Dynamic enantioselective high-performance liquid chromatography as a tool to probe configurational lability: Investigation of a chiral tetrahydrofuran building block.

Dynamic high-performance liquid chromatography (DHPLC) was employed as a primary analytical tool to investigate the configurational lability of a chiral tetrahydrofuran-based hemiaminal (1), obtained via nickel-catalyzed electrochemical C-H amination. On a polysaccharide-based chiral stationary phase containing amylose tris(3,5-dimethylphenylcarbamate) as the chiral selector, using n-hexane-ethanol 60:40 as the mobile phase, compound 1 exhibited on-column interconversion between enantiomeric forms, directly evidenced by temperature- and flow rate-dependent peak deformation and plateau formation phenomena. Systematic variation of chromatographic conditions, including temperature and acidic or basic additives, enabled detailed characterization of interconversion kinetics and identification of the transition between chromatographic and dynamic regimes. At 35 °C, the addition of 0.01% trifluoroacetic acid lowered the barrier from 22.7 kcal mol⁻¹ to 21.1 kcal mol⁻¹, while in the presence of 0.1% diethylamine, a value of about 20 kcal mol⁻¹ was determined at 10 °C. Complementary off-column kinetic measurements and solution-state NMR studies revealed that acid- and base-mediated racemization proceeds through two distinct mechanistic pathways. Under these conditions, additional chromatographic peaks were observed and assigned to species involved in the racemization process. Overall, this study highlights dynamic chromatography as a powerful and versatile approach for probing the stereochemical stability of chiral compounds and for gaining mechanistic insight into their interconversion processes.