Exploring new dipeptides based on phenylglycine and C α-methyl phenylglycine as hosts in inclusion resolutions

Abstract

Twelve homo-dipeptides derived from phenylglycine, Phg, and C α-methyl phenylglycine, (αMe)Phg, were synthesized and tested as resolving agents in resolutions through selective crystallization of inclusion compounds. The 3D-structure of a hydrated (αMe)Phg dipeptide host was also solved by single crystal X-ray diffraction. These dipeptides were examined in the co-crystallization with 15 different racemic guests, mainly alcohols and sulfoxides. Next to confirming the literature results for the resolution of methylphenylsulfoxide, a rather limited scope was found for new resolutions. Only racemic solketal could be resolved with H-( S)-(αMe)Phg-( S)-(αMe)Phg-OH in modest efficiency using various experimental techniques. This resolution was complicated by the formation of polymorphic host–guest crystals. Whereas a wide array of similar dipeptides could be explored as resolving agents, it is expected to be difficult to rationally design potentially successful molecular structures. Compared to resolution by diastereomeric salt formation, inclusion complexes are less readily formed and therefore of a more limited scope and preparative applicability.