Transcript D7 Taxol® * a chiral auxiliary case study (HL)

Option D HL
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When a molecule contains a carbon atom
bonded to four different groups, it is said to
be chiral and two mirror images (known as
enantiomers) exist.
These enantiomers can behave very
differently in the body as a result of their
different shapes. E.g. one enantiomer can
combine with a specific protein because its
functional groups are in correct position.
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Developed in Germany in the
1953.
Used as a tranquilizer (19571962).
Prescribed to combat morning
sickness in the early months of
pregnancy.
Marketed widely in Europe but
never approved by the FDA in
the USA.
Caused major birth defects in
ABOUT 10,000 children whose
mothers had taken thalidomide.
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Thalidomide has
two optical isomers,
one of which is a
powerful teratogen.
Chiral
Carbon
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Thalidomide is both a tranquilizer and a teratogen
It is sometimes used to
treat some symptoms
of Hansen’s disease.
(Leprosy)
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Many drug with chiral center are synthesized
from materials that have no chiral center.
The product is racemic mixture. To obtain
single enantiomer chiral auxiliary center is
used.
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A chiral auxiliary is one enantiomer of an
optically active substance that is temporarily
incorporated into a non-chiral molecule to
produce a single enantiomer of a product in
an organic synthesis reaction.
Chiral auxiliary allows reagent to approach
from the one side of the molecule, so forcing
the reaction to produce only one type of
enantiomer.
Once reaction is complete chiral auxiliary is
removed
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Chiral auxiliaries are successfully used in
semi-synthesis of anticancer drug Paclitaxel
(Taxol).
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Paclitaxel is used to treat several forms of
cancer – mainly breast, ovarian and lung
cancer. It is usually given intravenously as
part of a course of chemotherapy to treat
cancer. Paclitaxel acts by preventing cell
division – it does this by binding to
microtubules in the cytoplasm, preventing
them from breaking down during cell
division.
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Paclitaxel was originally obtained from Pacific
yew tree bark – however, it took the bark from
more than one tree to provide enough paclitaxel
to treat just one patient and so semi-synthetic
processes were developed that involved making
paclitaxel from another natural product derived
from the needles of yew trees.
Semi-synthesis of the drug allowed it to be made
on a larger scale and reduced the environmental
impact – extracting the drug from its natural
source results in killing of the trees.
Nowadays paclitaxel is also made by
fermentation using plant cell cultures.
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Optically active enantiomers can be
distinguished using polarimeter, because
they rotate plane polarized light in opposite
directions
A simple polarimeter consists of a source of
light (usually a sodium lamp producing one
specific wavelength), two polarising filters, a
sample tube and a scale to measure the
degree of rotation of the plane-polarised
light
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An enantiomer that rotates plane-polarised light
clockwise (to the right – dextrorotatory) is called
the (+)-enantiomer and one that rotates the
plane anticlockwise (to the left – levorotatory) is
called the (−)-enantiomer.
An enantiomer can be identified from its specific
rotation. The specific rotation, [α], is worked out
from the angle though which the plane-polarised
light is rotated in degrees (α), the path length of
solution that the light passes through (l) in dm
and the concentration of the solution (c) in
g/cm−3:.
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Science is both systematic and creative.
Systematic screening of a large number of
plant extracts identified paclitaxel as a
possible anticancer drug. When the demand
for paclitaxel exceeded the supply from
natural sources scientists had to develop
ways of making this important drug. A great
deal of creativity was involved in designing
ways of making paclitaxel.