Separation of Enantiomers: Classical Resolution Demystified

Introduction
The rational synthesis of the growing number of chiral chemicals (drugs, agrochemicals etc and intermediates) either on a laboratory or industrial scale, calls for efficient methods for providing these compounds in enantiomerically pure form. Although many strategies may be considered (asymmetric synthesis, synthesis from the chiral pool, chromatography etc), optical resolution via diastereomeric salt formation remains the most widely used method for preparing pure enantiomers, both in the lab and in production.
This course covers in detail this important chemical process. The physico-chemical background on enantiomeric and diastereomeric mixtures will be presented, as well as the theory and practice. The theory is necessary to be able to devise and understand the practical methods for resolving compounds and to understand the critical parameters (choice of solvent, stoichiometry, resolving agent, concentration etc) to achieve the desired result. A large number of examples from the literature from industrial practice will be presented.

Course Outline

Day 1 Morning
Introduction
Physico-chemical properties of enantiomeric
mixtures
Basic Principles of Optical Resolutions
Physico-chemical properties of diastereomeric
mixtures

Day 1 Afternoon
Resolving Agents, Selection of the Resolving
Agent
Problem session and discussion:
Construction of a binary phase diagram
Alternative Methods for fractional crystallisation
Problem session and discussion:
Construction of a ternary phase diagram

Day 2 Morning
Resolution in Practice:
Selection of the Parameters 1
Resolution by direct crystallisation
Resolution in Practice:
Selection of the Parameters 2
Structural background of resolutions

Day 2 Afternoon
Optical Resolution by Complex Formation
Problem session and discussion:
Resolution in Practice

Optically active compounds are increasingly important in organic chemistry and in industry. Approximately half of the thousands of drugs known have chiral structures, many of which show dramatic differences in the properties of the stereoisomers (enantiomers) and thus an increasing proportion are marketed as single enantiomers. In the agrochemical field, many marketed compounds have been "switched" from a racemic to single enantiomer form for environmental reasons, since the inactive isomer contributes to pollution. In the flavour and fragrances industry and in molecular electronics, chirality is a key issue in R&D and manufacture.