Expedited Selection of NMR Chiral Solvating Agents for Determination of Enantiopurity

Abstract

The use of NMR chiral solvating agents (CSAs) for the analysis of enantiopurity has been known for decades, but has been supplanted in recent years by chromatographic enantioseparation technology. While chromatographic methods for the analysis of enantiopurity are now commonplace and easy to implement, there are still individual compounds and entire classes of analytes where enantioseparation can prove extremely difficult, notably, compounds that are chiral by virtue of very subtle differences such as isotopic substitution or small differences in alkyl chain length. NMR analysis using CSAs can often be useful for such problems, but the traditional approach to selection of an appropriate CSA and the development of an NMR-based analysis method often involves a trial-and-error approach that can be relatively slow and tedious. In this study we describe a high-throughput experimentation approach to the selection of NMR CSAs that employs automation-enabled screening of prepared libraries of CSAs in a systematic fashion. This approach affords excellent results for a standard set of enantioenriched compounds, providing a valuable comparative data set for the effectiveness of CSAs for different classes of compounds. In addition, the technique has been successfully applied to challenging pharmaceutical development problems that are not amenable to chromatographic solutions. Overall, this methodology provides a rapid and powerful approach for investigating enantiopurity that compliments and augments conventional chromatographic approaches.

Discrimination of supramolecular chirality using a protein nanopore

“…Diastereotopic relationships can also be manifested in a non-covalent supramolecular context, as illustrated by stereoselective synthesis, 1 chiral HPLC 2 and the use of chiral shift agents in NMR spectroscopy. 3 , 4 However, the control and characterisation of supramolecular chirality in self-assembled systems 5 , 6 becomes more challenging as chemists seek to construct increasingly complicated assemblies. 7 , 8 Indeed, the expression, recognition and control of supramolecular chirality is essential for life.…”

High throughput analysis enables high throughput experimentation in pharmaceutical process research

“…12). We recently reported a high throughput screening workflow that expedites the selection of chiral solvating agents for the NMR analysis of enantiopurity, 96 which is especially useful for these challenging compounds. Additional separation challenges for closely related compounds are illustrated in Fig.…”

Synthesis and shift-reagent-assisted full NMR assignment of bacterial (Z8,E2,ω)-undecaprenol

“…Although our use of Eu(hfc) 3 as a shift reagent for the NMR assignment of achiral alkene-containing structure has precedent in the use of chiral shift reagent analysis of racemic alkene-containing structures, 17 we emphasize (as have others 18, 19 ) that optimization of the choice of chiral-shift reagent, its stoichiometry, and of solvent can disperse effectively resonances with minimal line broadening. As both pure 1 H shift-pulse sequences 20 and computer-assisted methods for NMR spectra interpretation 21 require a difference in chemical shifts , our decisive NMR differentiation of the two undecaprenol stereoisomers—one from bacteria, and one from plants—affirms the argument 18 of a continuing relevance of the shift reagent to the de novo NMR assignment of complex chemical structure. The ability to prepare these valuable synthetic lipids with full spectral characterization opens opportunities for the exploration of their roles in the intricate biochemical pathways of living organisms.…”