- Noncanonical RNA Nucleosides as Molecular Fossils of an Early Earth—Generation by Prebiotic Methylations and Carbamoylations
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The RNA-world hypothesis assumes that life on Earth started with small RNA molecules that catalyzed their own formation. Vital to this hypothesis is the need for prebiotic routes towards RNA. Contemporary RNA, however, is not only constructed from the four canonical nucleobases (A, C, G, and U), it also contains many chemically modified (noncanonical) bases. A still open question is whether these noncanonical bases were formed in parallel to the canonical bases (chemical origin) or later, when life demanded higher functional diversity (biological origin). Here we show that isocyanates in combination with sodium nitrite establish methylating and carbamoylating reactivity compatible with early Earth conditions. These reactions lead to the formation of methylated and amino acid modified nucleosides that are still extant. Our data provide a plausible scenario for the chemical origin of certain noncanonical bases, which suggests that they are fossils of an early Earth.
- Schneider, Christina,Becker, Sidney,Okamura, Hidenori,Crisp, Antony,Amatov, Tynchtyk,Stadlmeier, Michael,Carell, Thomas
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supporting information
p. 5943 - 5946
(2018/04/30)
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- PROCESS FOR THE SYNTHESIS OF 2'-O-SUBSTITUTED PURINES
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The present invention provides an improved process for the synthesis of 2′-O-substituted purine nucleosides. The process includes anhydro or thioanhydro ring opening of a selected 8,2′-cyclopurine nucleoside with a weak nucleophile in the presence of a Lewis acid ester, followed by reduction to afford the desired 2′-O-substituted purine nucleoside.
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Page/Page column 8
(2008/12/07)
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- An efficient process for synthesis of 2′-O-methyl and 3′-O-methyl guanosine from 2-aminoadenosine using diazomethane and the catalyst stannous chloride
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An improved strategy for the selective synthesis of 2′- O -methyl and 3′- O -methyl guanosine from 2-aminoadenosine is reported by using the catalyst stannous chloride. The regioselectivity of the 2′ and 3′- O -alkylation was achieved by optimizing the addition, timing, and concentration of the catalysts and diazomethane during the methylation reaction. An efficient and selective alkylation at 2′-OH of 2-aminoadenosine was achieved by mixing a stoichiometric amount of stannous chloride at room temperature in DMF. The reaction mixture was stirred at 50°C for 1 min and immediately followed by addition of diazomethane. The resulting 2′- O -methyl 2-aminoadenosine was treated with the enzyme adenosine deaminase, which resulted in an efficient conversion to the desired 2′- O -methylguanosine (98% yield). The product was isolated by crystallization. In contrast, the methylation at 3′-OH of 2-aminoadenosine was achieved by mixing a stoichiometric amount of stannous chloride in DMF and stirring at 50°C for 15 min, followed by addition of diazomethane. The resulting mixture containing 3′- O -methyl-2- aminoadenosine in 90% yield and 2′- O -methyl-2-aminoadenosine in 10% yield was treated with the enzyme adenosine deaminase, which preferentially deaminated only 3′- O -methyl-2-aminoadenosine, resulting in the production of 3′- O -methylguanosine in 88% yield. Due to the extremely low solubility 3′- O -methylguanosine, the compound precipitated and was isolated by centrifugation. This synthetic route obviates the chromatographic purification. Selective monomethylation is achieved by using the unprotected ribonucleoside. As a result, the method described herein represents a significant improvement over the current synthetic approach by providing superior product yield and economy, a much more facile purification of 2′,3′- O -methylated isomers, and eliminating the need for protected ribonucleosides reagents. Copyright Taylor & Francis Group, LLC.
- Kore, Anilkumar,Parmar, Gaurang,Reddy, Srinu
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p. 307 - 314
(2007/10/03)
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- Novel synthesis of 2′-O-methylguanosine
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An efficient and chemoselective synthesis of 2′-O-methylguanosine (6) has been accomplished in high yield without protection of the guanine base. The salient feature of the synthesis of 6 lies in the application of methylene-bis-(diisopropylsilyl chloride), (MDPSCl2, 2) as a new 3′,5′-O-protecting group for nucleosides. Use of CH3Cl as a weak electrophile and NaHMDS as a mild base was crucial to the success of the 2′-O-methylation of 3′,5′-O-protected guanosine.
- Chow, Suetying,Wen, Ke,Sanghvi, Yogesh S.,Theodorakis, Emmanuel A.
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p. 1631 - 1634
(2007/10/03)
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- MDPSCL2: a new protecting group for chemoselective synthesis of 2'-O-alkylated guanosines.
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An improved strategy for the synthesis of 2'-O-methyl-guanosine (6) and 2'-MOE-guanosine (8) is reported. The regioselectivity of the alkylation was attained using a novel silicon-based protecting group, methylene-bis (diisopropyl-silylchloride) (MDPSCl2, 2). The alkylation proceeded in a chemoselective manner using NaHMDS as the base and MeCl or MOE-Br as the appropriate electrophiles.
- Chow, Suetying,Wen,Sanghvi, Yogesh S,Theodorakis, Emmanuel A
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p. 583 - 587
(2007/10/03)
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- Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
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The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.
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- Improved synthetic approaches toward 2'-O-methyl-adenosine and guanosine and their N-acyl derivatives
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We developed several improved approaches toward 2'-O-methyl adenosine and guanosine and their N-acyl derivatives. (a) Transglycosylation of N4- acetyl-5', 3'-di-O-acetyl-2'-O-methyl cytidine with N6-Bz-adenine provided N6-benzoyl-5'3'-di-O-acetyl-2'-O-methyl adenosine in 50% yield. (b) Regioselective methylation of 2-amino-6-chloro purine riboside with MeI/NaH followed by hydrolysis provided 2'-O-Me-guanosine in high yield. The same 2'- O-Me-precursor was transformed into 2'-O-Me-adenosine in 58% yield. (c) Very efficient transformation of 2,6-diamino-purine riboside into N2-isobutyryl (isopropylphenoxyacetyl) 2'-O-Me-guanosine through methylation of 5',3'-O- TIPDSi derivative followed by selective N2-acylation, deamination and desylilation provided target compounds in 70% combined yield. (d) Mg2+ and Ag+ directed methylation of N1-Bzl-guanosine proceeded in >80% yield with ratio of 2'-O-Me-3'-O-Me=9:1. The same methylation of adenosine with Ag+ and Sr2+ acetylacetonates provided 2'-O-Me-adenosine in 75-80% yield. (C) 2000 Elsevier Science Ltd.
- Beigelman, Leonid,Haeberli, Peter,Sweedler, David,Karpeisky, Alexander
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p. 1047 - 1056
(2007/10/03)
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- Chemical syntheses of 2'-O-methoxy purine nucleosides
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Several processes for the chemical synthesis of 2'-O-methoxy purine nucleosides are herein disclosed.
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- Process for the preparation of 2'-O-alkyl purine phosphoramidites
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2'-O-alkylated guanosine, uridine, cytidine, and 2,6-diaminopurine 3'-O-phosphoramidites are prepared by alkylating nucleoside precursors, adding suitable blocking groups and phosphitylating. Alkylation is effected on 2,6-diamino-9-(β-D-ribofuranosyl)purine followed by deamination to prepare guanosine 2'-O-alkylated 3'-O-phosphormidites. Alkylation is effected on a dialkyl stannylene derivative of uridine to prepare uridine 2'-O-alkylated 3'-O-phosphormidites. Alkylation is effected directly on cytidine to prepare cytidine 2'-O-alkylated 3'-O-phosphormidites. Alkylation is effected directly on 2,6-diaminopurine to prepare 2,6-diaminopurine 2'-O-alkylated 3'-O-phosphormidites.
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- Protection of the guanine residue during synthesis of 2'-O-alkyl-guanosine derivatives
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Highly selective 2'-O-alkylation of 3',5'-O-(tetraisopropyldisiloxane-1,3-diyl)guanosine has been achieved by using an alkyl halide and a sterically hindered strong organic base, when the 6-O atom is protected with either a 2-nitrophenyl or a tert-butyldiphenylsilyl group prior to the alkylation.A minimum of chromatography is required, the yields are high and none of the unwanted isomer is produced.Moreover, the highly versatile intermediates enable the synthesis of several new 2'-O-alkylguanosine derivatives as well as base-modified analogues.
- Groetli, Morten,Douglas, Mark,Beijer, Barbro,Garcia, Ramon Gueimil,Eritja, Ramon,Sproat, Brian
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p. 2779 - 2788
(2007/10/03)
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- A Simple Method for the Synthesis of 2'-O-Alkylguanosine Derivatives
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A new synthetic route has been devised for the preparation of 2'-O-alkyl guanosine derivatives. Utilizing a strategy of minimal protection, the alkylation was performed on partly protected guanosine using an alkyl halide and a sterically hindered strong organic base.
- Groetli, Morten,Douglas, Mark,Beijer, Barbro,Eritja, Ramon,Stroat, Brian
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p. 425 - 428
(2007/10/03)
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- 2'-O-alkylnucleotides as well as polymers which contain such nucleotides
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Oligonucleotides having the general formula, STR1 in which B denotes an arbitrary nucleobase, A equals 0 or CH2 ; X or Z equals O, S, NH or denotes CH2 whereby X and Z can be the same or different, V and W denote O, S, Se, NH2/
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- 176. Nucleosides part LXI: A simple procedure for the monomethylation of protected and unprotected ribonucleosides in the 2′-O- and 3′-O-position using diazomethane and the catalyst stannous chloride
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Intensive studies on the diazomethane methylation of the common ribonucleosides uridine, cytidine, adenosine, and guanosine and its derivatives were performed to obtain preferentially the 2′-O-methyl isomers. Methylation of 5′-O-(monomethoxytrityl)-N 2-[2-(4-nitrophenyl)ethoxycarbonyl]-O 6-[2-(4-nitrophenyl)ethyl]-guanosine (1) with diazomethane resulted in an almost quantitative yield of the 2′-nd 3′-O-methyl isomers which could be separated by simple silica-gel flash chromatography (Scheme 1). Adenosine, cytidine, and uridine were methylated with diazomethane with and without protection of the 5′-O-position by a mono- or dimethoxytrityl group and the aglycone moiety of adenosine and cytidine by the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) group (Schemes 2-4). Attempts to increase the formation of the 2′-O-methyl isomer as much as possible were based upon various solvents, temperatures, catalysts, and concentration of the catalysts during the methylation reaction.
- Cramer, Hagen,Pfleiderer, Wolfgang
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p. 2114 - 2136
(2007/10/03)
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- Nucleic acid related compounds. 36. Synthesis of the 2'-O-methyl and 3'-O-methyl ethers of guanosine and 2-aminoguanosine and correlation of O'-methylnucleoside 13C nmr spectral shifts
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A modified trimethylsilylation of guanosine (1) followed by in situ replacement of the 6-trimethylsilyloxy group with ammonia at 150 deg C gave 2,6-diamino-9β-D-ribofuranosylpurine (2) in 92percent yield.Treatment of 2 with diazomethane in the presence of tin(II) chloride dihydrate gave the 2'-O-methyl (3) and 3'-O-methyl (4) ethers of 2 in 98percent combined yield.The ratios of 3/4 could be varied from 51:47 to 34:64 by changing the amount of catalyst used.Treatment of 3 and 4 with adenosine deaminase resulted in clean conversion of these 2-aminoadenosine ethers to 2'-O-methylguanosine (5) and 3'-O-methylguanosine (6), respectively, in optimized yields of 40percent and 54percent overall from 1.The 13C nmr data for six ribonucleosides and their isomeric methyl ether derivatives have been correlated to provide a convenient method of identification.
- Robins, Morris J.,Hansske, Fritz,Bernier, Salwa E.
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p. 3360 - 3364
(2007/10/02)
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- Methylation study of ribonucleosides, deoxyribonucleosides, and 2′-O-methylribonucleosides with trimethylsulphonium hydroxide and trimethylsulphonium iodide. Influence of the 2′-hydroxy-groups on the reactivity of the base moieties of ribonucleosides
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Methylations of the naturally occuring ribonucleoside (1), deoxyribonucleoside (2), and 2′-O-methylribonucleoside (3) were carried out using trimethylsulphonium hydroxide (Me3SOH) and trimethylsulphonium iodide (Me3Sl). The base moiety of (2) and (3) are more reactive than the corresponding base moiety of (1). The sites and extent of methylation of (2) are considerably different from those of (1), but are almost identical with those of (3). The reactivities of (1)-(3) are discussed in connection to an intramolecular interaction of the 2′-OH groups with the base moiety of (1). The methylating characteristics of Me 3SOH and Me3Sl are also described. The kinetics indicate an SN2 mechanism for methylation of nucleosides by Me 3S+ ions.
- Yamauchi, Kiyoshi,Nakagima, Toru,Kinoshita, Masayoshi
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p. 2787 - 2792
(2007/10/02)
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- Methylation of Nucleosides with Trimethylsulfonium Hydroxide. Effects of Transition Metal Ions
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The effect of transition metal acetylacetonates on the methylation of ribo- and deoxyribonucleosides with trimethylsulfonium hydroxide was studied.With ribonucleosides the metal complexes promoted O'-methylation at the 2' and 3' positions of the ribosyl group.A comparable effect was not observed in methylation of deoxyribonucleosides.These results are attributed to an increase in the nucleophilicity of the 2'-OH and 3'-OH groups of the ribosides through complex formation with the metal ion; such a complex cannot form with the deoxyribose derivatives.The activity of the metal ions studied for promoting this O'-methylation increased in the order Mn2+ 2+ = Zn2+ 2+ 2+ 3+.These M(AA)n also suppressed N-methylation of the purine and pyrimidine rings of adenosine and cytidine.It is suggested that this result may be caused by coordination of the metal ions with ring nitrogens.
- Yamauchi, Kiyoshi,Nakagima, Toru,Kinoshita, Masayoshi
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p. 3865 - 3868
(2007/10/02)
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