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4) Reaction of thymine (IX) with 1-O-acetyl-2,3,5-tri-O-benzoylribose (X) and hexamethyldisilazane, trimethylsilyl chloride and trifluoromethanesulfonic acid in acetonitrile, followed by cleavage of the protecting groups with sodium methoxide in methanol gives 5-methyluridine (XI). Compound (XI) is converted to (XII) by means of 2-acetoxyisobutyryl bromide in acetonitrile, subsequent reaction of (XII) with zinc-copper in dimethylformamide yields (XIII), which is finally deprotected with sodium methoxide in methanol. 5) 5-Methyluridine (XI) can also be converted to (XIV) by means of trimethylorthoacetate in acetic acid. Compound (XIV) is then treated with hydrobromic acid to give (XV), which is treated with zinc in acetonitrile and EDTA or is successively treated with acetic anhydride, zirconium oxide and tributylamine.

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Other methods based on the modification of carbohydrates have also been described: 7) Protection of readily available (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (XIX) with tert-butyldiphenylsilyl chloride gives ether (XX), which is converted to the seleno derivative (XXI) on treatment with lithium hexamethyldisilazide and trimethylchlorosilane in tetrahydrofuran, followed by reaction with phenylselenylbromide. Reduction of (XXI) with diisobutylaluminum hydride in toluene followed by acetylation gives compound (XXII), which is reacted with (XXIII) and trimethylsilyltriflate in dichloroethane to afford stereoselectively compound (XXIV). The latter is finally submitted to elimination and deprotected by successive treatment with hydrogen peroxide in pyridine and tetrabutylammonium fluoride in tetrahydrofuran. 8) A related route involves treatment of (XX) with lithium diisopropylamide in tetrahydrofuran and diphenylsulfide in HMPA to give (XXV), which is reduced and acetylated to yield (XXVI). Compound (XXVI) is treated with (XXIII) in the presence of tin tetrachloride in dichloromethane to afford (XXVII), which is oxidized with sodium periodate and submitted to elimination by treating in toluene-pyridine, to yield compound (XXVIII). Finally, compound (XXVIII) is deprotected with tetrabutylammonium fluoride in tetrahydrofuran. 9) A third procedure begins with the protection of (XIX) as a tert-butoxycarbonyl ester to yield (XXIX), reduction with diisobutylaluminum hydride in tetrahydrofuran to afford (XXX) and elimination after treatment with thionyl chloride in dichloromethane and potassium tert-butoxide in tetrahydrofuran to give (XXXI). Subsequent reaction of compound (XXXI) with thymine (IX) in the presence of hexamethyldisilazane and trimethylsilyl chloride and N-chlorosuccinimide in tetrahydrofuran gives compound (XXXII), which is treated with potassium tert-butoxide in tetrahydrofuran and deprotected with sodium methoxide in methanol.

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A new synthesis of stavudine has been reported: The condensation of thymine (I) with methyl 2-deoxyribofuranoside (II) by means of N-bromosuccinimide (NBS) followed by protection with TBDPS-Cl gives the intermediate (III), which is cyclized by means of trimethylsilyl triflate (TMS-OTf), yielding the cyclothymidine derivative (IV). The deprotection of (IV) with tetrabutylammonium fluoride affords the unprotected compound (V), which is finally treated successively with triflate anhydride, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and Zn/acetic acid. The unprotected intermediate compound (V) can also be obtained by cyclization of thymidine (VI) by means of NBS in DMF, catalyzed by trifluoroacetic acid.

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The synthesis of [1'-14C]-labeled stavudine has been published: The reaction of labeled D-ribofuranose (I) first with methanol and acetyl chloride and then with benzoyl chloride gives 2,3,5-tri-O-benzoyl-1-O-methyl-D-ribofuranoside (II), which is acetylated with acetic anhydride and acetic acid to 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranoside (III). The condensation of (III) with thymine (IV) by means of hexamethyldisylazane (HMDS), trimethylsilyl chloride (TMS-Cl) and trifluoromethanesulfonic acid, followed by a basic hydrolysis with NaOMe affords 1-(beta-D-ribofuranosyl)thymine (V), which is treated with methanesulfonyl chloride in pyridine giving the trimesylate (VI). The reaction of (VI) with sodium benzoate in hot DMF yields the benzoylated internal ether (VII), which is treated with acetyl bromide in acetic acid/HBr affording 1-[2-bromo-2-deoxy-5-O-benzoyl-3-O-(methanesulfonyl)-beta-D-ribofuranos yl]thymine (VIII). The reaction of (VIII) with Zn in the same solvent as before gives 5'-O-benzoylstavudine (IX), which is finally debenzoylated with NaOCH3 in methanol.

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A new synthesis of clevudine has been described: Peracetylation of L-arabinose (I) with acetic anhydride and pyridine provides acetylated arabinose (II), which is then brominated by means of HBr in AcOH/Ac2O to furnish the bromo-sugar (III). Treatment of the sugar (III) with Zn dust, CuSO4 and NaOAc in AcOH/H2O, followed by chromatographic separation, gives L-arabinal (IV), which is then converted to the fluoro derivative (V) by reaction with Selectfluor?(F-TEDA-BF4) in refluxing nitromethane/H2O. Deacetylation of compound (V) with NaOMe in MeOH yields compound (VI), which is then converted into the methyl furanoside (VII) by treatment with H2SO4 in MeOH. Benzoylation of the furanoside (VII) with benzoyl chloride in pyridine affords a mixture of isomers, from which (VIII) is separated by chromatography and then brominated with HBr/AcOH in CH2Cl2 to provide the bromo-sugar (IX). Condensation of the sugar (IX) with the silylated pyrimidine derivative (X) in refluxing chloroform affords 3,5-di-O-benzoylclevudine (XI), which is finally deprotected by treatment with n-butylamine in refluxing methanol. Compound (X) is obtained by treatment of thymine (XII) with HMDS (1,1,1,3,3,3-hexamethyldisilazane) and ammonium sulfate in refluxing chloroform.

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The condensation of 2-nitrophenol (I) with 2,2,2-trrifluoroethyl p-toluenesulfonate (II) by means of K2CO3 in DMF gives 2-(2,2,2-trifluoroethoxy) nitrobenzene (III), which isreduced with H2 over PtO2 in ethanol yiedling the aniline (IV). The cyclization of (IV) with bis (2-chloroethyl)amine (V) and K2CO3 affords the piperazine (VI), which is condensed with 1-benzyl-3-(3-chloro-propyl)-5-methylpyrimidine-2,4(1H,3H)-dione (VII) by means of K2CO3 in refluxing acetonitrile to give the benzylated target compound (VIII). Finally, this compound is deprotected by hydrogenation with ammonium formate and Pd/C. The intermediate pyrimidine (VII) has been obtained by benzylation of thymine (IX) with benzyl bromide and K2CO3 to give the 1-benzylthymine (X), which is alkylated with 1-bromo-3-chloropropane and K2CO3 to the target intemediate (VII).

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5-Methyluracil (VII) was protected with SEM-Cl (VIII) to yield the 1-SEM derivative (IX), which was subsequently alkylated with 1-bromo-3-chloropropane (X) under phase-transfer conditions to provide chloride (XI). Alkylation of piperazine (VI) with chloride (XI) in the presence of NaI and K2CO3 furnished adduct (XII). The title compound was then obtained by deprotection of (XII) upon treatment with tetrabutylammonium fluoride in THF.

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In a different protection strategy, sulfonylation of 5-methyluracil (VII) by means of p-toluenesulfonyl chloride under Schotten-Baumann conditions furnished the 1-tosyl derivative (XIII). This was condensed with 1-bromo-3-chloropropane (X), yielding chloride (XIV). Removal of the tosyl protecting group of (XIV) by hydrolysis with H2SO4 afforded 3-(3-chloropropyl)-5-methyluracil (XV). Finally, alkylation of piperazine (VI) with chloride (XV) led to the title compound.

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The reaction of L-arabinose (I) with acetic anhydride and HBr gives tri-O-acetyl-b-L-arabinopyranosyl bromide (II), which is treated with Zn and Cu-Zn couple in aqueous AcOH to yield 3,4-di-O-acetyl-L-arabinal (III) (1). Reaction of compound (III) with HCl followed by treatment with refluxing methanol affords methyl 3,4-di-O-acetyl-2-deoxy-L-riboside (IV), which is deacetylated by means of NaOMe in methanol to provide methyl 2-deoxy-L-riboside (V). Reaction of riboside (V) with benzoic acid gives 2-deoxy-L-ribofuranose (VI), which, alternatively, can be obtained directly from diacetate (III) by treatment with aqueous HClO4 in AcOH/Ac2O. Reaction of ribofuranose (VI) with p-toluoyl chloride and methanol gives methyl 3,4-di-O-toluoyl-2-deoxy-L-riboside (VII), which is demethylated with HCl to yield 3,4-di-O-toluoyl-2-deoxy-L-ribose (VIII). Acylation of the ribose (VIII) with Ac2O and pyridine affords 1-O-acetyl-3,4-di-O-toluoyl-2-deoxy-L-ribose (IX), which is treated with HCl to provide the chloro-ribose (X). Condensation of compound (X) with thymine (XI) by means of HgCl2 and CdCO3 gives the acylated thymidine (XII), which is finally deacylated by treatment with NaOMe in methanol.

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