Homooligomers of substituted prolines and beta-prolines: syntheses and secondary structure investigation

Homooligomers of enantiomerically pure (2S,3R)-3-methyl-proline, (3R,4R)-4-methyl-beta-proline and (3R,4S)-3,4-dimethyl-beta-proline were synthesized and studied using circular dichroism (CD) in water, methanol and propanol and using NMR in water. Changes in the far-UV CD spectrum were observed from dimers to hexamers, but little change was observed from hexamers to octa-or nonamers, both in water and methanol. CD and NMR data allowed us to conclude that oligomers of 3-substituted prolines with more than six residues adopt a characteristic PPII secondary structure both in water and aliphatic alcohols. Oligomers of (3R, 4R)-4-methyl-beta-proline bear the same CD signature as non-substituted beta-proline oligomers, suggesting that substitution at position 3 is not sufficient to reduce conformational heterogeneity in beta-proline oligomers. In the case of 3,4-disubstituted-beta-proline oligomers, an atypical signature with an extra negative band at around 225 nm was observed, together with a concentration dependent CD spectrum indicating association properties. Nevertheless, NMR studies of C-13 labelled oligomers of 3,4-disubstituted-beta-prolines revealed a complex mixture of cis-trans conformers even for longer oligomers.