Can the absolute configuration of cyclic peptides be determined with vibrational circular dichroism?

Cyclic peptides show a wide range of biological activities, among others as antibacterial agents. These peptides are often large and flexible with multiple chiral centers. The determination of the stereochemistry of molecules with multiple chiral centers is a challenging and important task in drug development. Chiroptical spectroscopies such as vibrational circular dichroism (VCD) can distinguish between different stereoisomers. The absolute configuration (AC) of a stereoisomer can be determined by comparing its experimental spectra to computed spectra of stereoisomers with known AC. In this way, the AC of rigid molecules with up to seven chiral centers has been assigned (Bogaerts et al., Phys. Chem. Chem. Phys., 2020, 22, 18014). The question arises whether this is possible with more conformationally flexible molecules such as cyclic peptides. We here investigate to what extent the AC of cyclic peptides can be determined with VCD. More specifically, we investigate the maximum number of chiral centers a cyclic peptide can have in order to be able to unambiguously assign the AC with VCD. We present experimental and computed IR and VCD spectra for a series of eight tetrapeptides and hexapeptides with two, three and four chiral centers. We use our recently developed computational protocol with a conformational search based on sampling with meta-dynamics. We use visual inspection to compare the computed spectra of different stereoisomers with an experimental spectrum of the corresponding cyclic peptide with known AC. We find that the AC of the investigated cyclic peptides with two chiral centers can be unambiguously assigned with VCD. This is however not possible for all of the cyclic peptides with three chiral centers and for none of those with four chiral centers. At best, one can limit the number of possible stereoisomers in those cases. Our work shows that other techniques are needed to assign the AC of cyclic peptides with three or more chiral centers. Our study also constitutes a warning that the spectra of all stereoisomers should be computed before attempting to match to an experimental spectrum, to avoid an accidental erroneous match.