The Art and Science of Assymetric Catalysis

Chirality as a concept was first descried by Louis Pasteur during his work on Racemic acid, but its importance in biological molecules became widely accepted after the 1960s thalidomide disaster (1). Another important event, from a business perspective, was when Astrazeneca isolated the S -enantiomer of their drug Prilosec and successfully received clearance to market it as a brand new drug Nexium to continue their monopoly over proton pump inhibitors (2). As you might expect, this was a rather controversial issue.

With a greater understanding of the importance of chirality, the question became: how do you make a pure chiral substance? In tis context, purity refers to having only one of two possible enantiomers of a given substance. Generally, biomolecules found in nature are chiral by default but synthesizing such compounds in the laboratory under normal conditions leads to a 50:50 mixture of both enantiomers (i.e a racemic mixture) most of the time. The reason for this can be deduced by observing the mechanism of the common reactions and in this case, I will use an SN1 reaction as an example:

As observed above, the carbocation intermediate is flat, the incoming nucleophile (Nu) can attack from either the top or the bottom with exactly the same ease. As there is no physical or energetic reason for the nucleophile to prefer one side over the other this results in a 50/50 split: half the molecules end up “right-handed” (R) and half “left-handed” (S). SN2 reactions offer better control in terms of stereochemical control, but the catch is that the resulting product has a reversed stereochemistry.

Furthermore, the initial reacting material must contain only one stereoisomer or you’d end up with exactly the same number of diastereomers.

In the past, chemists would have to make the racemic mixture, separate them and discard the unwanted stereoisomer, a wasteful approach. These days, thanks to Dr. William S. Knowles, Professor Ryoji Noyori, and Professor K. Barry Sharpless, we use asymmetric catalysis to solve this problem. Asymmetric catalysis is defined as a process in which a chiral catalyst is used to direct the formation of a new element of chirality in a molecule so that the resulting stereoisomers are formed in different amounts (3). Here, I’ll be covering the three quintessential asymmetric catalysis reactions.

Knowles’ Catalytic Asymmetric Hydrogenation

In 1968 William Knowles at Monsanto Company St. Louis, demonstrated that a chiral transition metal based catalyst could transfer chirality to a nonchiral substrate to produce a chiral product in which one of the enantiomers was in excess (4).

Although the yield was less than ideal, 15% enantiomeric excess to be exact (4), and too small to be of any practical use, the result proved that catalytic asymmetric hydrogenation was indeed possible and paved the way for future developments.

How does it work?

The cationic rhodium(I) complex typically features a chiral diphosphine ligand. After the catalyst loses its stabilizing ligands, a prochiral alkene substrate can then bind to the metal centre forming two distinct diastereomeric intermediates (5). The major adduct is the thermodynamically favoured diastereomer (i.e. more stable) and thus exists in higher concentrations in the solution. The minor adduct is less stable and thus exists in much lower concentrations. Under normal conditions, it would be reasonable to expect that the more stable intermediate will determine the stereochemistry of the final product. However, Knowles’ method allows for the opposite to occur. The enantioselective step is triggered by the introduction of hydrogen gas which undergoes oxidative addition to the rhodium centre. Since the minor adduct reacts with hydrogen significantly faster than the major adduct, nearly all the final product comes from this pathway, fixing the stereochemistry of the molecule (5).

Now this was a significant step, but as mentioned earlier, the enantiomeric excess (ee) was poor, so the next challenge was to solve this yield problem. The challenge was to find a proper match between ligand and substrate to achieve synthetically useful efficiencies. Knowles and co-workers at Monsanto discovered that a cationic rhodium complex containing DiPAMP, a chelating diphosphine with two chiral phosphorus atoms, catalyses highly enantioselective hydrogenations of enamides (6). In the key step of the syntheses of L-DOPA enamide intermediate is hydrogenated in the presence of a catalytic amount of [Rh(R,R)-DiPAMP) COD] + BF4 affording the protected amino acid B in quantitative yield and in 95% ee (7). A simple acid-catalyzed hydrolysis step completes the syntheses of L-DOPA.

The so-called Monsanto Process was the first commercialized catalytic asymmetric synthesis employing a chiral transition metal complex and its success contributed significantly to the explosive growth of research aimed at the development and application of other catalytic asymmetric reactions. It is still used till this day.

Noyori to the rescue

Now L-Dopa is an important molecule, and its synthesis was a milestone, but the Monsanto process that Knowles had developed was limited to the synthesis of L-Dopa. This poses obvious problems with regards to the synthesis of other crucial chiral compounds. In 1980, Professor Ryoji Noyori reported the discovery of atropoisomeric chiral diphosphine, BINAP (6).

Rhodium(I) complexes paired with BINAP enantiomers enable the precise production of amino acid derivatives through the hydrogenation of (acylamino)acrylic acids (or esters). They are used to convert allylic amines into enamines with remarkably high selectivity (8). The high selectivity of BINAP stems from the specific, lopsided shapes formed when a metal atom binds to the C2-symmetric ligand (8). However, the real breakthrough came with the replacement of Rhodium with Ruthenium. Both metals gave high ee values in AH of enamides but with an ‘opposite’ sense of asymmetric bias. This reaction, unlike Rh(I)-catalysed hydrogenation, proceeds via a metal monohydride mechanism and shows higher enantioselectivity (8). Using ruthenium catalysts paired with BINAP and halogens (like Cl, Br, or I), a wide variety of ketones can be converted into specific enantiomers with high selectivity. This process is very reliable because specific functional groups can act as directing groups in the reaction (8).

This new BINAP/Ru system greatly extended the reaction scope to allow for the asymmetric synthesis of a wide range of compounds. However, his greatest contribution was moving the field from ‘trial and error’ to a rational design approach by delineating how catalysts could differentiate between mirror-image transition states with high accuracy.

Oxidation

Around the same time as Noyori, Sharpless and Kazuki accomplished the stereoselective epoxidation of allylic alcohols using titanium(IV) tetraisopropoxide, tert-butyl hydroperoxide, and an enantiomerically pure dialkyl tartrate (9). When the D-(-)-tartrate ligand (D-(-)-DET) is used in epoxidation, the oxygen atom is delivered to the top face of the compound while The L-(+)-tartrate ligand (L-(+)-DET) epoxidizes the bottom face making the reaction very predictable (10). Sharpless further enhanced the scope of this reaction after reporting that the asymmetric epoxidation process can be carried out with catalytic amounts of the enantiomerically pure titanium-tartrate complex by adding molecular sieves to the epoxidation reaction mixture (11). This led to the large-scale production of (S)- and (R)-glycidol and (S)- and (R)-methylglycidol which are versatile building blocks for the synthesis of chiral molecules especially pharmaceuticals (11).

Today, asymmetric catalysis has quietly become the cornerstone of the synthesis of essential (and non-essential) compounds. Perhaps the next time you reach for a menthol, you should remember the amount of work that went into producing the technique that made isolating the right isomer possible.

References

1 G. Vantomme and J. Crassous, Chirality, 2021, 33, 597–601.

2 Walid F. Gellad, Phillip Choi, Margaret Mizah, Chester B. Good, and Aaron S. Kesselheim, The American Journal of Managed Care.

3 T. Saget, M. Mellah, P. Dauban and E. Schulz, ACS Cent. Sci., 2026, 12, 280–299.

4 W. S. Knowles and M. J. Sabacky, Chem. Commun. (London), 1968, 1445.

5 C. R. Landis and J. Halpern, J. Am. Chem. Soc., 1987, 109, 1746–1754.

6 W. S. Knowles and R. Noyori, Acc. Chem. Res., 2007, 40, 1238–1239.

7 A. J. Minnaard, B. L. Feringa, L. Lefort and J. G. De Vries, Acc. Chem. Res., 2007, 40, 1267–1277.

8 S. Akutagawa, Applied Catalysis A: General, 1995, 128, 171–207.

9 T. Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 1980, 102, 5974–5976.

10 A. Riera and M. Moreno, Molecules, 2010, 15, 1041–1073.

11 Y. Gao, J. M. Klunder, R. M. Hanson, H. Masamune, S. Y. Ko and K. B. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765–5780.