Determination of AbsoluteConfiguration and Conformationof a Cyclic Dipeptide by NMR and Chiral Spectroscopic Methods.

Increasing precision of contemporary computational methodsmakesspectroscopies such as vibrational (VCD) and electronic (ECD) circulardichroism attractive for determination of absolute configurations(AC) of organic compounds. This is, however, difficult for polar,flexible molecules with multiple chiral centers. Typically, a combinationof 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, Ramanoptical activity (ROA), and nuclear magnetic resonance (NMR) techniquesfor AC determination were investigated. The spectra were interpretedwith the aid of density functional theory (DFT) calculations. Foldedgeometries stabilized by van der Waals and electrostatic interactionsbetween the diketopiperazine (DKP) ring and the indole group are predictedto be preferred for CAT, with more pronounced folding due to Arg-Trpstacking in the case of SS/RR-CAT. The RS/SRisomers prefer a twist-boat puckering of the DKP ring, which isrelatively independent of the orientation of the side chains. Calculatedconformer-averaged VCD and ECD spectra explain most of the experimentallyobserved bands and allow for AC determination of the tryptophan side-chain,whereas the stereochemical configuration of the arginine side-chainis visible only in VCD. NMR studies provide characteristic long-range 2J(C,H) and 3J(C,H) coupling constants, and nuclear Overhauser effect (NOE) correlations,which in combination with either ECD or VCD also allow for completeAC determination of CAT. [ABSTRACT FROM AUTHOR]