Liquid-phase synthesis and conformational analysis of pseudoproline-containing turn mimics

We have recently described the synthesis of oligomers of (4S,5R) 4-methyl 5-carboxybenzyl oxazolidin-2-ones (L-Oxd) and L-pyroglutamic acid (L-pGlu) and we have demonstrated that these molecules fold in ordered structures characterized by a semi-extended helical conformation, analogous to polyproline II and do not exhibit the amide cis-trans dynamic equilibrium typical of the related poly (L-Pro)n I and poly (L-Pro)n II helices. This effect is due to the presence of an imidic bond which always adopts only the trans conformation, even in the dimer. A typical effect of this behaviour is that the Halpha chemical shift of the amino acid nearby is strongly deshielded by the N-acyl derivative. We have demonstrated that the anomalous chemical shift value is associated with the occurrence of a weak alpha-CH…O=C hydrogen bond. The liquid-phase synthesis and the conformational analysis of a small library of fully protected tetramers containing L-pyroglutamic acid (L-pGlu), (4S,5R) 4-methyl 5-carboxybenzyl oxazolidin-2-one (L-Oxd), (4R,5S) 4-methyl 5-carboxybenzyl oxazolidin-2-one (D-Oxd) or 4(S)-oxazolidineacetic acid, 2-oxo (Oxac) as residue i+1 are reported, to test the tendency of these oligomers to assume a beta-hairpin conformation. The preferential conformations have been checked by IR absorption and 1H NMR analysis. The findings have been confirmed by DFT calculations, which provide an interpretation for the available experimental data, and agree with the reported observations.