- Stereoselective N-glycosylation with N4-acyl cytosines and efficient synthesis of gemcitabine
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Through systematical comparison of various N4-protected cytosine derivatives in the glycosylation step of gemcitabine synthesis, highly beta-stereoselective and high yielding TBAI catalyzed N-glycosylation was achieved with N4-Bz cytosine and anomeric mixture of 2,2‘-difluororibose mesylate donor. The subsequent global deprotection gave gemcitabine efficiently. Meanwhile, the anomeric chloride intermediate and fluoride-displaced side products of this N-glycosylation were identified, too. This new glycosylation method reveals the importance of N4-protection in the stereoselective preparation of pyrimidine nucleoside, also provides a potential alternative to current industrial process to gemcitabine.
- Liu, Tongchao,Tang, Jiadeng,Liang, Jianpeng,Chen, Yabin,Wang, Xiaowen,Shen, Jingkang,Zhao, Dongmei,Xiong, Bing,Cen, Jun-Da,Chen, Yue-Lei
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p. 1203 - 1213
(2019/01/29)
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- Preparation method of cytidine
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The invention provides a preparation method of cytidine 1, which comprises the following steps: (1) carrying out a condensation reaction on a compound 6 and a compound 7 in the presence of stannic chloride to generate a compound 8; (2) removing an alpha-isomer and other reaction impurities in the compound 8 to obtain the beta-isomer compound 8; and (3) carrying out a deprotection reaction on the beta-isomer compound 8 in the presence of an alcohol solvent, and then carrying out a salt forming reaction with hydrochloric acid to obtain a compound 1. The nucleoside compound 8 can be obtained withhigh beta-stereoselectivity starting from a cheap raw material 7 with a mixed anomeric carbon configuration, especially the raw material 7a, and a slightly excessive basic group 6, especially the basic group 6a; the trace alpha-compound 8 isomer impurities can be removed from the nucleoside compound 8 through a simple pulping method; and subsequently, deprotection and salifying reactions for beta-compound 8 have high yield, so that the method can reduce the production cost of the compound 1.
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Paragraph 0081-0083
(2019/12/10)
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- A general method for N-glycosylation of nucleobases promoted by (p-Tol)2SO/Tf2O with thioglycoside as donor
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Based on a preactivation strategy using the (p-Tol)2SO/Tf2O system, a series of nucleosides were synthesized by coupling various thioglycosides with pyrimidines and purines under mild conditions. High yields and excellent β-stereoselectivities were obtained with either armed or disarmed N-glycosylation donors by tuning the amount of (p-Tol)2SO additive.
- Liu, Guang-Jian,Zhang, Xiao-Tai,Xing, Guo-Wen
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supporting information
p. 12803 - 12806
(2015/08/06)
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- One-pot synthesis of acyclic nucleosides from carbohydrate derivatives, by combination of tandem and sequential reactions
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(Chemical Equation Presented) The design of processes which combine tandem and sequential reactions allows the transformation of readily available precursors into high-profit products. This strategy is illustrated by the one-pot synthesis of acyclic nucle
- Boto, Alicia,Hernandez, Dacil,Hernandez, Rosendo,Alvarez, Eleuterio
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p. 9523 - 9532
(2008/03/28)
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- The triphosphate of β-d-4′-C-ethynyl-2′,3′-dideoxycytidine is the preferred enantiomer substrate for HIV reverse transcriptase
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The enantioselective synthesis of the β-d (1) enantiomer of 4′-C-ethynyl-2′,3′-dideoxycytidine confirms an earlier stereochemical assignment that was strictly based on the ability of HIV reverse transcriptase and its M184V mutant to discriminate between t
- Siddiqui, Maqbool A.,Marquez, Victor E.
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p. 283 - 287
(2008/02/03)
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- A 4′-C-ethynyl-2′,3′-dideoxynucleoside analogue highlights the role of the 3′-OH in anti-HIV active 4′-C-ethynyl- 2′-deoxy nucleosides
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4′-C-Ethynyl-2′-deoxynucleosides belong to a novel class of nucleoside analogues endowed with potent activity against a wide spectrum of HIV viruses, including a variety of resistant clones. Although favorable selectivity indices were reported for several
- Siddiqui, Maqbool A.,Hughes, Stephen H.,Boyer, Paul L.,Mitsuya, Hiroaki,Van, Que N.,George, Clifford,Sarafinanos, Stefan G.,Marquez, Victor E.
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p. 5041 - 5048
(2007/10/03)
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- Synthesis and biological evaluation of novel thioapio dideoxynucleosides.
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On the basis of the bioisosteric rationale to apio dideoxynucleosides, novel thioapio dideoxynucleosides have been synthesized, starting from 1,3-dihydroxyacetone via thioapio sugar acetate as a key intermediate. The intermediate was condensed with silylated pyrimidine bases such as N(4)-benzoylcytosine, uracil or thymine in the presence of TMSOTf to give the beta-anomers and alpha-anomers, respectively. The intermediate was also condensed with silylated 6-chloropurine to give the 6-chloropurine derivatives and which were converted to adenine derivatives and, N(6)-methyladenine derivatives and, and hypoxanthine derivatives and, respectively. The guanine analogues and were also synthesized from the condensation of sugar acetate with 2-acetamido-6-chloropurine. All synthesized final compounds were tested against HIV-1. Most of the synthesized compounds exhibited toxicity-dependent anti-HIV-1 activity, among which 6-chloropurine derivative was found to be the most cytotoxic and showed good cytotoxicity against colon cancer cell lines. Although we could not find good anti-HIV agents in this study, findings of some anticancer activity in this series will allow this class of nucleosides to be the new template for the development of new anticancer agents (Fig. 1).
- Moon, Hyung Ryong,Kim, Hea Ok,Lee, Sang Kook,Choi, Won Jun,Chun, Moon Woo,Jeong, Lak Shin
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p. 1499 - 1507
(2007/10/03)
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- 2′-C-branched ribonucleosides. 2. Synthesis of 2′-C-β-trifluoromethyl pyrimidine ribonucleosides
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(matrix presented) The first synthesis of 2′-C-β-trifluoromethyl pyrimidine ribonucleosides is described. 1,2,3,5-Tetra-O-benzoyl-2-C-β-trifluoromethyl-α-D-ribofuranose (3) is prepared from 1,3,5-tri-O-benzoyl-α-D-ribofuranose (1) in three steps and converted to 3,5-di-O-benzoyl-2-C-β-trifluoromethyl-α-D-1-ribofuranosyl bromide (5). The 1-bromo derivative (5) is found to be a powerful reaction intermediate for the synthesis of ribonucleosides. The reaction of silylated pyrimidines with (5) in the presence of HgO/HgBr2 affords exclusively the β-anomers (6-8). Deprotection of (6-8) with ammonia in methanol yields the 2′-C-β -trifluoromethyl nucleosides (9-11).
- Li, Nan-Sheng,Tang, Xiao-Qing,Piccirilli, Joseph A.
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p. 1025 - 1028
(2007/10/03)
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- 2'-C-branched ribonucleosides: Synthesis of the phosphoramidite derivatives of 2'-C-β-methylcytidine and their incorporation into oligonucleotides
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We describe a strategy for the incorporation of a 2'-C-branched ribonucleoside, 2'-C-β-methylcytidine, into oligonucleotides via solid- phase synthesis using phosphoramidite derivatives. 4-N-Benzoyl-2'-C-β- methylcytidine (2b) was synthesized by coupling persilylated 4-N- benzoylcytosine with 1,2,3,5-tetra-O-benzoyl-2-C-β-methyl-α-(and β)-D- ribofuranose (1) in the presence of SnCl4 in acetonitrile, followed by selective deprotection with NaOH in pyridine/methanol. The 3'- and 5'- hydroxyl groups were blocked as a cyclic di-tert-butylsilanediyl ether 3 by treatment with di-tert-butyldichlorosilane/AgNO3 in DMF. The 2'-hydroxyl group was then protected as a tert-butyldimethylsilyl ether 4a by treatment with tert-butylmagnesium chloride followed by addition of tert- butyldimethylsilyl trifluoromethanesulfonate in THF. As an alternative to 2'- silyl protection, the corresponding 2'O-tetrahydropyranyl ether 4b was prepared by treatment of 3 with 4,5-dihydro-2H-pyran in the presence of a catalytic amount of 10-camphorsulfonic acid in methylene chloride. The di- tert-butylsilanediyl groups of 4a and 4b were removed by treatment with pyridinium poly(hydrogen fluoride) to afford 5a and 5b, respectively. Protection of the 5'-hydroxyl group as a dimethoxytrityl ether and phosphitylation of the 3'-hydroxyl group by the standard procedure gave the phosphoramidite derivatives 7a and 7b. Both 7a and 7b could be used to incorporate 2'-C-β-methylcytidine into oligonucleotides efficiently via standard solid-phase synthesis, but the tetrahydropyranyl group of 7b was more readily removed from oligonucleotides than the tert-butyldimethylsilyl group of 7a. Oligonucleotides containing 2'-C-β-methylcytidine undergo base- catalyzed degradation analogous to natural RNA.
- Tang, Xiao-Qing,Liao, Xiangmin,Piccirilli, Joseph A.
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p. 747 - 754
(2007/10/03)
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- Synthesis of thymine, cytosine, adenine, and guanine containing N-Fmoc protected amino acids: Building blocks for construction of novel oligonucleotide backbone analogs
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A convenient synthesis is described for thymine, cytosine, adenine, and guanine containing, glucosamine-based N-Fmoc protected amino acids. These molecules are building blocks for the construction of novel oligonucleotide analogs via N-Fmoc type peptide chemistry.
- Goodnow Jr., Robert A.,Richou, Anne-Roberte,Tam, Steave
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p. 3195 - 3198
(2007/10/03)
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- Synthesis of 2'-C-α-methyl-2',3'-dideoxynucleosides
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A general method for the synthesis of 2'-C-α-methyl-2',3'-dideoxynucleosides is presented. Stereofacial selectivity of the 2-C-methylation reaction of γ-lactone has been investigated, in which the presence of a bulky group at the 5-hydroxymethyl produced the α-isomer as a major product. During glycosylation, the α-methyl group directed the formation of nucleosides in favor of the β-isomer. This methodology is applied to the synthesis of some new pyrimidine and purine nucleosides.
- Giri,Bolon,Chu
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p. 183 - 204
(2007/10/03)
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