Thymidine, 2,5 -anhydro

C24H25NO 127927-43-9) see Saquinavir tris(trimethylsilyloxy)ethylene (CiiH2g03Si3 69097-20-7) see Saquinavir (-)-(S)-l-trityl-2-(aminomethyl)pyrrolidine (C24H26N2 98598-84-6) see Remoxipride 5 -0-trityl-2,3 -anhydro thymidine (C29H24N2O4 25442-42-6) see Zidovudine trityl chloride... 

Deoxy-3 -fluorothymidine (813), a selective inhibitor of DNA synthesis, was prepared " in moderate yields from 3 -0-mesyl- or 3, 5 -di-O-mesyl-thymidine, through 2,3 -anhydro-1 -(2-deoxy- -D-t/2reopentofur-anosyl)thymine (808), by treatment with hydrogen fluoride (0.1% HF in l,4-dioxane-AlF3, 3.764 hf in DMF-AlFj, or 10% HF in DMF ),... 

C. Wodarski, J. Eisenbarth, K. Weber, M. Henze, U. Haberkorn, M. Eisenhut, Synthesis of 3 -deoxy-3 -[F-18]fluoro-thymidine with 2,3 -anhydro-5 -0-(4,4 -dimethoxytrityl)thymidine, J. Label. Compds Radiopharm. 43 (2000) 1211-1218. 

Despite the fact that secondary hydroxyl groups of nucleosides also react with 23 (see later), selective iodination of only the primary hydroxyl group in some unprotected, pyrimidine nucleosides can also be achieved.82 Thus, brief treatment of thymidine with 1.1 mol-equivalents of 23 in N,N-dimethylformamide gave crystalline 5 -deoxy-5 -iodothymidine in 63% yield. It was even possible to effect some selective iodination of the 5 -hydroxyl group of 2,2 -anhydrouri-dine without excessive cleavage of the (quite labile) anhydro linkage. 

Di-0-(methanesulfonyl)thymidine (248 g, 0.62 M) was added in portions to a stirred solution of sodium hydroxide (74.7 g, 1.87 M) in water (1.6 L). On addition the reaction mixture became a yellow-orange solution. This stirred solution was then heated to reflux for 2 h. Once the reaction mixture had cooled to room temperature, 6 N hydrochloric acid (100 ml) was added. The reaction mixture was concentrated in vacuo by removing 1.3 L of water. The resulting slurry was cooled in an ice bath for 2 h. The solid was then filtered and washed sparingly with ice water, and then vacuum dried to constant weight (103.7 g, 74%). The l-(3,5-anhydro-2-deoxy-p-D-threo-pentofuranosyl)thymine, melting point 188°-190°C (lit. 190°-193°C) was used without further purification. 

Anhydronucleosides are usually prepared from appropriate mono- or di-sulfonates [1]. l-(2-Deoxy-3,5-anhydro)- -D-r/ireo-pentosylthymine (96), an example of the oxetane-type of anhydronucleoside, was prepared from dimesyl thymidine by the action of an alkali. The first synthesis of 2, 3 -dideoxy-2, 3 -didehydro-thymidine (d4T) was accomplished in 1966 by Hor-witz et al. from this compound, which can be now prepared in quite large scale according to a slightly modified procedure proposed by the group from Bristol-Myers. The 5 -tritylated derivative of 3 -0-mesyl-thymidine was converted into 3, 2-anhydroucleoside 95, from which... 

In order to preserve optimal stability in the hybridization of RNA by sugar-modified oligonucleotides, nucleosides substituted at the 2 -position must retain a C3 -endo puckered conformation. To this end, the 2 -0- 2-[iV,N-(dimethylamino)oxy]ethyl and the 2 -0- 2-[Ar,lV-(diethylamino)oxy]-ethyl 3 -phosphoramidite derivatives of thymidine (38a, 38b) have been synthesised. The nucleoside precursors were prepared from a phthalimido-derivative obtained from 2,2 -anhydro-5-methyluridine which had been treated, after appropriate protection, with a borate ester generated in situ and then reacted with PPha, DEAD and AT-hydroxyphthalimide. The incorporation of (38a) and (38b) in oligonucleotides and oligodeoxynucleotides resulted in high binding affinity for... 

Sodium ferf-butoxide in N,N-dimethylformamide at KXP was found to be very effective in promoting intramolecular displacements408 and 2,5 -anhydrothymidine was obtained directly from 5 -0-(methyl-sulfonyl)thymidine with these reagents. The same conditions have also been used to synthesize the anhydronucleosides 121 and 122 from a pseudouridine derivative408 and from a D-ribosyl derivative of 2,4-quinazolinedione.410 The same reagents with 3 -0-p-tolylsulfonyl-uridine gave mainly 1 -(2,3 -anhydro-y3-D-xylofuranosyl)uracil.408... 

The favored, intramolecular displacement at C-3 in the presence of a 5 -methylsulfonyloxy group, observed402 with 3, 5 -di-0-(methyl-sulfonyl)thymidine (115), was also evident in the formation,3 from l-[2,3,5-tri-0-(methylsulfonyl)-/3-D-arabinofuranosyl]uracil (144), of 2,3 - anhydro -1 - [2,5 - di - O (methylsulfonyl) -/3-D-lyxofuranosyl]uracil (145). 

The first example of a pyrimidine anhydronucleoside containing an imino bridge was prepared by treatment of 2,5 -anhydro-3 -0-(methylsulfonyl)thymidine (152) with liquid ammonia at room temperature.422 Under these reaction conditions, displacement of the 3 -methylsulfonyloxy group of the presumed isocytidine intermediate... 

Wittig methylenation of 3,5-di-0-benzyl-2-deoxy-D-erythrofuranose then reaction with MCPBA-boron trifluoride etherate afford 2,5-anhydro-4,6-di-0-benzyl-3-deoxy-D-ribohexitol. Mesylation of the latter followed by addition of the anion derived from adenine, furnished derivative 11. Cytidine and thymidine could be treated in a similar manner and de-O-benzylated by standard methods. Structures were verified by X-ray analysis. ... 

There has been a fuller account given of the formation of the 2,2 -anhydro-system 18 ftom the 2, 3 -ene by treatment with N-bromoacetamide (see Vol. 26, p. 227). Treatment of 18 with NaOH in acetone formed the D-Zyro-epoxide 19. When the xylose-derived nucleoside 20 was treated with diphenyl carbonate and NaHCOs, the 2,2 -anhydronucleoside 21 was obtained, and it was proposed that the mechanism of this process proceeded through the 3 ,5 -cyclic carbonate and the 2, 3 -ribo-epoxide as intermediates. Treatment of 21 with pyridinium bromide followed by hydrogenolysis gave thymidine. The oxazoline 22 can be used as a precursor of various 5-substituted 2,2 -anhydrouridine derivatives, as in the case shown in Scheme 2. The... 

The 1-deoxypsicofuranosyl nucleoside 14 has been converted to the 1,3,4-trideoxy-derivative by stepwise deoxygenations, and 2, 5 -dideoxy-5-fluorouridine (45) has been made by trans-glycosylation of 5 -deoxythymidine using thymidine phosphorylase. The anhydro-thionucleoside 46 was prepared by intramolecular glycosidation (see Vol. 8, p. 149 for a similar case), and on treatment with Raney nickel gave the 2, 5 -dideoxynucleoside 47. 2... 

L-Ascorbic acid can be converted to the separable epimers 219 and 220 (Scheme 22) sequential oxidative degradation of each of them then gave routes to both the L-(-)- and D-(+)-enantiomers, 221 and 222 respectively, of dioxolane-C, together with the a-anomers.306 Other workers have also describe fully the synthesis of 222 and its thymidine analogue firom 1,6-anhydro-D-mannose (see Vol. 25, p. 211), and have used a similar approach, with 1,6-anhydro-L-gulose as precursor, to L-(-)-dioxolane-C 221, and to L-(+)-dioxolane-T. The L-(-)-isomer 221 of dioxolane-C was found to have higher antiviral activity against HIV and hepatitis B virus than the enantiomer... 

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