Pyrrolidine N-alkylphosphonates and related nucleotide analogues: synthesis and stereochemistry

Abstract: N-Phosphonoalkyl-trans-3,4-dihydroxypyrrolidine derivatives were synthesized and exploited as synthons for the preparation of hydroxypyrrolidine nucleoside phosphonic acids, the 3′-deoxynucleoside 5′-phosphate analogues. Simultaneously, an alternative route, the N-phosphoalkylation of the preformed pyrrolidine nucleosides employing Mannich- and Michael-type reactions, was investigated to obtain desired nucleotide analogues. In contrast to the latter approach, the former resulted in the formation of two diastereoisomers very likely due to the existence of two possible SN2 transition states during a nucleophilic displacement. The stereochemistry of the prepared nucleotide analogues was studied by NMR spectroscopy. [Copyright &y& Elsevier]