Enantiopurity by Directed Evolution of Crystal Stabilities and Nonequilibrium Crystallization

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.