Design, Synthesis, Resolution, Determination of Absolute Configuration, and Evaluation of a Chiral Naproxen Selector

Article abstract of DOI:10.1021/jo00102a013

A rigid chiral selector intended to differentiate between the enantiomers of α-arylpropionic acids (profens) has been designed and synthesized.The ?-acidic, hydrogen bond donor, and β-basic interaction sites deemed essential to chiral recognition are supported on a <2.2.2>bicyclooctane framework to form a cleft-like "active site" in which enantiodiscrimination occurs.The racemic selector has been resolved chromatographically and the absolute configurations of the enantiomers have been established by a combination of HPLC and NMR methods.Immobilized on silica, this selector affords a chiral stationary phase which shows appreciable levels of enantioselectivity toward the profens, members of an important group of nonsteroidal antiinflammatory drugs.Immobilization has been accomplished in two ways.The selector has been hydrosilylated with either dimethylchlorosilane or with polymethylhydrosiloxane.The former leads to a brush-type CSP whereas the latter leads to a polymeric CSP coated and bonded to the silica support.The polysiloxane-based phase exhibits higher enantioselectivity and shorter retention times than does its brush-type counterpart.A mechanistic hypothesis advanced to account for the enantiodiscrimination observed suggests that relatively simple changes in the structure of the selector might further improve its enantioselectivity.