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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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2-Deoxy-L-ribose (VI) is converted into 1-chloro-1,2-dideoxy-3,5-di-O-p-toluoyl-L-ribose (X) by using Hoffer's method for the D-enantiomer. Treatment of 2-deoxy-L-ribose with MeOH in HCl/MeOH provides methyl 2-deoxy-L-riboside (XIII), which is condensed with p-toluoyl chloride by means of KHCO3 in pyridine to give methyl 2-deoxy-3,5-di-O-p-toluoyl-L-riboside (VII). Chlori-nation of riboside (VII) with glacial AcOH and HCl affords 1-chloro-1,2-dideoxy-3,5-di-O-p-toluoyl-L-ribose (X), which is condensed with 5-methyl-2,4-bis(trimethylsilyl-oxy)pyrimidine (XIV) by means of p-nitrophenol in chloroform to yield the protected thymidine (XII). Finally, this compound is deprotected by means of NH3 in methanol.

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Cyclization of L-arabinose (VI) with cyanamide and NH3 in methanol gives the bicyclic oxazoline (XV), which is submitted to a cycloaddition with methyl propynoate (XVI) in refluxing ethanol/water to yield the tricyclic pyrimidinone system (XVII). Benzoylation of the two OH groups of compound (XVII) with either benzoyl cyanide and triethylamine in DMF or benzoyl chloride in anhydrous pyridine affords the dibenzoate (XVIII), which is treated with HCl in hot DMF to provide the chlorouridine derivative (XIX). Dechlorination of compound (XIX) by means of Bu3SnH and AIBN in refluxing benzene gives 3,5-di-O-benzoyl-2'deoxy-b-L-uridine (XX), which is debenzoylated by means of NaOMe in methanol to yield 2'-deoxy-b-L- uridine (XXI). Finally, this compound is methylated by reaction with formaldehyde and KOH in hot water followed by hydrogenation with H2 over Pd/C in EtOH/HCl. Optionally, telbivudine can be purified by benzoylation with benzoyl cyanide and TEA, crystallization in EtOH/ether and final hydrolysis with refluxing MeOH/ NaOMe.

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Reaction of L-xylose (XXII) with acetone and H2SO4 gives the acetonide (XXIII), which by acylation with benzoyl chloride in pyridine/chloroform yields the dibenzoate (XXIV). The hydrolysis of acetonide (XXIV) with acetic acid to the dihydroxy sugar (XXV) followed by acylation with acetic anhydride provides the tetracylated L-xylose (XXVI). Condensation of compound (XXVI) with 2,4-bis(trimethylsilyloxy)pyrimidine (XXVII) - obtained by silylation of uracil (XXVIII) with hexamethyldisilazane - by means of trimethylsilyl triflate in 1,2-dichloroethane affords nucleoside (XXIX). Selective hydrolysis of the acetate ester of compound (XXIX) using hydrazine and AcOH in pyridine yields the dibenzoylated xylofuranosyl-uracil (XXX). Isomerization of compound (XXX) to the arabinofuranosyl analogue (XXXI) is achieved by reaction with dicyclohexylcarbodiimide and dichloroacetic acid in DMSO/benzene, followed by treatment with NaBH4 in EtOH/benzene. Subsequent deoxygenation of the 2'-hy-droxyl group of compound (XXXI) to afford 2'-deoxynucleoside (XX) is effected via condensation with phenyl chlorothionoformate, and then reduction of the resulting thiocarbonate (XXXII) with tris(trimethylsilyl)silane and AIBN. Iodination of the uracil ring of (XX) with I2 and cerium ammonium nitrate (CAN) in acetonitrile produces the 5-iodo derivative (XXXIII), which is protected at the 3-nitrogen atom by condensation with p-toluoyl chloride to yield the protected nucleoside (XXXIV). Introduction of the 5-methyl group to give the thymidine derivative (XXXV) is then effected by reaction of the 5-iodouracil (XXXIV) with tetramethyltin in the presence of palladium catalyst. Finally, all protecting groups of compound (XXXV) are removed by treatment with methanolic ammonia.

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Condensation of 1-(b-L-ribofuranosyl)thymine (XXXVI) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (XXXVII) in pyridine gives the cyclic disiloxane nucleoside (XXXVIII), which is acylated with thiocarbonyldiimidazole (TCDI) in DMF to yield the 2'-O-thioester derivative (XXXIX). Reduction of this compound by means of 2,2'-azobis(methylpropionitrile) (ABMP) and Bu3SnH in refluxing toluene affords the silylated 2'-deoxynucleoside (XL), which is finally desilylated by means of TBAF in THF.

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Condensation of the bicyclic oxazoline (XV) with 2-(chloromethyl)acrylic acid ethyl ester (XLI) - obtained by treatment of the hydroxymethyl analogue (XLII) with SOCl2 - in dimethylacetamide gives the aduct (XLIII), which is treated first with hydroquinone and Na2CO3 in water and then with H2 over Pd/Al2O3 in the same solvent to provide 2,2'-anhydro-b-L-thymidine (XLIV). Reaction of compound (XLIV) with acetyl bromide in DMF/AcOEt yields 2'-bromo-3',5'-di-O-acetyl-b-L-thymidine (XLV), which is debrominated with H2 over Pd/Al2O3.to afford the 2'-deoxynucleoside (XLVI). Finally, this compound is deacetylated by means of NH3 in MeOH.

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The oxidative cleavage of 1,2,5,6-di-O-isopropylidene-D-galactofuranose (XLVII) with NaIO4 and H5IO6 gives aldehyde (XLVIII), which is reduced with NaBH4 in methanol to yield the 1,2-di-O-isopropylidene-L-arabinose (XLIX). Protection of the OH groups of compound (XLIX) with benzyl chloride and KOH in refluxing dioxane affords the dibenzyl ether (L), which is submitted to cleavage of the acetonide group by means of HCl in methanol to provide the methyl dibenzyl-L-arabinoside (LI). Reaction of the free OH group of (LI) with triflic anhydride and pyridine in dichloromethane gives the triflate (LII), which is reduced with Bu4NBH4 in refluxing benzene to yield methyl 3,5-di-O-benzyl-2-deoxy-L-riboside (LIII). Deben-zylation of (LIII) wit H2 over Pd/C affords methyl 2-deoxy-L-riboside (LIV), which is finally treated with Dowex [H+] in hot water to provide the telbivudine intermediate 2-deoxy-L-ribose (VI).