THEORETICAL CONFORMATIONAL STUDIES OF PODANDS CONTAINING (2S,4R)-4-HYDROXYPROLINE MOIETIES

Abstract

Podands derived from (2S,4R)-4-hydroxyproline and containing two oxygen atoms in the oxyethylene moiety were selected for computational studies of their conformational behavior in solutions and further theoretical studies of their role as chiral inductors of Biginelli reaction. Qualitative differences were identified between the conformations of the basic podand and its bis(trifluoroacetate) derivative. Molecular dynamics simulations and quantum-chemical calculations showed that the bicationic form of podand, in contrast to the corresponding basic one, featured an intramolecular hydrogen bond between the 4-hydroxyproline moieties of terminal groups, which led to a noticeable increase in the averaged rotational energy barriers and a greater energy difference between the predominant conformer structures. The subsequent theoretical evaluation of chemical shifts for the various conformers and comparison of the observed values with experimentally obtained 1Н NMR data allowed to confirm the differences between the conformational behavior of (2S,4R)-4-hydroxyproline podand and its bicationic salt in stereoselective Biginelli reactions.