DSM researchers Jeroen Boogers, Laurent Lefort, Andre de Vries, David Ager and Johannes de Vries reveal how they developed "MonoPhos" ligands, which can be used to produce instant ligand libraries for high throughput screening of catalysts for asymmetric hydrogenation
In bulk chemicals, the use of catalysis is the rule rather then the exception. In the production of pharmaceuticals, use of catalysis is limited to a mere 15% of all steps. Within that category, heterogeneous catalysis is mainly used for hydrogenation and hydrogenolysis; homogeneous catalysis for aromatic substitution reactions, asymmetric hydrogenation, catalysed oxidations and CO chemistry; and biocatalysis mainly for the production of chiral intermediates, using lipases, lyases and alcohol dehydrogenases.
There are two main reasons for the relatively limited use of catalysis in the production of pharmaceuticals. One is the high cost of the catalysts; the other is the limited time available for process development due to the pressure to get products to market as fast as possible.
To cope with the latter problem, many companies have started to use High throughput Screening (HTS) as a means of rapidly identifying a selective and economical catalyst.
Asymmetric hydrogenation using a rhodium catalyst with chiral phosphorus ligands is an important technology for the production of enantiopure Pharma intermediates.1 The paradigm of requiring a bidentate ligand for these reactions has recently been broken by the invention of chiral monodentate ligands,2 such as phosphonites, phosphites, and phosphoramidites (see fig. 1).3
This latter class of ligands - which DSM call MonoPhos - has proven highly successful for the asymmetric reductions of a wide variety of functionalised alkenes and ketones (Scheme 1).4 Their preparation is very easy and requires two synthetic steps starting from the BINOL (1,1'-Bi-2-naphthol). In contrast to bisphosphines that require lengthy synthetic sequences, these ligands are easily prepared overnight.
Both the substitution pattern on the BINOL as well as the amine portion of the phosphoramidite can be varied. Substituted binaphthols are available with many substitution patterns. Coupled with the thousands of commercially available amines, the number of possible combinations climbs into the hundred thousands.
These ligands are then combined with metal precursors based on Rh, Ru and Ir.5 Even though there are many bisphosphines known, their number is dwarfed by the number of phosphoramidites that can be made overnight.
DSM has realised the full potential of these modular ligands by developing a method for their parallel synthesis in 96-well plates, which we call Instant Ligand Libraries.6
Not only can we synthesize and screen 96 ligands in the robot within 48 hours; we can also use the outcome to design a more focused library. Such iterations are unthinkable with bidentate phosphines.
In the course of screening ligands for the asymmetric hydrogenation of an alpha-alkylated cinnamic acid derivative, a first screening revealed a rhodium/MonoPhos catalyst that was able to hydrogenate the substrate with 50% ee using 1 mol% of the catalyst.
Confident that we would be able to augment the rather low ee by using the instant ligand library approach, we first concentrated on increasing the rate of the reaction. Since it is known that electron rich complexes lead to faster hydrogenation reactions, we randomly screened a library of 32 electron rich additives such as phosphines, bisphosphines, amines, pyridines and a number of salts. From this screen, the triarylphosphines emerged as powerful accelerators.
These phosphines are not simply additives, they actually bind to the metal in the complex, resulting in a mixed phosphoramidite/phosphine catalyst. These mixed complexes are up to a 100 times faster than the parent phosphoramidite complexes.
Having solved the rate problem we resumed screening for high ee. As a first screen had revealed the importance of the substituents in the 3,3'-position of BINOL, we screened a library of 96 ligands based on 3,3'dimethyl-BINOL. This eventually led to the development of an economic hydrogenation process in which the product was obtained with 90% ee.7
Through the invention of the mixed ligand approach the number of possible catalysts now climbs even more.8 With just 10 ligands, the number of different combinations is 55; with hundreds of thousands of ligands available, the number of different combinations becomes almost inconceivable.
A trillion possibilities?
Looking at figure 4, we see a catalyst that can be put together from:
25 BINOLS
2000 amines and anilines (and 500 alcohols and phenols)
4 metals
> 100 000 auxiliary ligands!
5 anions
Although maybe not quite a trillion, it comes down to an astonishing number. Do we really need to perform so many screens? Of course not! Using an iterative approach, in which we zoom in on the hits of the first library to compose a next focused library, usually leads to results very quickly.
DSM now uses this iterative approach to library screening on a daily basis to develop catalysts for their customers.
CPHI Innovation Award-winner - silver
The MonoPhos instant ligand library concept was awarded with the silver CphI 2007 Innovation Award in Milan this year.