(S)-5-(Hydroxymethyl)tetrahydrofuran-2-one (I) was converted into bromide (II) by reaction with CBr4 and PPh3. Subsequent reduction of the lactone with DIBAL-H in toluene at -78 C, followed by acetylation of the resulting lactol (III) with Ac2O and pyridine, afforded acetate (IV) as a 1:1 mixture of isomers cis and trans. The phosphonate group was then introduced by a TiCl4-catalyzed Arbuzov reaction with triethyl phosphite at low temperature, to give a mixture of geometric isomers, from which the desired cis compound (V) was isolated by column chromatography. Condensation of this bromide with 2-amino-6-chloropurine (VI) in the presence of Cs2CO3 in DMF gave (VII). The phosphonate ester was hydrolyzed by treatment with excess Me3SiBr to produce an intermediate trimethylsilyl ester, and then the target compound was obtained by simultaneous hydrolysis of the silyl ester to phosphonic acid and the 6-chloropurine group to guanine in boiling water, followed by conversion to the corresponding ammonium salt with NH4OH.

(S)-5-(Hydroxymethyl)tetrahydrofuran-2-one (I) was converted into bromide (II) by reaction with CBr4 and PPh3. Subsequent reduction of the lactone with DIBAL-H in toluene at -78 C, followed by acetylation of the resulting lactol (III) with Ac2O and pyridine, afforded acetate (IV) as a 1:1 mixture of isomers cis and trans. The phosphonate group was then introduced by a TiCl4-catalyzed Arbuzov reaction with triethyl phosphite at low temperature, to give a mixture of geometric isomers, from which the desired cis compound (V) was isolated by column chromatography. Condensation of this bromide with 2-amino-6-chloropurine (VI) in the presence of Cs2CO3 in DMF gave (VII). The phosphonate ester was hydrolyzed by treatment with excess Me3SiBr to produce an intermediate trimethylsilyl ester, and then the target compound was obtained by simultaneous hydrolysis of the silyl ester to phosphonic acid and the 6-chloropurine group to guanine in boiling water, followed by conversion to the corresponding ammonium salt with NH4OH.

(S)-5-(Hydroxymethyl)tetrahydrofuran-2-one (I) was converted into bromide (II) by reaction with CBr4 and PPh3. Subsequent reduction of the lactone with DIBAL-H in toluene at -78 C, followed by acetylation of the resulting lactol (III) with Ac2O and pyridine, afforded acetate (IV) as a 1:1 mixture of isomers cis and trans. The phosphonate group was then introduced by a TiCl4-catalyzed Arbuzov reaction with triethyl phosphite at low temperature, to give a mixture of geometric isomers, from which the desired cis compound (V) was isolated by column chromatography. Condensation of this bromide with 2-amino-6-chloropurine (VI) in the presence of Cs2CO3 in DMF gave (VII). The phosphonate ester was hydrolyzed by treatment with excess Me3SiBr to produce an intermediate trimethylsilyl ester, and then the target compound was obtained by simultaneous hydrolysis of the silyl ester to phosphonic acid and the 6-chloropurine group to guanine in boiling water, followed by conversion to the corresponding ammonium salt with NH4OH.

(S)-5-(Hydroxymethyl)tetrahydrofuran-2-one (I) was converted into bromide (II) by reaction with CBr4 and PPh3. Subsequent reduction of the lactone with DIBAL-H in toluene at -78 C, followed by acetylation of the resulting lactol (III) with Ac2O and pyridine, afforded acetate (IV) as a 1:1 mixture of isomers cis and trans. The phosphonate group was then introduced by a TiCl4-catalyzed Arbuzov reaction with triethyl phosphite at low temperature, to give a mixture of geometric isomers, from which the desired cis compound (V) was isolated by column chromatography. Condensation of this bromide with 2-amino-6-chloropurine (VI) in the presence of Cs2CO3 in DMF gave (VII). The phosphonate ester was hydrolyzed by treatment with excess Me3SiBr to produce an intermediate trimethylsilyl ester, and then the target compound was obtained by simultaneous hydrolysis of the silyl ester to phosphonic acid and the 6-chloropurine group to guanine in boiling water, followed by conversion to the corresponding ammonium salt with NH4OH.