Abstract
Crystallization is a powerful method to isolate enantiopure molecules from racemates if enantiomers self-sort into separate enantiopure crystals. Unfortunately, this behavior is unpredictable and rare (5-10%), as both enantiomers predominantly crystallize together to form racemic crystals, hindering any such chiral sorting. These unfavorable statistics might be overcome using nonequilibrium conditions. Therefore, we systematically characterize energy differences (ΔG(Φ)) between racemic and enantiopure crystal phases for libraries of target molecules (phenylglycine, praziquantel) with different chemical modifications. Surprisingly, these libraries reveal wide but similar continuous distributions of ΔG(Φ), wherein similar chemical modifications group together. This grouping allows a directed evolution strategy to discover racemic crystals with low ΔG(Φ) for isolating desired enantiomers by crystallization under nonequilibrium conditions. Comparison with over a hundred previously reported compounds suggests that as many as half of all chiral molecules may kinetically form enantiopure crystals (∼50%). These insights open new previously unconsidered possibilities for isolating enantiopure molecules.