合成路线1

1) The cyclization of ketene diethylketal (I) with diethyl fumarate (II) in hot tert-butanol gives trans-3,3-diethoxycyclobutane-1,2-dicarboxylic acid diethyl ester (III), which is saponified with KOH in hot methanol to the corresponding racemic diacid (IV). The condensation of (IV) with (R)-(-)-2-phenylglycinol (V) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane followed by fractionated crystallization of the resulting diastereomeric mixture yields the diamide (VI). The hydrolytic reduction of (VI) by sequential treatments with trimethylsilyl chloride and imidazole, dinitrogen tetraoxide and finally with LiBH4 affords (S,S)-trans-3,3-diethoxycyclobutane-1,2-dimethanol (VII), which is benzoylated with benzoyl chloride in pyridine to the dibenzoate (VIII). The cleavage of the ketal group of (VIII) with H2SO4 in acetonitrile gives the cyclobutanone (IX), which is reduced with LS-Selectride in THF yielding [1S-(1alpha,2beta,3beta)]-3-hydroxycyclobutane-1,2-dimethanol 1,2-dibenzoate (X). The reaction of (X) with p-toluenesulfonyl chloride affords the corresponding tosylate (XI), which is condensed with 6-O-benzylguanidine (XII) by means of K2CO3 and 18-crown-6 in hot DMF giving [1R-(1alpha,2beta,3alpha)]-6-O-benzyl-9-[2,3-di(benzoyloxymethyl) cyclobutyl]guanine (XIII). Finally, this compound is treated with sodium methoxide in hot methanol. 2) The reaction of 6-chloropurine-2-amine (XIV) with 47% HI gives 6-iodopurine-2-amine (XV), which is condensed with [1S-(1alpha,2beta,3beta)]-3-(trifluoromethylsulfonyloxy)cyclobutane-1,2-dimethanol 1,2-dibenzoate (XVI) (obtained by treatment of the previously described cyclobutanol [X] with trifluromethanesulfonyl anhydride [Tf2O]) by means of benzyltriethylammonium hydroxide and pyridine in dichloromethane to afford the condensed iodopurine (XVII). The reaction of (XVII) with sodium methoxide hydrolyzes the benzoyl groups affording the 6-O-methylguanine derivative (XVIII), which is finally treated with aqueous HCl at 95 C.