Asymmetric Synthesis Involving Dynamic Enantioselective Crystallization

Abstract

An approach to obtain products with high enantiomeric purity by utilizing the chirality generated by crystallizing organic materials is introduced. If a racemic mixture forms a conglomerate in which each single crystal is assembled from a single-handed enantiomer, it is possible to resolve each enantiomer from the racemic mixture by the preferential crystallization method. Furthermore, when preferential crystallization is applied under conditions in which fast racemization proceeds in the mother liquor, it becomes possible to converge the entire system to the desired single-handed enantiomer. This method is called crystallization-induced enantiomer transformation (CIET), a type of crystallization-induced stereoisomer transformation (CIST), and is a total resolution method realized by amino acids, pharmaceutical intermediates, axially chiral materials, etc. In recent years, even dynamic systems with relatively low racemization rates have been applied to chiral amplification by attrition-enhanced deracemization. In this chapter, recent advances in asymmetric synthesis by a methodology combining a chemical reaction that forms a chiral center from prochiral starting materials with deracemization by dynamic enantioselective crystallization are introduced. This method is applied to various asymmetric syntheses and is a phenomenon in which crystals of a product with high enantiomeric purity can be obtained only by crystallizing the product from the reaction system in solution. Various types of reactions have been developed by adjusting the conditions for the reversible reaction or the racemization of asymmetric centers with enantioselective crystallization. This method will be widely developed in the future and is also applicable on an industrial scale.