Friedel-Crafts dealkylation reaction mediated by a stereoselective proton transfer in the fragmentation of protonated cyclic indolyl α-amino esters

Abstract

Rationale: Chiral cyclic indolyl α-amino esters are valuable substructures of peptides and peptidomimetics. Systematically exploring the fragmentation behavior of the protonated cyclic indolyl α-amino esters by a combination of high-resolution high-energy collisional dissociation mass spectrometry, hydrogen-deuterium exchange experiments and density functional theory (DFT) calculations is useful for further understanding their intrinsic properties and the fragmentation mechanisms of peptidomimetics constructed with them.

Methods: All high-resolution high-energy collisional dissociation tandem mass spectrometry experiments were carried out using electrospray ionization hybrid Quadrupole-Orbitrap mass spectrometry in positive ion mode. Only the labile hydrogens were exchanged with deuterium in hydrogen-deuterium exchange experiments. Theoretical calculations were carried out by the DFT method at the B3LYP level with the 6-311G(d,p) basis set in the Gaussian 03 package of programs.

Results: In the fragmentation of protonated cyclic indolyl α-amino esters, when the two labile hydrogens on the N(8) position are successively transferred to the C(3) and C(4) positions, a Friedel-Crafts dealkylation reaction takes place spontaneously, with concomitant formation of an ion-neutral complex of [cyclic N-sulfonyl ketimino esters/protonated indoles]. Direct separation of this complex formed the protonated indoles, while a stereoselective proton transfer between the two components in the complex gave rise to protonated cyclic N-sulfonyl ketimino esters, which coincided with the hydrogen-deuterium experiments.

Conclusions: Using H/D exchange experiments combined with theoretical calculations, a Friedel-Crafts dealkylation reaction mediated by a stereoselective proton transfer in the [cyclic N-sulfonyl ketimino esters/protonated indoles] complex was proposed for the fragmentation of protonated cyclic indolyl α-amino esters in high-energy collisional dissociation tandem mass spectrometry for the first time. Copyright © 2016 John Wiley & Sons, Ltd.