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

• Published in: The journal of physical chemistry. A, Molecules, spectroscopy, kinetics, environment, & general theory Vol. 117; no. 8; pp. 1721 - 1736
• Main Authors: Li, Xiaojun, Hopmann, Kathrin H, Hudecová, Jana, Isaksson, Johan, Novotná, Jana, Stensen, Wenche, Andrushchenko, Valery, Urbanová, Marie, Svendsen, John-Sigurd, Bouř, Petr, Ruud, Kenneth
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 28.02.2013
• Subjects: Arginine - chemistry; Atomic and molecular physics; Calculations and mathematical techniques in atomic and molecular physics (excluding electron correlation calculations); Constants; Cyclization; Density-functional theory; Dipeptides - chemistry; Electronic structure of atoms, molecules and their ions: theory; Electronics; Exact sciences and technology; General molecular conformation and symmetry; stereochemistry; Magnetic Resonance Spectroscopy; Mathematical analysis; Molecular Conformation; Molecular properties and interactions with photons; Nuclear magnetic resonance; Nuclear resonance and relaxation; Physics; Properties of molecules and molecular ions; Spectra; Spectroscopy; Stacking; Stereoisomerism; Thermodynamics; Tryptophan; Tryptophan - chemistry; Coupling constants; Frontier orbital; Nitrogen heterocycle; Electrostatic interaction; Theoretical study; Isomers; Circular dichroism; Calculation methods; Absolute configuration; Dipeptides; Density functional method; Flexible molecule; NMR spectra; Indole derivatives; Organic compounds; Conformation; Polar molecule
• ISSN: 1089-5639; 1520-5215
• DOI: 10.1021/jp311151h

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.