Regiospecific synthesis of cyclopentane analogs of (2′- and 3′-deoxy-threo-pentofuranosyl)-uracil and -2-thiouracil nucleosides

Abstract

Aminohydroxycyclopentanemethanols are important precursors for the synthesis of cyclopentane analogs of purine and pyrimidine nucleosides. The regiospecific synthesis of two new aminohydroxycyclopentanemethanols, 17 and 22, is described. In these syntheses the desired configuration in the cyclopentane ring is obtained by opening the cis-acetoxy-1,3-cyclopentanedicarboxylic acid anhydride 3 with either ammonia or methanol. The attack by each nucleophile occurs at the carbonyl carbon farthest away from the acetoxy group to give a carbamoyl or an ester function at this position. Since the ester function is destined to become the hydroxymethyl substituent and the carbamoyl function the amino substituent, the type of nucleophile used to open the anhydride determines whether the 2-deoxy or the 3-deoxy isomer is obtained. Coupling of the aminohydroxycyclopentanemethanols with 3-ethoxypropenoyl isocyanate followed by cyclization of the acyl ureas in 2 N H2SO4 gave two new cyclopentane analogs of uracil nucleosides. Coupling of the aminohydroxycyclopentanemethanols with 3-ethoxypropenoyl isothiocyanate followed by cyclization of the acyl thioureas in 15 N aqueous ammonia gave two new cyclopentane analogs of 2-thiouracil nucleosides.