Synthesis of 2′-Deoxy-6,2′-Ethano-Cyclouridine1 (Nucleosides and Nucleotides. Part 57)

Abstract

Synthesis of a carbon-bridged cyclouridine,2′-deoxy-6,2′-ethano-cyclouridine, was accomplished starting from a 2′-ketouridine via the 2′-deoxy-2′-iodoethyl-5-chlorouridine derivative through a radical cyclization.     

Nucleosides and Nucleotides. 125. Synthesis and Biological Evaluation of 2′,3′-Dideoxy-3′-fluoro-2′-methylidene Pyrimidine Nucleosides

Abstract

Reaction of 2′-deoxy-2′-methylidene-5′-O-trityluridine (1) with diethylamino-sulfur trifluoride (DAST) in CH₂Cl₂ resulted in the formation of a mixture of (3′R)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivative 3 and 2′,3′-didehydro-2′,3′-dideoxy-2′-fluoromethyl derivative 4 (3:4 = 1:1.5) in 65% yield. A similar treatment of 1-(2-deoxy-2-methylidene-5-O-trityl-β-D-threo-pentofuranosyl)uracil (19) with DAST in CH₂Cl₂ afforded (3′S)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivatives 20 and 4 in 38% and 17% yields respectively. Transformation of the uracil nucleosides 4, 12, and 20 into cytosines followed by deprotection furnished the corresponding cytidine derivatives 29, 18, and 25, respectively. The corresponding thymidine congener 27 was also synthesized in a similar manner. All of the newly synthesized nucleosides were evaluated for their inhibitory activities against HIV and for their antiproliferative activities against L1210 and KB cells.     

Synthesis of An Acid-Stable 2,5′-Cyclo-2-oxo Analogue of Wyosine (Nucleosides and Nucleotides. Part 611)

Abstract

Methylation of a 4-desmethylwyosine derivative fixed in anti-conformation has afforded a higher yield of fluorescent N-4-methyl isomer, 2,5′-cyclo-2-oxo-2′,3′-O-isopropylidenewyosine (7), which has been shown to be relatively stable in acidic media.     

Nucleosides and Nucleotides. 232. Synthesis of 2′-C-Methyl-4′-thiocytidine: Unexpected Anomerization of the 2′-Keto-4′-thionucleoside Precursor

The synthesis of 2′-C-methyl-4′-thiocytidine (16) is described. Since the 2′-keto-4′-thiocytidine derivative 2β unexpectedly isomerized to 2α and the methylation of 2β proceeded predominantly from the less hindered α-face to give 7, the desired product 16 was synthesized via the Pummerer reaction of the sulfoxide 14 and N ⁴ -benzoylcytosine.     

The Structure of 2′ (R)-Mercapto-2′-deoxyneplanocin A (Nucleosides and Nucleotides 48.)

Abstract

The molecular and crystal structure of 2′(R)-mercapto-2′-deoxyneplanocin A, C₁₁H₁₃N₅O₂S M.W.=279.32, has been determined by X-ray analysis. The space group is P2₁2₁2₁ with a=10.322(1), b=22.870(2), c=5.273(1)Å and z=4. The structure was solved by direct method, and least-squares refinement using 1806 reflections with |Fo| > 30(F) led to the final R value of 0.045. The sugar C(2′) atom is displaced by 0.35Å opposite to the base N(9), i.e., C(2′)-exo conformation and the torsion angle about the N(9)-C(1) bond is 26.3(4)° (anti conformation).     

Synthetic Nucleosides and Nucleotides. XX1. Synthesis of Various 1-β-D-Xylofuranosyl-5-Alkyluracils and Related Nucleosides

Abstract

Treatment of D-xylose (1) with 0.5% methanolic hydrogen chloride under controlled conditions followed by benzoylation and acetolysis afforded crystalline 1-O-acetyl-2, 3, 5-tri-O-benzoyl-α-D-xylofuranose (4) in good yield. Coupling of 4 with 2, 4-bis-trimethylsilyl derivatives of 5-alkyluracils (methyl, ethyl, propyl and butyl) (5a-5d), 5-fluorouracil (5e) and uracil (5f) in acetonitrile in the presence of stannic chloride gave 1-(2,3,5-tri-O-benzoyl-β-D-xylofuranosyl)-nucleosides (6a-6f). Saponification of 6 with sodium methoxide afforded 1-β-D-xylofuranosyl-5-substituted uracils (7a-7f). Condensation of 4 with free adenine in similar fashion and deblocking gave carcinostatic 9-β-D-xylofuranosyladenine (7g).     

Chemical Conversion of Uridine to 3′-Branched Sugar Nucleosides (Nucleosides and Nucleotides. 421.)

Abstract

Deamination of 1-(3-amino-3-deoxy-β-D-glucopyranosyl)-uracil gave a ring contracted nucleoside, 3′-deoxy-3′-formyluridine as a hemiacetal form, and uracil. Similar treatment of the 2′-deoxyderivative, 1-(3-amino-2,3-dideoxy-β-D-glucopyranosyl)uracil, gave the corresponding 2′,3′-dideoxy-3′-formyluridine in high yield. The 3′-epimerization of the 3′-formyluridine derivative was achieved and after reduction of the formyl groups, 2′,3′-dideoxy-3′(R and S)-hydroxymethyluridine were obtained.     

Stereoselective Synthesis of 1′-C-Branched Uracil Nucleosides from Uridine

Abstract

Face-selective electrophilic addition (bromo-pivaloyloxylation) to 1-[3,5-bis-O-(tert-butyldimethylsilyl)-2-deoxy-D-erythro-pent-1-enofurano-syl]uracil (1), when combined with nucleophilic substitution using organosilicon or organoaluminum reagents, provides a new and highly divergent C-C bond forming method at the anomeric position.     

Synthesis of 2′-N-Formamido Nucleosides and Biological Evaluation

The 2′-N-formamide derivatives of adenosine, cytidine, and 9-β-d-arabinofuranosyladenine were synthesized and tested (as triphosphate) for their substrate capacities for the HCV NS5B polymerase.     

Synthesis of 2′, 3′ -Dideoxy-6, 3′-Methano-cyclouridine and a Furanosyl To Pyranosyl Ring-isomerization In The C-cyclo-nucleoside (Nucleosides and Nucleotides. 531)

Abstract

Synthesis of a C-cyclouridine fixed by a 6, 3′-methylene unit, 2′, 3′ -dideoxy-6, 3′ -methano-cyclouridine, was accomplished by utilizing a 3′-hydroxymethyluridine via an intramolecular radical addition as the key step. A furanosyl to pyranosyl ring-isomerization was observed in this reparation and the mechanism for this isomerization is presented.     

Synthesis of 2′-Amino-LNA Purine Nucleosides

The first reported synthesis of 2′-amino-LNA purine nucleosides via a transnucleosidation is accomplished enabling the preparation of oligonucleotides incorporating 2′-amino-LNA with all four natural bases.     

Nucleosides. LIV1 Synthesis and Properties of 3′-Azido- and 2′,3′-Dideoxy-6,7-diphenyllumazine Nucleosides

Abstract

The best approach for the synthesis of1-(3-azido-2,3-dideoxy-β-D-erythro-pento-furanosyl)lumazine (5) and its 6,7-dimethyl- (4) and 6,7-diphenyl derivatives (3) has been found in the interconversion of the corresponding 1-(2-deoxy- β-threo-pentofuranosyl)-lumazines. Monomethoxytritylation at the 5′-position (1 7, 3 4, 4 9) followed by mesylation at the 3′-OH group and subsequent nucleophilic displacement by lithium azide afforded 1 9, 2 9 and 4 7 which were deprotected by acid treatment to give 3–5 in good yields. The syntheses of 1-(2,3-dideoxy-β-D-glycero-pentofuranosyl)-6,7-diphenyllumazine (6) and its 6,7-dimethyl derivative (7) were achieved from 1-(2-deoxy-β-D-erythro-pentofuranosyl)-6,7-diphenyllumazine and the corresponding 6,7-dimethyllumazine (2 6) via their 5′-O-p-toluoyl- (2 0, 3 0), and 3′-deoxy-3′-iodo derivatives (2 4, 3 1) to form, after radical dehalogenation and final deprotection, 6 and 7. The newly synthesized lumazine nucleosides have been characterized by elemental analyses, UV-and NMR spectra.     

Nucleosides and Nucleotides. 106. Synthesis and Biological Activity of 1-(2-Deoxy-2-hydroxyimino- or Methoxyimino-β-D-erythro-pentofuranosyl)-thymine and -Cytosine§,1

Abstract

Reaction of 1-(3,5-Otetraisopropyldisiloxan-1,3-diyl-β-D-erythro-2-pentofuran-2-ulosyl)uracil (8) with hydroxylamine hydrochloride in pyridine at room temperature for 24 h or at 80°C for 3 h gives the 2′-deoxy-2′-hydroxyiminouridine derivative 9 in good yield. Similarly, oximation of 8 with methoxyamine has been done to obtain 2′-deoxy-2′-methoxyimino derivatives 11 in a high yield. Compound 9 was converted into 1-(2-deoxy-2-hydroxyimino-β-D-erythro-pentofuranosyl)cytosine (3). Cytotoxicity in vitro of these nucleosides against murine leukemia L1210 cells was also examined.     

A Stereoselective Synthesis of α - and β-2′-Deoxy-2-thiouridine

Abstract

A stereoselective glycosylation procedure is described for the synthesis of protected α- and β-2′-deoxy-2-thiouridine (dS²U) in 68% and 94% yield, respectively. Evidence is presented that suggests the reaction proceeds through a silylated thio-glycoside intermediate. This intermediate undergoes an efficient S² → N¹ rearrangement mediated by SnCl₄. The phosphoramidite and phosphodiester synthons and a dS²U dinucleotide are also synthesized and the X-ray structure of β-dS²U is presented.     

Nucleosides and Nucleotides. 140. Synthesis and Antileukemic Activity of 5-Carbon-Substituted 1-β-d-Ribofuflranosylimidazole-4-Carboxamides

Abstract

Synthesis of 5-carbon-substituted 1-β-d-ribofuranosylimidazole-4-carboxamides are described. Treatment of 5-iodo derivative 8 with methyl acrylate in the presence of palladium catalyst gave (E)-5-(2-carbomethoxyvinyl)-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxamide (9), followed by appropriate manipulations to afford various 5-carbon-substituted imidazole derivatives 1–7. The antileukemic activities of these imidazole nucleosides are also described.

     

Commercial-Scale Synthesis of Protected 2′-Deoxycytidine and Cytidine Nucleosides

Abstract

Transformation of 2′-deoxyuridine and uridine analogs to protected 2′-deoxycytidine and cytidine analogs has been investigated by two different methods. First, traditional triazolation protocol and second p-nitrophenoxylation method. Our studies conclude that the triazolation method is better and suitable for commercial scale--up.     

Nucleosides. 145. Synthesis of 2,5′-Anhydro-2-Thiouridine and its Conversion to 3′-O-Acetyl-2,2′-Anhydro-5′-Chloro-5′-Deoxy-2-Thiouridine. Studies Directed Toward the Synthesis of 2′-Deoxy-2′-Substituted arabino Nucleosides (7)

Abstract

In an attempt to introduce a substituent at C-2′ in the “up” arabino configuration directly by nucleophilic displacement reaction of a preformed pyrimidine ribonucleoside, we synthesized 2,5′-anhydro-5′-deoxy-2-thiouridine (6) in three steps from uridine. Compound 6 was converted into the 3′-O-acetyl derivative 7. Upon treatment of 7 with triflyl chloride in methylene chloride in the presence of triethylamine and p-dimethylaminopyridine, 2,2′-anhydro-1-(3-O-acetyl-5-chloro-2,5-dideoxy-β-D-arabinofuranosyl)-2-thiouracil (9) was obtained as the only isolable product. Obviously, the intermediate 3′-O-acetyl-2,5′-anhydro-2′-O-triflyl-2-thiouridine (8) was attacked by the chloride nucleophile at C-5′ first giving the 2′-O-triflyl-2-thiouridine intermediate from which 9 was formed by intramolecular nucleopilic reaction.     

Synthetic Nucleosides and Nucleotides. 40. Selective Inhibition of Eukaryotic DNA Polymerase α by 9-(β-D-Arabinofuranosyl)-2-(p-n-butylanilino)adenine 5′-Triphosphate (BuAaraATP) and Its 2′-Up Azido Analog: Synthesis and Enzymatic Evaluations†

Abstract

Starting from 2′,3′,5′-tri-O-acetyl-2-iodoadenosine, 9-(β-D-arabinofuranosyl)-2-(p-n-butylanilino)adenine and its 2′(S)-azido counterparts were synthesized in seven steps. These exhibited only moderate growth-inhibitory effects against mouse leukemic P388 cells (IC₅₀ = 13–24 μM), although 5′-triphosphate derivatives showed strong and selective inhibitory action on calf thymus DNA polymerase α, but not on β- and ?-polymerases from eukaryotes.

     

Stereoselective Synthesis of 2-Deoxy-2-Fluoroarabinofuranosyl-α-1-Phosphate and Its Application to the Synthesis of 2′-Deoxy-2′-Fluoroarabinofuranosyl Purine Nucleosides by a Chemo-Enzymatic Method

Stereoselective introduction of a phosphate moiety into 2-deoxy-2-fluoroarabinofuranose derivatives at the anomeric position was investigated by two methods. One involved a stereoselective hydrolysis of 1-bromo-derivative, and the consecutive phosphorylation of 2-deoxy-2-fluoro-α-D-arabinofuranose via a phosphoramidite derivative. The other method involved stereoselective α-phosphorylation of the 1-bromo-derivative at the 1-position. The resulting α-1-phosphate was utilized to prepare 2′-deoxy-2′-fluoroarabinofuranosyl purine nucleosides by an enzymatic glycosylation reaction. This chemo-enzymatic method will be applicable to the synthesis of some 2′F-araNs, and three important 2′F-araNs were actually obtained in 30–40% yields from 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinose with high purity.     

Nucleosides. IL. Synthesis and Properties of 2,4-Quinazolinedione N-1-2′ Deoxy-, 3′-Deoxy- and 2′,3′-Dideoxynucleosides

Abstract

A series of 6- and/or 7-substituted 2,4-quinazoline-dione N-1-deoxyribofuranosides have been synthesized and characterized. The 2′-deoxy-β-D-ribofuranosides 23–28 have been prepared by transformation of the corresponding ribofuranosides by chemical deoxygenation. Direct glycosidation to the β-anomers with a 2′-deoxyribofuranosyl donor to pure anomers failed due to missing diastereoselectivity and difficult separation of the reaction products. The synthesis of the 3′-deoxy-β-D-ribofuranosides 54–58, however, was achieved by glycosidation of the trimethylsilylated 2,4-quinazolinediones 43–47 with an appropriate 3′-deoxyribofuranosyl donor (48). The 2′,3′-dideoxy-β-D-ribofuranosyl derivatives 63–66 were again obtained by chemical deoxygenation of the corresponding 2′-deoxy-β-D-nucleosides, since all experiments of direct glycosidation with a 2′,3′-dideoxyribofuranosyl donor as well as the chemical conversion of the corresponding ribonucleosides into the 2′,3′-dideoxynucleosides failed due to side reactions. The newly synthesized compounds have been identified by UV and ¹H-NMR spectra as well as elemental analyses.