Resolution of enantiomers by non-conventional methods

Despite unprecedented advances in enantioselective synthesis and separation techniques, large scale production of enantiopure substances, such as required by the pharmaceutical and pesticide industries, is still heavily dependent upon the separation of diastereomers obtained from the enantiomers and an optically active resolving agent. Economy of the process can be much enhanced when only a half-equivalent of the resolving agent is used. Substitution of the other half-equivalent by some achiral compound, as well as separation of the unreacted portion of the substrate from the diastereomer by various physical methods, is discussed. Methods for selecting optimal conditions of resolution and for the purification of partially resolved mixtures are also discussed. 1 Introduction and Historical Background 2 Resolution Methods Using a Half-Equivalent of Resolving Agent 3 Selection of the Optimal Resolving Agent and Solvent 4 Phase Transformations of Diastereomeric Salts or Complexes (Kinetic and Thermodynamic Control) 5 Resolution by Formation of Covalently Bound Diastereomers 6 Racemization of an Unwanted Enantiomer 7 Deracemization 8 Resolution of Conglomerate-Forming Racemates by Induced Crystallization 9 Purification of Partially Resolved Mixtures by Crystallization of Conglomerate-Forming and Racemic-Phase-Forming Compounds 10 Purification of a Partially Resolved Mixture of Racemic-Phase-Forming Enantiomers by Fractional Precipitation 11 Resolution by Supercritical Fluid Extraction or Distillation 12 The Non-Linear Character of the Resolution Processes.