Complete analysis of the H-1 and C-13 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

Abstract

Complete analysis of the H-1 and C-13 NMR spectra obtained with and without a chemical shift reagent (Eu(fod)(3)), of bis-lactim ether 1 (Schollkopf 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- ((5)J(H2),(H5) = 4-5.7 Hz) and for anti-isomers (5J(H2,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 (n)J(HH) (n = 3, 4, 5, 6) coupling constants for the indole and 2,5-dihydropyrazine moieties deduced from the calculated NMR spectra were supported by 1 D TOCSY and gCOSY experiments and gauge invariant atomic orbital (GIAO) calculations. The magnitude of the coupling constants (5J(H2,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 H-1 NMIR data (chemical shifts and coupling constants) for 2-syn- and 2-anti-diastereomers in CDCl3. Copyright (C) 2009 John Wiley & Sons, Ltd.