Structural features of thePip/AzPip couple in the crystalline state: influence of the relative AzPip location in an azadipeptide sequence upon the induced chirality and conformational characteristics

Abstract

Azapipecolic (AzPip) is a pipecolic (Pip) residue analogue containing a nitrogen atom in place of the C(alpha)H group. AzPip was introduced into two reverse dipeptide sequences, Piv-AzPip-L-Ala-NHiPr I and Boc-L-Ala-AzPip-NHiPr II in order to evaluate, in the crystalline state, the influence of the L-Ala-induced chirality upon the prochiral AzPip residue, and therefore the resulting conformational characteristics, according to the relative position of the AzPip residue. Piv-DL-Pip-NHMe III served as a control derivative for comparison between the properties of the two different heterocycles of Pip and AzPip residues. Piperidine and hexahydropyridazine rings have a few characteristics in common: chair conformation, axial disposition of the C-terminal backbone substituent and the cisoid form of the N-terminal tertiary amide function. An almost pure sp3 hybridization state is observed for the substituted nitrogen atom N(alpha), so that L-Ala induces an AzPip (R) or (S) chirality when it follows or precedes, respectively, the azaresidue in such a pseudodipeptide sequence. If both I and II compounds present a short NH...N contact between the sp2 tertiary amide nitrogen atom and the NH of the next secondary amide function, whatever the chiral nature of the sequence, the heterochiral azadipeptide I adopts a rather totally extended conformation while the homochiral azadipeptide II is folded by a beta-VI turn-like structure stabilized by a classical 4-->1 intramolecular hydrogen bond.

Conformational Preferences of Proline Analogues with Different Ring Size

“…In addition, the values of torsion angles φ and ψ for X-ray structures of these two peptides are different from our calculated ones in the gas phase and in solution. The piperidine ring can adopt chair and boat conformations but only the chair conformation preferentially exists in X-ray structures of Pip-containing peptides, [32][33][34] which is consistent with our calculated results for the Pip dipeptide. The backbone torsion angles φ and ψ of an X-ray structure for t-Boc-Pip-NHMe 33 are quite similar to those of a preferred conformation tDc for the Pip dipeptide in chloroform and water.…”

Configurationally driven folding of model tetrapeptides containing L‐ or D‐morpholine‐3‐carboxylic acids as β‐turn nucleators

“…12) resulted in a folded structure having the morpholine nucleus shifted at position i12 of a b-turn and bearing the C¼ ¼O group at position 3-axial, in analogy with the folding propensity of pipecolic and azapipecolic acid-containing peptides, as reported. 60 The b-turn structure was stabilized by a 10- membered pseudo-cycle intramolecularly hydrogenbonded between Gly NH and the acetyl group, in accordance with NMR data for such amide proton. Also, dihedral angles of the global minimum conformer corresponding to / and w values at positions i11 and i12 suggested L-Mor to induce a type-VIa b-turn (see Table 5, entries 1 and 9).…”

Induction of chirality: experimental evidence of atropisomerism in azapeptides

“…A facile access, superior to reported methods, 4 was established (see ESIw). Next, 1 was coupled with 1,2-dimethylsemicarbazide (5), prepared from potassium cyanate and 1,2-dimethylhydrazine dihydrochloride, to produce Cbz-Gly[CCONMe]-azaAla-NH 2 (9).…”

“…It might be taken into consideration that the nitrogen N 2 of compounds 6-9 adopts an sp 3 hybridization state as it has been observed for the acylated azapipecolic amide motif in peptides. 5 Restricted pyramidal inversion of that nitrogen could then produce two enantiomers and would thus be the source of chirality. However, as expected, our crystallographic data indicate the sp 2 hybridization state of N 2 in azadipeptide amides 7 and 9 (for bond distances and angles, see CIF file, ESIw).…”