Nucleosides and their analogs and derivatives are an important class of therapeutic agents. For example, a number of nucleosides have shown antiviral activity against viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and human T-lymphotropic virus (HTLV). Among the nucleosides shown to have biological activity are 3'-azido-3'-deoxythymidine (AZT) and 2', 3'-dideoxycytidine (DDC).

Most nucleosides and nucleoside analogs and derivatives contain at least two chiral centers in positions 1'and 4', and therefore exist in the form of two pairs of optical isomers (i. e. two in the cis-configuration and two in the trans-configuration).

However, generally only the cis-isomers (ß-configuration) exhibit useful biological activity. Different enantiomeric forms of the same cis-nucleoside may, however, have very different antiviral activities.

Many of the known processes for producing optically active 2', 3'-dideoxy nucleosides and their analogs and derivatives modify naturally occurring, optically active nucleosides by altering the base or by altering the sugar via procedures such as deoxygenation or radical initiated reductions. These transformations involve multiple steps, including protection and deprotection and usually result in reduced yields. Moreover, they begin with and maintain the optical activity of the starting nucleoside. Thus, the nucleosides produced by these processes are limited to specific analogs of the enantiomeric form of the naturally occurring nucleoside () 3-D-configuration). In addition, these procedures require the availability of the naturally occurring nucleoside, often an expensive starting material.

Therefore, P-L-nucleosides their analogs and derivatives as well as nucleoside analogs bearing bases different from the naturally occurring purines and pyrimidines can not be formed by these procedures.

Other known processes for producing optically active nucleosides rely on conventional glycosylation procedures to add-the sugar to the base. These ; procedures invariably give anomeric mixtures of cis-and trans-isomers which require. tedious separation and result in lower yields of the desired biologically active cis-nucleoside.

Improved glycosylation methods designed to overcome the problem of selective formation of the desired (3-product involve the usage of chiral auxiliaries, the application of enzymatic methods, or the use of asymmetric palladium catalysis. Further processes require the addition of a 2'-or 3'-substituent to the sugar. Because the 2'-or 3'-substituent is only useful in controlling the cis-nucleoside synthesis in one configuration (when the 2'-or 3'-substituent is trans to the 4'- substituent), multiple steps are required to introduce this substituent in the proper configuration. The 2'-or 3'- substituent must then be removed after glycosylation, requiring additional steps. Optionally, the deoxygenation of the 2'-and 3'-hydroxy function is performed after the formation of the glycosidic bond.

Furthermore, to obtain an optically pure nucleoside product, the starting sugar must be optically pure. This also requires a series of time-consuming syntheses and purification steps.

According to the present invention P-D-and ß-L-2', 3'- dideoxy nucleoside analogs are prepared starting from furan derivatives using catalytic hydrogenation as key step for the formation of the P-configuration. The use of achiral catalysts gives way to ß-D-and ß-L-2', 3'-dideoxy nucleosides as a racemic mixture which can be separated by kinetic resolution.

Employing asymmetric catalytic hydrogenation leads to the preferential formation of one enantiomer.

The present invention is characterized in that 2- substituted furan derivatives of the general formula (I) wherein R is a hydroxymethyl-synthon, i. e. a group which- under appropriate conditions-can easily be converted into. hydroxymethyl, like a suitably protected methoxy group, a suitably protected carbaldehyd group or a suitably protected carboxylic group are in a first step activated by reaction with an alcohol R'OH, wherein R'means an optionally substituted Cl-C6 alkyl group (e. g. methyl, ethyl, isopropyl, 2-chloroethyl, and others).

Suitable protecting groups for the Hydroxymethyl-Synthon are well known to a person skilled in the art and can also be found in the state of the art, like e.g. in #Protective Groups in Organic Synthesis", T. W. Greene and P. G. M. Wuts, third edition, John Wileys & Sons, Inc.

Specifically, R can be: -CH2OX with X= Cl-C6 alkyl-or C5-C7 arylester (e. g. acetate, 2, 2-dimethylpropionate) ; C1-C6 alkyl-, (C5-C7)-aryl-(C1-C6)-alkyl- or Cl-cl arylether (e. g. methoxymethyl, benzyl) ; silylethers (e. g. trimethylsilyl, t-butyldiphenylsilyl) ; Cl-C6alkyl-or Cs- C7 arylcarbonates (e. g. methoxymethyl-, p-nitrophenylcarbo- nate); Cl-C6 alkyl-or Cg-C, arylsulfonates (e. g. mesylate, to- sylate); -COOY with Y= Cl-C6 alkyl or (C5-C7)-aryl-(C5-C7)-aryl ; -cyclic or acyclic acetals and thioacetals protected aldehydes.

-ZC=CZ, or -C#CZ with Z= Cl-C6 alkyl, Cl-cl aryl or H.

The thus obtained activated furan derivative (II) is then coupled in the presence of a Lewis acid with a (optionally activated) N-heterocycle (III), like optionally substituted azoles, diazoles, triazoles, and their sixmembered eqivalents but preferentially with purine-and pyrimidine bases or analogs or derivatives or anions (IV) thereof (step 2) and rearomatized by reaction with a Lewis acid, preferably a Lewis acid as disclosed in US 5,756, 706 B1, the content of which is hereby incorporated by reference. Rearomatization is then followed by hydrogenation of the planar, prochiral furyl nucleoside (VI) thus obtained to give an intermediate product (VIII) (step 3) and finally deprotection to yield the desired product (step 4).

Step 3 and step 4 may also be performed in reversed order. In addition, P-D-and P-L-nucleoside derivatives can be accessed separately by either kinetic resolution of the racemic mixture obtained by hydrogenation using achiral catalysts (step 3/path A) or by asymmetric catalytic hydrogenation of the furyl nucleosides (step 3/path B). /step 1 RoOR'step 2a. RoN step. 2b R \O/ , R'O ling R"0 out (I), (11)'M « 1) step 3/path B step 3/path A hydrogenation hydrogenation R. p 1 J. p R R O J andlor (VIII) + (V'"D) (VIII) (VIIIp). racemic mixture kinetic resolutio deprotection ex and/or (IXo) CX,) (IXL) (IXD) racemic mixture scheme 1 It has to be emphasized that the process of the present invention is highly suitable for the synthesis of (3-D-and (3-L- nucleoside derivatives starting from inexpensive materials. In contrast to syntheses for nucleoside analogs according to the state of the art, the process according to the present invention employs the cis-selectivity of the hydrogenation reaction for the formation of the necessary (3-configuration.

Furthermore, a general synthesis for furyl nucleosides - (VI) has not yet been reported. Until now such compounds have only been obtained as side products during the modification of naturally occurring nucleosides.

In summary the present invention comprises: A completely new synthetic approach to 2', 3'-dideoxy X nucleoside analogs starting from 2-substituted furans, a method that allows equally simple pathways to both P-D- and P-L-nucleoside analogs, int introducing the formation of the necessary (3-configuration highly stereospecific via catalytic hydrogenation, hovel intermediate compounds (V) and (VI) which are nucleoside analogs and therefore of biological interest.

Step 1: Activation of the 2-substituted furan starting materials of general formula (I) The activation of the 2-substituted furan starting materials of general formula (I) can be achieved by the formation of the corresponding 2-substituted 2, 5-dialkoxy-2, 5- dihydrofuranes of general formula (II) and/or 2,5-diacyloxy- 2,5-dihydrofuranes by either chemical or electrochemical means.

In this context and as shown in table 1, the electrochemical approach to compounds (II) is very effective.

The process of the present invention tolerates a great variety of substituents R, but preferably carboxylic acid derivatives and protected alcohols are used, as they can be easily converted into the pharmacologically essential hydroxymethyl group. Furthermore, the alcohol used can also be varied to a certain extent making the reaction even more flexible.

Scheme 2 General procedure for the formation of compounds (II) from (I) : Method A (activation of furan carboxylic esters): A solution of compound (I) in dry alcohol is poured into a reaction vessel equipped with an electrolysis cell consisting of a Pt-anode and a Ni-cathode and stirred. The mixture is cooled to-15°C and-cone. HSO is added as electrolyte. The cell is then fed with an appropriate current using an ordinary power supply. The reaction is monitored by GC-MS. After consumption of the starting material the solution is poured into lM NaOMe. solution in methanol. The mixture is stirred for half an hour. After evaporation of methanol under reduced pressure, the residue is distilled in vacuo.

# Method B (for the activation of furfurol derivatives): A solution of compound (I) in dry alcohol is poured into a reaction vessel equipped with an electrolysis cell consisting of a Pt-anode and a Ni-cathode and stirred. The mixture is cooled to-15°C and NH4Br (0.2 equivalents) is added as electrolyte. The cell is fed with an appropriate current using an ordinary power supply. The reaction is monitored by GC-MS.

After consumption of the starting material the solution is concentrated in vacuo. The residue is diluted with CH2C12 and the solution is extracted with a saturated aqueous NaHCO3 solution. The aqueous phase is extracted twice with CH2C12 and the combined organic layers are dried over Na2SO4. After evaporation of the solvent under reduced pressure the residue is distilled in vacuo.

Step 2: Coupling of 2, 5-Dialkoxv-2, 5-dihydrofuran derivatives with N-heterocycles and reåromatization The activated 2,5-dihydrofuran derivatives (II) obtained by either chemical or electrochemical alkoxy-or acyloxylation of 2-substituted furans (I) can be coupled with N-activated heterocycles (e. g. optionally substituted azoles, diazoles, triazoles, and their sixmembered eqivalents) but preferentially with purine-and pyrimidine bases or analogs or derivatives thereof (III) or anions (IV) thereof. The coupling using silylated bases is catalysed by Lewis acids as depicted in Scheme 3. R OR- R'O) + t) \Lewis åcid (II) "-r r (III) ( '' R'O V YOR' (II) (w o . Q "M R-0=y S Scheme 3 A previously silylated (or silylated in situ) N- heterocycle, preferably a purine or pyrimidine base or analog or derivative thereof is coupled with a catalytic to overstoichiometric amount of Lewis acid (e. g. boron halides, aluminium halides (optionally substituted by alkyl groups), titanium halides, tin (IV) halides, zinc halides, and any other species well known to be used in glycosylation reactions) but preferably with. Lewis acids of the general structure (VII) as disclosed in US 5.756. 706 B1, wherein R1, R2 and R3 are independently selected from the group consisting of hydrogen, cl-20 alkyl (e. g. methyl, ethyl, t-butyl), optionally substituted by halogens (F, Cl, Br, I), C16 alkoxy (e. g. methoxy) or C620 aryloxy (e. g. phenoxy); C720 aralkyl (e. g. benzyl), optionally substituted by halogen, C1-20 alkyl or C1 20 alkoxy (e. g. p- methoxybenzyl) ; C6-20 aryl (e. g. phenyl), optionally substituted by halogen, C alkyl or Cl20 alkoxy ; trialkylsilyl; halogens (F, Cl, Br, I). R4 is selected from the group consisting of halogen (F, Cl, Br, I) ; CI-20 sulfonate esters, optionally substituted by halogens (e. g. trifluoromethane sulfonate) ; C1-20 alkyl esters, optionally substituted by halogens (e. g. trifluoroacetate) ; polyvalent: halides (e. g. triiodide); trisubstituted silylgroups of the general formula (Rl) (R2) (R3) Si (wherein Rl, R2 and R3 are as defined above) ; saturated or unsaturated selenenyl C620 aryl ; substituted or unsubstituted C620 arylsulfenyl ; substituted or unsubstituted Cl-20 alkoxyalkyl ; and trialkylsiloxy, in the presence of polar or. nonpolar solvents (e. g. CHCl, CCl4, toluene, ClCH2CH2Cl, DMF, DMSO) but preferably in CH2Cl2 and CH3CN to obtain compounds of the general formula (V) which can be isolated-in analytically pure form by recrystallisation from appropriate solvents (e. g. ethanol). Treatment of compounds (V) with a catalytic to overstoichiometric amount of Lewis acid (e. g. boron halides, aluminium halides (optionally substituted by alkyl. groups), titanium. halides, tin (IV) halides, zinc halides, and any other species well known to be used in glycosylation reactions) but preferably with Lewis acids of the general structure (VII) in aprotic organic solvents as described above yield furyl nucleosides of the general formula (VI) which can be isolated in analytically pure form by recrystallisation from appropriate solvents (e. g. ethanol).

Compounds (V) are novel compounds which have not yet been described in the literature. The sequence of coupling and rearomatisation to the furyl nucleoside analogs may be performed in one pot without isolation of compounds (V).

Examples for this procedure are shown in table 2 and 3.

General procedure for the formation of compounds (V) from (II): A solution of 1 equivalent of compound (II) and 1.1 equivalents of a silylated base (III) in an appropriate solvent (CH3CN, CH2C12, etc) is cooled to-20°C and 0-1 equivalents of Lewis acid (VII) (e. g. TMSOTf, TMSBr, TMSI, etc. ) is added. The mixture is stirred at 0°C until complete consumption of (II) is detected by TLC. Then saturated NaHCO3 solution is added and the aqueous phase is extracted with CHCl. The organic layer is dried (NA2SO4) and the solvent evaporated under reduced pressure. The residue is recrystallised from ethanol to yield compound (V) in analytically pure form.

General procedure for the formation of compounds (VI) from (V): A solution of 1 equivalent of compound (V) in an appropriate solvent (CH3CN, CH2C12, etc) is cooled to-20°C and 0-1 equivalents of Lewis acid (VII) (e. g. TMSOTf, TMSBr, TMSI, etc) is added. The mixture is stirred at 0°C until complete consumption of (V) is detected by TLC. Then saturated NaHCO3 solution is added and the aqueous phase is extracted with CH2Cl2. The organic layer is dried (Na2SO4) and the solvent evaporated under reduced pressure. The residue is recrystallised from ethanol to yield compound (VI) in analytically pure form.

Step 3: Hydrogenation of furyl nucleosides The hydrogenation of the furan ring in compound (VI) can be achieved chemoselectively by the choice of an appropriate catalyst/solvent system to yield ß-D-and ß-L-nucleoside derivatives (VIII). Achiral as well as chiral catalysts can be employed in this step.

Step 3/path A: Hydrogenation using achiral catalyst Using achiral catalysts for the hydrogenation step a racemic mixture of P-D-and P-L-nucleoside derivatives is obtained (Scheme 4). H2 R R O O (Vl) achiral Catalyst (víll,) (VIIID) P-L-Nucleoside P-D-Nucleoside racemic mixture Scheme 4 Heterogeneous catalysis : As heterogeneous catalyst platinum metals in their dispersed form, as metal oxides (e. g. PtO2) or on various supports (e. g. Rh/Al2o3l Pd/C, Pd (OH) 2/C, Pd/C (optionally poisoned with Pb (OAc) 2), Rh/C and others) can be used.

As solvents water, alcohols (e. g. methanol, ethanol, isopropanol, and others), aromatic and non aromatic hydrocarbons (e. g. toluene, hexane), halogenated aromatic-and non aromatic hydrocarbons (e. g. CHZCl2), nitriles (e. g. CH3CN)', amides (e. g. DMF), ketons (e. g. acetone), ethers (e. g. THF) or esters of carboxylic acids (e. g. ethyl acetate) and mixtures thereof can be employed. Additives such as acids or bases may be utilized if necessary.

The hydrogenation'is performed at temperatures between 20°C and 100°C using hydrogen pressures between 1 bar and 100 bar with a catalyst to substrate ratio from 1: 5 to 1: 2000.

# Homogeneous catalysis : As catalytically active homogeneous catalysts, complexes formed by the reaction of metal precursors of the general formula [M(L)A]2 (X), wherein M may be Rh (I) or Ir (I) and L may be one C4 12 diene or two C2 12 alkenes and A'is a halogen, [M(L)2]+B- (XI), wherein L may be one C4 12 diene, two C2-12 alkenes or one C2-12 alkene together with a diketocompound and B is the anion of an acid or Lewis acid (e. g. Cl04-, SO3F-, CH3SO3-, CF3SO3-, BF4-, BF6-, AsF6-, SbFs, SbCl6-), or [Ru (L) A,], (XII), wherein L may be one C4 12 diene, two C2-12 alkenes or one substituted or unsubstituted arene and A is a halogen or C, 20 carboxylate (optionally substituted by halogens), with ligands containing phosphor, nitrogen, oxygen or sulfur (e.g. PPh3, dppf) can be employed. In each of the general formulas (X), (XI) and (XII) L has to be achiral or a racemic mixture.

As solvents water, alcohols (e.g. methanol, ethanol, isopropanol, and others), aromatic and non aromatic hydrocarbons (e. g. toluene, hexane), halogenated aromatic and non-aromatic hydrocarbons (e. g. CH2Cl2), nitriles (e. g. CH3CN), amides (e. g. DMF), ketons (e. g. acetone), ethers (e. g. THF) or esters of carboxylic acids ethyl acetate) and mixtures thereof can be employed. Additives such as acids or bases may be utilized if necessary.

The hydrogenation is performed at temperatures between 20°C and 100°C using hydrogen pressures between 1 bar and 100 bar with a catalyst to substrate ratio from 1: 5 to 1: 10000.

# Step 3/path B : Hydrogenation using chiral catalyst The use of chiral catalysts generally allows preferential formation of one single enantiomer ((3-D- vs. P-L-nucleoside derivatives; Scheme 5)-. O N f.. 2 R R O. O and/or chiral Catalyst (Vt) iL) (V P-L-Nucleoside p-D-Nucieoside Scheme 5 As catalytically active homegeneous catalysts complexes formed by the reaction of metal precursors of the general formula [M (K) A], (XIII), wherein M may be Rh (I) or Ir (I) and K may be one C412 diene or two C2l2 alkenes and A is a halogen, [M(K)2]+B- (XIV), wherein K may be one C412 diene, two C212 alkenes or one C212 alkene together with a diketocompound and B is the anion of an acid or Lewis acid (e. g. Cl04, SO3F-, CH3SO3-, CF3SO3-, BF4-, BF6-, AsF6, SbF6-, SbCl6-), or [Ru (K) A2 (XV), wherein K may be one C412 diene, two CI-12 alkenes or one substituted or unsubstituted arene and A is a halogen or C120 carboxylate (optionally substituted by halogens)] with chiral ligands containing phosphor, nitrogen, oxygen or sulfur (e.g. binap, ferrocenylphosphines) can be employed. In each of the the general formulas (XIII), (XIV) and (XV) K has to be chiral.

As solvents water, alcohols (e. g. methanol, ethanol, isopropanol, and others), aromatic and non aromatic hydrocarbons (e. g. toluene, hexane), halogenated aromatic and non aromatic hydrocarbons (e. g. CH2Cl2), nitriles (e. g. CH3CN), amides (e. g. DMF) ; ketons (e. g. acetone), ethers (e. g. THF) or esters of carboxylic acids (e. g. ethyl acetate) and mixtures thereof can be employed. Additives such as acids or bases may be utilized if necessary.

The hydrogenation is performed at temperatures between 20°C and 100°C using hydrogen pressures between 1 bar and 100 bar with a catalyst to substrate ratio from 1: 5 to 1: 10000.

Alternatively, a heterogeneous catalyst in combination with chiral additives (e. g. cinchona alkaloids) may be employed for an asymmetric hydrogenation.

General Procedure for the Hvdroctenation of Compounds (VI) 'Heterogeneous catalyst : To a solution of 1 equivalent of compound (VI) in an appropriate solvent (e. g. methanol, ethyl acetate, THF) in a round bottomed flask, 0.2 equivalents of a heterogeneous catalyst (e. g. Rh/Al203, Pd/C) are added. Optionally, an acid or base as well as a chiral additive may be added. The flask is evacuated and then purged with hydrogen (three times), then charged with hydrogen to the specified reaction pressure (1 bar - 100 bar). The reaction takes place at temperatures between 20°C and 100°C. The flask is placed into an autoclave if necessary. The mixture is stirred virgorously under the above mentioned conditions until complete consumption of (VI) is detected by TLC. The catalyst is removed by filtration, the filtrate is evaporated to dryness under reduced pressure and the residue is subjected to column chromatography or purified by recrystallisation.

Prior to the catalytic hydrogenation, compounds (VI) may be deprotected by known procedures. In the case of esters a reduction to the corresponding alcohols may be performed as described in the literature.

Homogeneous catalyst : A flask filled with a solution of 1 equivalent of compound (VI) (optionally an acid or base may be added) in an appropriate solvent (e. g. methanol, ethyl acetate, THF) is evacuated and purged with a dry and oxygen free. inert gas (e. g. argon, nitrogen) (three times) using standard Schlenk techniques. Then 0. 2 equivalents of the catalyst precursor (e. g. bicyclo [2.2. 1] hepta-2, 5-diene-rhodium (I) chloride-dimer) and the chiral or achiral ligand (0.2 equivalents for bidentate and 0.4 equivalents for monodentate ligands) are added under a positive pressure of inert gas. The flask is evacuated and purged with hydrogen (three times) and then charged with hydrogen to the specified reaction pressure (1 bar-100 bar).

The reaction takes place at temperatures between 20°C and 100°C. The flask is placed into an autoclave if necessary. The mixture is stirred virgorously under the above mentioned conditions until complete consumption of (VI) is detected by TLC. The solvent is removed by evaporation under reduced pressure and the residue is subjected to column chromatography or purified by recrystallisation.

Prior to the catalytic hydrogenation, compounds (VI) may be deprotected by known procedures. In the case of esters a reduction to the corresponding alcohols may be performed as described in the literature.

Step 4: Deprotection of Compounds (VI) and (VIII) Deprotection can be realized at any stage after coupling (step 2).

The cleavage of the employed protecting groups as well as the reduction of esters can be performed by known procedures.

General procedure for the deprotection of acetyl groups : Compounds bearing an acetyl protecting group are dissolved in a saturated solution of NH3 in dry methanol. The solution is stirred at room temperature until complete consumption of the starting material is detected by TLC. After evaporation under reduced pressure the. residue is either purified by recrystallisation or column chromatography.

General procedure for the deprotection of pivalovl groups : Compounds bearing a pivaloyl protecting group are dissolved in a 0.1M solution of NaOMe in dry methanol. The solution is stirred at room temperature until complete consumption of the starting material is detected by TLC. After evaporation under reduced, pressure the residue is either purified by recrystallisation or column chromatography. <BR> <BR> <BR> <BR> <BR> <BR> i<BR> <BR> Kinetic resolution of racemates If the hydrogenation is performed with achiral catalysts, a racemate is obtained (step 3/path A). The kinetic resolution of these racemates can easily be carried out by a person skilled in the art (e. g. formation of salts with chiral acids or bases, fractionated crystallisation, enzyme catalysed resolution, chromatography using chiral stationary phases etc.).

The present invention will now be explained by way of the following examples without being restricted thereto.

Step 1 : Preparation of 2, 5-dimethyl-2, 5-dihydrofurane-2- carboxylic acid methyl ester: 100g (0.71 mol) furane carboxylic acid ethyl ester are dissolved in 700 mL dry methanol and the electrolysis cell consisting of a Pt-anode and a Ni-cathode is placed into the reaction vessel and stirred. The mixture is cooled to-15°C and 3mL conc. His04 are added as electrolyte. The cell is fed. with 7 V current using an ordinary power supply. The reaction is monitored by GC-MS. After consumption of the starting material the solution is poured into 150mL 1M NaOMe solution in methanol. The mixture is stirred until complete conversion into the methyl ester is observed (GC-MS). After evaporation of methanol under reduced pressure the residue is distilled in vacuo to yield 95g (0.5 mol; 70%) analytically pure 2,5- dimethyl-2, 5-dihydrofurane-2-carboxylic acid methyl ester, bp (10. 5 mbar) 106-108°C.

NMR: 1H-NMR (CDCl3, 200MHz) # 3. 23,3. 30 (2s, 3H, H3-8), 3.41, 3.51 (2s, 3H, H3-9) 3.78 (s, 3H, H3-7), 5.67, 5.91 (2s, 1H, H-5), 6. 05 - 6. 17 (m, 2H, H-3, H-4).

13C-NMR (CDCl3, 50.3MHz) 8 50.7, 51. 1 (C- 7), 53. 0, 53. 1 (C-8), 54.8, 56.5 (C-9), 108. 6,109. 2 (C-5), 109.8, 110.3 (C-2), 130.6, 131.3 (C-4), 133.4, 133. 5 (C-3), 168. 2, 168. 5 (C-6).

Following the above mentioned procedure and using appropriatly substituted starting compounds, the following compounds (II) were obtained: Table 1 Compound (II) 1H-NMR Bp O (CDC13, 200 MHz) : ' 3. 23, 3. 30 (2s, 3H, H3-8), 3. 41, Me0 6 2 s OMe. 3. 51 (2s, 3H, H3-9) 3. 78 (s, 3H, H3-106-108°C MeO 7), 5. 67, 5. 91 (2s, 1H, H-5), 6. 05- (10. 5 mbar) cis l trans 6. 17 (m, 2H, H-3, H-4).. CiS/trans O (CDC13, 500 MHz) : 81. 20 (s, 9H, 3xH3-9), 3. 17 (s, 3H, 7 H3-10), 3. 46 (s, 3H, H3-11), 4. 11 (d, 116-120°C \ 2 O. 5. OMe ig 11. 48Hz, Ha-6), 4. 35 (d, 1H, MeO-H 11. 48Hz, Hb-6), 5. 78. (s, 1H, H-5),. Me0 3-4 H 5. 93 (d, 1H,. 5. 86Hz, H-3), 6. 12 (d, cis 1H, 5. 86Hz, H-4). (CDC13 500 MHz) : cS 1. 17 (s, 9H, 3xH3-9), 3. 25 (s, 3H, s s O , H3-10), 3. 54 (s, 3H, H3-11), 4. 03 (d, 1H, 11. 23Hz, Ha-6), 4. 42 (d, 1H, 11. 23Hz, Hb-6), 5. 51 (s, 1H, H-5) > (. m ar) 10 3 4 11 5. 89 (d, 1H 5. 86Hz, H-3), 6. 09 (d, M1H, 5. 86Hz, H-4). 0 (CDCl3, 200MHz) : '-b 2. 03 (s, 3H, H3-7), 3. 13 (s, 3H, '° -8. 40 s 3H H-3. 75 d. ''104-110°C 5\OOMe lH. 12. 75HzH.-5), 4. 23 (d, lH, niR MeO/\H 12. 75Hz, Hb-5) 5. 74 (s, 1H, H-4), (11. 8 mbar) 8 2 3 5. 86-6. 11 (m, 2H, H-2, H-3). cis (CDC13, 200 MHz) : ) 0 6 2. 02 (s, 3H, H3-7), 3. 20 (s, 3H, /° \ H3-8), 3. 49 (s, 3H, H3-9), 4. 01 d "lH. 11. 42Hz H.-5), 4. 29 (d, 1H, ,. 11. 42Hz, Hb=5) 5. 48 (s, 1H, H-4) ; (11. 8 mbar) MeO-OMe 8 2 3 5. 86-6. 11 (m, 2H, H-2, H-3). trans 9 (CDC13, 200 MHz) : 10 13 6 3. 24, 3. 25 (2s, 3H, H3-12), 3. 51, OMe 3, 52 (2s, 3H, H3-13), 4. 48-4. 69 (m, 108-114°C S0/\ t 4H, H2-6, H2-7), 5. 50, 5. 51 (2s, 1H, (0. 15 Inbar) 10 \/H-5), 5. 99-6. 11 (m, 2H, H-3, H- 12 3 4 cis/trans 4), 7. 25-7. 35 (m, 5H, Ph). (CDC13, 200 MHz) : \\ 8 1. 14-1. 17 (2s, 9H, Hg-8'), 3. 50- 0 3. 72 (m, 4H, H2-10'and H2-12'), \ H 3. 70-4. 12 (m, 4H, H2-9'alld H2-ll'), 171°C 4.. 0 (d, 11. 43 Hz, 1H, Hi-5a'), 4. 40'., 0 O, , cis/trans 1H, H-1'), 5. 88-5. 94 (dd, 0. 87 Hz, 5. 7 Hz, 1H, H-2'), 6. 08-6. 16 (dd, 0. 87Hz, 5. 7Hz, 1H, H-3'). o (CDC13, 200 MHz) : /tO 2. 00-2. 05 (2s, 3H, H3-7'), 3. 51- . 7' 0 H 3. 70 (m, 4H, H2-9'and H2-11'), 156°C 10, 3. 71-4. 10 (m, 4H, H2-8'and H2-10'), cy'o 4-'o. ci 4. 18-4. 40 (m, 2H, H2-5'), 5. 62 (d, (. m ar "'1H, H-1), 5. 82-6. 02 (mi 1H, H-2'), cis l trans 6. 10-6. 20 (m, 1H, H-3').

In addition to the electrochemical alkoxylations using methanol, successful experiments using other alcohols (e. g. 2- chloroethanol) have been accomplished.

Step 2a: Preparation of 1- (2, 5-dihydro-5-methoxycarbonyl-furan- 2-yl) thymine 10. 8 g (57 mmol, 1 equivalent) of 2, 5-dimethyl-2, 5- dihydrofurane-2-carboxylic acid methyl ester and 17 g (63 mmol, 1.1 equivalents) of silylated thymine (obtained by reaction of 1 equivalent thymine with 6 equivalents hexamethyldisilazane (HMDS) and a catalytic amount of (NH4)2SO4 under reflux until the mixture turns clear and consecutive evaporation of HMDS under reduced pressure) are dissolved in 100 mL dry CH3CN and the mixture is cooled under argon atmosphere to-20°C. Then 10.3 mL (57 mmol, 1 equivalent) (trimethylsilylmethyl)- trifluoromethanesulfonate (TMSOTf) are added dropwise. After stirring for 2h at-20°C the. reaction mixture is allowed to warm up to 0°C and is stirred at that temperature until complete consumption of 2, 5-dimethyl-2, 5-dihydrofurane-2- carboxylic acid methyl ester is observed by TLC (cyclohexane/ethyl acetate 5/1). Then, the reaction mixture is poured into a saturated solution of NaHCO3 in water. The aqueous layer is extracted with CH2Cl2 until no product can be detected in the aqueous phase by TLC (cyclohexane/ethyl acetate 1/4). The combined organic phases are dried (Na2504). and the solvent removed by evaporation under reduced pressure. The residue is recrystallised from ethanol to yield 14.5 g (51 mmol ; 90%) analytically pure 1- (2, 5-dihydro-5-methoxycarbonyl- furan-2-yl) thymine, mp 150-154°C.

NMR: 1H-NMR (CDCl3, 200MHz) # 1.90 (s, 3H, H3- 7), 3.33, 3. 42 (2s, 3H, H3-7), 3.82, 3. 85 (2s, 3H, H3-6), 6.13-6. 31 (m, 2H, H-2, H-3), 7.05, 7. 15 (2s, 1H, H-1), 7.22 (s, 1H, H-6), 9. 52 (s, 1H, NH).

13C-NMR (CDC13, 50.3MHz) 8 12. 8 (C-7), 51.4, 53.0 (C-6)., 53.3, 53.5 (C-7), 89.1, 89.9 (C-1), 110. 1, 111.1 (C-5), 112.0, 112.3 (C-4), 131.3, 132.5 (C-2), 132. 7,133. 2 (C-3), 135.3, 135. 5 (C-6), 150.8, 151.1 (C-2), 164.0 (C-5'), 167.5, 168.13 (C-4).

Following the above mentioned procedure for coupling of activated bases with. 2,5-dialkoxy-2, 5-dihydrofurans (II), the following compounds (V) were obtained: Table 2: Compound (V) 1H-NMR mp Q (CDCl3, 200MHz) : 6t 81,. 90 ; (s, 3H, H3-7), 3. 33, 3. 42 Met 0 14 (2s, 3H, H3-7'), 3. 82, 3. 85 (2s, 11N 3H, H3-6'), 6. 13-6. 31 (m, 2H, 150-154°C MeO-6 2'H-2', H-3'), 7. 05, 7. 15 (2s, 1H, H-1 ), 7. 22 (s, 1H, H-6), 9. 52 (s, cis l trans. 1H, NH). (CDC13, 200 MHz) : p tN 6 3. 33, 3. 42 (2s, 3H, H3-7'), MeOA ° N1 t 3. 82, 3. 85 (2s, 3H, H3-6'), 5. 76, 5. 80 (2d, 1H, 3. 08Hz, H-5), 6. 14 145-148°C Met-6-6. 32 (m, 2H, H-2', H-3'), 7. 15 cis l trans-4 ( H, H-1 ; H-6), 9. 63 (bs, 1H, NH). (bs, 1H, NH). (DMSO-d6, 500 MHz) : //0 93NA NH 6 3. 18 (s, 3H, H3-7'), 3. 72 (s, 3H, 234NH2 H3-6'), 5. 74 (d, 1H, 7. 82Hz, H- 5 5), 6. 32 (d, 1H, 5. 86Hz, H-3j, MeO 6 6. 50 (d, lH, 5. 86Hz, H-2'), 7. 12 cis' (s, 1H, H-1'), 7. 23 (d, 1H, 228-229°C 7. 82Hz, H-6), 7. 31 (bs, 1H, NH). (DMSO-d6, 500 MHz) : isomers) MeO-4. 0 o 83. 22 (s, 3H, H3-7'), 3. 73 (s, 3H, isomers) H3-6'), 5. 78 (d, 1H, 7. 33Hz, H- MeO \==/N 5), 6. 39 (d, 1H, 5. 86Hz, H-3'), '' (. 6. 44 (d, lH, 5. 86Hz, H-2'), 6. 94 (s, 1H, H=1), 7. 26 (d, 1H, nu2 7. 33Hz, H-6), 7. 35 (bs, 1H, NH). 0 NH (CDC13, 200 MHz) : O y 3Nn N °. 6 2. 30 (s, 3H, H3-8), 3. 34, 3. 44 O N. (2s, 3H, H3-7), 3. 83, 3. 86 (2s, MeO' \"/3H. H3-6'), 6. 16-6. 53 (m, 2H, sirup MeO-6 8 H-2', H-3'),. 7. 18 (bs, 1H, H-l'), 7 3 z 7. 49 (d, 1H, 7. 47Hz, H-5), 7. 73, cis l trans 8. 14 (2d, 7. 47Hz, H-6). O H (DMSO d6, 200'MHz) : b 3. 19, 3. 26 (2s, 3H, H3-7'), 3 0 N, 4 3. 74, 3. 75 (2s, 3H, H3-6'), 6. 40- MeO is, 4 6. 55 (m, 2H, H-2', H-3'), 6. 78, 177-186°C MeO e 0 7. 00 (2s, 1H, H-1'), 7. 57, 7. 73 (2s, 1H, H-6), 11. 85, 11. 89 (2s, cis trans 1H, NH). -o H (DMSO46, 200 MHz) : o 0 S 3. 19, 3. 26 (2s, 3H, H3-7'), 3. 73 (s, 3H ; H3-6 ), 6. 37-6. 50 (m, 1 MeOw < \t 2H, H-2', H-3'), 6. 80, 7. 02 (2s, 143-148°C MeO \-/' H-l'), 7. 48, 7. 56 (2d, 1H, 6. 6Hz 7 3 z and 7. 03Hz, H-6), 12. 01, 12. 04 cis/trans (2s, 1H, NH). (CDC13, 200 MHz) : N 8 3. 35, 3. 41 (2s, H3-7'), 3. 82, meo. 6 0 N5 6 ci 3. 86 (2s, 3H, H3-6'), 6. 38-6. 56 MeO-41 (m, 2H, H-2', H-3'), 7. 23, 7. 36 112-128°C sN/N (2s, 1H, H-l'), 8. 23, 8. 32 (2s, cis/trans 2 1H, H-8), 8. 77, 8. 78 (2s, 1H, H- (CDC13, 500 MHz) : 8'0 0H 8 1. 22 (s, 9H, 3xH3-8'), 1. 94 (s, e'O . 3ho r. 3H, H3-7), 3. 27 (s, 3H, H3-9'), 24 4. 18 (d, 1H, 12. 21Hz, Ha5') 6 4 ! 0 1'5 4. 55 (d, 1H, 12. 21Hz, Hb-5'), MeO-6 7-6. 08 (d, 1H, 5. 86Hz, H-2'), 6. 25 (d, 1H, 5. 86Hz, H-3'), 7. 03 (s, cis 1H, H-1'), 7. 14 (s, 1H, H-6), 8. 78 (bs, 1H, NH). (mixture of (CDC13, 500 MHz) : (mixtureof b 1. 22 (s, 9H, 3xH3-8'), 1. 91 (s, isomers) H 3H, H3-7), 3. 39 (s, 3H, H3-9'), 4. 12 (d, 1H, 11. 72Hz, Ha 5), MeO-N A2 4. 53 (d, 1H, 11. 72Hz, Hb-5'), Me0 3, 2, N, 2 3NH 6. 10 (d, 1H, 5. 86Hz, H-2'), 6. 26 trans 6 < (d, 1H, 5. 86Hz, H-3'), 6. 93 (s, g \xO 1H, H-1'), 7. 16 (s, 1H, H-6), 8. 69 (bs, 1H, NH). (CDC13, 500 MHz) : 81. 21 (s, 9H, 3xH3-8'), 3. 26 (s, \\ ° NH 3H, H3-9'), 4. 15 (d, 1H, a 90 t3 pO 12. 21Hz, Ha5'), 4. 57 (d, 1H, N, 12. 21Hz, Hb-5),, 5. 75 (d, 1H, 8. 30dz, H-5), 6. 07 (d, 1H, Me 5. 87Hz H-2'), 6. 27 (d, 1H, 9'3'2'5. 87Hz, H-3'), 7. 05 (s, 1H, H- CIS 1'), 7. 45 (d, 1H, 8. 30Hz, H-6), 140-142°C 8. 93 (bs, 1H, NH). (mixture of isomers) i (CDC13, 200 MHz) : 8''6 1. 21 (s, 9H, 3xH3-8'), 3. 38 (s, 3H, H3-9'), 4. 14 (d,'1H, a r s0 p H o H 11. 73Hz, Hua-5), 4. 52 (d, 1H, 0 11. 73Hz, Hb-5'), 5'. 76 (d, 1H,' ''MeO\====/N- 7. 82Hz, H-5), 6. 11 (d, 1H, 9'3 2'/3NH 5. 86Hz H-2'), 6. 25 (d, 1H, trans 6<s 5. 86Hz, H-3'), 6. 93 (s, 1H, H- 5 0 1 «), 7. 36 (d, 1H, 7. 81Hz, H-6), 8. 83 (bs, 1H, NH). (DMSO-d6, 200 MHz) : S 1. 09, 1. 13 (2s, 9H, 3xH3-8'), 8 N H 2. 10 (s, 3H, H3-8), 3. 14, 3. 16 (2s, 6'0 2r 3 N 3H, H3-9'), 4. 03-4. 41 (m, 2H, i 3,. N 3H, H3-9) ,, N 5 /'Ha 5 Hb-S ) s 6. 18-6. 55 (m, siru P ro 2HI H-2', H-3'), 6. 75, 6. 93 (2s, MeO 8 1H, H-1'), 7i21, 7. 23 (2d, l. H, 7. 47Hz each, H-5), 7. 85, 7. 89 cis l trans (2d, 1H, 7. 47Hz each, H-6), 10. 95, 10. 98 (2bs, 1H, NH). Q (DMSO-dc, 500 MHz) : 0 N 8 1. 15 (s, 9H, 3xi3-8'), 3. 12 (s, i N 4 3H, H-9'), 4. 07 (d, 1H, 11. 72Hz, \ Sk4 0, N1 1 Ha5'), 4. 34 (d, 1H, 11. 72Hz, s \/\. ") Hb-5'), 6. 20 (d, lH, 5. 86Hz, H- MeO \/H 2'), 6. 50 (d, 1H, 5. 86Hz, H-3'), cis 6. 80 (s, 1H, H-l'), 7. 64 (s, 1H, H-6), 11. 86 (s, 1H, NH). 192-195°C O (DMSO d6, 500 MHz) : (mixture of \ t 61. 13 (s, 9H, 3xH3-8'), 3. 21 (s, isomers) 8'0 3H, H-9'), 4. 06 (d, 1H, 11. 48Hz, Ha 5), 4. 31 (d, 1H, 11. 48Hz, Ho-5 ), 6. 35 (d, 1H, 5. 86Hz, H- meon 9. z./'. 3NH 2'), 6. 41 (d, 1H, 5. 86Hz, H-3'), trans 6 4 6. 62 (s, 1H,. H-1'), 7. 67 (s, 1H, /5 o H-6), 11. 86 (s, 1H, NH). I (CDC13, 200 MHz) : 0 0 H 8 1. 21 (s, 9H, 3xH3-8'), 3. 24, ZON 3. 40 (2s, 3H, H3-9'),. 4. 10-4. 64 8-60 23\0 -, TTTT TT .'n< ; 8X-tO t3Nto (m, 2H, Ha-5 ; Hb-5'j, 6. 05- 8t 9 t + 6. 30 (m, 2H, H-2'? H. 3'), 6. 93, 160-165°C $ Me0 6 F 7. 02 (2d, 1H, 1. 76and 1. 31Hz, 9 3 2 H-1'), 7. 43, 7. 54 (2d, 1H, 6. 15 cis l trans and 5. 72Hz, H-6), 9. 62, 9. 74 (2bs, 1H, NH). (DMSOLd6, 200 MHz) : O 61. 16 (s, 9H, 3xH3-8'), 3. 09 (s, 8@So 3H, H3-9'), 4. 07 (d, 1H, ) =N'11. 43Hz. Ha-5'), 4. 33 (d, 1H, s 6 Cl'l 1. 43Hz, Hb-5'), 6. 44 (d, 1H, 152-155°C 4 5. 71Hz, H-2'), 6. 75 (d, IH,' sNi 5. 71Hz, H-3'), 6. 92 (s, 1H, H- cis l trans 2 1 ), 8. 77 (s, 1H, H-8), 8. 84 (s, 1H, H-2). O (CDC13, 200 MHz) : 8. g 4 õ 1. 12, 1. 19 (2s, 9H, 3xH3-8'), N 3. 24, 3. 27 (2s, 3H, H3-9'), 4. 05- 3 4. 50 (m, 2H, Ha-S', Hb-5'), 6. 15 sirup Me0 N-6. 45 (m, 2H, H-2', H-3'), 6. 60, v z 6. 82 (2s, 1H, H-1'), 7. 98 (s, 1H, cis I tråns H-3), 8. 33, 8. 35 (2s, 1H, H-5). (DMSO-d6, 200MHz) : 0 H 81. 77 (s, 3H, H3-7), 2. 02 (s, 3H, . 0 N-H3-7'), 3. 12 (s, 3H, H3-8'), 4. 04 's 12 4 Is (d, 1H, 11. 43Hz, Ha5'), 4. 28 (d, 1H, 11. 43Hz, Hb-5), 6. 24 (dd, MéO/\=/1H, 1. 76Hz, 5. 71Hz, H-2'), 6. 44 (d, 1H, 5. 71Hz, H-3'), 6. 94 (d, cis 1H, 1. 76Hz, H-l'), 7. 20 (s, 1H, 151-153°C H-6), (mixture of 0 (DMSO-46, 200 lM) : isomers) 81. 77 (s, 3H, H3-7), 2. 04 (s, 3H" 7|/6'0 o H3-7'), 3. 19 (s, 3H, H3-8'), 4. 07 O (d, 1H, 11. 43Hz, Ha-5'), 4. 23 (d, MeO4)'N4NH 1H, 11. 43Hz, Hb-5), 6. 34 (d, 1H, 8.-3 6. 16Hz, H-2'), 6. 42 (d, 1H, 6 ! _ 4-3'), 6. 64 (s, 1H, H- l 1'), 7. 24 (s, 1H, H-6), 11. 48 (s, 7 1H, NH). 0 (DMSO d6, 200MHz) : \ ° NH õ 2. 01, 2. 02 (2s, 3H, H3-7'), 3/6O t 3 pO 3. 11, 3. 17 (2s,. 3H, H3-8'), 4. 00- 5 4. 27 (m, 2H, Ha-54 Hb-5'), 5 62 175-178°C Nl :", X-5. 71 (m, 1H, H-5), 6. 23-6. 46"" Me0 (m, 2H, H-2', H-3'), 6. 64, 6. 94 (2s, 1H, H-l'), 7. 35-7. 42 (m, cis l trans 1H H-6) 11. 45 (bs, 1H, NH). (DMSO-d6, 200MHz) : 0 8 1. 99, 2. 03 (2s, 3H, H3-7'), 2. 10 N H (s, 3H, H3-8), 3. 14, 3. 16 (2s, 3H, y 6 Ov ° H3-84) 4. 00-4. 31 (m, 2H, Ha- N'5 8 5', Hb--5'), 6. 22-6. 52 (m, 2H, 72-74°C MeO \=/6 8 H-2', H-3'), 6. 74, 7. 00 (2s, 1H, 8'3 2'H-1 ;) s 7. 22 (d, 1H, 7. 47Hz, H- cis l trans 5), 7. 85 (d, 1H, 7. 47Hz, H-6), 10. 93 (s, 1H, NH). ° H (DMSOX6, 200 MEz) : 3 O_N ° 2. 01 (s, 3H, H3-7'), 3. 11, 3. 20 \, A° (2s, 3H, H3-8'), 4. 00-4. 31 (m, 2H, Ha=5 , Hb-5 ), 6. 14-6.. 43 186-190°C MeO \=/6 F (m, 2H, H-2', H-3') j 7. 61, 7. 62 8'3'2'. (2d, 1H, 6. 60Hz and 7. 04Hz, H- cis trans 16), 12. 01 (bs, 1H, NH).

Step 2b: Preparation of 1- (5-methoxycarbonylfuran-2-yl) thymine 2. 1g (7.4 mmol, 1 equivalent) of 1- (2, 5-dihydro-5- methoxycarbonyl-furan-2-yl) thymine are dissolved in 20 mL dry CH3CN and the solution is cooled to-20°C under argon atmosphere. Then, 1.4 mL (7. 4 mmol, 1 equivalent) TMSOTf are added dropwise. The reaction mixture is allowed to warm up to room temperature and stirred until no starting material is detected by TLC (cyclohexane/ethyl acetate 1/4). The reaction mixture is then poured into a saturated solution of NaHCO3 in water. The aqueous layer is extracted with CH2Cl2 until no product can be detected in the aqueous phase by TLC (cyclohexane/ethyl acetate 1/4). The combined organic phases are dried (Na2SO4) and the solvent removed by evaporation under reduced pressure. The residue is recrystallised from ethanol to yield 1.7g (6.8 mol; 94%) analytically pure 1- (5-methoxy- carbonylfuran-2-yl) thymine, mp: 218-220°C.

NMR: H-NMR (DMSO-d6, 200MHz) 6 1, 83 (s, 3H, H3- 7), 3.83 (s, 3H, H3-6), 6.74 (d, 1H, 3. 52Hz, H-2), 7.44 (d, 1H, 3.52Hz, H- 3), 7.73 (s, 1H, H-6), 11. 76 (s, 1H, NH).

13C-NMR (DMSO-d6, 50.3MHz) 8 11.7 (C-7), 51. 9 (C-6), 105.2 (C-2), 110.9 (C-5), 120.1 (C-3), 137. 3 (C-6), 139. 9 (C-4 ), 146. 5 (C-1'), 148. 9 (C-2), 157.8 (C-5'), 163.5 (C-4).

Following the above mentioned procedure and using appropriate starting compounds (V), the following compounds (VI) were obtained : Table 3: Compound (VI) 1H-NMR mp O H (DMSO46,'2-00 MHz) : r çN O o 1. 83 (s, 3H, H3-7), 3. 83 (s, 3H, 4-0 N_, 24 H3-6'), 6'. 74 (d, 1H, 3. 52Hz, H- Me) ; 7. 44 (d, 1 H, 3. 52Hz, H-3 ), 6'6 7 7. 73 (s, 1H, H-6), 11. 76 (s, 1H, 3'2'NH)-' 1V11. (DMSO-d6, 200 MHz) : u 0 N 8 3. 83 (s, 3H, H3-6'), 5. 84 (d, 1H 7. 91Hz, I'4, H 5) ; 6. 76 (d, 1H, 99-, 01°C 6te "4 3. 52Hz, H-2'). 7. 44 (d, 1H, 1-201 L met 3'2'7. 91Hz, H-6), 11. 76 (s, 1H, NH). O (DMSO d6, 200MHz) : O N NH s 3. 83 (s, 3H, H3-6'), 5. 94 (d, 1H, 7. 47Hz, H-5), 6. 74 (d, 1H, 228-229°C 6 ! 5 3 52Hz, H-2'), 7. 41 (bs, 2H,' met 3'z NH2), 7. 84 (d, 1H, 7. 47Hz, H-6). (DMSO-d6, 200 MHz) : O H O-d 8 3. 83 (s, 3H, H3-6'), 6. 75 (d, 1H, 3. 51Hz, H-2'), 7. 42 (d, 1H, 232234°C MeO'\\/r f\, 3. 51Hz, H-3'), 8. 29 (s, 1H, H-6), 12. 07- (s, IH, NID. 3 2 (DMSO-d6, 200MHz) : 0'r2 3. 83' (s, 3H, H3-6'), 6. 74 ( (bd, 4 IH, 3. 52Hz, 1. 76Hz, H-2'), 7. 43 205-210°C 5 (dd, 1H, 3. 52Hz, 1. 32Hz, H-3'), -" 'met 6), 12. 22 (bs, 1H, NH). o 8 N (DMSO46, 200 MHz) : s CI F 3. 88 (s, 3H, H3-6'), 7. 08 (d, 61 N46 IH, 3. 52Hz, H-2'), 7. 61 (d, 1H, 166-168°C 3. 52Hz, H-3'), 8. 94 (s, 1H, H-8), 9. 13 (s, 1H, H-2). O (DMSO d6, 200MHz) : \ 8 1-. 15 (s, 9H, 3xi3-8'), 1. 80 (s, 8. 6-0 34 3H, H3-7), 5. 05 (s, 2H, H2-5'), Ni 6. 52 (d, 1H, 3. 08Hz, H-2'), 6. 63 134-136 C lut 6 7 (d, 2H, 3. 08Hz, H-3'), 7. 64 (s, 1H, H-6), 11. 65 (s, 1H, NH). 0 (DMSO-d6, 200 MHz) : 0H. 8 1. 15 (s, 9H, 3xH3-8'), 5. 06 (s, v t3NsC ; o 2H, H2-5'), 5. 75 (d, 1H, 7. 91Hz, H-5), 6. 53 (d, 1H, 3. 52Hz, H-163-164°C 2'),. 6. 63 (d, 1H, 3. 52Hz, H-3'), 7. 74 (d, 1H, 7. 91Hz, H-6), 11. 66 (s, 1H, NH). 0 (DMSO-dg, 200 MHz) : Ns 1. 13 (s,. 9H, 3xH3-8'), 5. 04 (s, 2H, H2-5'), 6. 52 (d, 1H, 3. 07Hz, 170 180°C N'5 H-2'), 6. 61 (d, 1H, 3. 07Hz, H- 3'), 8. 22 (s, 1H, H-6), 11. 98 (s, 1H, NH). Q (DMSO-dg, 200 MHz) : Ei'0 N 1. 14 (s, 9H, 3xH3-8'), 5. 04 (s, X s Xs 2H, H2-5) ; 6 51 (d, 1H, 3. 07Hz, 215-220OC' N'H-2'), 6. 62 (d, 1H, 3. 07Hz, H- 3), 8. 22 (d, 1H, 6. 15Hz, H-6), 12. 14 (bs, 1H, NH). O (DMSO-d6, 200. MHz) : 0 H 8 1. 79 (s, 3H, H3-7), 2. 05 (s, 3H, H3-7 ), 5. 02 (s, 2H, H2-5'), 6. 51 152 153°C ''4, O,, 152-153°C N (d, 1H, 3. 52Hz, H-2'), 6. 64 (d, 1H, 3. 52Hz, H-3'), 7. 64 (s, 1H, 3 2'H-6), 11. 63 (s, 1H, NH). O (DMSO d6, 200MHz) : \\ ° N 6 2. 04 (s, 3H, H3-7'), 5. 02 (s, 2H, /6 2 3 4 O H2-5), 5. 73 (d, 1H, 7. 91Hz, H- ''a o r', 5), 6. 52 (d, 1H, 3. 08Hz, H-2'), 155-157°C 6. 64 (d, 1H, 3. 08Hz, H-3'), 7. 74 (d, 1H, 7. 91Hz, H-6), 11. 63 (bs, 1H, NH). 0 (DMSO-d6, 200 MHz) : 0 0 N H 8 2. 05 (s, 3H, H3-7'), 2. 13 (s, 3H, zozo O H3-8), 5. 05 (s, ZH, H2-5 ), 6. 67 sirup N 1 5 ro (s, 2H, H-2', H-3'), 7. 32 (d, 1H, 6 8 7. 47Hz, H-5), 8. 22 (d, 1H, 3'Z 7. 47Hz, H-6), 11. 10 (s, 1H, NH).

Step 3: Preparation of aL-cis-1- (5-methoxycarbonyltetrahydro- furan-2-yl) thymine 4 g (16 mmol, 1 equivalent) of 1- (5-methoxycarbonylfuran- 2-yl) thymine are dissolved in 15 mL dry methanol and 7 mg (3 mmol Rh, 0.2 equivalents) of 5% Rh/Al203 are added. The flask is evacuated and purged with hydrogen (three times) and then charged with hydrogen to 1 bar. The mixture is stirred vigorously until no starting material is detected by TLC (cyclohexane/ethyl acetate 1/4). The catalyst is removed by filtration, the filtrate is evaporated to dryness under reduced pressure and the residue is subjected to column chromatography (cyclohexane/ethyl acetate 1/2) to yield 3. 8 g (15 mmol; 94%) analytically pure DL-CiS-1- (5-methoxycarbonyltetrahydrofuran-2- yl) thymine, mp: 174-178°C ; de > 97% (determined by HPLC).

H-NMR (DMSO-d6, 200MHz) : # 1. 78 (s, 3H, H3-7), 1. 80-2.20 (m, 2H, H2-2'), 2.20- 2.40 (m, 2H, H2-3), 3.71 (s, 3H, H3-6), 4. 58 (t, 1H, H-4), 6.06 (t, 1H, H-1 ), 7. 86 (s, 1H, H-6), 11. 30 (s, 1H, H-3).

13c-NMR (DMSO-d6, 75. 5MHz) : # 13. 1 (C-7), 29. 2 (C-2), 30.8 (C3-), 52. 9 (C-6), 77. 4 (C-4), 86. 8 (C-1), 109.8 (C-5), 136.8 (C-6), 151, 2 (C-5), 164. 4 (C-2), 173. 3 (C-4).

Following the above mentioned procedure and using appropriate starting compounds (VI), the following compounds (VIII) were obtained: Table 4: Compound (VIII) tH-NMR Mp (CDCl3, 200 MHz) : - N 8 1. 20-1. 62, 1. 80-2. 20, 2. 22-2. 56 (m, 4 7''4 4H, H2-2'and H2-3'), 1. 43 (d, 3H, , N'i s. 6. 16 Hz, H3-5), 1. 94 (s, 3H, H3-7), 142-145°C 6 7 4. 08-4. 30 (m, 1H, H-4'), 6. 02 (dd, 3 z 1H, 3. 08 Hz, 6. 6 Hz, H-1'), 7. 26 (s, 3 1H, H-6), 9. 0 (bs, 1H, H-3). (DMSO-d6, 200 MHz) : ° 1. 15 (s, 9H, H9-8'), 1. 79 (3H, s, . j ? 7'° H3-7), 1. 14-2. 28 (m, 4H, H2-2'and ho-3), 4. 20 (s, 2H, H2-5'), 3. 90-4. 30 7 Sirup (m, 1H, H-4'), 5. 97-6. 02 (m, 1H, H- 3 2 1'), 7. 39 (s, 1H, H-6), 11. 29 (s, 1H, H-3). (DMSO-d6, 500 MHz) : 1. 13 (s, 9H, H3-8'), 1. 74-1. 82 (m, 0 N 1H, H-2a'), 1. 92-2. 02 (m, 2H, H2- 3), 2. 28-2. 38 (m, 1H, H-2b'), 4. 21 4'lb, 6 (s, 3H, H-4'and H-5'), 5. 58 (dd, 1H, 101-105°C 4 oHb b} Jl = 2. 2Hz, J2 = 8. 06Hz, H-5), 5. 97 (dd, 1H, Ji = 3. 91 Hz, J = 7. 33Hz, H-1'), 7. 61 (d, 1H, J = 8. 06Hz, H-6), 11. 28 (s, 1H, H-3) (DMSO-d6, 200 MHz) : N 0 b 1. 78 (s ; 3H, H3-7), 1. 80-2. 20 (m, \\ 0 5 2H, H2-2'), 2. 20-2. 40 (m, 2H, H2-3'), 0 174-178 C 1. 1, 3. 71 (s, 3H, H3-6'), 4. 58 (t, 1H, H- 3-2'41), 6. 06 (t, lH ; H-1')', 7. 86 (s, 1H, H-6), 11. 30 (s, 1H, H-3).

Step 4: Preparation Step 4: Preparation of DL-3-dideoxythymidine To a stirred suspension of 100 mg (0. 40 mmol, 1 equivalent) DL-cis-1- (5-methoxycarbonyltetrahydrofuran-2-yl)- thymine in 2 mL ethanol was added at 0°C 30 mg (0.80 mmol, 2 equivalents) of sodium bbrohydride. The mixture was stirred for 5 min at 0°C and the cooling bath was removed. The stirring was continued at room temperature until no starting material could be detected by TLC (cyclohexane/ethyl acetate 1/4). Then, 2 drops of concentrated ammonium hydroxide were added and the mixture was stirred for 15 min. After removal of the solvent under reduced pressure the residue was subjected to column chromatography (methanol/dichloromethane 1/20) to yield 62 mg (0.27 mmol ; 70%) analytically pure DL-3-dideoxythymidine, mp: 154-156°C.

NMR: H-NMR (DMSO-d6, 200MHz) : # 1.63 (s, 3H, H3-7), 1.70-2. 00 (m, 2H, H2-2), 2.09- 2.30 (m, 2H, H2-3), 3.57 (s, 2H, H2-5), 4. 45 (t, 1H, 5. 28Hz, 7. 91Hz, H-4), 5.93 (t, 1H, 4. 40Hz, 6. 15Hz, H-l'), 7.71 (s, 1H, H-6).

C-NMR (DMSO-d6, 75. 5MHz) : # 12.1 C-7),.

25.0 (C-3), 31. 8 (C-2), 62. 8 (C-5), 81.4 (C-4), 84. 8 (C-1), 109.0 (. C-5), 136,7 (C-6), 150. 4 (C-2), 163.7 (C-4).

Following the above mentioned procedure and using appropriate starting compounds (VI), the following compounds were obtained: Table 5 Compound O H (DMSO-d6, 200 MHz) : 6HO ; t3t0 6 4. 37 (s, 2H, H2-5'), 5. 31 (bs, 1H, N'H-6'), 6. 41 (d, 2H, H-2'and H-3'),.1182-185°C 6 8. 21 (s, 1H, H-6), 11. 93 (bs, 1H, H- 31 z 3). o H (DMSO-d6, 200MHz) : 6'Ho 38 0 6 4. 38 (s, 2H, H2-5'), 5. 33 (bs, 1H, H-6'), 5. 73 (d, 7. 91, 1H, H-5), 6. 36- 159-168°C. 6. 50 (m, 2H, H-2'and H-3'), 7. 71 (d, 7. 91, 1H, H-6), 11. 6 (bs, IH, H-3). o (DMSO-d6, 200 MHz) : 6HO 3s NH2 4. 22-4. 36 (m, 2H, Ha-5), 5. 42 (t, r 4'114 H '''260°C (dec.) 5), 6. 32 (s, 2H, H-2'and H-3'), 7. 42 (s, 1H, H-7a), 7. 65 (d, 7. 03, 1H, H- 6), 7. 86 (s, 1H, H-7b). (DMSO-d6, 200 MHz) : \E N 51. 79 (s, 3H, H3-7), 4. 37 (s, 2H, H2- 6'5'), 6. 42 (dd, 2H, JH2'-H3'= 7. 47Hz, N 45 JH3,-H2-'= 7. 9lHz-H-2'and H-3'), 136-1420C '7. 60 (s, 1H, H-6), 11. 57 (bs, 1H, H- 3t 2 3)