Synthesis and Analysis of the Conformational Preferences of 5‐Aminomethyloxazolidine‐2,4‐dione Scaffolds: First Examples of β²‐ and β^2, 2‐Homo‐Freidinger Lactam Analogues

Abstract

Constrained peptidomimetic scaffolds are of considerable interest for the design of therapeutically useful analogues of bioactive peptides. We present the single-step cyclization of (S)- or (R)-α-hydroxy-β(2)- or α-substituted-α-hydroxy-β(2, 2)-amino acids already incorporated within oligopeptides to 5-aminomethyl-oxazolidine-2,4-dione (Amo) rings. These scaffolds can be regarded as unprecedented β(2)- or β(2, 2)-homo-Freidinger lactam analogues, and can be equipped with a proteinogenic side chain at each residue. In a biomimetic environment, Amo rings act as inducers of extended, semi-bent or folded geometries, depending on the relative stereochemistry and the presence of α-substituents.

Controlling Cyclopeptide Backbone Conformation with β/α‐Hybrid Peptide–Heterocycle Scaffolds

“…The i Ser building block was incorporated into the peptide sequences without protection of the OH group. Under the optimized, reaction conditions described above, by‐products originating from reactivity of the OH group (e.g., depsipeptides) were not observed, as confirmed by 1 H NMR spectroscopy and RP‐HPLC MS analysis of the crude reaction mixtures. In all cases, epimerization during the cyclization of i Ser was excluded on the basis of the NMR and HPLC analyses (see Exp.…”

“…Sketches of the likely geometries of the linear precursors of the Amo‐CTPs 1 , 3 or 2 , 4 , including homo‐ or heterochiral Amo‐Phe scaffolds, respectively. Similar geometries can be hypothesized for the linear precursors of the Amo‐CPPs 5 – 8 .…”

“…In contrast to native β‐turns,, , which require four residues to form the 10‐membered hydrogen‐bonded structure in the direction 1→4 of the sequence, the pseudo‐β‐turn requires only two residues to delimit a nine‐membered hydrogen bond in the 2→1 opposite direction. This kind of pseudo‐retro‐β‐turn has been observed very rarely in short sequences; it is more common in foldamers composed of repeating α/β‐hybrid peptide units , . The ROESY‐derived geometry of 7 was maintained during the unrestrained MD simulation, although ( R )‐AmoNH and ( R )‐PheC=O, and TrpNH and AlaC=O, were prone to rotate, leading to occasional loosening of the hydrogen bonds.…”

“…Recently, we proposed the expedient cyclization, in solution or in solid phase, of isoserine ( i Ser) or other α‐hydroxy‐β‐amino acids, already embedded in a oligopeptide sequence. Treatment with disuccinimidyldicarbonate (DSC) and a catalytic amount of base gave a 5‐(aminomethyl)oxazolidine‐2,4‐dione (Amo) dipeptide scaffold, comprising i Ser and the amine group of the next residue (Scheme ) …”

Exploiting β‐Amino Acid Enolates in Direct Catalytic Diastereo‐ and Enantioselective C−C Bond‐Forming Reactions

“…Furthermore, lactam moieties embedded in peptide main chains are established b-turn inducers in the contexto fa-peptides. [23] To briefly evaluatet he influence of the additional carbon in b-aminoa cidso nt he peptide conformation, [24] spiro compound 13 was further elongated by standard procedures to afford the constrained a/b-hybrid peptide. Preliminary NMR and circulard ichroism (CD) spectral analysis of 15 suggested that the tendency of this short peptidet of orm ad iscrete secondary structure was rather modesti nc omparison to that of a-peptides;f urther detailede xamination is at opic for future investigation.…”