Analogues of the conformationally dynamic Claritin (loratadine) and Clarinex (desloratadine) scaffolds have been enantio- and chemoselectively N-oxidized using an aspartic acid containing peptide catalyst to afford stable, helically chiral products in up to >99:1 er. The conformational dynamics and enantiomeric stability of the N-oxide products have been investigated experimentally and computationally with the aid of crystallographic data. Furthermore, biological assays show that rigidifying the core structure of loratadine and related analogues through N-oxidation affects antihistamine activity in an enantiomer-dependent fashion. Computational docking studies illustrate the observed activity differences.