Detection and Verification of a Key Intermediate in an Enantioselective Peptide Catalyzed Acylation Reaction

Abstract

Until now, the intermediate responsible for the acyl transfer of a highly enantioselective tetrapeptide organocatalyst for the kinetic resolution of trans-cycloalkane-1,2-diols has never been directly observed. It was proposed computationally that a π-methylhistidine moiety is acylated as an intermediate step in the catalytic cycle. In this study we set out to investigate whether we can detect and characterize this key intermediate using NMR-spectroscopy and mass spectrometry. Different mass spectrometric experiments using a nano-ElectroSpray Ionization (ESI) source and tandem MS-techniques allowed the identification of tetrapeptide acylium ions using different acylation reagents. The complexes of trans-cyclohexane-1,2-diols with the tetrapeptide were also detected. Additionally, we were able to detect acylated tetrapeptides in solution using NMR-spectroscopy and monitor the acetylation reaction of a trans-cyclohexane-1,2-diol. These findings are important steps towards the understanding of this highly enantioselective organocatalyst.

Quantifying Intermolecular Interactions in Asymmetric Peptide Organocatalysis as a Key toward Understanding Selectivity

“…The stabilization of ions in general is unfavorable in nonpolar organic solvents; thus, the concentration of ionic species appears to be low. Nevertheless, the acetylated peptide (PAc + ) was detected NMR spectroscopically in toluene at a high peptide concentration and an excess of acetic anhydride …”

Site‐Selective Acylation of Pyranosides with Immobilized Oligopeptide Catalysts in Flow

“…Synthetic oligopeptides as organocatalysts turned out to be especially useful to provide insights into how enzymes work as already a few amino acids are sufficient to form secondary structures [3–7] . These structures, which typically form due to noncovalent interactions such as H‐bonds and London dispersion interactions, [4,8–9] are important for peptide catalysts to perform selective reactions [10–13] . Still, the oligopeptides must retain some flexibility, allowing them to adapt to the substrate and hence perform reactions comparable to enzymes [7,9,14–17] .…”

“…[3][4][5][6][7] These structures, which typically form due to noncovalent interactions such as H-bonds and London dispersion interactions, [4,[8][9] are important for peptide catalysts to perform selective reactions. [10][11][12][13] Still, the oligopeptides must retain some flexibility, allowing them to adapt to the substrate and hence perform reactions comparable to enzymes. [7,9,[14][15][16][17] Over the years, peptides were used to catalyze various reactions like oxidations, [18][19][20][21] reductions, [22][23] group transfers, [15,[24][25][26] among others.…”