Determination of Absolute Configuration and Conformation of a Cyclic Dipeptide by NMR and Chiral Spectroscopic Methods

Abstract

Increasing precision of contemporary computational methods makes spectroscopies such as vibrational (VCD) and electronic (ECD) circular dichroism attractive for determination of absolute configurations (AC) of organic compounds. This is, however, difficult for polar, flexible molecules with multiple chiral centers. Typically, a combination of several methods provides the best picture of molecular behavior. As a test case, all possible stereoisomers with known AC (RS, SR, SS, and RR) of the cyclic dipeptide cyclo(Arg-Trp) (CAT) were synthesized, and the performances of the ECD, infrared (IR), VCD, Raman, Raman optical activity (ROA), and nuclear magnetic resonance (NMR) techniques for AC determination were investigated. The spectra were interpreted with the aid of density functional theory (DFT) calculations. Folded geometries stabilized by van der Waals and electrostatic interactions between the diketopiperazine (DKP) ring and the indole group are predicted to be preferred for CAT, with more pronounced folding due to Arg-Trp stacking in the case of SS/RR-CAT. The RS/SR isomers prefer a twist-boat puckering of the DKP ring, which is relatively independent of the orientation of the side chains. Calculated conformer-averaged VCD and ECD spectra explain most of the experimentally observed bands and allow for AC determination of the tryptophan side-chain, whereas the stereochemical configuration of the arginine side-chain is visible only in VCD. NMR studies provide characteristic long-range (2)J(C,H) and (3)J(C,H) coupling constants, and nuclear Overhauser effect (NOE) correlations, which in combination with either ECD or VCD also allow for complete AC determination of CAT.

Synthesis of α‐Dawson‐Type Silicotungstate [α‐Si2W18O62]8− and Protonation and Deprotonation Inside the Aperture through Intramolecular Hydrogen Bonds

“…Whereas ECD is suited for detecting long‐range interactions of chromophores and is the method of choice for the determination of axial chirality (e.g., in biaryls22–26), VCD operates on the smaller‐length scale of bond vibrations and should be more appropriate for analysis of central chirality 8,27,28. We therefore recorded the VCD spectrum of 2 (CDCl 3 solution) in a low‐dead‐volume BaF 2 sample cell.…”

Development and evaluation of cationic amphiphilic antimicrobial 2,5‐diketopiperazines

“…The influence of stereochemistry has been studied in details for short linear AMPs by Isaksson et al The results from that study suggest that it is possible to create effective antimicrobials with mixed stereochemistry but also that optimized isomers allowing for internal hydrogen bonding are preferred and are able to form amphiphilic adducts in solution suited for membrane insertion . Mixed functional 2,5‐DKPs are capable of forming several different conformations that can be challenging to determine, and it was outside the scope of the current study to separate and analyze the different possible isomers . In our current studies, we have restricted our molecular design and synthetic methods to yield mixtures and also a substitution pattern placing all the hydrophobic bulk on the amide nitrogens via alkylation creating mainly symmetric DKPs.…”

The chemical bonding and spectral assignments of rhodium(III)-catalyzedcloso-dodecaborate complexes: Ab initio study

“…In the computation, the singlet and triplet spin states (spin multiplicities 2 S + 1 = 1, 3) were considered for initial structure. Dispersion‐corrected DFT (DFT‐D3(BJ)) proposed by Grimme was utilized, which overcomes the conventional density functionals in properly describing the long‐range dispersion effects, and is very accurate and efficient for the modeling of the complexes with weak interaction . The RhCD structure was optimized without any symmetry constraints.…”

“…The molecular orbitals (MOs) were plotted with the isodensity surfaces (0.02 e 1/2 /(bohr) 3/2 ), and the molecular graphs were visualized using the VMD program . The long‐range corrected functional CAM‐B3LYP was used to calculate the excited states within the framework of the time‐dependent density functional theory . Chemical bonding analyses were carried out using the adaptive natural density partitioning (AdNDP) method proposed by Zubarev and Boldyrev .…”