Unraveling the Mystery of Drug Chirality

[nymbler_064]

Hi Everyone!

I am having a little trouble understanding the concept of drug chirality... I know what they are, but am unsure about how they are formed in the first place (is it a random chance that one enantinomer will be formed over the other, can the be specifically created...?). Also, how is it possible that they can be separated/only one form manufactured.

I would really appreciate it if anyone would be able to provide some insight into this issue. I have spent hours researching already, but have not been able to find much information.

Kind regards.

 

[Ygggdrasil]

Chemists are able to specifically synthesize one enantiomer of a drug. There are various strategies for doing so (see the following wikipedia page http://en.wikimedia.org/wiki/Asymmetric_synthesis ). One strategy is to start with a chiral molecule (for example, some widely available chiral molecules produced by living organisms like sugars or amino acids) and use these molecules to generate the stereocenters that give the drug its chirality. Alternatively, one can synthesize chiral catalysts (or engineer enzymes) that are capable of selectively producing one enantiomer over another. There are also means of separating enantiomers as well.

 

[nymbler_064]

Thanks very much for your response. Would it be true to say that when the drug is manufactured normally, both enantinomers are formed randomly in equal proportions?

 

[Yanick]

Thanks very much for your response. Would it be true to say that when the drug is manufactured normally, both enantinomers are formed randomly in equal proportions?

In general yes but not always. Most reactions lead to racemic mixtures, however there are chemical reactions which tend to be stereoselective or may involve inversions of stereo centers etc.

 

[Ygggdrasil]

If the chemists producing the drug plan their synthesis correctly, they can sometimes create much more of the desired enantiomer than the undesired enantiomer.

 

[nymbler_064]

How would a chemist go about this? For example, how is levobupivacaine synthesized from bupivacaine?

 

[Ygggdrasil]

For levobupivacaine specifically, you can start with L-lysine (a chiral amino acid produced by living organisms) and use the chirality of the lysine to end up with the correct enantiomer of levobupivacaine. See http://dx.doi.org/10.1016/0040-4039(96)01357-3

 

[nymbler_064]

Thanks so much for this - really appreciated. I just wanted to check, is then when you start with a racemic mixture of both enantinomers of bupivacaine? And the enzyme reacts with one enantiomer, while lidocaine remains?

I am a little confused about the specifics of this reaction...

EDIT: I have done a little more research involving the resolution of enatiomers using salts etc. What I would really like to find out now, is that why the S-enatiomer is less soluble than the other (why it can crystalize)?

 

[Ygggdrasil]

In the example I posted, I'm talking about synthesizing levobupivacaine from scratch. You begin from a chiral starting material (L-lysine) and end up with a chiral product. If you were to start with a racemic mixture of lysine and follow the same procedure, you would end up with a racemic mixture of the two enantiomers of bupivacaine. This approach of planning your drug synthesis so that you obtain only the desired enantiomer at the end is called asymmetric synthesis.

If you have a racemic mixture of bupivacaine and want to isolate only one enantiomer, then you would need some strategy for chiral resolution, the separation of two enantiomers. Chiral resolution is based on the principle that, while enantiomers have identical chemical and physical properties in an achiral environment, their properties differ in chiral environments. In the case of resolving enantiomers using salts, you can take your racemic mixture and react it with the pure enantiomer of a chiral acid or base to form a what is called a diastereomeric salt (basically a salt having at least two chiral centers). Having the chiral acid/base around creates a chiral environment where the two enantiomers of your drug will show different properties (e.g. solubility).

These strategies represent the two main approaches to creating a chiral drug. You can either design an asymmetric synthesis to produce only the desired enantiomer at the end, or you can design a normal synthesis, producing a racemic mixture, and employ a chiral resolution strategy to separate out the two enantiomers at the end.

 

[nymbler_064]

Thanks very much for your detailed and thoughtful response. It helped a lot!

I was also just wondering if you knew why S diastereomer salt has a lower solubility that its diastereomeric counterpart, causing it to crystallize?

 

[Ygggdrasil]

It probably has to do with how well the two compounds can pack together to form a crystal. As an analogy, consider the two enantiomers of your hands and the two enantiomers of your gloves. Your right hand is able to form a very tight complex with a right-handed glove but not with a left-handed glove.

 

[nymbler_064]

I really like where you are going with this analogy, but am still confused as to why one enantiomer has a higher solubility (sorry, I'm a bit thick...). Or is it merely that each type forms a big crystal with each other, so the two types can be differentiated between? However, that doesn't seem to explain the different solubilities...

Thanks for being so patient with me :)

 

[Mike H]

Enantiomers are indistinguishable by standard achiral physical/chemical methods. They will have the same solubility in an achiral environment. Diastereomers are just like other isomers and can be resolved by physical & chemical analytical/separation methods.

When you add your chiral resolving agent to a mixture of enantiomers, the resulting products are diastereomers. Their solubilities (and crystal packing contacts, and other properties) are going to be different. This is what allows you to separate them, and you can then (usually) remove the chiral resolving agent so you have an enantiomerically pure final product.

 

[Ygggdrasil]

What does it mean for a compound to be soluble? Ultimately, the question is one of energetics and thermodynamics. Are the intermolecular interactions between molecules of the salt stronger than the interactions between the molecule and the solvent? If the molecule prefers interaction with itself more than the solvent, it will crystallize. If the molecule prefers interacting with the solvent, it will stay in solution. Therefore, in order for two compounds to exhibit different solubilities, they will have to show differences in the thermodynamics of solid formation.

Let's go back to the example of a racemic mixture of "right-hand" molecules and "left-hand" molecules. In order to try to resolve the two molecules, you add your chiral resolving agent, a "right-handed glove" molecule that forms a salt with the two molecules. Of course, the right-hand molecules fit very well into the right-glove molecules and form very many energetically favorable contacts (for example, let's say the tips of the fingers of the right hand are negatively charged and the fingertips of the gloves are positively charged). In contrast, the left-hand molecules do not fit very well into the right glove molecules, and therefore, it cannot form as many energetically favorable contacts and the contacts that it does form are weaker (for example, if the fingers can't get all the way into the fingertips of the gloves, the positive and negative charges will be separated by a larger distance in the left-right diastereomer than in the right-right diastereomer. The larger separation of charges leads to a weaker overall interaction).

From this, it should be obvious that the energetics of forming a crystal are different for the two forms of the salt: the right-right diastereomer will release much more energy than the left-right diastereomer when it forms a crystal (i.e. the ΔH for the crystallization will be different). Of course, this difference can be somewhat small and there will be solvents where both diastereomers will crystallize or both diastereomers will remain soluble. However, because of the diastereomers crystalize with different energetics, one can find conditions where the right-right diastereomer will crystalize while the left-right diastereomer will stay in solution.

 

[nymbler_064]

Thankyou so much! Your easy to understand explanation has helped me out profusely.