Chiral Recognition and Separation Mechanisms
A Pre-Conference 1- Day Course
Monday, January 22nd, 2007
09:00 – 18:00, including lunch
By Nelu Grinberg, Ph.D.
Senior Principal Scientist
Boehringer Ingelheim Pharmaceuticals, Inc.
Chemical Development, Process Development Laboratory
Ridgefield, Connecticut, USA
The course will focus on specific interactions between the enantiomeric analytes
and each specific chiral stationary phase, rather than the techniques used to
separate enantiomers. This approach will allow the participants to understand
the strategies for development of a separation of enantiomers. The conditions to
achieve each type of interaction will be presented.
An outline with the description of each section of the course is presented below.
Introduction
The course will open with a short historical review of the development of stereochemistry
and enantiomeric separations. The general description of chriality will be given. Chirality
plays a major role in biological processes and the enantiomers of a bioactive molecule
often possess different biological properties. For example, while the D-enantiomer of the
amino acids Asparagine, Isoleucine, Triptophan, etc., has a sweet taste, the Lenantiomer is either tasteless or bitter. Additionally R-(-)-carvone, a terpene, has a
spearmint odor, while its enantiomer has a caraway odor.
Numerous drugs are synthetic racemic compounds and used as such. Although this has
often been adequate, the possibility may exist that one of the two enantiomers is
undesirable. Thalidomide is such an example. The drug was used as a sedative and
sleeping drug in the early 1960’s and was given to pregnant women in the early stages
of pregnancy, causing serious malformations in newborn children. Later it was shown
that the (S)-(-)-enantiomer of thalidomide possessed teratogenic action. Furthermore,
this enantiomer was without importance for the desired sedative or sleep inducing
property. The pharmaceutical industry is becoming more and more interested in
methods to resolve racemates into optical antipodes in order to be able to be able to
subject these racemates individually to pharmacological testing. It is therefore also
desirable to have reliable methods for a determination of the optical purity of the two
forms.
Unfortunately, developing an enantiomeric separation involves a great deal of trial and
error, due to the large number of chiral columns on the market. Often column switching
devices are used, along with a number of columns, chosen without any rationale.
Therefore this section will briefly summarize approaches for choosing a stationary phase
based on the intimate relationship that exists between the analytes and the chiral
selectand.
Separation of Enantiomers through the Formation of Diastereomers
Different approaches for the indirect separation of enantiomers will be presented.
Different ways of generating diastereomeric compounds based on derivatization of
various functional groups will be discussed, along with a discussion of the general
interactions underlining their separation.
Main Types of Molecular Interactions leading to Enantiomeric Separation
and Thermodynamics Aspects of Enantiomeric Separation.
H-Bonds
Inclusion complexes
Charge transfer
This section will bring in the main interactions leading to chiral separation, i.e. through
the formation of hydrogen bonds, inclusion compounds, and charge transfer. Each type
of interaction will be illustrated with examples which demonstrate separation through a
particular type of transient diastereomeric species.
Mixed types of interactions
Polysaccharide Phases
Antibiotic Phases
Protein Phases
This section will present the types of stationary phases exhibiting a combination of
interactions (i.e. hydrogen bonds and inclusion, hydrogen bonds and charge transfer,
etc.). Chiral phases such as antibiotic phases, polysaccharide phases, and protein
phases will be discussed, along with examples of separation using such stationary
phases.
Ligand Exchange
The concept of enantiomeric separation through the formation of diastereomeric
complexes with transitional metals will be presented. The mechanism to form such
complexes will be presented and examples of separations using this approach will be
provided
Tailor-made Sorbents
This section will present tailor-made sorbents, describing several modes of producing
such stationary phases. Different modes of polymerization around different templates
will be presented, along with selection criteria for engineering optimal performance for a
given separation, and a system of choosing the monomers capable of producing the
best imprinted polymers.
Chiral Mobile Phases
This section will examine separations of enantiomers using chiral mobile phases such as
cyclodextrins, copper complexes, ion pairing compounds etc.
Strategies for method development in chiral separation
In this section, the strategies for developing a separation of enantiomers based on
previously gained knowledge in previous sections will be presented.