Backbone modifications in cyclic pep tides Conformational analysis of a cyclic pseudopentapeptide containing a thiomethylene ether amide bond replacement

Publisher Website
Google Scholar
Abstract
NMR and X‐ray crystallographic studies have shown that cyclic pentapeptides of the general structure cyclo(D‐Xxx‐Pro‐Gly‐Pro‐Gly) possess β‐ and γ‐turn intramolecular hydrogen bonds. As part of our continuing series surveying the compatibility of various amide bond replacements on peptide structure, we have synthesized cyclo(D‐Phe‐Proψ [CH2S]Gly‐Pro‐Gly). The pseudopeptide was prepared by solid phase methods and cleaved from the resin by a new procedure involving phase transfer catalysis using K2CO3 and tetrabutylammonium hydrogen sulfate. Cyclization was carried out with the use of DPPA, HOBt, and DMAP to afford the product in 69% yield. The conformational behavior of the pseudopeptide was analyzed by 1H and 13C (1D and 2D) NMR techniques. The backbone modification replaced the amide bond that is involved in a γ‐turn intramolecular hydrogen bond in the all‐amide structure. In CDCl3, the pseudopeptide adopted the same all‐trans conformation as its parent, although the remaining β‐turn hydrogen bond was weaker according to Δδ/ΔTNH measurements. In DMSO‐d6, the all‐trans conformer and a second conformer were observed in a ratio of 55:45. These conformers, which slowly inter converted on the NMR time scale, could be separately assigned; peaks due to chemical exchange were readily distinguishable by the ROESY technique as reported earlier by others. 13C and ROESY experiments suggested the minor conformer contained one cis amide bond at the Gly1‐Pro2 position. Thus, both the location and type of amide surrogate are important determinants affecting the compatibility of the replacement with a particular conformational feature.

This publication has 36 references indexed in Scilit: