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

Abstract

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. NMR in aligning media, either lyotropic liquid crystals (LLC) or polymer gels, in combination with molecular modelling is a unique framework to solve complex structural problems whose analytical wealth lies in the establishment of non-local structural correlations. As an alternative to 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 ( 2 H-RQCs) can be extracted from 2 H 2D-NMR spectra recorded at natural abundance level in samples oriented in a homopolypeptide LLC (PBLG). These 2 H-RQCs were successfully used to address non-trivial 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 2 H-RQCs, being in this case at 2 H natural abundance.

Molecular enantiodiscrimination by NMR spectroscopy in chiral oriented systems: Concept, tools, and applications

“…In case of artemisinin, the smallest Q-factor was below 0.02, with a very small of RD average below 4%. 177 with permission This result has been obtained with the stereoisomer of absolute configuration 1S, 4R, 5S, 6R, 7S, 10R, and 11R, namely, the known absolute configuration. These results have therefore demonstrated that the 3D structure/ relative configuration of complex bioactive molecules could be unambiguously determined using 2 H-RQCs, being in this case at 2 H natural abundance.…”

“…of 2 H-RQCs extracted from ANAD NMR 2D spectra, assuming that the sensitivity is nowadays a real drawback. 177 The performance of this last tool has been examined for two multicyclic chiral, natural compounds of pharmaceutical interest oriented in PBLG-based oriented samples: the strychnine, a poison, and artemisinin, an antimalarial drug used against Plasmodium falciparum malaria, as examples. Figure 37 shows the ANAD Q-resolved Fz 2D spectrum of artemisinin recorded within 15 h with only (50 mg [MW = 282.3], i.e., a molar concentration for each monodeuterated isotopomer of about 35 μmolÁL À1 ) where unambiguous 15 (over 16) 2 H-QDs can be experimentally measured and used.…”

Study and quantification of the enantiodiscrimination power of four polymeric chiral LLCs using NAD 2D-NMR

“…So far, the recent exploitation of 2 H-RQCs has been performed using the MSpin-RQC program, 51,52 a variant of MSpin, initially able to manage RDCs or RCSAs as input data. 30,53 In this work, another computational approach delivering orientational data 5) including their atomic numbering; the red and blue colors are used for identifying them.…”

“…63 Another possibility could be to explore all possible combinations of signs for each inequivalent site, using a screening-protocol computational approach. 52 Currently, the experimental approach used in this work consists in exploiting additional 13 C data ( 1 T CH ) extracted from the analysis of simple proton-coupled 1D experiments (inverse gate/single pulse) with the help of heteronuclear ( 1 T CH /2)-or ( 1 T CH /4)-resolved heteronuclear 2D spectra (see Fig. S7 and S8, ESI †).…”

Single experiment measurement of residual dipolar couplings in aqueous solution using a biphasic bisperylene imide chromonic liquid crystal

“…NMR in weakly aligned media has become a firmly established tool for structural elucidation of organic compounds. [1][2][3] Although most applications to structural elucidation problems involved the use of residual dipolar couplings (RDCs), [4,5] mostly one-bond proton-carbon 1 D CH ones, residual chemical shift anisotropies (RCSAs), [6,7] and even 2 H residual quadrupolar couplings (RQCs) [8] have come recently into play.…”