Here’s a good short review on a subject that doesn’t come up too often in drug discovery, but can be a major headache when it does: atropisomerism. There are all sorts of structural isomers possible for organic compounds, and students in their second-year class have a joyful time learning them and keeping them straight. But what all those diastereomers and enantiomers in the textbooks have in common is that, fundamentally, they come down to invariant arrangements of the atoms and groups of each molecule. Enantiomers (like D-threonine and L-threonine), or diastereomers (like D-threonine and D-allo-threonine) differ from each other at a fundamental level of which atom is attached to which, and in which direction. Nothing can change that, without turning the molecule into another substance.
Atropisomers, though, are weirder. They happen when structures that would normally be identical through bond rotation are hindered enough for two separate species to exist. The example at right is the first pair that was ever described in the literature, back in the 1920s. If things were freely rotating around that bond between the two aryl rings, these two conformational isomers could never be seen alone. But the groups flanking the central bond keep things from being able to rotate, and you get the pair of enantiomers (mirror-image compounds) shown. They can be separated by making salts with chiral amines, and the resulting free acids do not interconvert, and have opposite optical rotations. They’re enantiomers, all right, although they don’t have any chiral carbons in their structures at all.
You can get into this situation in several kinds of structures. Ortho-substituted aryl rings shoved together are the classic way, as shown, but you can also have hindered amides that don’t rotate any more, medium-sized rings that sort of chunk back and forth between two conformations (as in this case), bicyclic structures that can’t quite get out of their own way, and more. As you might imagine, there’s a whole range of these things. Freely rotating bonds are zipping around so fast that you’ll never distinguish things, but atropisomers can interconvert on time scales of seconds, minutes, days, or years, depending on their structure and on the temperature you’re observing them at.
This neat effect can be a major pain in drug development, though. As enantiomers, the two members of an atropisomeric pair can (and in fact almost certainly will) show different effects in living systems. We’re very markedly chiral, after all (try to find some L-glucose or D-phenylalanine in your body). So what if you take a dose of a pure atropisomer, and over the hours that it’s in your bloodstream, it slowly converts to a mixture of two different enantiomers? What if it does that over a period of weeks on the pharmacy shelf? There are, for sure, conventionally chiral drugs with labile chiral centers on them, although we try to avoid that sort of thing. Atropisomerism, though, can sneak up on you, because you’re not always aware that you’ve up and made a chiral molecule.
In fact, as that review shows, what often happens when atropisomerism shows up in a lead series is that the med-chemists sigh and go back to the bench to find some way to get rid of it. There are two ways you can go – loosen things up to where everything is freely rotating again, or tighten things down to where the rate of interconversion slows down to where it can be ignored. There are successful examples of each approach. What doesn’t work, though, is just hoping the problem will go away – come to think of it, that doesn’t work too well in general.