Biomedical Engineering Reference
In-Depth Information
5.5.2.4 Miscellaneous Phases
Polysaccharide-based stationary phases such as Chiralcel OB and Chiralpak AD can be used with a
variety of organic solvents in the mobile phase. Hence a variety of drugs can be resolved both ana-
lytically and preparatively. CSPs based on cyclodextrins (cyclic oligosaccharides) have been used
for analytical and preparative separation of a variety of compounds. Enantioselectivity relies on
differences between inclusion complexes formed inside the hydrophobic cavities of cyclodextrins.
Macrocyclic antibiotics (e.g., vancomycin) have been incorporated into stationary phases, allowing
mainly analytical resolution of amino acids.
5.5.2.5 Simulated Moving Bed Chromatography
Large-scale separation of chiral drugs (a priority in the pharmaceutical industry) can be achieved
with this method. In simulated moving bed chromatography (SMBC) 6-12 columns containing a
CSP are joined in a ring and the l uid is circulated using 4-5 pumps. As the racemate travels through
the columns a zone of one enantiomer leads the rest of the injected sample while a zone of the opposite
enantiomer lags behind. Using a computer-controlled system, some of the leading enantiomer, and,
independently, some of the trailing enantiomer are withdrawn at intervals. As polysaccharide-based
columns have a high loading capacity they have been widely used for chiral SMBC separations
of up to 1.5 kg of racemate per kilogram of CSP per day. SMBC has been applied for the separation
of a number of chiral drugs and intermediates such as propranolol, analgesic tramadol, antiasthmatic
agent formoterol, antidepressant citalopram, and antitussive agent guaifenesine.
5.5.3 A
SYMMETRIC
S
YNTHESIS
Asymmetric synthesis to obtain individual enantiomers of chiral molecules is one of the most
widely investigated and rapidly growing areas of organic chemistry. The predominant methods
by which individual enantiomers of chiral molecules are synthesized are discussed briel y in the
following sections.
5.5.3.1 The Chiral Pool
This involves the use of a chiral template from which the target compound can be assembled. These
chiral templates are obtained from the vast diversity of natural products. The template chosen usu-
ally has the same stereochemistry as a fragment of the desired product. The chiral unit itself may
also be capable of exerting a degree of inductive stereocontrol in subsequent steps of the synthesis.
In order to be of use these natural products must be readily available and moderately inexpensive.
A wide variety of compounds have been used as templates including alkaloids, terpenes, carbohy-
drates, and amino acids.
5.5.3.2 Stereoselective Synthesis
Methodologies of stereoselective synthesis have evolved rapidly but essentially involve forming
new stereogenic centers in the substrate via the presence of another asymmetric group (ultimately
derived from the chiral pool). Examples of methods of stereoselective synthesis are described briel y
in the following sections.
5.5.3.3 The Use of a Chiral Auxiliary
In this methodology a “chiral group” is purposefully attached to the achiral substrate solely for the
purpose of controlling the stereochemical outcome of subsequent reactions. The unit chosen is not
an integral part of the target compound, but instead is removed once it has performed its function.
The advantage of this methodology is that the reaction of the chiral substrate (i.e., with auxiliary
attached) produces a diastereomer. Therefore, even if a high level of induction in subsequent reac-
tions is not produced the products can potentially still be separated to isolate the pure enantiomer.
