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Chirality in Pharmaceutical Synthesis
• Explain that the synthesis of pharmaceuticals
often requires the production of a single
optical isomer.
• Explain that synthetic molecules often
contain a mixture of optical isomers, whereas
natural molecules often have only one optical
isomer.
• Explain that the synthesis of a
pharmaceutical that is a single optical isomer
increases costs, reduces side effects and
improves pharmacological activity.
• Describe strategies for the synthesis of a
pharmaceutical with a single optical isomer.
Week 9
Pharmacological activity depends on whether or not a drug can interact with a
receptor site in a biological system.
© Pearson Education Ltd 2009
This document may have been altered from the original
Optical Isomerism in Nature
• Many of the natural biochemical reactions
which take place in living systems require
molecules of a specific shape for reactions to
occur. E.g. neurotransmitters interact with
sites on nerve cells which have to fit exactly
both the shape and intermolecular forces of
the molecules.
• This is true for all “lock and key” interactions.
• Dopa is a neurotransmitter which exhibits
optical isomerism – only the L form is active in
the brain.
• The structure of L-Dopa follows.
Draw the displayed formula for this
molecule.
Identify the chiral centre.
Draw the 2 stereoisomers on either side of
a mirror plane.
Optical Isomerism in Nature
• L-Dopa is used as a treatment for Parkinson’s
Disease.
• It must be free of D-Dopa which has
unpleasant side effects.
• Undesirable side effects were a particular
problem with the drug Thalidomide,
prescribed as a sedative and anti-emetic (to
prevent morning sickness) for pregnant
women in the 1960s.
• One stereoisomer was effective but the
other proved to be teratogenetic.
Week 9
Stereoisomers of thalidomide
© Pearson Education Ltd 2009
This document may have been altered from the original
Modern Pharmaceuticals
• Computers are now used to examine the
relationship between a molecule and a
receptor site.
• Molecular modelling has greatly speeded up
the process of designing new medicines.
• Now only molecules that show potential after
computer tests are made and tested in the
real world.
• If a single stereoisomer can be made risks
from undesirable side effects are reduced.
• The risk of litigation is reduced.
Modern Pharmaceuticals
• Drug dosages are reduced (by half) which
does reduce some packaging costs.
• However the synthesis of single isomer drugs
is more expensive due to the need to separate
the optical isomers.
• Most synthetic routes involve reactions of
functional groups where incoming reagents
can attack from the ‘back’ or the ‘front’ of
the molecule. This causes the production of
the racemic mixtures.
Modern Pharmaceuticals
• Complicated separation techniques are
required to separate the enantiomers because
they usually have very similar physical
properties.
• Methods used include enzyme reactions,
electrophoresis and chromatography.
• These are expensive and time consuming.
Modern Chiral Synthesis
• Single isomer preparation methods used include:
• Using bacteria or enzymes as catalysts since they are
all stereospecific.
• Use of natural α-amino acids and sugars as starting
materials – so-called chiral pool synthesis.
• Use of transition metal catalysts (chiral catalysts)
particularly using supercritical carbon dioxide as
solvent.
• Use of strained cyclic molecules (like cyclopropane)
which can only react on one ‘side’ of the molecule
because the other is blocked.
• Using reagents fixed onto polymer supports with
reactants flowing over them.