Determination of absolute configuration and conformation of a cyclic dipeptide by NMR and chiral spectroscopic methods.
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.
Centre for Theoretical and Computational Chemistry, University of Tromsø, N-9037 Tromsø, Norway.
Xiaojun
X
Li
Kathrin H
KH
Hopmann
Jana
J
Hudecová
Johan
J
Isaksson
Jana
J
Novotná
Wenche
W
Stensen
Valery
V
Andrushchenko
Marie
M
Urbanová
John-Sigurd
JS
Svendsen
Petr
P
Bouř
Kenneth
K
Ruud
D001120:Arginine / Q000737:chemistry; D003500:Cyclization; D004151:Dipeptides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D013237:Stereoisomerism; D013816:Thermodynamics; D014364:Tryptophan / Q000737:chemistry
D004151:Dipeptides; D014364:Tryptophan; D001120:Arginine