Cyclo(D‐Pro‐L‐Pro‐D‐Pro‐L‐Pro): Structural properties and cis/trans isomerization of the cyclotetrapeptide backbone

Abstract

Ulm, Federal Republic of Gennany SynopsisCombinations of L-and D-proline residues are useful compounds for finding new structures and properties of cyclic peptides. This is demonstrated with one striking example, the cyclic tetrapep-For this molecule composed of strictly alternating D-and L-configurated residues, a highly symmetrical structure is expected, which should be an optically inactive meso-form. Cyclization of the enantiomeric pure linear precursor D-P~o-L-P~o-D-P~o-L-P~o, however, yields a racemic mixture of two enantiomeric cyclotetrapeptides, both with twofold symmetry and a cis-trans-cis-trans sequence of the peptide bonds. Remarkably, this formation of a racemate was not caused by racemization, but by &/trans isomerization of all peptide bonds in the ring. This procans may occur in the,linear precursor during the ring formation (cyclization of conformers with trans-cis-trans or cis-trans-cis arrangement of the amide bonds) as well as in the enantiomeric pure cyclic tetrapeptide at higher temperature. In the latter case, an all& structure should exist as the intermediate, which can form a cis-truns-cis-truns sequence in two equivalent ways, leading finally to two enantiomeric cyclotetrapeptides. In the first one, the cis peptide bonds are attributed to the L-residues and the trans peptide bonds to the &residues; in the second one, the cis bonds belong to the D and the trans bonds to the bresidues. The mixture of these two enantiomers does not crystallize in the racemic form, but in enantiomeric pure separate crystals. The structural properties could be proved by 'H-and 13C-nmr spectroscopy and x-ray analysis. The cis/truns isomerization process was confirmed by optical rotation measurements and CD spectroscopy, as well as DREIDING model studies. Calorimetric measurements in the solid state suggest the existence of the expected all-cis intermediate. The backbone conformation of the 12-membered medium-sized ring shows only slight deviations-up to 6"-from the planarity of the peptide bonds. On the other hand, the four pyrrolidine rings show different types of puckering of the C, or the C, atoms.

Conformational study of linear alternating and mixed D‐ and L‐proline oligomers using electronic and vibrational CD and fourier transform IR

“…22,44 at the University of Ulm to examine the influence of substituting D-amino acid residues on the backbone conformation of an Lamino acid peptide by performing cyclization reactions on diastereomeric D,L-oligoprolines. These are the source of the complete series of N-terminally Boc-protected ( Boc=tert-butyloxycarbonyl) peptide sequences with 3 to 8 alternate D-and L-proline residues used in this study, which include Boc-LDL-Pro3, BOC-DLDL-PTO~, and BOC-DLDLDLDL-Pr08, using the notation introduced above.…”

Polarizability tensor theory by Green’s function matrix: Circular dichroism and ultraviolet absorption band shape calculations of cyclo(Gly-Pro-Gly-D-Ala-Pro) having β- and γ-turns

“…54,55 Also, Mästle et al 56 reported that the two different enantiomers isolated from the racemic mixture of a cyclic tetrapeptide, cyclo͑D-Pro-L-Pro-D-Pro-L-Pro͒ show, qualitatively, almost completely inverse CD spectra, in which the enatiometric compound B has the negative n* bands around 230 nm. This may be explained by the fact that these two cycloenantiomers have symmetrically opposite ring directions ͑opposite helical senses͒.…”

c[D‐pro‐Pro‐D‐pro‐N‐methyl‐Ala] adopts a rigid conformation that serves as a scaffold to mimic reverse‐turns

“…Unlike cyclic tripeptides and pentapeptides which contain either only cis-, or largely transamide bonds, respectively, CTPs contain a mixture of both cis-and trans-peptide bonds. 24 This ''sweet spot'' of CTPs seems ideal for fine tuning of various rigid structures since the positions of cis/trans-amide bonds largely determines the conformation of the mimetic scaffold. The CTP c[Pro-proPro-pro] is a combination of these two reverse-turn mimetic approaches shown to exist with stable cis-trans-cis-trans and trans-cis-trans-cis amide bond conformers at room temperature in water.…”