-3,6-bis-O-(t-butyldimethylsilyl)-α-D -glucopyranoside ( 19b ) yields methyl 2-acetamido-4-azido-3,6-bis-O-(t-butyldimethylsilyl)-2,4-dideoxy-α-D -galactopyranoside ( 23 ; 16%) and the isomerized product methyl 2-acetamido-4,6-bis-O-(t-butyldimethylsilyl)-2-deoxy-α-D -glucopyranoside ( 19d ; 45%). Under the same conditions the disilylated methyl 2-acetamido-2-deoxy-glucoside 20b leads to methyl 2-acetamido-4-azido-3,6-bis-O-(t-butyldimethylsilyl)-2,4-dideoxy-β-D -galactopyranoside ( 24 ). - All Structures were assigned by ¹H-NMR. analysis of the corresponding acetates.     

Reaction of methyl-4-methylene-2,3-<Emphasis Type="Italic">O</Emphasis>-isopropylidene-β-D-ribofuranoside with <Emphasis Type="Italic">N</Emphasis>-bromosuccinimide in aqueous tetrahydrofurane

Methyl-4-methylene-2,3-O-isopropylidene-β-D-ribofuranoside prepared from D-ribose reacted in a system NBS-THF-H₂O to give a mixture of stereoisomeric products of regioselective bromohydroxylation of a double bond. The reaction involved a hydrolysis of the glycoside bond, but the acetonide protective group was retained. The mechanism of the selective hydrolysis originating from the ring-chain tautomerism of bromohydrins obtained was proved by the ¹H NMR spectra of the steroisomeric methyl-5-deoxy-5-bromo-4-hydroxy-2,3-O-isopropylidene-β-D-ribofuranosides. By crotonic cyclization of the formed masked 1,4-dicarbonyl compounds at heating in benzene in the presence of neutral Al₂O₃ a new chiral cyclopentenone block, 2-bromo-4,5-isopropylideneoxycyclopent-2-en-1-one, was obtained in a low yield.     

Synthesis of Sialic Acid Analogues with the Oxime Group at C-4 Or C-5 of KDN 1

Abstract

The readily available methyl (methyl 3-deoxy-5,8:7,9-di-O-isopropylidene-β-D-glycero-D-galacto-2-nonulopyranosid)onate (7) was converted in five synthetic steps into methyl (methyl 4-acetamido-3,4-dideoxy-β-D-glycero-D-talo-2-nonulopyranosid)onate (11). Selective protection of the C-4, C-7, C-8 and C-9 hydroxy groups of methyl (methyl 3-deoxy-8,9-O-isopropylidene-β-D-glycero-D-galacto-2-nonulpyranosid)onate (2) followed by oxidation of the C-5 hydroxy group and then its oximination gave 5-hydroxyimino derivatives (15 and 16).

     

<Superscript>1</Superscript>H NMR study on intramolecular hydrogen bonding in 2,3-<Emphasis Type="Italic">O</Emphasis>-isopropylidene-D-ribofuranosides and their 5(4)-hydroxy derivatives

¹H NMR study showed the possibility for intramolecular hydrogen bonding in 5(4)-hydroxy derivatives of 2,3-O-isopropylidene-β-D-ribofuranose in CDCl₃. The obtained data were used to interpret differences in the ¹H NMR spectra of structurally related 5-halo-2,3-O-isopropylidene-D-ribofuranosides and four newly synthesized diastereoisomeric 5-bromo-5-deoxy-4-hydroxy-2,3-O-isopropylidene-D-ribofuranosides.     

Enantiomerically pure 7-oxabicylo[2.2.1]hept-5-en-zyl derivatives as synthetic intermediates. Part III. Total synthesis of D- and L-ribose derivatives

Enantiomerically pure methyl 5-bromo-5-deoxy-2,3-O- isopropylidene-β-D - (D - 5b ) and -β-l-ribofuranoside (l- 5b ) have been derived from (?)-(1R,2S,4R)-2-exo-cyano-7-oxabicylo[2.2.1]hept-5-en-endo,-yl (1′S)-camphanate ( 1 ) and (+)-(1S,2R,4S)-2-exo-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl(1′R)-camphanate ( 2 ), respectively, in 5 synthetic steps and 28% overall yield. Hydrolysis of D-5b and L - 5b afforded methyl 2,3-O isopropylidene-β-D -ribofuranoside (D -5a) and methyl 2,3-O-isopropylidene β-L-ribofuranoside (L-5a), respectively. The intermediate (+)-(1R,4R,5R,6R) 5-exo,6-exo-(isopropylidenedioxy)- 7 -oxabicyclo[2.2.1]heptan-2-one ((+)- 7 ) and its enantiomer(–)-7 were also obtained enantiomerically pure by resolution of (=)- 7 by the Johnson-Zeller method. In bothe approaches, the chiral auxiliaries ((–)- and (+)-camphanic acids, or (+)-(S)-N,S-dimethyl-S-phenylsulfoximide) were recovered at an early stage of the synthesis.     

Expeditious Synthesis of a Trisubstrate Analogue for α(1→3)Fucosyltransferase

Abstract

The synthesis of cyclohexyl 2-acetamido-2-deoxy-3-O-{2-O-[2-(guanosine 5′-O-phosphate)ethyl]-α-L-fucopyranosyl}-β-D-glucopyranoside (1), a potential inhibitor of α(1→3)fucosyltransferases, is described. Target compound 1 was assembled via fucosylation of cyclohexyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-β-D-glucopyranoside (6) with ethyl 2-O-[2-(benzoylhydroxy)ethyl]-3,4-O-isopropylidene-1-thio-β-L-fucopyranoside (5) followed by debenzoylation, subsequent condensation of the resulting compound with 3′,4′ -di-O-benzoyl-5′ -O-(2-cyanoethyl-N,N-diisopropylphosphoramidite)-2-N-diphenylacetylguanosine (10) and deprotection.     

Synthesis of New Five Membered Nitrogen Containing Heterocycles Bearing D-Galactose Side Chains

The synthesis of 5-[6′-deoxy-(1′,2′:3′,4′-di-O-isopropylidene-α-D-galactopyranos-6′-yl)]tetrazole and its reaction with acetic anhydride and 1,2:3,4-di-O-isopropylidene-6-O-(4-toluenesulfonyl)-α-D-galactopyranose are described.     

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.