Regioselective halogenation of some 2,3-anhydro pyrimidine nucleosides with dilithium tetrahalocuprates.

The reaction of 1-(2,3-anhydro-5-O-trityl-beta-D-lyxofuranosyl)-2-O-methyluracil (1a) and its thymine analogue (1b) with dilithium tetrahalocuprate (Li2CuX4) revealed excellent to perfect regioselectivity, yielding 2,2'-anhydro-3'-halonucleosides (2a-d), while the same reactions with 2,3-anhydro uracil and thymine nucleosides (4a,b) gave arabinosyl (5a-d) and xylosyl halohydrins (6a-d) with the respective product ratio of 7:3 to 8:2. compounds 5 and 6 were isolated as the 2-O-(7) and 3- O-mesyl derivatives (8).     

Efficient Synthesis of 2′-Bromo-2′-Deoxy-3′,5′-O-TPDS-pyrimidine Nucleosides by Boron Trifluoride Catalyzed Reaction of O2,2′-Anhydro-(1-β-D-Arabinofuran0Syl)pyrimidine Nucleosides with Lithium Bromide

Abstract

Efficient syntheses of 2′-bromo-2′-deoxy-3′,5′-O-TPDS-uridine (5a) and 1-(2-bromo-3,5-O-TPDS-β-D-ribofuranosyl)thymine (5b) from uridine and 1-(β-D-ribofuranosyl)thymine are described, respectively. The key step is a treatment of 3′,5′-O-TPDS-O²,2′-anhydro-1-(β-D-ardbinofuranosyl)uracil (4a) and -thymine (4b) with LiBr in the presence of BF₃-OEt₂ in 1,4-dioxane at 60°C to give 5a and 5b in 98%, and 96% yield, respectively.

     

Synthesis of Chlorodideoxynucleosides Using Tris(2,4,6-tribromophenoxy)-dichlorophosphorane (BDCP)

Abstract

5′-Chloro-5′-deoxy-N,3′-O-dibenzoylthymidine (3a), 5′-chloro-5′-deoxy-N⁴, 3′-O-dibenzoyldeoxycytidine(3b), 5′-chloro-5′-deoxy-N⁶,3′-O-dibenzoyldeoxyadenosine(3c), N-benzoyl-1-(3-chloro-2,3-dideoxy-5-O-trityl-ß-D-xylofuranosyl)thymine (5a) and N⁶-benzoyl-9-(3-chloro-2,3-dideoxy-5-O-trityl-ß-D-xylofuranosyl)adenine (5b) have been synthesized in very high yields using a new efficient reagent, tris(2,4,6-tribrom-ophenoxy)dichlorophosphorane (BDCP). The reaction time was greatly reduced to 5–8 min. NOE data suggested an inversion of configuration at C₃-position and thus an SN2 mechanism has been proposed for the chlorination reaction.

     

Nucleosides VI: A Novel and Convenient Synthesis of Purine S-Cyclonucleosides Via Mitsunobu Reaction

Abstract

Two representative S-cyclonucleosides, 8,5′-anhydro-2′, 3′-O-isopropylidene-8-mercaptoadenosine (3) and 8,2′-anhydro-3′,5′-O-(tetraisopropyldisiloxane-1,3-diyl)-8-mercaptoguanosine (8), were prepared in good yields by dropwise addition of one equivalent each of triphenylphosphine and DEAD in DMF into a mixture of 2′,3′-O-isopropylidene-8-mercaptoadenosine (2) or 3′,5′-O-(tetra-iso-propyldisiloxane-1,3-diyl)-8-mercaptoguanosine (7), respectively, in DMF. Treatment of compound 2 with two equivalents each of triphenylphosphine and DEAD in DMF afforded N-[8,5′-anhydro-2′,3′-O-isopropylidene-8-mercaptopurin-6-yl]triphenylphospha-λ5-azene (4) in 87% yield.     

Formation of an Unexpected 2-Deoxy-α-D-Threo-Pentofuranosyl Azide by Reaction of O2,3′-Anhydro-5′-O-trityl-2′-deoxycytidine with Lithium Azide

Abstract

Reaction of 0²,3′-anhydro-5′-0-trityl-2′-deoxycytidine (1) with LiN₃s in DMF resulted in the formation of 1-(3-azido-2,3-dideoxy-5-0-trityl-β-D-erythro-pentofuranosyl) cytosine (2) and 3-0-(4-amino-1,3-pyrimidin-2-yl)-5-0-trityl-2-deoxy-α-D-threo-pentofuranosyl azide (3) (2:3 = 1:1) in 88% yield. Compound 3 was deprotected with 80% aqueous AcOH yielding 4     

3-(3-Azido-2,3-Dideoxy-β-D-erythro pentofuranosyl)-thymine from 3′-Azido-3′-deoxythymidine (AZT). An Intriguing Rearrangement

Abstract

During the course of preparation of 3′-azido-3′-deoxythymidine (AZT), we observed consistent formation of an isomer of AZT (2-4%) which was isolated and the structure established as 3-(3-azido-2,3-dideoxy-β-D-ezythro pentofuranosyl)thymine. In a more detailed study, this rearrangement was found to occur during the treatment of 2,3′-anhydro-5′-O-tritylthymidine (1) with LiN₃ in aqueous DMF.     

Synthesis of Methylene-Bridged Analogues of Nicotinamide Riboside,Nicotinamide Mononucleotide and Nicotinamide Adenine Dinucleotide

Abstract

5-O-tert-Butyldimethylsilyl-1,2-O-isopropylidene-3(R)-(nicotinamid-2-ylmethyl)-α-D-ribofuranose (11a) and ?3(R)-(nicotinamid-6-ylmethyl)-α-D-ribofuranose (11b) were prepared by condensation of 5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-α-D-erythro-3-pentulofuranose (10) with lithiated (LDA) 2-methylnicotinamide and 6-methylnicotinamide, respectively, and then deprotected to give 1,2-O-isopropylidene-3-(R)-(nicotinamid-2-ylmethyl)-α-D-ribofuranose(12a) and 1,2-O-isopropylidene-3(R)-(nicotinamid-6-ylmethyl)-α-D-ribofuranose (12b). Benzoylation as well as phosphorylation of compounds 12 afforded the corresponding 5-O-benzoate (13b) and 5-O-monophosphates (14a and 14b). Treatment of 13b with CF₃COOH/H₂O caused 1,2-de-O-isopropylidenation with simultaneous cyclization to the corresponding methylene-bridged cyclic nucleoside - 3′,6-methylene-1-(5-O-benzoyl-β-D-ribofuranose)-3-carboxamidopyridinium trifluoro-acetate (8b) - restricted to the “anti” conformation. In a similar manner compounds 14a and 14b were converted into conformationally restricted 2,3′-methylene-1-(β-D-ribofuranose)-3-carboxamidopyridinium-5′-monophosphate (9a - “syn”) and 3′,6-methylene-1-(β-D-ribofuranose)-3-carboxamido -pyridinium-5′monophosphate (9b - “anti”) respectively. Coupling of derivatives 12a and 12b with the adenosine 5′-methylenediphosphonate (16) afforded the corresponding dinucleotides 17. Upon acidic 1,2-de-O-isopropylidenation of 17b, the conformationally restricted P¹-[6,3′-methylene-1-(β-D-ribofuranos-5-yl)-3-carboxamidopyridinium]-P²-(adenosin-5′-yl)methylenediphosphonate 18b -“anti” was formed. Compound 18b was found to be unstable. Upon addition of water 18b was converted into the anomeric mixture of acyclic dinucleotides, i. e. P¹-[3(R)-nicotinamid-6-ylmethyl-D-ribofuranos-5-yl]-P²-(adenosin-5′-yl)-methylenediphosphonate (19b). In a similar manner, treatment of 17a with CF₃COOH/H₂O and HPLC purification afforded the corresponding dinucleotide 19a.

     

Synthesis of (E)-5-(2-cIOdovinyl)-3′-0-(1-Methyl-1,4-Dihydropyridyl-3 -Carbonyl)-2′-Fluoro-2′-Deoxyuridine (Ivfru-Cds) for Brain Targetted Delivery of Ivfru,an Antiviral Nucleoside

Abstract

(E)-5-(2-lodovinyl)-2′-fluoro-3′-0-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11) was synthesized for future evaluation as a lipophilic, brain-selective, pyrimidine phosphorylase-resistant, antiviral agent for the treatment of Herpes simplex encephalitis (HSE). Treatment of (E)-5-(2-iodovinyl)-2′-fluoro-2′-deoxyuridine (6) with TBDMSCI in the presence of imidazole in DMF yielded the protected 5′-O-t-butyldimethylsilyl derivative (7). Subsequent reaction with nicotinoyl chloride hydrochloride in pyridine afforded (E)-5-(-2-iodovinyl)-2′-fluoro-3′-O-(3-pyridylcarbonyl)-5′-O-t-butyldimethylsily-2′-deoxyuridine (8). Deprotection of the silyl ether moiety of 8 with n-Bu₄N⁺F^? and quaternization of the resulting 3′-O-(3-pyridylcarbonyl) derivative 9 using iodomethane afforded the corresponding 1-methylpyridinium salt 10. The latter was reduced with sodium dithionite to yield (E)-5-(2-iodovinyl)-2′-fluoro-3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11).     

Preparation of 2,3′-Anhydropyrimidine Nucleosides using N,N-Diethylaminosulfur Trifluoride (DAST)

Abstract

2,3′-Anhydro-2′-deoxy-5′-0-(triphenyl methyl) and 5′-0-(monomethoxytriphenylmethyl) pyrimidine nucleosides of uracil, thymine, and cytosine were synthesized in a single step from their 2′-deoxy-5′-0-(triphenylmethyl) or 5′-0-(monomethoxytriphenylmethyl) precursors using N,N-diethylaminosulfur trifluoride (DAST). The anhydronucleosides were either isolated or directly converted to their respective 2-deoxy-β-D-threo-pentofuranosyl nucleosides using sodium hydroxide in ethanol.     

Synthesis of an Epoxide Derivative of Thymidine as a Potential Enzyme Inhibitor

Abstract

Attempts to prepare I -[7,8-anhydro-2,5,6-trideoxy-α-L-lyxo-(and β-n-ribo)-octofuranosyl]thymine (10) by treatment of halohydrins 6–9 with sodium hydride in DMF or sodium methoxide in methanol gave mixtures of the epoxides 10 or 11 and the 3′,8′-anhydronucleoside 12. The structure of 12 was confirmed by oxidation to the cyclic ketone 14. The successful synthesis of 10 involved a Wittig reaction on the thymidine-5′-aldehyde 16 to give the unsaturated ketoacetate 18 which was reduced in two steps to the diacetate 20. The 7′-O-tosyl derivative 21 upon treatment with sodium methoxide in chloroform gave the pure epoxide 10 which was marginally toxic to L1210 cells in culture (I₅₀=25 μM) and demonstrated borderline in vivo activity (24% ILS) against P388 murine leukemia.     

Synthesis,In Vitro Anti-HIV Activity,and Biological Stability of 5′-O-Myristoyl Analogue Derivatives of 3′-Fluoro-2′,3′-Dideoxythymidine (FLT) as Potential Bifunctional Prodrugs of FLT

Abstract

A group of 5′-O-myristoyl analogue derivatives of FLT (2) were evaluated as potential anti-HIV agents that were designed to serve as prodrugs to FLT. 3′-Fluoro-2′,3′-dideoxy-5′-O-(12-methoxydodecanoyl)thymidine (4) (EC₅₀ = 3.8 nM) and 3′-fluoro-2′,3′-dideoxy-5′-O-(12-azidododecanoyl)thymidine (8) (EC₅₀ = 2.8 nM) were the most effective anti-HIV-1 agents. There was a linear correlation between Log P and HPLC Log retention time for the 5 ′-O-FLT esters. The in vitro enzymatic hydrolysis half-life (t½), among the group of esters (3–8) in porcine liver esterase, rat plasma and rat brain homogenate was longer for 3′-fluoro-2′,3′-dideoxy-5 ′-O-(myristoyl)thymidine (7), with t½ values of 20.3, 4.6 and 17.5 min, respectively.     

Synthesis of 2,2′-Anhydro-1 - (3′ -deoxy -3′ -iodo-β-D-arabino-furanosyl) thymine and Its Derivatives as Versatile Synthetic Intermediates

Abstract

2,2′ -Anhydro-1- (3′ -deoxy-3′ -iodo-5′ -O-trityl-B-D-arabinofuranosyl)-thymine (2) was synthesized from 2′,3′ -didehydro-3′-deoxythymidine (DHT) (1). Compound 2 was readily converted into 2′,3′-anhydro-lyxofuranosyl derivatives 4-6. Reaction of 4a with some nucleophiles (N₃ -, OMe-, Cl-) gave the corresponding 3′-substituted arabinonucleosides (7b,d,f) together with the minor xylosyl isomers (8a,c). Compounds 7b,d,f and 8a were deprotected to 7c,e,g and 8b, respectively.     

Facile Synthesis of 8, 2′-S-Cyclopurine Nucleoside

Abstract

This paper describes the synthesis of 8,2 -anhydro-8-mercapto-9-(β-D-arabinofuranosyl)purine (8,2′-S-cyclopurinenucleoside, 1) via the shorter route from 3′,5′-di-O-acectyl-8,2′-S-cycloadenosine (6) and by direct reductive deamination with n- pentyl nitrite in tetrahydrofuran (THF) and deacetylation. The preparation of 8,2′-S-cycloadenosine (2) was achieved in good yield by the cyclization of the protected 8-mercaptoadenosine with triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF at room temperature, under Mitsunobu reaction conditions.     

A Novel Method for the Synthesis of ddA and F-ddA Via Regioselective 2′-O-Deacetylation of 9-(2,5-DI-O-Acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl)adenine

Abstract

Regioselective 2′-O-deacetylation of 9-(2,5-di-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl)adenine (1) is achieved by treatment of 1 with β-cyclodextrin (β-CyD) / aq. NaHCO₃ or N₂H₄·H₂O / EtOH. The 9-(5-O-Acetyl-3-bromo-3-deoxy-β-D-xylo-furanosyl)adenine (2) obtained is a common intermediate for the synthesis of 2′,3′-dideoxy-adenosine (ddA) (7) and 9-(2-fluoro-2,3-dideoxy-β-D-threo-pentofuranosyl)-adenine (F-ddA) (9).     

Photobromination of 1,5-Anhydro-2,3-O-isopropylidene-β-d-ribofuranose and Synthesis of (5R) and (5S)-(5-2H1)-d-Riboses

The photobromination of 1,5-anhydro-2,3-O-isopropylidene-β-d-ribofuranose gave the corresponding (5S)-5-bromo compound. The reduction of the bromide with triphenyltindeuteride gave (5S)-(5-²H₁)-1,5-anhydro-2,3-O-isopropylidene-β-d-ribofuranose, with a chiral purity of 76% at C-5, which was converted to (5R)- and (5S)-(5-²H₁)-d-riboses and other ribofuranose derivatives.     

Synthesis of AZT analogues: 7-(3-azido-2hydroxypropyl)-, 7-(3-amino-2-hydroxypropyl)-, 7-(3-triazolyl-2-hydroxypropyl)theophyllines

Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3-p-toluenesulfonyloxypropyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2). Reduction of the 3-azido group in 2 with Ph₃P/Py/NH₄OH afforded the 3-amino derivative 4, alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with N¹-propargyl thymine (6) afforded the regioisomeric triazole 7.     

The Synthesis of Novel Carbohydrates Amenable to the Synthesis of 2′,3′-Dideoxy-3′-Branched Nucleosides

Abstract

The facile synthesis of several substituted carbohydrates that are amenable for the preparation of 2′,3′-dideoxy-3′-hydroxymethyl nucleosides are reported. Elaboration of a previously reported analog, 5-O-benzoyl-3-deoxy-3-(benzyloxy)methyl-1,2-O-isopropylidene-β-D- ribofuranose (4) has provided two 2,3-dideoxy-3-branched ribose derivatives 5-O-benzoyl-2,3-dideoxy-3-(benzyloxy)methyl-1-O-methyl-β-D-ribofuranose (7) and 1.5-di-O-benzoyl-2,3-dideoxy-3-(benzyloxy)methyl-(α,β)-D-ribofuranose (10). Due to problems involved with the separation of anomeric mixtures when these carbohydrates were condensed with an heterocycle, another versatile synthon 5-O-benzoyl-3-deoxy-3-(benzyloxy)methyl-2-O-t-butyldimethylslyl-1-O- methyl-β-D-ribofuranose (12) was synthesized. The utility of this compound (12) is demonstrated in the total synthesis of 1-[3-deoxy-3-hydroxymethyl-β-D-ribofuranosyl]thymine (20).     

Ferulic acid dehydrodimers from wheat bran: isolation,purification and antioxidant properties of 8-0-4-diferulic acid

Summary

Wheat bran contains several ester-linked dehydrodimers of ferulic acid, which were detected and quantified after sequential alkaline hydrolysis. The major dimers released were: trans-5-[(E)-2-carboxyvinyl]-2-(4-hydroxy-3-methoxy-phenyl)-7-methoxy-2,3-dihydrobenzofuran-3-carboxylic acid (5–8-BendiFA), (Z)-β-(4-[(E)-2-carboxyvinyl]-2-methoxy-phenoxy)-4-hydroxy-3-methoxycinnamic acid (8-O-4-diFA) and (E,E)-4,4′-dihydroxy-5,5′-dimethoxy-3,3′-bicinnamic acid (5–5-diFA). trans-7-hydroxy-1-(4-hydroxy-3methoxyphenyl)-6-methoxy-1,2-dihydro-naphthalene-2,3-dicarboxylic acid (8–8-diFA cyclic form) and 4,4′-dihydroxy-3,3′-dimethoxy-β,β'-bicinnamic acid (8–8-diFA non cyclic form) were not detected. One of the most abundant dimers, 8-O-4-diFA, was purified from de-starched wheat bran after alkaline hydrolysis and preparative HPLC. The resultant product was identical to the chemically synthesised 8-O-4-dimer by TLC and HPLC as confirmed by ¹H-NMR and mass spectrometry. The absorption maxima and absorption coefficients for the synthetic compound in ethanol were: λ_max: 323 nm, λ_min: 258 nm, ε_λmax (M^?1cm^?1): 24800 ± 2100 and ε₂₈₀ (M^?1cm^?1): 19700 ± 1100. The antioxidant properties of 8-O-4-diFA were assessed using: (a) inhibition of ascorbate/iron-induced peroxidation of phosphatidylcholine liposomes and; (b) scavenging of the radical cation of 2,2′-azinobis (3-ethyl-benzothiazoline-6-sulphonate) (ABTS) relative to the water-soluble vitamin E analogue, Trolox C. The 8-O-4-diFA was a better antioxidant than ferulic acid in both lipid and aqueous phases. This is the first report of the antioxidant activity of a natural diferulate obtained from a plant.     

Two new anti-plasmodial flavonoid glycosides from Duranta repens

The CHCl₃-soluble fraction of the whole plant of Duranta repens showed anti-plasmodial activity against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum, with IC₅₀ values of 8.5?±?0.9 and 10.2?±?1.5?μg/mL, respectively. From this fraction, two new flavonoid glycosides, 7-O-α-d-glucopyranosyl-3,4′-dihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6-dimethoxyflavone (1) and 7-O-α-d-glucopyranosyl(6′′′-p-hydroxcinnamoyl)-3,4′-dihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6-dimethoxyflavone (2), along with five known flavonoids, 3,7,4′-trihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6-dimethoxyflavone (3), 3,7-dihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6,4′-trimethoxyflavone (4), 5,7-dihydroxy-3′-(2-hydroxy-3-methyl-3-butenyl)-3,6,4′-trimethoxyflavone (5), 3,7-dihydroxy-3′-(2-hydroxy-3-methyl-3-buten-yl)-5,6,4′-trimethoxyflavone (6), and 7-O-α-d-glucopyranosyl-3,5-dihydroxy-3′-(4′′-acetoxy-3′′-methylbutyl)-6,4′-dimethoxyflavone (7), have been isolated as anti-plasmodial principles. Their structures were deduced by spectroscopic analysis including 1D and 2D NMR techniques. The compounds (1–7) showed potent anti-plasmodial activities against D6 and W2 strains of Plasmodium falciparum, with IC₅₀ values in the range of 5.2–13.5?μM and 5.9–13.1?μM, respectively.     

Synthesis and Conformational Studies of O 5′, 6-Methanouridine—A New Type of Pyrimidine Cyclonucleoside

Abstract

The 5-oxo-6-methylene-pyrimidine-2,4-dione intermediate (6) that is formed when 5-acetoxy-6-acetoxymethyl-1-β-D-(5-O-acetyl-2,3-O-isopropylidene)-ribofuranosyluracil (5) is treated with sodium hydroxide undergoes cyclization at pH 14 to give 2′,3′-O-isopropylidene-5-hydroxy- O ⁵, 6-methanouridine (8) in good yield. Conversion of 8 into the 5-triflate ester 14 followed by reduction with [(Ph)₃P]₄Pd/Bu₃SnH and deblocking with acetic acid then affords O ^5′, 6-methanouridine (4) Conformational studies (NOE difference spectra, vicinal ¹H-¹³C coupling constants, NOESY and CD spectra, molecular modeling) indicate that the C7-methylene group of 4 projects towards the furanose ring oxygen atom, producing a glycosyl rotation angle of about ? 160°.