Asymmetrical poke method

In the field of asymmetric catalysis, there is a lack of theoretical justification: it is often unclear which catalyst will work and which will not, and why. And there is no talk at all about rational design of catalysts. Recently, chemists from MIPT, INEOS RAS and HSE published article about the synthesis of a chiral catalyst based on a ruthenium complex. One of the authors of the study, Mikhail Boym, talks about what it’s like to develop chiral catalysts blindly.

Chirality induction

If the mirror image of a molecule does not match its original image, then such a molecule (or more broadly, any object) is called chiral, and the “reflections” are called enantiomers. They are usually designated by the letters R and S before the name of the molecule. The difference between enantiomers can be very large: one can be a medicine, and the other a poison. For example, (S)-penicillamine is used for treatment Wilson's diseaseAnd his (R)-isomer neurotoxic. So it would be nice to be able to obtain from chiral molecules the enantiomers we strictly need, eliminating the possibility of obtaining their “evil twins”. This is the task of asymmetric catalysis.

Now we use catalysts with a metal atom and a chiral ligand for this – an organic molecule covalently bound to the metal. When the starting materials interact with such a catalyst, so-called chirality induction occurs: the chiral ligand makes the reagents coordinated to the complex turn in the most energetically favorable way, and one enantiomer of the product is obtained at the output. Or it doesn't. As luck would have it. If the ligand's influence on the reagents is weak, then it makes no difference to them which side they approach each other, and in this case a racemate is formed – a mixture in which the enantiomers are equally divided. If there is even a slight influence, one of the enantiomers will be more. Our task is to find a combination of metal and ligand so that the reaction with them yields one enantiomer at the output.

In articles, the ratio of enantiomers is characterized by enantiomeric excess, the difference between their molar fractions, expressed as a percentage. For example, if the ratio in a mixture is 30 percent of one enantiomer to 70 percent of the other, then the enantiomeric excess will be 40 percent.

Finding a good chiral ligand still requires a trivial search. Some time-tested ligands that are often used can be bought at a reagent store. But they may not work, and then you have to develop new ones. Every time you conduct an enantioselective reaction, you send the product to an analytical chromatograph. At the output, you get a chromatogram in which each enantiomer corresponds to a certain peak. By the peak areas, you understand what ratio of enantiomers you got.

Of course, we all dream of 99 percent. If you get 90 percent or more, and the reaction is new and useful, there is a chance that the catalyst will be named after you. If 80 percent, then everything is fine, but there are questions. 70 percent is already a bit weak. In general, with each percent, your chances of getting a personalized parking spot in the synthetic chemists' parking lot, or even just publishing an article in a good journal, fade.

Chiral arenas

I have been working on chiral arene complexes of ruthenium for four years now. We are pioneers in this sense, no one has ever used them in any enantioselective reactions. More precisely, no one has ever used a chiral arene ligand attached to ruthenium to induce chirality. My scientific advisor came up with a ligand structure based on natural camphor – it was a great idea, because the starting material is cheap and accessible. We synthesized the ligand and obtained its ruthenium complex.

We knew that ruthenium complexes can catalyze reactions of carbon-hydrogen bond activation, in which at one stage of the catalytic cycle the catalyst breaks the carbon-hydrogen bond and then attaches some organic piece to the carbon. These reactions were discovered not so long ago, but it has already become clear that they allow obtaining various heterocycles in one stage, which were previously cooked in a long way. And these heterocycles often turn out to be biologically active substances, so CH activation has become a very fashionable topic. No one has carried out these reactions enantioselectively on arene complexes of ruthenium, and we decided to try.

We ran several activations with the resulting ruthenium complex, and none of them worked. We assumed that the problem was that the bond between our ligand and the metal was too weak, and calculations confirmed this. However, article about our complex was accepted for publication. And at the same time in the magazine Angewandte Chemie came out An article by Chinese professor Wang Jun on how to obtain a chiral arene complex of ruthenium and use it in enantioselective CH activation.

Wang Jun achieved what we were aiming for, but by barbaric methods. The catalyst that the Chinese scientists made was, in our opinion, too complicated to synthesize. The chemists obtained it from a not very accessible derivative of paracyclophane in 10 preparative stages (versus four for us). However, the article itself fit perfectly into the general framework of successful articles on asymmetric catalysis – the enantiomeric excess of the products was over 90 percent.

After the failure with camphor, we came up with another ligand that could be welded in one step from simple reagents – tetralin and tert-butyl chloride. And we got its complex with ruthenium – all this took about a week. But we chose an achiral ligand. The idea was to attach it to ruthenium, get a chiral complex in the form of a racemate, and then separate the complex itself into individual enantiomers.

Developing the separation process took a few more months, and eventually we had an orange powder of a ready-made chiral catalyst in our hands. It catalyzed the C-H activation reaction of hydroxamic acid derivatives, which produces chiral tetrahydroisoquinolones, quite well. But the problem was in the numbers. Here are the first four numbers from our enantiomeric excess table: 0, 9, 0, 9. The fifth was a joy — 25. The sixth — 26. The seventh — 20. Pain.

Where's the excess, Lebowski?

If you open an article in the field of asymmetric catalysis in any good journal, the enantiomeric excess values ​​in it will be more than 80 percent. Less effective catalysts rarely make it to print. Well, or they appear in journals that young and ambitious scientists don’t really want to read. And then you get the impression that while you’re slaving away over the desired percentage of enantiomeric excess, changing the reaction conditions, rational catalyst design has long been invented, and everyone uses it without exception and doesn’t skimp on praising its creator. And if something doesn’t work out, they take quantum chemistry, artificial intelligence, magic supplement and get their way. Basically, everyone knows how to make the right catalyst, and you're sitting here and suffering over your lousy 25 percent.

In fact, the problem is not in knowledge. The basis is this: the more space a chiral catalyst occupies next to a coordinated substrate, that is, the more physically large it is, and the more rigid its structure, the better it will give an enantiomeric excess. It doesn't sound very elegant, but there are no other good rules for selecting a chiral ligand for a reaction that has not yet been tested for enantioselectivity. There are many exceptions to this rule, but there are simply no alternative principles – and this is the problem with asymmetric catalysis. That is, there is a rule, it is bad, we have not yet discovered other rules. This is science for now.

Of course, for each individual reaction, if it is well studied, there are considerations about which chiral catalyst might fire. For example, catalytic hydrogenation reactions researched in great detail. And the mechanism is well known, and there are many working ligands. Inventing another working one is not a problem, because you know what the structure of the ligand should look like, and in what places it makes sense to modify it. In addition, exists a set of chiral organic fragments that are used particularly often, and they work reliably well, although not always.

The scientific community published exactly two articles about our specific case: ours and one more. So we went to play the lottery, engaged in scientific poking. We cooked another catalyst – it turned out to be worse than the previous one. We tried a few more reactions. We tweaked the experimental conditions. In the end, having sacrificed yields and a wide range of substrates, we got to 60-80 percent, sent the manuscript to the journal.

One of the reviewers made the following claim about our work: the problem, they say, is not even in the low values ​​of the enantiomeric excess, but in the fact that we did not explain this very low enantioselectivity. There is no description of experiments and calculations in the text that could provide some rational explanation for the final result. And he was absolutely right – but we really did not have good rational explanations that could be confirmed or refuted by the experiment! That is, of course, we presented him with a calculation in response, the reviewer was satisfied, the article was published.

But questions remain.

Why does it hurt so much?

Why does our reaction proceed only in the presence of fluorinated alcohols? Why does enantioselectivity increase if we dilute it with regular alcohol? How does the ligand structure affect the yield and enantioselectivity of the reaction? We have a hypothetical answer to each of these questions, but it is very difficult to verify them experimentally.

Firstly, because the mechanism of our reaction is not reliably known. Opened in 2021, and studying all the features of the mechanism is a task for years or decades. Usually, several scientific groups are engaged in this, each with its own focus. Someone makes high-level calculations, someone isolates intermediates, someone puts it all together. But not every reaction has enough fans to be studied in detail. And, secondly, because arene ligands in ruthenium complexes are very mobile: the arene ring rotates over ruthenium and can turn in any way. And in order to carry out high-quality calculations, it is necessary to take into account each way of ligand rotation, and this takes a lot of time and effort.

Interest in how chirality is induced arose with the first works on catalytic hydrogenation in the 1960s. At that time, scientists found the first effective catalysts based on phosphine complexes of rhodium and learned to obtain products with enantiomeric excesses of about 80 percent. In the 1970s, it became clear that phosphine ligands with the C2 symmetry axis worked better than others in hydrogenation, and the first explanations for this phenomenon appeared, the first hypotheses about the process of inducing chirality. And the first industrial applications of asymmetric catalysis also appeared – synthesis chiral menthol and the Parkinson's disease drug levodopa.

In 2001, Ryoji Noyori, William Knowles, and Barry Sharpless received the Nobel Prize in Chemistry for their breakthrough work in asymmetric catalysis. In his Nobel lecture, Knowles reasons about the mechanism of chirality induction in catalytic hydrogenation and proposes a model for determining the optical configuration of the product. In the same lecture, he says that although the proposed model works well, it does not agree with new experimental data. In general, problems with theoretical justifications began immediately.

At that time, it was very difficult to find out the details of the mechanism, including because quantum-chemical calculations took a lot of time. Now, thanks to the development of density functional theory and the increase in computer power, things are better. And the mechanism of induction of chirality in rhodium-catalyzed hydrogenation is described in detail studied.

However, to find out how chirality is induced in a single reaction, we first have to find out what paths it can take, then find the stages of the catalytic cycle where chirality is induced, then calculate how the ligand structure affects the induced chirality at these stages. In addition, if a solvent capable of solvating the reagents and catalyst is used in the reaction, it also needs to be taken into account in the calculations. And there are simply no reliably working solvation models yet. As a result, it turns out that figuring out chirality induced in a single reaction is a huge collection of problems for several research groups.

In general, there are good data on the mechanisms of chirality induction, to put it generously, for about a dozen of the most studied reactions. Everything else is a dark forest. There is no general theory, because each reaction has so many features that it is unclear from which end to take this theory. And whether it is possible to develop it at all. That is, it is clear that at some point a chiral ligand makes one of the initial substances turn in a certain way. But at what point and which ligand should be taken for this to happen more effectively, is never clear in advance. And until chemists accumulate more data on well-run enantioselective reactions, and supercomputers for quantum chemical calculations do not become available to everyone, asymmetric catalysis will continue to run on luck and the number of free hands.

It is necessary to develop enantioselective reactions despite the difficulties. Firstly, to accumulate these very data, which will one day help someone understand chirality induction. Secondly, to obtain optically pure preparations for medicinal chemistry. The order of these reasons can be changed – it depends on what is closer to you as a scientist, the applied or fundamental value of science. In addition, reactions with an enantiomeric excess approaching 100 percent are especially valuable. If the excess is so high, then most likely the reaction proceeds along one specific path, and studying chirality induction becomes easier, because all other scenarios can be discarded in the calculations.

This means that I still have a chance to name the catalyst after myself. As do many of my colleagues. Although – and here, of course, my purely my values ​​come into play – it would be better, of course, for us to have a theory.