- A short de novo synthesis of nucleoside analogs
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Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of D- or L-nucleoside analogs, locked nucleic acids, iminonucleosides, and C2′- and C4′-modified nucleoside analogs. This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.
- Adluri, Bharanishashank,Britton, Robert,Campeau, Louis-Charles,Cohen, Ryan,Lehmann, Johannes,Meanwell, Michael,Silverman, Steven M.,Wang, Yang
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p. 725 - 730
(2020/09/02)
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- Synthesis method of beta-thymidine
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The invention discloses a synthesis method of beta-thymidine. The synthesis method takes trimethylchlorosilane and 5-methyluracil as raw materials to react; in a reaction line process, tetraacetylribose, trifluoromethanesulfonic acid, N,N-dimethylformamide and acetylchloride are introduced; then hydrogenation reaction and hydrolysis reaction are carried out to finally obtain a beta-thymidine finished product and the yield is 89 percent. Compared with an existing synthesis method, the synthesis method of the beta-thymidine has the advantages that the price of raw materials is low, the content of the beta-thymidine in the final product is high, and pollution to the environment in a production process is small; in a synthesis process, the content of generated impurities is less. According to the synthesis method disclosed by the invention, an obtained result is stable and the operation is simple; demands on equipment and preparation environments are not strict so that large-scale popularization is facilitated.
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Paragraph 0039; 0040
(2017/08/14)
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- Antifreeze protein-induced selective crystallization of a new thermodynamically and kinetically less preferred molecular crystal
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The formation of a new, dihydrate crystalline form of 5-methyluridine (m5U) was selectively induced by a protein additive, antifreeze protein (AFP) in a highly efficient manner (in 10-6molar scale, whereas known kinetic additives nee
- Wang, Sen,Wen, Xin,Golen, James A.,Arifin, Josh F.,Rheingold, Arnold L.
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p. 16104 - 16112
(2014/04/03)
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- An integrated chemo-enzymatic route for preparation of β-thymidine, a key intermediate in the preparation of antiretrovirals
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A chemo-enzymatic method for production of β-thymidine, an intermediate in the synthesis of antiretrovirals, is described. Guanosine and thymine were converted by means of enzymatic transglycosylation to yield 5-methyluridine (5-MU), which was reproducibly synthesised at a 10-20-L scale in 85% yield at a final product concentration of ～80 g?L-1. A downstream processing (DSP) protocol was designed to remove reaction components interfering with the subsequent synthetic step. The crystallised 5-MU produced in the biocatalytic reaction was found to behave similarly to commercially available 5-MU, and the integration of the initial biocatalytic and subsequent three-step chemical process to β-thymidine was successfully demonstrated at bench scale.
- Gordon, Gregory E. R.,Bode, Moira L.,Visser, Daniel F.,Lepuru, M. Jerry,Zeevaart, Jacob G.,Ragubeer, Nasheen,Ratsaka, Molala,Brady, Dean,Walwyn, David R.
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experimental part
p. 258 - 265
(2011/10/04)
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- Synthesis and anti-viral activity of a series of D- and l-2′-deoxy-2′-fluororibonucleosides in the subgenomic HCV replicon system
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Based on the discovery of (2′R)-D-2′-deoxy-2′- fluorocytidine as a potent anti-hepatitis C virus (HCV) agent, a series of D- and L-2′-deoxy-2′-fluororibonucleosides with modifications at 5- and/or 4-positions were synthesized and evaluated for their in vitro activity against HCV and bovine viral diarrhea virus (BVDV). The key step in the synthesis, the introduction of 2′-fluoro group, was achieved by either fluorination of 2,2′-anhydronucleosides with hydrogen fluoride-pyridine or potassium fluoride, or a fluorination of arabinonucleosides with DAST. Among the 27 analogues synthesized, only the 5-fluoro compound, namely (2′R)-D-2′-deoxy-2′,5-difluorocytidine (13), demonstrated potent anti-HCV activity and toxicity to ribosomal RNA. The replacement of the 4-amino group with a thiol group resulted in the loss of activity, while the 4-methylthio substituted analogue (25) exhibited inhibition of ribosomal RNA. As N4-hydroxycytidine (NHC) had previously shown potent anti-HCV activity, we combined the two functionalities of the N4-hydroxyl and the 2′-fluoro into one molecule, resulting (2′R)-D-2′-deoxy- 2′-fluoro-N4-hydroxycytidine (23). However, this nucleoside showed neither anti-HCV activity nor toxicity. All the L-forms of the analogues were devoid of anti-HCV activity. None of the compounds showed anti-BVDV activity, suggesting that the BVDV system cannot always predict anti-HCV activity.
- Shi, Junxing,Du, Jinfa,Ma, Tianwei,Pankiewicz, Krzysztof W.,Patterson, Steven E.,Tharnish, Phillip M.,McBrayer, Tamara R.,Stuyver, Lieven J.,Otto, Michael J.,Chu, Chung K.,Schinazi, Raymond F.,Watanabe, Kyoichi A.
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p. 1641 - 1652
(2007/10/03)
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- Anti-HCV nucleoside derivatives
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The present invention comprises novel and known purine and pyrimidine nucleoside derivatives which have been discovered to be active against hepatitis C virus (HCV). The use of these derivatives for the treatment of HCV infection is claimed as are the novel nucleoside derivatives disclosed herein.
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- Synthesis of peracylated derivatives of L-ribofuranose from D-ribose and their use for the preparation of β-L-ribonucleosides
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A practical synthesis of peracylated derivatives of β-L-ribofuranose 13-15 from D-ribose was accomplished in 6 steps (total yield: 30-45percent). Compound 13 was employed for the preparation of 1-(β-L-ribofuranosyl)thymine (16) and -cytosine (17), which are key intermediates for the preparation of the nucleoside derivatives with β-L-configuration. Simultaneous transformation of 17 into β-L-ddC (19) and β-L-3′dC (20) was studied.
- Sivets, Grigorii G.,Klennitskaya, Tatjana V.,Zhernosek, Elena V.,Mikhailopulo, Igor A.
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p. 253 - 259
(2007/10/03)
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- A stereospecific synthesis of L-deoxyribose, L-ribose and L-ribosides
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Using an inexpensive D-galactose from the chiral pool, L-deoxyribose, L-ribose and their derivatives were synthesized via mild reaction conditions. During the synthesis of L-deoxyribose, the key deoxygenation of the 2-hydroxy group of 3,5-O-dibenzyl-methyl-L-arabinofuranoside was performed by reduction of the corresponding triflate with tetrabutylammonium borohydride in high yield. During the synthesis of L-ribose, the key step of inversion of the 2-hydroxy group in the same substrate was carried out by intramolecular SN2 tandem reaction. Then the L-ribosyl donors were submitted to glycosidations according to Vorbrüggen's conditions to give L-ribosides (L-uridine, L-5-fluorouridine, L-iodouridine, L-thymidine, L-puridine, L-adenosine and L-guanosine) in excellent yields.
- Shi, Zhen-Dan,Yang, Bing-Hui,Wu, Yu-Lin
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p. 3287 - 3296
(2007/10/03)
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- A stereospecific synthesis of L-ribose and L-ribosides from D-galactose
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An inexpensive D-galactose was converted into L-ribose and its derivatives via mild reaction conditions. The L-ribosyl donor was submitted to a glycosidation according to Vorbrüggen's conditions to give L-ribosides in high yields.
- Shi, Zhen-Dan,Yang, Bing-Hui,Wu, Yu-Lin
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p. 7651 - 7653
(2007/10/03)
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- Synthesis and enzymatic digestion of an RNA nonamer in both enantiomeric forms
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The D- and L-RNA nonamers of the sequence r(GCUUCGGC)T have been synthesised for X-ray crystallographic purposes. In vitro digestion of the unnatural optical antipode by snake venom phosphodiesterase I takes place at an approximately 1800-fold slower rate than that of the natural D-nonamer. The digestion experiments showed - to our knowledge for the first time - that L-RNA can indeed be cleaved enzymatically when phosphodiesterase I from snake venom is used - as opposed to a number of cellular ribonucleases - which sheds an interesting light on the evolution and possibly structure/function relationship of venom versus cellular degradation enzymes. The broad substrate specificity of this enzyme could be taken advantage of to study and further optimise the resistance towards biodegradation of therapeutic L-RNA aptamers. (C) 2000 Elsevier Science Ltd.
- Moyroud, Elisabeth,Biala, Ewa,Strazewski, Peter
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p. 1475 - 1484
(2007/10/03)
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