3’-Deoxy nucleoside

All NRTIs, as exemplified for AZT (Fig. 7), act in a similar fashion following their uptake by the cells, they are phosphorylated successively to their 5 -monophosphate, 5 -diphosphate, and 5 -triphosphate form (De Clercq 2002). Unlike the first phosphorylation step in the metabolic pathway of the acyclic guanosine analogues (see above), which is carried out by a virus-encoded enzyme (thymidine kinase), the first as well as the subsequent phosphorylations of the 2, 3 -dideoxynucleosides are carried out by cellular enzymes, that is, a 2 -deoxynucleoside (e.g., dThd) kinase, a 2 -deoxynucleotide (e.g., dTMP) kinase, and a (2 -deoxy)nucleoside 5 -diphosphate (NDP) kinase. 

Lewis, M. A. Graff Yoerg, D. Bolton, J. L. Thompson, J. A. Alkylation of 2 -deoxy-nucleosides and DNA by quinone methides derived from 2,6-di-tert-butyl-4-methyl-phenol. Chem. Res. Toxicol. 1996, 9, 1368-1374. 

Otherwise, compound 30, and differently 0-substituted analogues, can be made efficiently from O-protected 2-deoxy nucleosides. Heating thymidine diether 29 in refluxing 1,1,1,3,3,3-hexamethyldisalazene in the presence of ammonium sulfate under an inert atmosphere gives 30 in 47% overall yield from the nucleoside. A notable feature of this approach is that thymidine itself can be converted directly to the unprotected parent of diether 30 with 80% efficiency.26... 

The 2 -phenyl-2 -selenoglycopyranosyluracil derivatives obtained by this method were efficiently transformed into the corresponding 2 -deoxy nucleosides by tri-n-butyltin hydride. 

The levulinoyl esters are prepared from the free hydroxyl group by treatment of levulinic acid with DCC [255,256] or l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC) [257] in the presence of DMAP (O Scheme 38). Additionally, 3 - and 5 -0-levulinyl protected derivatives of 2 -deoxy nucleosides have been prepared by regioselective enzymatic acylation using a variety of lipases and acetonoxime levulinate as acylating agent [258]. In contrast to other ester substituents, the 0-levulinoyl group is far less prone to migration [259]. 

A novel solid phase method for the synthesis of 2 -amino-2 -deoxynucleoside 5 -triphosphates has been developed in which the 3 -azidonucleoside precursors are first linked to support-bound triphenylphosphine as their phosphinimines 116. Following conversion into the triphosphate, the desired 2 -amino-2 -deoxy-nucleoside 5 -triphosphates are released from the support by treatment with ammonia in the Staudinger reaction. ... 

A method using polyvinylpyridinium hydrofluoride (PVPHF), as fluoride source, at low temperature was suitable for the relatively sensitive 2-deoxy-nucleosides. This low temperature reaction was probably successful due to the instability, i.e. high reactivity, of diazonium salts at the a-position of azines, and may not be general for other heterocycles. 

S-ethyl-3-thio-D-xt/Zo isomer, and Raney nickel desulfurization of 6-amino-9- (2-first synthesis of a naturally occurring purine 2-deoxy-nucleoside to be reported. A number of nucleoside analogs were prepared by modification of the purine moiety before desulfurization. ... 

Chiral 2, 3 -. eco-2 -deoxy nucleosides were conveniently prepared from uridine 75 (R = OH) and its analogue l-(a-D-ara/)/rtofuranosyl) uracil. The 3, 5 -dihydroxy groups in 2, 3 -5m )-uridine 77 or 82, obtained from 76 or... 

Regioselective debenzoylation of nucleoside 2, 3 5-tri-O-benzoates using hydrazine hydrate has been reported. With 1 mol reagent in acetic acid-pyridine the 3 5-di-O-benzoyl derivative was produced when the bases were adenine, guanine, or indole, whereas with excess hydrazine hydrate in 1 1 chloroform-methanol, 98% of the 5-O-benzoyl derivative was produced (base = adenine or uracil). 3, 5-Di-O-benzoyl-2-deoxy-nucleosides gave a 90% yield of a 1 1 mixture of 3 - and 5-O-benzoyl nucleosides with 1 mol hydrazine hydrate in pyridine. Treatment of the mannose orthoacetate (5) with benzoyl chloride in pyridine gave 2,3,4,6-tetra-O-acetyl-a-D-mannopyranosyl chloride and ethylbenzoate, whereas the related orthoester of mu co-inositol (6) gave 66% of the correspond-... 

In view of screening the structural and functional properties of deox-yoligonucleotides incorporating 3, 5 -bicyclic 2-deoxy nucleosidic building blocks, Leumann developed a synthetic sequence to prepare the thymine-based phosphoramidite (11) in which the bicyclic system incorporates a 5-membered ring ribose adjacent to a six-membered carbocyclic ring. In this isomer, the cyclohexyl ring adopted a chair conformation with the 5 -substituent in an axial position while the furanoside moiety adopted a... 

Other references to nucleoside antibiotics, including microbial synthesis of 2 -amino-2 -deoxy-nucleosides and Ara-A, the synthesis of oc-2 -deoxynucleosides, and the synthesis of radio-labelled... 

Treatment of (2 -deoxy)nucleoside derivatives of type 197 with pyrc hosphate anitm, followed by aqueous ammcMiia, gives access u> (deoxy)nucleoside 5 -0-(l,l-didiiotripho ates) (see VoL 25, p. 267 for earlia woik).237... 

The arabinofuranosyl nucleoside (17) has been prepared by oxidation-reduction from the analogous D-n i o-compound, and the 2 -deoxy nucleoside was also reported.3 4... 

H and C n.m.r. spectra of O- and N-methylated 2 -deoxy-nucleosides have been recorded, and n.m.r. measurements together with U.V. data used to investigate the pH dependence of their stability. 0 n.m.r. data have been used to study hydration equilibria of nucleoside-water complexes 2, 3 -0-isopropylidene uridine enriched at either 0-4 or 0-2 with 0 showed that hydration occurs more extensively with the 4-carbonyl group, and both mono- and di-hydrates are formed. 

As usual, standard syntheses of nucleotides are not included in this survey. 5 -(B-D-Glucopyranosyl) monophosphates of nucleosides and 2 -deoxy-nucleosides have been synthesized by orthoester glycosylation of the 5 -phosphates. Deoxy-nucleoside 5 -monophosphates have been prepared from unprotected nucleosides by treatment with phosphorus oxychloride in trialkyIphosphite followed by incubation with nuclease PI, which cleaves the... 

Much of our effort has been directed toward the development of procedures that yield 2 -deoxynucleoside 3 -phosphorothioamidites in high yield and free of impurities. Since these monomers cannot be purified via the column chromatography procedures that are used for the standard 2 -deoxynucleoside 3 -phosphoramidites, reaction conditions are required whereby these monomers can be obtained free of unwanted and reactive byproducts. Using conditions similar to those previously developed in this laboratory (17,18), a one-pot, two-step synthesis has been devised (Scheme 1). Phosphitylation is achieved with tris(pyrrolidino)phosphine under tetrazole catalysis to give a bis-(pyrrolidino)phosphite intermediate. Without isolation, this intermediate is converted to the phosphorothioamidite product by treatment with monobenzoylethanedithiol and additional tetrazole. After an aqueous work-up to remove tetrazole and tetrazolide salts, the 2 -deoxy-nucleoside 3 -phosphorothioamidite is isolated by precipitation from heptane in very good yields (90% at 90-95% purity by P-NMR). The precipitation step removes excess thiol and phosphines, while yielding the synthons as stable powders. 

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