Synthesis of Proline-Derived Helical Copolyacetylenes as Chiral Stationary Phases for HPLC Enantioseparation

Abstract

A series of optically active copolymers with various feed ratios have been synthesized through helix-sense-selective copolymerization catalyzed by [Rh(norbornadiene)Cl]₂-triethylamine. This process involves two proline-derived acetylene monomers, (S)-N-(4-chlorophenyl)carbamoyl-2-ethynyl pyrrolidine (MCl) and (S)-N-(tert-butoxycarbonyl)-2-ethynyl pyrrolidine, followed by acidic deprotection and neutralization. These copolymers adopt helical conformations with a preferred handedness, as demonstrated by nuclear magnetic resonance spectroscopy and a series of spectroscopic analyses. The chiroptical activity intensity of copolymer has been found to increase with MCl content. Consequently, the enantioseparation capabilities of copolymers containing 95 mol%, 90 mol%, and 85 mol% MCl units have been assessed as chiral stationary phases in high-performance liquid chromatography because of their good chiroptical activities. These chiral stationary phases effectively enantioseparate racemic alcohols, sulfoxides, amides, and metal complexes. Notably, the copolymer with 90 mol% MCl shows superior chiral recognition ability, especially for 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (α=1.19) and 4-methylbenzenesulfinamide (α=1.47). Insights from molecular dynamic simulation and autodock analysis indicate that hydrogen bonding and π-π stacking interactions between the chiral stationary phases and enantiomers play a key role for successful chiral separation. Our contribution not only demonstrates the importance of hydrogen bonding donor and copolymer chiroptical activity of chiral stationary phases for chiral resolution, but will also provide valuable insights for the future development of novel stationary phases.