Enzymatic Resolution of Aminocyclopentenols as Precursors to d- and l-Carbocyclic Nucleosides

Abstract

Racemic cis-4-aminocyclopent-2-en-1-ols were synthesized in three steps utilizing hetero Diels−Alder chemistry. Starting from suitably protected hydroxylamines, oxidization with sodium periodate and trapping with cyclopentadiene afforded cycloadducts (±)-5a−d. The N−O bond of the cycloadducts was reduced with Mo(CO)6 to afford (±)-cis-4-aminocyclopent-2-en-1-ols (±)-6a−d. These compounds, or their corresponding acetates, were kinetically resolved by enzymatic acetylation or hydrolysis, respectively. Enzymatic acetylation of cis-N-(benzylcarbamoyl)-4-aminocyclopent-2-enol [(±)-6a] with Candida antarctica B lipase and Pseudomonas species lipase gave the corresponding acetate (−)-7a in 90% and 92% ee, respectively, after 40% conversion. Enzymatic hydrolysis of cis-N-acetyl-4-aminocyclopent-2-enol 1-O-acetate (±)-7d with electric eel acetylcholine esterase was successful in providing both cis-N-acetyl-4-aminocyclopent-2-enols (+)-6d and (+)-7d in 92% ee (99% ee after a single recrystallization) after 40% conversion. Further synthetic transformations of these resolved synthetic building blocks and derivatives are also reported.