Long‐Range Residual Dipolar Couplings: A Tool for Determining the Configuration of Small Molecules

Abstract

Together with NOE and J coupling, one-bond residual dipolar coupling (RDC), which reports on the three-dimensional orientation of an internuclear vector in the molecular frame, plays an important role in the conformation and configuration analysis of small molecules in solution by NMR spectroscopy. When the molecule has few C-H bonds, or too many bonds are in parallel, the available RDCs may not be sufficient to obtain the alignment tensor used for structure elucidation. Long-range RDCs that connect nuclei over multiple bonds are normally not parallel to the single bonds and therefore complement one-bond RDCs. Herein we present a method for extracting the long-range RDC of a chosen proton or group of protons to all remotely connected carbon atoms, including non-protonated carbon atoms. Alignment tensors fitted directly to the total long-range couplings (T=J+D) enabled straightforward analysis of both the long-range and one-bond RDCs for strychnine.

Determination of Relative Configuration from Residual Chemical Shift Anisotropy

“…Molecular alignment in these gels is induced by compressing or stretching the gel matrix within the NMR tube in an adjustable fashion. 27,28 The aforementioned 1 H- 13 C RDCs, either one-bond [10][11][12][13][14][15] or long-range, 32 report on the relative orientations of inter-atomic vectors in the molecule. In contrast, RCSAs report on the relative orientations of chemical shielding tensors of individual atoms.…”

Probing Long‐Range Anisotropic Interactions: a General and Sign‐Sensitive Strategy to Measure 1H–1H Residual Dipolar Couplings as a Key Advance for Organic Structure Determination

“…Indeed, most experiments yield the absolute value of the sum of both couplings | T ij |=| J ij + 2 D ij | and, since for long‐range couplings the magnitude of J ij is generally smaller or comparable to 2 D ij , this results in sign ambiguity for D ij . Although it is possible to perform structure optimization based on the magnitude of the total coupling T ij , this inevitably amplifies restraint ambiguity and sacrifices much of the valuable information content. Until now, the pursuit of long‐range RDCs was mostly aimed at heteronuclear ( 1 H– 13 C) couplings .…”

“…Although it is possible to perform structure optimization based on the magnitude of the total coupling T ij , this inevitably amplifies restraint ambiguity and sacrifices much of the valuable information content. Until now, the pursuit of long‐range RDCs was mostly aimed at heteronuclear ( 1 H– 13 C) couplings . These methods work well in particular cases, but the low sensitivity at the natural abundance of 13 C is a severe limitation, while at the same time, obtaining the RDC sign remains challenging.…”

Computer‐Assisted 3D Structure Elucidation of Natural Products using Residual Dipolar Couplings

“…Thel evel of confidence between models with similar AIC could be easily increased by including more RDCs,s uch as selected long-range couplings, [30,[33][34][35] or extending the procedure to the combined use of RDCs and other observables such as J-couplings or NOEdetermined distances.N ote that the dimensionless character of the AIC factor makes it easy to mix observables of different natures,aslong as their respective uncertainties are correctly estimated. Thel evel of confidence between models with similar AIC could be easily increased by including more RDCs,s uch as selected long-range couplings, [30,[33][34][35] or extending the procedure to the combined use of RDCs and other observables such as J-couplings or NOEdetermined distances.N ote that the dimensionless character of the AIC factor makes it easy to mix observables of different natures,aslong as their respective uncertainties are correctly estimated.…”