One-Shot Determination of Residual Dipolar Couplings: Application to the Structural Discrimination of Small Molecules Containing Multiple Stereocenters

Abstract

A novel approach for the fast and efficient structural discrimination of molecules containing multiple stereochemical centers is described. A robust J-resolved HSQC experiment affording highly resolved J/T splittings along the indirect dimension and homodecoupled H signals in the detected dimension is proposed. The experiment enables in situ distinction of both isotropic and anisotropic components of molecules dissolved in compressed PMMA gels, allowing a rapid and direct one-shot determination of accurate residual dipolar coupling constants from a single NMR spectrum.

Examining the importance of the level of computational theory used in solution‐phase structural determinations by NMR using residual dipolar couplings

“…It is the goal of this work to evaluate to what extent the choice of computational method effects the quality of agreement with observed RDCs, and so a well‐known molecule was chosen to avoid additional complexity. This methodology determines the RDCs observed in solution based on the comparison of two J resolved homo‐decoupled HSQC spectra . One spectrum in isotropic solution displays the 1 J CH couplings clearly and the other in anisotropic solution displays the sum of the scalar and dipolar couplings.…”

Isotropic/Anisotropic NMR Editing by Resolution‐Enhanced NMR Spectroscopy

“…In such conditions, sizeable 1 H chemical shift dispersions between iso and aniso components (Δ δ =δ iso ‐δ aniso ) around 0.1 ppm (≈50 Hz at 500 MHz) could be observed in a J SB‐HSQC spectrum . These simultaneous J / T measurements have been further refined in more extreme sample conditions showing smaller magnetic susceptibility differences, such as found in poly(methyl methacrylate) PMMA/CDCl 3 media, in where more optimal analytical conditions due to the relatively longer T 2 relaxation times and narrower signals are often available . In this Communication, a step forward is introduced by extending this optimal, direct recording of 1 H‐ 13 C RDCs at the same time that Δδ( 1 H) and Δδ( 13 C) are also detected in molecules dissolved in PMMA/CDCl 3 gels.…”

“…Besides, the determination of the tiny 1 D (CH) of +0.3 Hz in H‐22 due to the very similar 1 J (C22‐H22) and 1 T (C22‐H22) values is only feasible due to its observable Δδ( 13 C) of +6.7 Hz. As recently reported, 1 J CH and 1 T CH measurements could also be performed along the indirect F1 dimension of complementary J CH ‐resolved HSQC ( J ‐HSQC) spectra . Figure A and 5B compare the SA‐PIP‐HSQC and J ‐HSQC cross‐peaks for the H13 and H15b protons, respectively, of 1 .…”

“…Note that the observed Δδ( 13 C) in the SA‐PIP‐HSQC spectrum is fundamental to distinguish both iso/aniso contributions because the similar values of Δδ( 1 H) and 1 J CH vs. 1 T CH on these signals prevent their precise measurements in the J ‐HSQC spectrum. The measured 1 H‐ 13 C RDCs and the magnitude and the sign of the Δδ( 13 C) and Δδ( 1 H) of 1 extracted from these reported PIP‐HSQC spectra are in strong agreement with those obtained from the 1D spectra and also with those published in previous reports under similar sample conditions …”

Pure shift 1H NMR: what is next?

“…An important practical application of the pure shift techniques is the determination of the magnitude and sign of scalar and residual dipolar coupling constants through the highly resolved and simplified pure shift spectra. [21,22,25,[48][49][50][51][52][53][54][55] Further promising applications are currently in their initial stage of development, such as the combination of pure shift with the dynamic nuclear polarization technique [56] or the use of pure shift spectra to carry out quantitative studies in metabolomics. [57] In the future, it could also be possible to explore the application of pure shift techniques to other nuclei (such as 19 F, 31 P or 2 H), in quality control processes, drug degradation studies and to monitor fast reactions, among others.…”