Chiral Discrimination of Acyclic Secondary Amines by ¹⁹F NMR

Abstract

Chiral aliphatic amine compounds exhibit a range of physiological activities, making them highly sought-after in the pharmaceutical industry and biological research. One notable obstacle in studying these compounds stems from the pronounced steric hindrance surrounding the nitrogen atom. This characteristic often leads to a weak affinity of acyclic secondary amines for molecular probes, making their chiral discrimination intricate. In response to this challenge, our research has unveiled a novel 19 Flabeled probe adept at recognizing and distinguishing between enantiomers of these acyclic secondary amines. By strategically incorporating a single fluorine atom as the 19 F label, we have managed to diminish the steric hindrance at the binding site. This alteration bolsters the probe's affinity toward bulkier analytes. As a testament to its effectiveness, we have successfully employed our probe in the chiral analysis of relevant pharmaceuticals, accurately determining their enantiocomposition.

Potential and performance of anisotropic 19F NMR for the enantiomeric analysis of fluorinated chiral active pharmaceutical ingredients

“…Basically, weak spectral enantio-separations (in frequency units) generally measured on routine 1 H NMR (<9.4 T) can be increased by recording spectra on very high-field NMR instruments (if accessible). Other approaches using 19 F NMR on fluorinated solutes 23 or even fluorinated CSA/CDA as recently reported, 24–27 can provide elegant tools. However, the need of designing a tailored CSA/CDA (not always commercially available) for a specific chemical group remains the main challenge and may limit the general use of these approaches.…”

“…The third advantage is based on the absence of possible differences in affinity between the analyte and the chiral agent which can lead to significant discrepancies between the real value and the measured value of the ee %. 24,27 De facto , no correction coefficient must be introduced to determine the ee % from the measurement of peak surfaces for each enantiomer. The last but not the least advantage is that several chiral polymers (as polypeptides) are commercially available, and no preliminary synthetical step is required to explore their potential.…”

NMR-Based Chiral Discrimination of Bulky Amines with a 19F-Tagged NNO Pincer Complex

“…Yet, their affinity toward secondary amines is too weak for chemosensing applications. We have recently developed a 19 F-labeled cyclopalladium complex aimed at the chiral discrimination of acyclic secondary amines, incorporating a small fluorine atom to minimize steric hindrance near the binding site . While effective, the sensitivity of this method is compromised by the limited number of 19 F atoms attached to the probe.…”