Chirality – Stereochemistry

by Adam Le Gresley, PhD

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    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.

    About the Lecture

    The lecture Chirality – Stereochemistry by Adam Le Gresley, PhD is from the course Chemistry: Introduction.

    Included Quiz Questions

    1. Quartz is a perfect example of an achiral inorganic molecule
    2. Chirality is a geometric property of a molecule, which enables it to rotate the plane-polarized light
    3. Non-superposable mirror images of chiral molecule known as enantiomers, exhibit optical activities
    4. D-amino acid and L-amino acids are the enantiomeric forms of an amino acid
    5. A chiral molecule is characterized by the presence of an asymmetric carbon center responsible for the structural features of organic molecules
    1. …the presence of D-deoxyribose sugar in its structure
    2. …the presence of L-deoxyribose sugar in its structure
    3. …the presence of L-nitrogenous base in its structure
    4. …the presence of D-nitrogenous base in its structure
    5. …the presence of phosphodiester bonds in its structure
    1. The natural amino acids are levorotatory as α-carbon atom exhibits the chirality
    2. The natural amino acids are dextrorotatory as β-carbon atom acts as a chiral center
    3. The amino acids exist as a racemic mixture of L- and D- enantiomers inside living systems
    4. The enzymatic machinery of living systems cannot differentiate between L- and D- forms of amino acids
    5. The amino acids are building blocks for nucleic acids
    1. The preparation of a compound in its one specific enantiomeric form for pharmaceutical purposes
    2. The preparation of a compound as a racemic mixture of its enantiomers for pharmaceutical purposes
    3. The preparation of a compound as a racemic mixture of its enantiomers in the ratio of 2:3 (L-form: R-form) for pharmaceutical purposes
    4. The preparation of a compound as a racemic mixture of its enantiomers in the ratio of 1:2 (L-form: R-form) for pharmaceutical purposes
    5. The preparation of a compound as a racemic mixture of its enantiomers in the ratio of 2:3 (R-form: L-form) for pharmaceutical purposes
    1. …interaction of the drug with its target molecule and drug-metabolizing enzymes
    2. …interaction with water molecules
    3. …interaction with the salts present in the blood plasma
    4. …interaction with the preservatives used in drug preparation
    5. …interaction with O2 and CO2 gases dissolved in the blood

    Author of lecture Chirality – Stereochemistry

     Adam Le Gresley, PhD

    Adam Le Gresley, PhD

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    By Daniel C. on 18. July 2019 for Chirality – Stereochemistry

    Enhanced understanding. Wish he talked about R and S configurations. The part was slightly confusing without the explanation of R and S