NMR spectroscopic detection of chirality and enantiopurity in referenced systems without formation of diastereomers

Abstract

Enantiomeric excess of chiral compounds is a key parameter that determines their activity or therapeutic action. The current paradigm for rapid measurement of enantiomeric excess using NMR is based on the formation of diastereomeric complexes between the chiral analyte and a chiral resolving agent, leading to (at least) two species with no symmetry relationship. Here we report an effective method of enantiomeric excess determination using a symmetrical achiral molecule as the resolving agent, which is based on the complexation with analyte (in the fast exchange regime) without the formation of diastereomers. The use of N,N′-disubstituted oxoporphyrinogen as the resolving agent makes this novel method extremely versatile, and appropriate for various chiral analytes including carboxylic acids, esters, alcohols and protected amino acids using the same achiral molecule. The model of sensing mechanism exhibits a fundamental linear response between enantiomeric excess and the observed magnitude of induced chemical shift non-equivalence in the 1H NMR spectra.

Dynamic Processes in Prochiral Solvating Agents (pro-CSAs) Studied by NMR Spectroscopy

“…From previous work on pro-CSA [13][14][15] two types of interaction (Type I and II, see below) can be recognized which dominate complex formation, including charge-transfer (acid-base) interactions or hydrogen bonding. They have significant influence on the performance of the system in terms of stoichiometry and type and quantity of chiral guest that can be detected.…”

“…H3 forms a 1:1 host-guest complex with a chiral guest analyte and is coupled by dipolar interaction (hydrogen bond). There is almost no change in the UV/Vis spectrum upon complexation even when a large quantity of analyte is added [15] and the binding mode is relatively weak compared to Type I systems. Type II binding mode leads to sharp well-resolved resonances in 1 H-NMR spectra ( Figure 4c).…”

“…Despite the limitation of the necessity for construction of a calibration curve, (which is inherent to pro-CSAs) it can lead to certain advantages (in specific tasks) over the classical ee discrimination methods. Recent studies of pro-CSAs [13][14][15] have been aimed at proving that diastereomers are not formed and are not necessary for operation of pro-CSAs. However, other processes of a dynamic nature that are involved in those systems were not resolved.…”

“…[14]; and (c) H3 (chloroform-d, 0.9 mM) with G9 (840 equiv.) [15] at optimal temperature. Reporting groups as shown in Figure 1 …”

“…We recently introduced a method for detection of ee which does not rely on formation of diastereomeric complexes in solution. This involves various symmetrical (achiral) conjugated tetrapyrrole molecules H1, H2 and H3 (Figure 1-upper structures) [13][14][15] as detectors of ee for a wide range of chiral analyte molecules, including carboxylic acids and their esters, N-protected amino acids and terpenoids ( Figure 2). These ee detectors (hosts) form non-covalent host-guest complexes with chiral analytes (guests) (Figure 1-lower structures) and can be referred to as prochiral solvating agents (pro-CSA) since the binding mode is similar to classical CSAs but the host molecule is prochiral (meaning that upon interaction with chiral analyte the originally achiral host becomes chiral).…”