Recent developments in the high-throughput separation of biologically active chiral compounds via high performance liquid chromatography

Isohexide-Based Tunable Chiral Platforms as Amide- and Thiourea-Chiral Solvating Agents for the NMR Enantiodiscrimination of Derivatized Amino Acids

“…The amino derivatives of isohexides were then converted to arylamides and arylthioureas by reacting diamines 6 with 3,5-dimethoxybenzoyl chloride and 3,5-bis (trifluoromethyl)phenyl isothiocyanate, respectively, under standard reaction conditions (Scheme 3). The enantiodiscrimination properties of the different amide derivatives 7a-c were assayed in 1 H NMR experiments towards both racemic ester 9c and acid 9b (Figure 2), and the results are presented in Table 1. These substrates were selected because of the presence of the 3,5-dinitrobenzoyl (DNB) group that can not only establish π-π interactions with the electronically complementary aromatic moieties of the isohexide derivatives, which is useful for the enantiodiscrimination, but that also presents some diagnos-Scheme 3.…”

“…The samples were analyzed in a CDCl 3 , DMSO-d 6 , or methanol-d 4 solution. 1 H and 13 C chemical shifts were referenced to tetramethyl silane (TMS) as the secondary reference standard; 19 F chemical shifts were referenceed against CFCl 3 and trifluoro-toluene (8a-8b) as the external standard with temperature control (25 ± 0.1 and 21 ± 0.1 • C for the spectrometer operating at 600 and 400 or 500 MHz, respectively). A 1 s relaxation delay and 200 increments of 4 transients, each with 2Kpoints, were employed for gCOSY (gradient Correlation SpectroscopY) and TOCSY (Total COrrelation SpectroscopY) experiments.…”

“…Over the years, chromatographic [1][2][3][4][5] and spectroscopic/spectrometric [6][7][8][9][10][11][12][13] methods have been developed and, among the latter, NMR spectroscopy has emerged as one of the most versatile investigation techniques. Beyond its analytical potentialities, the supremacy of NMR spectroscopy is also due to the possibility of easy investigation of the discrimination processes at a molecular level.…”

“…FigureSI26,1 H NMR spectrum of 7a, FigureSI27,13 C{ 1 H} NMR spectrum of 7a; FigureSI28,1 H NMR spectrum of 7b; FigureSI29,13 C{ 1 H} NMR spectrum of 7b; Figure SI30, 1 H NMR spectrum of 7c; Figure SI31, 13 C{ 1 H} NMR spectrum of 7c; Figure SI32, 1 H NMR spectrum of 8a; Figure SI33, 13 C{ 1 H} NMR spectrum of 8a, Figure SI34, 1 H NMR spectrum of 8b; Figure SI35, 13 C{ 1 H} NMR spectrum of 8b; Table SI1, Nonequivalence for racemic 11a in equimolar mixtures 11a/8a/DABCO in different solvents; Figure S1, Nonequivalences of 9c-d and 10b-e in equimolar mixtures with 8a and DABCO; Figure S2, Complexation stoichiometry of (R)-11g/8a/DABCO (left) and (S)-11g/8a/DABCO (right) based on the 1H resonances of the acetyl group of 11g; TableS1, Enantiomeric purity determination; TableS2, Complexation shift of 11a-c,11f, 11g in equimolar mixtures with 8a and DABCO; TableS3, Chemical shift of Ac protons of (S)-11g in the mixture (S)-11g/8a/DABCO; TableS4, Chemical shift of Ac of (R)-11g in the mixture (R)-11g/8a/DABCO; FigureS3, 1 H NMR spectra of the equimolar (5 mM) mixtures (R)-11g/8a/DABCO (S)-11g/ 8a/DABCO; FigureS4, 2D ROESY maps of the equimolar (5 mM) mixtures (R)-11g/8a/DABCO (S)-11g/ 8a/DABCO; FigureS5, 1D ROESY spectra of NH-8/NH-12 of (R)-11g (5 mM) in the equimolar (R)-11g/DABCO/8a; FigureS6, 1D ROESY spectra of H A of (R)-11g (5 mM) in the mixture (R)-11g/DABCO/8a; FigureS7, 1D ROESY spectra of the proton H B of (R)-11g (5 mM) in the mixture (R)-11g/DABCO/8a; FigureS8, 3D representation of (R)-11g; FigureS9, 1D ROESY spectra of H 1 and H 4 of (R)-/(S)-11g (5 mM) in the mixture (R)-/(S)-11g/DABCO/8a; FigureS10, 1D ROESY spectra of H c of (R)-/(S)-11g (5 mM) in the mixture (R)-/(S)-11g/DABCO/8a. Refs[46][47][48][49][50][51] are cited in Supplementary Materials.…”

Novel insights into the dependence of adsorption-desorption kinetics on particle geometry in chiral chromatography

“…Indeed, either fully (FPPs) or superficially porous particles (SPPs) with diameter less than 2 m have been developed. Nevertheless, this innovation was delayed for chiral stationary phases (CSPs) due to a series of challenges, especially in the functionalization and packing procedures, but also related to a lack of fundamental information about mass transfer and chiral recognition mechanism [ 1 , 2 ]. As a matter of fact, conversely to common expectations, it has been experimentally observed that in chiral chromatography (for defined conditions) SPPs do not always outperform FPPs in terms of kinetic performance [ 3 – 7 ].…”