Solid Phase Synthesis of Nucleobase and Ribose Modified Inosine Nucleoside Analogues (original) (raw)
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New synthesis of 3′--substituted nucleosides
Tetrahedron, 1993
The base catalyzed addition reactions at C-3' of 2'. 3'-dideoxy-3'-nitro-thymidine I or-t&dine 2 with para,formaldehyde, meihyl vinyl ketone, actylonitrile and ethyl propiolate have produced various I-(2~3J'-dideoxy-3~-~-;ubsn~ted-3'-ninolgD-pentofuranosyl)pyrimidine nucleosides 3-26 [a-substitution (major): @ubstitudon (minor)]. The stereochemistry of products formed in the reaction clearly suggest that the incipient ccl&anion at C3'preferentially attacks the electron-deficient reagent from the a-face of the sugar ring. Subsequently, the 3*-nitro group from 3,14,17. 22 and 25 was removed by the action of Bu3SnH and AIBN to give 3'-&ubstituted nucleosides 27-44 [three (major) and erythro (minor)] which suggested that the intermediary 3'-carbon radical abstracted the hydrogen atom preferentially from the a-face. The stereochemistry of the products from thebase-catalyzed aadition reactions &fleeradical promoted demtration reactions were ascertained by &toiled structure analysis by NMR spectroscopy. The results presented in this paper is the first example of the preparation of G-branched nucleosides using the base catalyzed addition reaction at the a-carbon of a nitrojitnction in the sugar moiety ofnucleoside. N. GARG et al. The results described herein constitute the first report of the base-catalyzed addition reaction at the acarbon of a nitro function in the sugar moiety of a nucleoside to introduce the Gsubstituent. This has been demonstrated through the reactions of 2',3'-dideoxy-3'-nitrothymidinele 1 and 2',3'-dideoxy-3'-nitrouridinele 2 with various reagents containing electron-deficient functions as in paraformaldehyde, methyl vinyl ketone, acrylonitrile and ethyl propiolate. Nitroaldol reactions98 as means to form a carbon-carbon bond have been explored extensively by Seebach and his co-workers on various simple acyclic or alicyclic systems.wc Subsequently, Vasella et al.9d.e performed base-catalyzed reaction of D-gluco-1-deoxy-1-nitroaldose with excess pamformaldehyde to give the anomeric mixture of D-gluco-2-deoxy-2-nitro-heptulopyranoses which were then den&rated under the influence of tributyltinhydride to give D-gulo-hepitol. Reaction of 2',3'-dideoxy-3'-nitrothymidine 1 and 2',3'-dideoxy-3'-nitrouridine 2 with par@ormaladehyde, acrylonitrile, ethyl propiolate and methyl vinyl ketone: Treatment of S-0-(4-monomethoxytrityl)~2',3'-dideoxy-3'-nitro-thymidinele 1 with pamformaldehyde in THF in presence of tetrabutyl ammonium fluoride (0.2 equiv) for 30 min at room temperature gave a diastereomeric mixture which was separated to give pure 3'-(R)hydroxymethyl-3'-nit-thymidine 3 (34 %) and 3'-(S)-hydroxymethyl-3'-nitro-thymidine 14 (55 96). The chemical shifts of H-2, H-4 H5'/5" and 3'-C&-OH were remarkably different in 3 and 14 [for 3: H-2' (62.52 ppm), H-4' (64.67 ppm), H5'/5" (63.73 and 3.41 ppm), 3'-C&-OH (64.04 ppm) and for 14: H-2' (82.90 ppm), H-4' (63.96 ppm), H5'/5" (63.47 ppm), 3'-C&-OH (64.26 and 3.91 ppm)]. The AJ1, (i.e. Jltz-Jl*z") for 3 and 14 is 2.9 Hz and 0.8 Hz, respectively (see lH-and 13C-NMR data in the experimental part). The presence of 3'-CHzOH group in 3 and 14, was also unequivocally proved (vide irlfra) by their straightforward conversions to the corresponding acetates 4 (85 %) and 15 (89 %), respectively. Similarly, the reaction of 1 with acrylonitrile for 20 min gave 3'-(R)-(P-cyanoethyl)-3'-nitro-thymidine 17 (83 8) as the major product (minor product was not isolable), whereas the treatment of 1 with ethyl propiolate for 10 min gave the diastereomeric mixture which was separated to give pure 3'-(R)-(ethoxycarbonylethylidene)-3'-nitro-thymidine 6 (18 96) and 3'-(S)-(etboxycarbonylethylidene)-3'-nitro-thymidine 19 (69 %) [for 6: H-2' (62.68 ppm) Jc H-4' (64.97 ppm), AJle = 4.6 Hz, for 19: H-2' (62.89 ppm) & H-4' (64.05 ppm), AJll = 0.9 Hz]. In the similar manner, the reaction of 1 with methyl vinyl ketone for 5 min gave 3'-(S)-(3-oxobutyl)-3'-nitro-N-3-(3-oxobutyl)thymidine 8 (4 %), 3'-(R)-(3-oxobutyl)-3'-nitro-N-3-(3-oxobutyl)thymidine 21 (9 %), 3'-(S)-(3-oxobutyl)-3'-nitro-thymidine 9 (9 %)
Synthesis of 3-Guaninyl- and 3-Adeninyl-5-hydroxymethyl-2-pyrrolidinone Nucleosides
The Journal of Organic Chemistry, 2011
Human immune-deficiency virus type 1 (HIV-1) is the causative organism for acquired immune-deficiency syndrome (AIDS), 1 and despite great progress in chemotherapeutic treatment and prevention, 2 millions have lost their lives. The World Health Organization estimates that as of 2009 33.3 million people were living with AIDS, and 1.8 million died in 2009. 3 Several forms of chemotherapy are based on key events in the life cycle of HIV-1, including interception of the viral enzyme, reverse transcriptase (RT). 4 The HIV-RT enzyme converts the viral RNA to proviral DNA, and there are two general classes of RT inhibitors: nucleoside-based reverse transcriptase inhibitors (NRTI's) 5 and non-nucleoside reverse transcriptase inhibitors (NNRTI's). 6 Significant toxicity is associated with many NRTIs, and there is evidence that much of this toxicity results from the inhibition of mitochondrial DNA replication. AZT (1), for example, is known to cause bone marrow suppression, but the delay of disease progression often outweighs the complications caused by treatment with AZT. 7 One FDA-approved anti-HIV NRTI treatment is abacavir (2), 8 which after the intracellular monophosphorylation, is converted to carbovir monophosphate, which is further phosphorylated to the biologically active carbovir triphosphate. Carbovir (3), 8 an anti-HIV drug marketed by GlaxoSmithKline, was first identified as a potent anti-HIV agent in 1990. It has comparable activity to the clinically used AZT and lower toxicity. There have been several syntheses of carbovir, with the first in 1990 by Vince and co-workers, 9a,d the discoverers of carbovir. In the scheme reported by Vince and co-workers, a guanine derivative was structurally modified to incorporate the cyclopentene unit, rather than begin with a cyclopentene and then attach a guanine unit. Analyses of 1À3 (see Scheme 1), as well as other related antiviral drugs, show that a nucleobase and a hydroxymethyl unit are attached to a relatively flat five-membered ring. The synthesis of such compounds remains an area of interest with respect to ' RESULTS AND DISCUSSION L-Glutamic acid is an attractive starting material due to its commercial availability, low cost, and widespread use. In a study that is highly relevant to our targeted compounds, Nielsen and co-workers reported a synthesis of conformationally restricted peptide nucleic acid (PNA) derivatives from D-glutamic acid (6). 11 As shown in Scheme 2, formation of 2-pyrrolidinone-5carboxylic acid (pyroglutamic acid) was followed by reduction to the hydroxymethyl derivative and protection of the alcohol and nitrogen to give the O-TBDPS, N-Boc derivative 7. R-Hydroxylation with MoOPH, via the lactam enolate anion, gave 8 as a key intermediate. The PNA monomer was prepared by conversion of 8 to 9 in several steps, followed by a Mitsunobu coupling that incorporated adenine, with clean inversion of configuration
Synthesis of 2‘-O-[2-[(N,N-Dimethylamino)oxy]ethyl] Modified Nucleosides and Oligonucleotides
The Journal of Organic Chemistry, 2002
A versatile synthetic route has been developed for the synthesis of 2′-O-[2-[(N,N-dimethylamino)oxy]ethyl] (abbreviated as 2′-O-DMAOE) modified purine and pyrimidine nucleosides and their corresponding nucleoside phosphoramidites and solid supports. To synthesize 2′-O-DMAOE purine nucleosides, the key intermediate B (Scheme 1) was obtained from the 2′-O-allyl purine nucleosides (13a and 15) via oxidative cleavage of the carbon-carbon bond to the corresponding aldehydes followed by reduction. To synthesize pyrimidine nucleosides, opening the 2,2′-anhydro-5-methyluridine 5 with the borate ester of ethylene glycol gave the key intermediate B. The 2′-O-(2hydroxyethyl) nucleosides were converted, in excellent yield, by a regioselective Mitsunobu reaction, to the corresponding 2′-O-[2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]ethyl] nucleosides (18, 19, and 20). These compounds were subsequently deprotected and converted into the 2′-O-[2-[(methyleneamino)oxy]ethyl] derivatives (22, 23, and 24). Reduction and a second reductive amination with formaldehyde yielded the corresponding 2′-O-[2-[(N,N-dimethylamino)oxy]ethyl] nucleosides (25, 26, and 27). These nucleosides were converted to their 3′-O-phosphoramidites and controlled-pore glass solid supports in excellent overall yield. Using these monomers, modified oligonucleotides containing pyrimidine and purine bases were synthesized with phosphodiester, phosphorothioate, and both linkages (phosphorothioate and phosphodiester) present in the same oligonucleotide as a chimera in high yields. The oligonucleotides were characterized by HPLC, capillary gel electrophoresis, and ESMS. The effect of this modification on the affinity of the oligonucleotides for complementary RNA and on nuclease stability was evaluated. The 2′-O-DMAOE modification enhanced the binding affinity of the oligonucleotides for the complementary RNA (and not for DNA). The modified oligonucleotides that possessed the phosphodiester backbone demonstrated excellent resistance to nuclease with t 1/2 > 24 h.
Synthesis of N-1 and ribose modified inosine analogues on solid support
Tetrahedron Letters, 2007
Herein, we report the synthesis and the use of new N-1-dinitrophenyl-inosine based solid supports, in which the C-2 of the purine base is strongly activated toward the attack of N-nucleophiles. The synthesized supports, binding the nucleoside by a 5 0 -O-monomethoxytrityl function, have been used to accomplish the synthesis of a small library of N-1 alkylated inosine and AICAR derivatives. In addition, cleavage of the 2 0 -3 0 ribose bond of N-1 alkylated inosine derivatives anchored to the supports allowed to prepare a new set of N-1 alkylated-2 0 ,3 0 -secoinosine derivatives in high yields.
Helvetica Chimica Acta, 2000
A new type of oligonucleosides has been devised to investigate the potential of oligonucleosides with a nucleobase-including backbone to form homo-and/or heteroduplexes (cf. Fig. 2). It is characterised by ethynyllinkages between C(5') and C(6) of uridine, and between C(5') and C(8) of adenosine. Force-field calculations and Maruzen model studies suggest that such oligonucleosides form autonomous pairing systems and hybridize with RNA. We describe the syntheses of uridine-derived monomers, suitable for the construction of oligomers, and of a dimer. Treatment of uridine-5'-carbaldehyde (2) with triethylsilyl acetylide gave the diastereoisomeric propargylic alcohols 6 and 7 (1 : 2, 80%; Scheme 1). Their configuration at C(5') was determined on the basis of NOE experiments and X-ray crystal-structure analysis. Iodination at C(6) of the (R)-configured alcohol 7 by treatment with lithium diisopropylamide (LDA) and N-iodosuccinimide (NIS) gave the iodide 17 (62%), which was silylated at OÀC(5') to yield 18 (89%; Scheme 2). C-Desilylation of 7 with NaOH in MeOH/H 2 O led to the alkyne 10 (98%); O-silylation of 10 at OÀC(5') gave 16 (84%). Cross-coupling of 18 and 16 yielded 63% of the dimer 19, which was C-desilylated to 20 in 63% yield. Cross-coupling of 10 and the 6-iodouridine 13 (70%), followed by treatment of the resulting dimer 14 with HF and HCl in MeCN/H 2 O, gave the deprotected dimer 15 (73%).
Molecules, 2021
A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms of the heterocycle moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione, alloxazine) or to the C-5 and N-3 atoms of the 6-methyluracil moiety was synthesized. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. Antiviral assays revealed three compounds, 2i, 5i, 11c, which showed moderate activity against influenza virus A H1N1 with IC50 values of 57.5 µM, 24.3 µM, and 29.2 µM, respectively. In the first two nucleoside analogues, 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via butylene linkers to N-1 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine, respectively). In nucleoside analogue 11c, two 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached via propylene linkers t...
Collection of Czechoslovak Chemical Communications, 2000
Cross-coupling reactions of 2-amino-6-chloro-9-{2-[(diisopropoxyphosphoryl)methoxy]-ethyl}purine (1) and 2-amino-9-{2-[(diisopropoxyphosphoryl)methoxy]ethyl}-6-iodopurine (2) with diverse types of organometallic reagents have been studied. Arylboronic acids reacted with 1 to give the corresponding 2-amino-6-arylpurines 3a-3d in good yields. Analogously, trialkylaluminium reagents were used for the preparation of 6-alkyl-2-aminopurines 3k and 3l from 1. Hetarylzinc halides and hetarylstannanes required the use of 2-amino-6-iodopurine 2 to give the corresponding 2-amino-6-hetarylpurines 3e-3j in fair to good yields. A CuI/KF mediated coupling of perfluoroalkylsilanes with 2 afforded the 2-amino-6-perfluoroalkylpurines 3m and 3n in moderate yields. Cleavage of the esters 3 with bromo(trimethyl)silane gave the target free phosphonates 4 that were purified by ionexchange chromatography. The title compounds were tested on antiviral and cytostatic activity.