Vibrational CD (VCD) spectra of a series of blocked linear, alternating D- and L-proline containing oligopeptides, dissolved in D2O and in CDCl3, are reported. For the Boc-LDL-Pro3 to Boc-DLDLDLDL-Pro8 oligomers, the VCD spectra in the amide I band is a positive couplet, opposite in sense to that obtained for (L-Pro)n oligomers. While this admits the possibility of their favoring a right-handed helical chain conformation, the amide I ir spectra for these DL oligomers in D2O indicate a mixed, apparently alternate, cis-trans conformation that prevents a simple conclusion. Their VCD in D2O evidence no narrowing and has a progressive loss in intensity (measured as delta A/A) with an increase in chain length. In CDCl3 a similar pattern of positive VCD couplets decreasing in intensity with length was seen, but the ir spectra are narrower. Their electronic CD (ECD), in the uv, also indicates a loss in intensity with increasing length. Oligomers with odd or even numbers of Pro residues have different ECD patterns, indicating that those spectra are strongly influenced by local contributions arising in the N-terminal groups. The VCD arises from dipolar and vibrational coupling of the amides in the helical structure. All the spectra are consistent with the chiral end groups leading to formation of an excess of one helical handedness. With an increase in length, the influence of this selectiveness is less and the overall CD measured decreases.
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.
The title compound represents the smallest member of cyclic proline peptides corresponding to the general formula c(DDLL-Pro4)n with a strictly D,D,L,L double-alternating sequence of the chiral amino acid residues. The cyclopeptides with n greater than or equal to 2 could be synthesized from both DDLL-Pro4 (1) and DLLD-Pro4 (2). The cyclic monomer (n = 1) resulted only from 2, whereas not even a trace could be found by cyclization of 1. The peptide exists in a strongly strained Ci symmetrical conformation (x-ray analysis) with alternating cis and trans peptide bonds (ctct form I). The cis peptide bonds deviate from planarity (omega = 22 degrees); two of the pyrrolidine rings show a "South" conformation (phi = -94 degrees), whereas the other residues exhibit C alpha-endo puckering (phi = -124 degrees). Two of the psi angles surprisingly occur at +41 degrees (anti-cis'), the others are located in the trans' region. A quantitative ring opening occurs with trifluoroacetic acid at room temperature. In solution the existence of an isomeric ctcc sequence (form Ia) is indicated. Dreiding model studies also suggested a favorable conformation with a tctc sequence (form II). Consequently, we performed molecular mechanics calculations, based on the CHARMM force field and semiempirical quantum mechanical AM1 calculations (MOPAC program). Pronounced differences in the backbone parameters were found using these two methods. However, the theoretical studies evidenced the experimentally obtained differences in the cyclization tendencies of the linear precursors.
2 3a-d 4a, b 5a-c 6 3a, R = R ' = M e 4a, R=fBu 5b, X = O , R = t B u 3b, R = R = i P r 4b, R = P h SC, X = O , R = P h 3d, R = M e , R = P h 6, X = S , R = n B u 3c, R, R'=-(CH&-5a, X = O , R = M e The yields of 3a, c, d and 5a, c are reduced by nucleophilic addition to the PC double bond of the products. The homogeneity and constitution of the distillatively purified 3a, c,d Ph\ K Y 7a, c, d C=P-Y
Cyclic tetrapeptides exclusively composed of L‐ and D‐Pro have been studied by theoretical means (conformational searches and molecular mechanics calculations using the CHARMM program) supported by 1H‐NMR spectroscopy, X‐ray analysis and chiroptical measurements. We explored the entire conformational space of the diastereomers cyclo(LLLL‐Pro4) (I), cyc1O(LDLD‐Pro4) (II) and CYClo(LLDD‐Pro4) (III) including the low‐energy conformations and the related interconversion paths. The conformational interconversions were found to be restricted to cis/trans isomerisations of the amide bonds. Owing to the polycyclic nature of cyclo(Pro4) most of the cis/trans transitions are hindered by energy barriers higher than 30 kcal/mol (up to 150–200 kcal/mol). A few transitions are characterized by computed energy barriers comparable to those found in linear ‐Xxx‐Pro‐ sequences (∼ 18 kcal/mol), and are therefore experimentally significant. Experimental evidence has been obtained in the case Of CyClo(LDLD‐Pro4), where two enantiomers are interconverted by a series of 4 cis/trans isomerisations ctct→cttt→tttt→tctt→tctc. The Eyring activation parameters of this reaction were determined in H2O and in DMF by chiroptical measurements (ΔH#= 44 and 28 kcal/mol; ΔS#=59 and 22 cal K −1 mol−1, respectively), and correlated with the calculated barriers. In I and III comparable series of four cis/trans isomerisations relate two main conformations with the peptide bond sequences ctct and tctc. In compound I pseudorotational images are interconverted via ctct→ccct→cctt→cctc→tctc. The pathway ctct→ccct→cctt→cctc→tctc. that relates diastereomeric main conformations of III involves exclusively low‐energy intermediates; however, the transitions leading to the all‐cis conformation are energetically unfavourable, and the conformational space is divided in three insulated domains.
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