00:00
So as I said before, chirality is best expressed
as a mirror image of the one thing. We can
see this in nature. And these are images which
are non superimposable. I take the example
of the shell as shown here on the board, which
is of the origins of chirality being from
the Greek word “cheir” or “hands”.
And here we have picture of some hands as
you can see the left or right hand are not
directly superimposable on top of each other.
00:30
Therefore they are considered chiral in nature.
We even see this in the universe with spiral
galaxies which themselves are non superimposable
and therefore chiral. Okay, let’s relate
this back to the chemistry shall we.
00:44
Chirality and enantiomers, as shown before
in perspective, a mirror plane with two molecules
on either side which are the mirror image
of each other. And I would like you to just
to take a couple of moments to try to superimpose
one of those molecules shown on the board
on top of the other one, so that all the colors
match up. You won’t be able to do it, not
without cheating. And this is directly
the result of the dissymmetry or the lack
of symmetry in a molecule and if you look
at this you can always spot a chiral carbon
otherwise known as a stereogenic carbon. And
this is where you have a carbon with four
different atoms or groups attached and this
is an element of dissymmetry. Such a carbon
atom is known as the chiral or stereogenic
center. Carbon atoms carrying four different
groups will always exhibit chirality. There
is no plane of symmetry through the molecule
and so therefore must be chiral. Okay, so
aside from the observation that when you actually
have a single carbon you can have four different
groups attached and yes, this gives you a
distribution which is chiral. The importance
of it relates directly to nature and those
targets within medicinal chemistry that we
would use. DNA itself is chiral. If we break
DNA down, we are showing here the ribonucleic,
the ribose part of ribonucleic acid, you
can see here that carbon 4, indicated by the
green arrow, actually has four different substituents
on it. Therefore it must be chiral. In this
case it is known as a D-sugar. D because it
is dextrorotationary, rotating the plane of polarized
light to the right. Many of these units together
form a structure which you will undoubtedly
be familiar with, which is DNA. DNA shown
here, which is a collection of bases linked
together by ribose sugar units and phosphates
on the back bone, giving rise to this highly
ordered structure, an essential blue print
for life as we know it.
03:07
Another place where chirality is encountered
is in the formation of proteins. I have shown
here an example of an amino acid. In this
case, a simple representation of any amino
acid that you will come across, otherwise
known as the alpha amino acids. The term alpha
is just a nomenclature to denote where the
chirality is actually occurring which is on
the carbon between the amine group, the NH2
and the carboxylic acid group COOH. In nature,
by and large, they exist in their levorotationary
forms. L amino acids are the common amino
acids. There are exceptions to this. However,
it is these individual amino acids which polymerise
together to form an alpha helix polypeptide,
which goes on to form the essential proteins
that regulate every aspect of every organism.
I also want to introduce you to something
else which you will also, may also be familiar
with, and this is how the chirality can influence
directly the biochemical interaction, that
a specific drug or food stuff can have with
a given receptor. Because biology is by its
very nature consisting of chiral controlled
proteins, proteins with a given stereochemistry,
it doesn't come or shouldn’t come as too
much of a surprise that their interaction
with other small molecules will depend very
much on their chirality as well. We see this
in how the body detects these two examples
of small molecules. We see (S)-carvone which
has the odor picked out by the chiral receptors
in the nose of caraway seeds. And we also
have R-carvone, which is instantly recognizable
as spearmint. Note the difference between
the two. They contain the same number of carbons,
same number of hydrogens and oxygen as shown
there. However, if you look at the lower part
of that cyclic ring, you will see that the
bond moving forward and the bond moving backward
impart a degree of chirality at that stereogenic
center which is detectable by human beings.
05:35
Let's apply that to something more medical.
Ephedrine, for example shown in green is used
as a bronchodilators, in bronchitis and asthma.
In fairness, not used as often anymore, salbutamol
and a number of other derivatives have succeeded
it but the principle remains the same. In
this particular case, the mixture of R and
S, enantiomers here, so R next to the oxygen
and S next to the nitrogen impart on it, a
completely different medical profile to pseudoephedrine
which is actually on the market for use as
a decongestant.
06:14
Note looking at stereochemistry you can say
that they have dissimilar stereochemistry
or where you have two individual stereogenic
carbons. This is otherwise known as diastereochemistry.
06:29
Another medical example is thalidomide. You
may already be familiar with the story of
thalidomide, but here is one of the background
stories to it in terms of the structure. If
you compare the two structures of (S)-thalidomide
which is the enantiomer of (R)-thalidomide,
you should be aware that the (R)-thalidomide
is actually quite an effective remedy against
morning sickness in pregnant women. However,
the S thalidomide is a teratogen, that is
it causes genetic mutations in children, causing
all sorts of birth defects including Phocomelia
and amelia with only 8000 surviving in the
first year.
07:14
Okay, so we have talked about the importance,
the relevance, and how often it occurs. That
is great. What we need to do now is understand
how we can best define a chirality, how to
give names to the two different enantiomers,
how we can identify those enantiomers, and
very important in the case of for example
of thalidomide and other drug molecules, how
we can separate them. We also, want to bear
in mind if we cannot separate them, how might
we synthesize one enantiomer over the other
preferentially. To this I will introduce you
to some basic asymmetric synthesis.