Deuterium Residual Quadrupolar Couplings: Crossing the Current Frontiers in the Relative Configuration Analysis of...

The determination of the 3D structure (configuration and preferred conformation) of complex natural and synthetic organic molecules is a long-standing but still challenging task for chemists, with various implications in pharmaceutical sciences whether or not these substances have specific bioactivities. Nuclear magnetic resonance (NMR) in aligning media, either lyotropic liquid crystals (LLCs) or polymer gels, in combination with molecular modeling is a unique framework for solving complex structural problems whose analytical wealth lies in the establishment of nonlocal structural correlations. As an alternative to the already well-established anisotropic NMR parameters, such as RDCs (residual dipolar couplings) and RCSAs (residual chemical shift anisotropies), it is shown here that deuterium residual quadrupolar couplings (²H-RQCs) can be extracted from ²H 2D-NMR spectra recorded at the natural abundance level in samples oriented in a homopolypeptide LLCs (poly-γ-benzyl-l-glutamate (PBLG)). These ²H-RQCs were successfully used to address nontrivial structural problems in organic molecules. The performance and scope of this new tool is examined for two natural chiral compounds of pharmaceutical interest (strychnine and artemisinin). This is the first report in which the 3D structure/relative configuration of complex bioactive molecules is unambiguously determined using only ²H-RQCs, which, in this case, are at ²H natural abundance.