I wrote here a few years ago about the Mysterious Sparteine Shortage, and it’s a problem that hasn’t gone away. Sparteine, for those who collect neither alkaloids nor asymmetric organic chemistry routes, is a naturally occurring compound (found in a South American species of lupine, among other places), and it’s also an interesting reagent. Its rigid ring structure and placement of two basic tertiary amines make it able to form asymmetric anionic complexes in solution, especially with organolithium reagents. This can allow some some really useful reactions that form only one enantiomeric product (a mirror image isomer), a feature that synthetic organic chemists are always on the lookout for.
The problem, as mentioned in that blog post, is that the asymmetric reagent needs to be available. An imbalance of chirality doesn’t just appear. If you have a compound that’s a single enantiomer, you had to make it or purify it via something else that was a single enantiomer. Things that aren’t capable of being mirror-image isomers (like plain water) or are fifty-fifty mixtures of such isomers aren’t able to separate or synthesize pure enantiomers themselves. If someone drops a shoe down a straight metal tube (a symmetric item), you’re not going to be able to tell if it’s a left-hand or right-hand shoe that’s rattling down the thing, but if you reach out with your (asymmetric) left or right hand and touch said shoe after it comes out, you can tell even with the lights off.
We have the lupine to thank for making asymmetric sparteine for us, but someone has to go to the trouble of isolating it or synthesizing it from a more available “chiral pool” precursor (for sparteine, that would be another alkaloid, cytisine). There was some sort of major hiccup in the supply several years ago, though, which was not the first time this had happened. This makes large-scale attempts to use the synthetic methods based on the compound risky – here, for example, is the process group at Vertex opting to go via another route rather than take the chance. They were also looking at “sparteine surrogate”, a very similar compound that can perform the same types of chemistry, but that one is also derived from cytisine and doesn’t necessarily get around the supply problems, especially for production work.
The O’Brien group at York that developed the surrogate now reports a gram-scale synthetic route to it, which might help. This one doesn’t require a plant to make you a single alkaloid enantiomer at all – instead, the asymmetry comes from the use of a bacterial lipase enzyme (from a Burkholderia species) to deliver a single enantiomer at a key step during the synthesis. That’s another good example of “chirality’s gotta come from somewhere” – trace any preparation of a single enantiomer back far enough, and you’ll almost certainly find something derived from a living creature, since biochemistry is by far the most ready source of asymmetric molecules.
All proteins and all carbohydrates in living organisms on Earth have the same “handedness”, which is a powerful argument for a single origin of life (or at the very least, a single surviving lineage of such origins). How we all ended up that way is a deeply controversial topic – is there something about one enantiomeric series that’s intrinsically better? That should be impossible, actually – chemically, the two are identical. Is there some way that an imbalance of two mirror isomer amino acids or sugar percursors could have developed before life got going? That takes us back to “chirality’s gotta come from somewhere” and all kinds of weirdo explanations that go back to subtle asymmetries in basic physical laws and the like (a topic I wrote about on this blog in 2002 – man, have I written a lot of blog posts). If our sorts of life is relatively easy to develop in the universe (which after all is swimming in water, amino acids, and so on), will we run into a fifty-fifty mix of isomeric life forms as we start to explore? I have no idea, and neither does anyone else – it’s one of the major open questions, and looks to remain so for a good time to come.
One more philosophical topic, since it’s Friday, after all: how do we ourselves recognize asymmetry? In other words, how do we know right from left? The question sounds ridiculous, but improves on inspection. Humans are (mostly) bilaterally symmetric, but the two hemispheres of the brain are a strong exception. I cannot mention that exception without sending people down the rabbit hole that is the Jaynes “bicameral mind” hypothesis – Ash Jogalekar has pointed out to me that Richard Dawkins once called that one “either complete rubbish or a work of consummate genius, nothing in between“, and I can’t disagree. How embryos develop such asymmetries in the first place is another unexpectedly deep question, and might come down to the direction that cilia are beating, which might well come down to the proteins involved in their construction, and we’re back to chirality-of-biochemistry again.
Recall as well that our eyes are wired separately into each hemisphere (which has led to a few spectacularly weird reports in the literature after the desperate surgical expedient of corpus callosotomy in severe cases of epilepsy. Severing the main neural connections between the two hemispheres in such a fashion has a number of side effects, and among these can be that a patient (at least at first) gives different answers to the same questions when they’re read by the left eye versus the right one (the different verbal fluencies of each hemisphere are a factor, too). So my hypothesis is that on a macroscopic level, our chirality-recognition system is based on asymmetries in our conscious processing of the world via our left and right eyes, and thus our left and right brain hemispheres. I will be happy to see people poke holes in this idea in the comments.