Complete analysis of the 1H and 13C NMR spectra of diastereomeric mixtures of (R,S- and S,S-)-3,6-dimethoxy-2,5-dihydropyrazine-substituted indoles and their conformational preference in solution

Complete analysis of the 1H and 13C NMR spectra obtained with and without a chemical shift reagent (Eu(fod)3), of bis‐lactim ether 1 (Schöllkopf auxiliary) and monosubstituted 3‐ or 2‐{(2R,5S or 2S,5S)‐5‐isopropyl‐3,6‐dimethoxy‐2,5‐dihydropyrazin‐2‐yl]methyl}‐1H‐indoles is presented using gradient‐selected one‐dimensional (1D) and two‐dimensional NMR techniques, such as 1D TOCSY, 1D NOESY (DPFGSE NOE), gCOSY, NOESY, ROESY gHETCOR, gHSQC and gHMBC. The contour plot of the gCOSY spectrum of 1–10 revealed cross peaks arising from the five‐bond coupling between the H2 and H5 resonances of the dihydropyrazine ring for syn‐ (5JH2, H5 = 4–5.7 Hz) and for anti‐isomers (5JH2, H5 = 3.4–3.8 Hz). The magnitude of the coupling constant was utilized to distinguish between the syn‐ and the anti‐isomers (diastereomers). The precise values of nJHH (n = 3, 4, 5, 6) coupling constants for the indole and 2,5‐dihydropyrazine moieties deduced from the calculated NMR spectra were supported by 1D TOCSY and gCOSY experiments and gauge invariant atomic orbital (GIAO) calculations. The magnitude of the coupling constants (5JH2, H5) indicates that the dihydropyrazine ring exists in a boat conformation. In both isomers, the indole group adopts a ‘folded’ conformation in which one diastereotopic face is effectively shielded by the aromatic benzene ring of the indole. This is supported by gradient‐selected 1D NOESY and 2D NOESY experiments. Theoretical calculations of the conformation were performed to support the through‐space shielding effect of the aromatic indole moiety based on the DFT/GIAO calculated 1H NMR data (chemical shifts and coupling constants) for 2‐syn‐ and 2‐anti‐diastereomers in CDCl3. Copyright © 2009 John Wiley & Sons, Ltd. On the basis of the coupling constant (5JrmH2, H5) and molecular mechanic optimization of structures for both syn and anti diastereomers, it is suggested that the indole group adopts a ‘folded’ conformation in 2‐10 in which one diastereotopic face is effectively shielded by the aromatic indole ring.