Screw sense alone can govern enantioselective extension of a helical peptide by kinetic resolution of a racemic amino acid

Abstract

Helical peptides built principally from the achiral quaternary amino acid Aib but with an induced preferred screw-sense exhibit enantioselectivity in their chain-extension reactions when presented with a racemic tertiary amino acid. This is the first demonstration that secondary structure alone, in the absence of local chiral residues, can direct the enantioselectivity of peptide coupling.

Helical Foldamers Incorporating Photoswitchable Residues for Light-Mediated Modulation of Conformational Preference

“…These findings are in agreement with previous reports that low polarity solvent and low temperature markedly favor higher stereoselectivity in chain extension reactions using racemic amino acid monomers . The effect of solvent on the stereoselectivity may be tentatively rationalized as follows.…”

“…These These findings are in agreement with previous reports that low polarity solvent and low temperature markedly favor higher stereoselectivity in chain extension reactions using racemic amino acid monomers. 52 The effect of solvent on the stereoselectivity may be tentatively rationalized as follows. As a results of cooperative effects, the extent to which N-acylated Aib homo-oligopeptide esters populate the 310-helical conformation depends on the maximum number of intramolecular hydrogen-bonds (C10 structures) that can be formed at a given main-chain length, ranging (in CDCl3 solution) from 41% and 69% for tri-and tetrapeptides to nearly 100% for octapeptides.…”

“…51 Conversely, EDC/HOBt mediated chain extension of Aib oligomers, induced to adopt a right handed screw sense by a remote L-(Me)Val residue, preferentially incorporate L-Val-OMe. 52 Chain extension of peptide oxazolone 7b led to preferential incorporation of L-Val-OMe, but it is not possible to use this result to deduce unequivocally the prevailing screw sense of the helical Aib domain.…”

Homochirality of β‐Peptides: A Significant Biomimetic Property of Unnatural Systems

“…For similar sequences, helicity alone can govern the direction of enantioselectivity. For example, P ‐helices favor the incorporation of l ‐amino acids, whereas M ‐helices prefer the coupling of the d ‐enantiomer …”

Controlling the conformational stability of coiled-coil peptides with a single stereogenic center of a peripheral β-amino acid residue

“…11 It was soon proved that a very useful approach for the development of foldamers is the introduction of unnatural amino acids into a-peptides in the process called foldamerization. 12,13 In terms of peptidomimetics, apart from widely studied foldamers based on higher homologues of a-amino acids, 14 there have been also studied the sequences containing a-aminoisobutyric acid (Aib), [15][16][17] oligoureas, 18 azapeptides, 19 a-hydrazido-peptides, 20 polyamides, 21 and others. [22][23][24] Foldamerization of sequences using b-amino acids shows two main advantages, namely, it improves both the conformational and proteolytic stability of peptides.…”