An Organocatalysis Nobel

Since I was not able to blog the Nobel Prizes as they were announced this year, I wanted to circle back around to the Chemistry award. This one was indeed chemistry, by anyone’s definition, so that cheered up the (many) chemists who feel that “their” prize has too often gone to worthy discoveries in other fields entirely. The award is for asymmetric organocatalysis, which practitioners of organic synthesis will most definitely have already heard about, but probably not too many others have. So let’s take that topic from the top – we’ll start out with some groundwork for folks completely outside the field, which readers can certainly skip over, and work our way up.

Intro to Chirality

To begin at the very beginning, it’s important to realize that many molecules are capable of existing in “right-handed” and “left-handed” forms. This property, called chirality, is a surprisingly deep subject when you start thinking about it. Consider the classic example of a right shoe versus a left one. That is a completely valid example of chirality (and how an object can exhibit it), but now imagine that instead of putting a shoe on your foot that you are standing, barefooted, on two rectangular pieces of cardboard of identical shape and size with no identifying marks at all. Now, those certainly do not exhibit “handedness”; such plain pieces of cardboard can be exchanged with each other with no effect. What if they’re labeled “Top” and “Bottom” on their faces? Well, you can still flip each one over and be back to where you started. But what if you cut a little curve into one side of each piece, to approximate an instep? We’re not going to get fancy with toes and heels and stuff – just make one side (the “inside” for each foot) a bit curved in. If you haven’t written “Top” and “Bottom”, then you can still do that same flip-em-over move and be back to where you started. But if you have put in those labels, you have suddenly lost the ability to do that.

Your two pieces of wood are now nonsuperimposable, in the lingo: you cannot flip or rotate them in any series of moves to make them be identical again. You now have a right-handed (well, footed) piece of cardboard and a left-handed one. They are basically mirror images of each other, and we call such matched pairs enantiomers. It’s making those faces and sides different that does it, of course – you eventually ruin the symmetry enough to make a chiral object. Imagine a really thin mirror, like a very stiff, very shiny piece of metal foil, but in this case able to magically pass right through any object like a knife blade that does no damage at all. For any object, if you can put such a “mirror plane” through an object so that its two halves reflect perfectly like each other (that is, if it has a “plane of symmetry”), then that object doesn’t have chirality. If there’s no way to do that, if it doesn’t have a plane of symmetry from any direction, then it has chirality. 

For drug molecules and biomolecules, the thing to concentrate on in many cases is the good ol’ single-bonded carbon atom. It has four bonds reaching out evenly in four evenly spaced directions, like the corners of a tetrahedron. If all four of those bonds connect to something different, then that atom has chiral “handedness”. But if there are two identical substituents, then you can run one of those mirror planes through it, and it’s not chiral. So methane isn’t chiral (a carbon with four hydrogens). Neither is monofluoromethane, nor difluroromethane, nor chlorofluoromethane. All of those still have at least two of the four positions as H atoms. But a carbon with a fluorine, a chlorine, and a bromine on it (with the remaining position as a hydrogen) now has four different substituents, and that one can be right-handed or left-handed. 

Chirality and Drugs

This means that a lot of biomolecules have chirality. All the common amino acids except glycine have a chiral carbon in the middle of them, and almost all the common sugars have no planes of symmetry, either. So there are your proteins and carbohydrates and the nucleic acids like RNA and DNA, too, since they have those sugars in their structures. The more simple lipids don’t have any chiral centers in them, but ones with branched structures can. As far as drug molecules go, if their structures are completely flat, then you can put a plane of symmetry  through them that way, and they’re achiral. Aspirin, acetaminophen, niacin, and fluorouracil are all in that category. But the greater majority of drug structures have chirality (and obviously all the monoclonal antibodies do, since they’re made of protein). Ibuprofen has one chiral carbon in its structure, for example, and that’s all you need – amphetamine is the same way. Those can exist as pure right-handed and pure left-handed compounds.

These isomers can do very different things indeed in the body, because remember, all those proteins (receptors, binding sites, transporters, enzymes) have chiral character, too. Now, some drugs with single chiral centers in them are still sold as the 50/50 mixture of right- and left-handed isomers, generally because all the activity is in one of the pair and the other one doesn’t do much of anything. Ibuprofen is in this category, as is warfarin. The regulatory authorities frown on this sort of thing now, though, and generally if you’re developing a chiral drug you’d better be prepared to manufacture just the active enantiomer. That warfarin link above will also illustrate that metabolism of drugs can create chiral centers in your compounds, too, as the various enzymes in the liver get to work on your structures. Everything gets more chirally complicated as you bring in more complex structures. A structure with two chiral centers (like ketamine) can have four isomers, and one with three can have eight (the number of possible isomers goes up as two-to-the-X power). Morphine has four chiral atoms in it, and azithromycin has eighteen

That means if you just bozo-ed your way through a total synthesis of azithromycin, starting from stuff that had no chiral centers and just fifty-fiftying your way along every time you hit a new one, your final product would have two-to-the-eighteenth different isomers in it: 262,144 different compounds, each of which might be doing something different after dosing. The great majority of those are surely lousy antibiotics, for one thing, but who knows what else they might do? God knows, no one has made them all separately and tested them, of that you can be completely sure. Some of those chiral centers are going to be a lot more important than others, and you can be sure about that, too.

Making Chiral Compounds

So you can see how being able to make exactly the chiral compounds you want is rather a big deal. And in the end, you have limited options on how to do that. Here’s a key point: you can’t just make chirality out of nothing. There has to be a chiral starting material or reagent involved somewhere, or there’s nothing to distinguish (nothing that can distinguish) a right-handed product from a left-handed one. So you can outsource your problem to the natural world, and start with molecules that have already been made by living creatures whose (chiral) enzymes have done the work for you. This “chiral pool” technique has long been popular, but not every molecule has a good starting point for this method (not even close), and some of those chiral starting materials are quite expensive or not available in large amounts. You can use a chiral reagent of some sort, perhaps even sticking a whole chiral piece reversibly onto your molecule of interest (making an ester or amide, for example, with a “chiral auxiliary”) to influence the chemistry. That can also get expensive, though, and you’ll need to recover the chiral reagent or auxiliary to re-use it if you’re doing this on any kind of scale (with all the separation and purification issues that entails).

Probably your slickest option would be to have a catalytic step where the catalyst itself is chiral. In that case, you’re using a small amount of this crucial additive (which can be as simple as proline), and it’s going around doing the work for you over and over. And that, folks, is what Ben List and David MacMillan were just awarded the Nobel for. They (and many, many others) have been at this for many years now, trying to find general methods for these sorts of reactions. As the Nobel background document notes, catalysis in general has been the subject of seven Nobels over the years, and that’s very fitting. A good catalytic method can have a major impact on the world, because that’s an extremely desirable method for industrial-scale reactions. A significant part of the human race is alive in the first place thanks to the metal-catalyzed Haber-Bosch process for making ammonia from nitrogen, for starters. But only two of these prizes have addressed chirality and catalysis at the same time: John Cornforth’s in 1975 for enzyme mechanisms (along with Vladimir Prelog for different fundamental work on chirality), and Noyori, Knowles and Sharpless in 2001, which is in many ways the prize closest to this one.

In this case, though, the reactive species is not a metal complex (as it is for the work recognized in 2001). Both List’s and MacMillan’s reactions have similarities with the idea of the chiral auxiliaries mentioned above. But the key is that their chiral compounds come in and make transient intermediate structures with the reactants, and are then released to start the whole process over again. This is actually how many enzymes work, forming some sort of transient reactive intermediate, and organocatalysis in general can be seen as an effort to enlist this sort of chemistry in flasks with less complex reagents, rather than in cells and with enzymes. In the current cases, the intermediates are generally nitrogen functionalities such as enamines, imines, and iminiums, and advantage is taken of the different reactivity of these species compared to the carbonyl starting materials that they’re formed from. A lot of workhorse reactions of organic chemistry can be enlisted – aldol condensations, Michael additions, Diels-alder and 1,3-dipolar cycloadditions, Mannich reactions, epoxidations, alpha-carbonyl bond-forming reactions, and more. Some of these mechanisms fit well into the similarly expansive field of photoredox chemistry, which has opened up still more possibilities. With careful planning, some of these reactions can cascade, one after the other, with the chiral catalyst helping out in each stop along the way.

There are times when the chemistry Nobel (and others, for sure) has been awarded to a discovery that’s old enough to be pretty well trampled down by the time the committee recognizes it. That is definitely not the case this time. The key papers the award cites are from 2000, and this is still a very active area of research. That’s because there are a great number of possible structures one could imagine using for the chiral catalytic species, and there are (as shown above) a great many ways to use them. There’s no reason to think that these reactions have taken their final form by now, and we’re not really at a stage where we can predict what’s likely to work the best. “Best” means overall yield, of course, and higher turnover (using smaller and smaller amounts of catalyst), and in these cases it especially means the chiral purity of the products. Getting all of these working in your favor simultaneously is not easy at all, so there’s a lot of semi-empirical let’s-try-this that’s gone on in the field, and out of these observations grow the general rules that later chemists can take advantage of. 

But catalysis is really the ideal towards which all organic synthesis looks to – when it works well, it feels like magic. Getting catalytic methods to produce chiral centers, an outstanding issue in the field ever since we realized what chirality was, is a very useful sort of magic indeed.