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Simon Muller
Simon Muller

Do you want to turn left or right? You have to choose, now! And believe me: your choice will alter everything! Just this one choice while you are waiting at a traffic light (ok, this is actually stolen from a Doctor Who episode). But really, left or right can mean the world to us… and to organic molecules! As it did once with Thalidomide, one of the most tragic stories in modern medicine. This story will explain to us how small differences can make such a devastating difference, and why it matters that we keep on improving our science.

Thalidomide entered the market as tranquillizer but also to treat morning sickness in pregnant women in 1957 in Germany. In 1957, drugs were largely considered safe and very little attention was paid to potential side-effects. Testing was not even remotely as strict and effective as it is today. And so it happened that terrible and lethal deformations occurred in babies born from mothers who had been taking Thalidomide during their pregnancy. There were around 10,000 reported cases in the world, being probably the most tragic misjudgement of a drug in history. So how could this happen?

The main reason surely was the lack of proper testing and clinical trials back then. It was later shown that these terrible side effects could have been detected much earlier if properly tested. Also, the scientific community didn’t know that there was something such as teratogenic effects from drugs (that means, that drugs could have an effect on babies in women during pregnancy). But there was also the problem that the molecule acted completely differently depending on if it was turning right or left.

What does it mean when we say a molecule turns (better: is oriented) left or right?

We need to know first: most pharmaceutically active molecules are organic molecules, which means they are based on the element carbon. Carbon has 4 electrons it can use to bind with other atoms, just as you have two arms to hold hands with other people. Now imagine you have four hands (that’s easy right? Ok…maybe not, but try it ). You could bind all your found hands to the same person, but that’s boring! Now you could bind with all four hands to four different people. Let’s call them randomly Homer, Marge, Lisa and Bart.

Of course, you would want them to be as far away from each other as possible (especially Lisa and Bart as they always fight). Your arms go therefore in every direction, up and down, left and right. You are asymmetrical or chiral. That is, if you look at yourself with all your Simpsons connected to you in the mirror, your reflection looks different from your actual structure. Check out the video, it explains it really well.

Why does this matter? Our carbon atom still has the same functional groups (Homer, Marge, Lisa and Bart) no matter in what orientation. It has very similar physical properties: same polarity, boiling point and melting point.

It matters because it reacts in a completely different manner with other chiral molecules. Proteins in the human body, for example, are chiral. Thus, the proteins will only react with us if Homer, Marge, Lisa and Bart are in the right positions. That is what happened in the case of Thalidomide mentioned above: one orientation (called: enantiomer) was responsible for the sedative and pain-releasing effects while the other enantiomer led to those horrible side-effects. The terrible mistake then was that the researchers didn’t realise that the one enantiomer was transformed into a mixture of both enantiomers, through a chemical reaction promoted by the conditions in a human body.

So how can a chemist separate the bad from the good enantiomer?

There are two main strategies from which we could choose: first, we could try to find a way to distinguish our two enantiomers in a chiral environment we created. This process is called chiral resolution, and for this it helps us a lot that nature is chiral, as we can use its vast amount of chiral building blocks to create a chiral environment.

How does this work?  We take a mixture of the two enantiomers of our molecule, called racemate (a lot of new words, I know). This mixture is now meeting an environment which is chiral. Only one of our enantiomers interacts efficiently with the chiral environment. With this technique we can separate out the enantiomer we want selectively. Unfortunately, we also lose half of our precious molecule, the one with the wrong orientation.

Can we do something about that?

Yes of course we can! This is our second strategy. All we need to do is find a way to synthesise the molecule in a chiral fashion from the very beginning. This means that we never actually make both enantiomers but we make just the one we want selectively and pure. The process is called asymmetric synthesis and is certainly the most vibrant field of research in organic chemistry today. The challenge: when you make a new bond in the molecule, you need to create an environment of the reaction where the two molecules that form this bond can only meet each other at a very specific angle, the one that gives you the enantiomer you need! And believe me, this is a hell of a challenge.

There are so many brilliant and great ideas to solve this, but this article is getting too long already, so let me finish by telling you what the ultimate challenge is these days: making single enantiomers in catalytic asymmetric synthesis using only catalytic quantities of your chiral environment.

Today, a repetition of the sad story of Thalidomide is probably impossible. We have learnt and understood the importance of chirality. But nevertheless there is much more to explore on how we can assemble complex molecules in a chiral fashion.