Role of solvent in the spontaneous resolution of amino acids via formation of supramolecular helices

Spontaneous resolution remains a great challenge. Despite efforts that have been made to design chiral species that can be structurally modified to allow spontaneous resolution, the role of the solvent in which the crystallization is performed has not been extensively explored. We report here the role of the solvent dimethyl formamide (DMF) in the spontaneous resolution of an aromatic amino acid, phenylalanine (F), which contains a bulky benzyl substituent, made in its helical derivatives acetylphenylalanine N -amido- N′ -phenylthiourea ( AcFH ) and N′ -( p -iodo)phenylthiourea ( AcFI ). Spontaneous resolution is achieved in DMF or 1:1:1 (v/v/v) DMF/CH 3 CN/CH 3 OH from which the crystals contain only DMF molecules. This is shown to result from bridging the formed neighboring supramolecular helices of the same helicity by DMF, a hydrogen-bonding solvent containing both the hydrogen-bonding donor and acceptor that are separated by a distance comparable to the size of the substituent in the amino acid residue.