The synthesis, ab initio calculations, and a comparative nuclear magnetic resonance study of a novel chiral mefloquine‐based selector (SO) are presented. On a series of variously N‐acyl protected leucine selectands (SAs), a feasibility study of mefloquine carbamate as a basic chiral solvating agent, and potential fluorophilic high‐performance liquid chromatography selector has been undertaken and evaluated. An analogy is drawn between the new SO and tert‐butylcarbamoyl quinidine as a reference. Chirality 24:936–943, 2012. © 2012 Wiley Periodicals, Inc.