Development of Asymmetric Hydrogenation Catalysts via High Throughput Experimentation
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D o s s i e r
Discovery and Optimization of Catalysts and Adsorbents Using High Throughput Experimentation
Découverte et optimisation de catalyseurs et d'adsorbants par expérimentations haut débit
Development of Asymmetric Hydrogenation Catalysts
via High Throughput Experimentation
J.G. de Vries and L. Lefort*
* Corresponding author
Résumé —Développement de catalyseurs d'hydrogénation asymétrique par criblage haut débit —
La découverte de nouvelles molécules pharmaceutiques a sa propre dynamique qui impose des
contraintes temporelles très strictes au chimiste en charge de développer la production du principe actif à
large échelle. En conséquence, ce dernier va se tourner vers l’utilisation de technologies éprouvées et
robustes quitte à rendre le procédé plus coûteux ou plus polluant. Afin de pouvoir faire face à des temps
de développement très courts et d’introduire en production des technologies modernes et non polluantes
comme l’hydrogénation asymétrique, nous avons développé une plateforme de criblage haut débit pour la
découverte de nouveaux catalyseurs. Dans cet article, nous décrivons une des facettes de cette plateforme
qui est la synthèse de librairies de ligands chiraux et leur application au cas réel d’une molécule
Abstract — Development of Asymmetric Hydrogenation Catalysts via High Throughput Experimentation —
The dynamics of drugs discovery imposes severe time constraints on the development chemist in charge
of implementing the large scale production of a new Active Pharmaceutical Ingredient (API). This results
in the use of well-established and robust transformations at the expense of the cost-efficiency and the
sustainability of the process. In order to cope with the short development time and allow the implementation
of new more efficient production technologies such as asymmetric hydrogenation, we have turned
towards the use of high throughput experimentation for the discovery of new catalysts. The protocol for
the preparation of a library of chiral ligands and its application to real-life pharmaceutical molecules is
described in this article.
Catalyst (metal + chiral ligand)
g Clinical trials
irn FDA approval...
S Start of process development
= Effect of delayed launch
INTRODUCTION: AN INDUSTRIAL PERSPECTIVE
ON ASYMMETRIC HYDROGENATION
In 2001, the Nobel Prize for chemistry was awarded to
W. Knowles and R. Noyori for their work on asymmetric
hydrogenation1. This technology consists of the
metalmediated enantioselective addition of H2 onto an unsaturated
bond (olefin: C = C; ketone: C = O and imine: C = N) of a
prochiral substrate (Fig. 1) [
]. Discovered in the late 60’s,
asymmetric hydrogenation allows the synthesis of the desired
enantiomer of a chiral molecule (i.e. in most cases, an
intermediate/building block towards an API) with 100%
theoretical yield and 100% atom-efficiency, thus generating
no waste by-product. From an industrial point of view, it is
consequently a very attractive methodology for large-scale
production. However, nowadays, the majority of enantiopure
molecules are still produced either by fermentation, i.e. with
the use of the synthetic machinery of a microorganism or by
classical resolution of the racemate, i.e. the separation of
diastereomeric salts where the maximum yield is only 50%.
In spite of its attractiveness asymmetric hydrogenation has
found limited use in large-scale production. Probably no
more than 20 processes were ever implemented [
The main reason for this paradoxical situation has to do
with the dynamics of drug discovery and development
]. The development of a new drug requires very large
upfront investments from the pharmaceutical companies.
Recovering those investments and further profits will come
only when the drug is finally launched on the market – i.e.
when all clinical trials have been passed successfully (Fig. 2).
During the development phase, little effort and resources are
dedicated to the design of a robust synthetic route fitted for
large-scale production. This is due to the large attrition rate
for drug candidates. The current average clinical success
rate is only 11% [
]. The majority of New Chemical Entities
(NCE) are abandoned during the clinical trials because they
can not be proven effective or appear to have significant
sideeffects. The quantities of Active Pharmaceutical Ingredients
(API) needed for the clinical trials during the development
phase are produced via a synthetic route identical or close to
the one initially used by the medicinal chemists who
discovered the new molecule, i.e. a synthetic route fitted to prepare
a few grams of compounds without concern for cost, safety
and sustainability. Once a new drug has finally been cleared
to enter the market, there is a strong pressure to start
production as soon as possible. This means that development times
for these processes are measured in months rather than years.
Since every month of delay in the launch of a new drug can
mean a substantial loss of revenues (see Fig. 2 for the effect
of a delayed launch), most development chemists choose to
fall back on well-established chemistry, i.e. classical
resolution processes for the production of chiral building blocks,
rather than embarking on a search for a new asymmetric
hydrogenation catalyst that can be lengthy and without full
guarantee of success.
Although asymmetric hydrogenation can be considered as
a rather mature technology, finding the right catalyst allowing
good conversion and high enantioselectivity for an entirely
new prochiral substrate remains a difficult problem. The
chiral ligand is the cornerstone of the catalyst assembly. It
determines not only the level of enantioselectivity but also
influences the activity of the catalyst. Since the pioneering
work of Knowles and Sabacky in the 1960’s [
chiral ligands2 have been prepared but most of them were
tested only with model substrates. Real-life substrates, i.e. the
prochiral intermediates towards a pharmaceutical target
molecule are certainly related to these model substrates (Fig. 3)
but they also exhibit specific geometries/configurations or
1 K.B. Sharpless was also a recipient of this Nobel Prize for his work in
2 A few 1 000 chiral ligands have been reported in the literature and a
few hundreds are commercially available.
Model substrates and real-life substrates for asymmetric hydrogenation. (The owner of the molecule and its applications are given in
contain additional functional groups that hinders the direct
application of a catalyst efficient for the model substrate to
the real substrate.
In other words, there is no such a thing as a universal chiral
catalyst that would work for every new substrate [
Consequently, for every new prochiral candidate for
asymmetric hydrogenation, a search is needed to find the adequate
catalyst. The parameters that can affect the outcome of an
asymmetric hydrogenation experiment are numerous and all
should be considered during the search for the optimal catalyst:
– metal: Ru, Rh, Ir are the most common metals used in
asymmetric hydrogenation. Rh is preferred for C = C, Ru
for C = O and Ir for C = N;
– chiral ligand: the chiral ligand determines e.e. (enantiomeric
excess) and activity. It is selected among those commercially
available or present in house. In some cases, existing chiral
ligands will not induce a sufficiently high enantioselectivity
for the substrate of interest, in which case the preparation
of an entirely new ligand will be required. This is an
extremely time consuming exercise with no guarantee of
success as “there is no such thing as ligand design”3. An
additional selection criterion that can be considered during
the screening for a hydrogenation catalyst is the cost of the
ligand. Not only the metals, such as rhodium, iridium and
ruthenium but also the chiral ligands that are often
An interesting quote stemming from Manfred T. Reetz addressing a
chemist involved in “ligand design”: “Can you tell me if you designed
your ligand to give the (R)- or the (S)-isomer of the product?”. It is
clear that no one can answer this question. Hence, there is no such
thing as ligand design. At best one can copy features that are present
in “privileged” ligands, i.e. ligands that have been successful in other
prepared using multi-step syntheses including racemate
resolutions can be extremely expensive4. If the target cost
for the process is set to very low, one can exclude the
most expensive ligands from the start;
– ancillary ligands, counterions: the other achiral entities
present around the metal centre can be of great importance
not only for activity and stability of the catalyst but also
for its enantioselectivity;
– method of catalyst preparation: depending on the reaction
conditions used during the catalyst preparation, different
metal complexes with different catalytic properties can be
– solvent used during the hydrogenation: in many cases, the
solvent is not innocent and can play a crucial role with
respect to activity and enantioselectivity;
– substrate to catalyst ratio: to be cost effective, a process
based on asymmetric hydrogenation must use as little as
possible of the expensive precious metal/chiral ligand. As
a rule of thumb, we consider that catalysts exhibiting a
T.O.N. (Turn Over Number). under 1 000 have little
chance to be implemented in production;
– temperature: in asymmetric hydrogenation, the
temperature rarely exceeds 100ºC. Higher temperatures have a
beneficial effect on the activity but are detrimental to the
– hydrogen pressure: increasing the hydrogen pressure
usually improves the activity. The effect on enantioselectivity
varies depending on the catalyst and substrate;
Most bisphosphines, except BINAP will cost between 50 000-150 000 €/kg.
additives: acids, bases, phase-transfer catalysts used in
various ratios relative to the catalyst or substrate can have
a significant effect.
Considering the numerous parameters to be tested to find
an efficient catalyst and the severe time constraints for process
development, it is not very surprising that until recently,
asymmetric hydrogenation was not part of the first-generation
processes of drugs and agrochemicals but used mostly in case
a second-generation processes was implemented.
It became clear to us that asymmetric hydrogenation could
only break through as a major production technology for new
drugs and agrochemicals if something could be done about
timelines – i.e. if a robust and efficient catalyst could be
discovered within the limited time allocated for process
development. That’s why, at DSM InnoSyn™, we decided to
apply High Throughput Experimentation (HTE) as a means
to cope with these severe time-constraints and to
substantially shorten the time necessary for catalyst screening and
process development [
1 HIGH THROUGHPUT EXPERIMENTATION
AND ASYMMETRIC HYDROGENATION
HTE is a methodology where a large number of chemical
entities are quickly synthesised and tested for a desired feature/
performance, thus leading to an extensive exploration of the
parameter space in a relatively short amount of time. In the
search for a new or improved enantioselective hydrogenation
catalyst, the HTE protocol consists of 3 steps: the preparation
of a library of chiral ligands and catalysts, the testing of this
library under different conditions, the analysis of the reaction
to determine both activity and enantioselectivity. Therefore,
high throughput screening cannot start without a library of
chiral ligands. There are 3 ways to assemble such libraries:
– purchasing commercially available chiral ligands: a few
hundred structurally diverse chiral ligands based on
phosphorus or nitrogen can simply be purchased from various
commercial sources [
– manually synthesizing a small set of ligands using a
modular approach: using traditional synthetic methods,
some groups prepared their own library of ligands from
the same family. Each ligand is synthesized and purified
individually, thus limiting the size of the library to, at the
most, a few dozen members. Diversity is introduced along
the way via divergent synthesis. In this approach, an
optically pure advanced intermediate is prepared on a
large scale and used to synthesize many different ligands
– synthesizing a library of ligands in parallel using
combinatorial chemistry techniques and automated equipment:
drawing its inspirations from the techniques used in
combinatorial chemistry for the automated synthesis of large
libraries of small organic molecules, very few groups have
developed protocols based on solid-phase synthesis [
to prepare libraries of ligands attached on polymer beads.
The ligands were not released from the beads and the
catalytic test was performed with the supported catalyst
directly. The main disadvantage of this method is that the
polymeric support can have a significant effect on the
catalyst performance. At DSM InnoSyn™, we were the first
to report the parallel synthesis of a large library of chiral
ligands in solution [
]. Our methodology, named “Instant
Ligand Library” is described later in this article.
The second important prerequisite to perform HTE is
hardware. For the preparation of the ligands and the catalyst,
many useful liquid-dispensing robots and synthesisers have
recently come on the market. We currently use two Zinsser
Lissy liquid handling robots both equipped with 4 dispensing
needles and many custom-designed trays and racks (Fig. 4)
]. One of our robots is placed within a glovebox to allow
the handling and the preparation of air-sensitive catalysts.
For the parallel hydrogenation, we mostly rely on two
parallel reactors, the Premex A96 (from the firm Premex, 96 high
pressure reactors with a common headspace – thus the same
pressure – and same temperature) [
] and the Endeavour™
(from the firm Biotage, 8 autoclaves with independent
Pictures of our high throughput equipement.
temperature and pressure) [
]. The A96 parallel reactor was
developed in collaboration with DSM and is now commercially
available to the scientific community. Analysis turned out not
to be a major bottleneck and conventional GC (Gas
Chromatography) and HPLC (High-Performance Liquid
Chromatography) could be used after some adaptation. In
addition, we have set up a flow NMR (Nuclear Magnetic
Resonance) system that can handle 1 sample per 3 minutes,
which can be used for analysis of reaction mixtures.
2 INSTANT LIGAND LIBRARY OF CHIRAL
Although we routinely include in our high throughput
screenings for asymmetric hydrogenation a large number of
commercially available ligands, we anticipated that the fast
preparation of a library of chiral ligands specially tailored to
the substrate of interest would be an even more powerful way
to tackle the problem of finding the best catalyst for a new
substrate. At the time we embarked into this endeavour, there
were only three reports in the literature on automated
synthesis of phosphorus ligands [
]. The scarceness of
reports describing ligand libraries is related to the difficulties
associated with such an endeavour. One of the most
important requirements is the ease of synthesis, which is a
prerequisite for the development of automated procedures. The
lengthy syntheses including chromatographic purification
associated with the current state-of-the-art chiral ligands (i.e.
bisphosphines) suggest that this class is not a viable target for
a library approach. For this reason, we decided to focus on
simple chiral ligands that can be prepared in 1-2 synthetic
steps. Binol based phosphoramidites developed by De Vries,
Feringa and Minnaard at the University of Groningen
appeared to fulfil this requirement (Fig. 5) [
Since these ligands are easily prepared, a protocol for their
automated synthesis in solution became an attainable goal. The
first step of the most common phosphoramidite synthesis, the
formation of the phosphochloridite from the BINOL and PCl3,
proceeds essentially quantitatively and purification is effected
by distilling off excess PCl3. The robotic synthesis can thus
start with stock solutions of the stable phosphochloridites
leaving only a single synthetic step. This last step usually
yields the ligands in a purity with respect to phosphorus of
90-95%, the main contaminant being triethylammonium
chloride. Thus, it is clear that the final purification is the only
hurdle that needs to be taken in order to effect this robotic
ligand synthesis. Although parallel column chromatography
is feasible, this solution is not very appealing. To verify if
purification is really necessary, a known phosphoramidite
(derived from (R)-2,2’-binaphthol and diethylamine) was
synthesized and tested without purification in a known
asymmetric hydrogenation reaction. This led to very poor results:
both conversion and enantioselectivity were substantially
lower than with the purified ligand. Since the main culprit is
the presence of soluble chloride, a known catalyst inhibitor,
the solvent for the ligand synthesis was switched from DCM
(DiChloroMethane) to toluene, allowing the complete removal
of the chloride salt by filtration. Remarkably, the ligand
purified in this manner had a very similar performance in the
hydrogenation reaction as the purified ligand. This simple
finding opened the door to automation. The coupling
reactions between phosphochloridite and amine were performed
in a 96 well microtiterplate equipped with an oleophobic
filter. After 2 hours of reaction, the microplate was placed
on a manifold, vacuum was applied and the filtered ligand
solutions were collected in another 96 well plate. This
protocol was initially tested on a set of 32 ligands, which were
subsequently screened in the Rh-catalysed enantioselective
hydrogenation of two model substrates (Fig. 6) [
Figure 7 shows the result of this library of 32
phosphoramidites used in the Rh-catalyzed enantioselective
hydrogenation of a model substrate, methyl Z-3-acetamido-2-butenoate
(1). As can be observed on the color-coded schemes
depicting the activity and the enantioselectivity of the 32 members
of the library, only a few catalyst shows good performance in
this transformation (B1, C1, B2, D7). Although ligand D7
based on a primary amine was known to give good results
with these substrates [
], the library shows that in general
all BINOL-based phosphoramidites that contain a primary
amine with branching in the α-position give excellent results
(B1, C1, B2). This is one of the added advantages of high
throughput screening where the large number of data
collected under very similar conditions uncovers general trends.
Two step synthesis of Binol-based phosphoramidites.
Compound 4 (Fig. 8) was discovered by Merck to be a potent
melanocortin receptor agonist potentially useful in the treatment
of obesity [
]. The Merck scientists demonstrated that one
of the chiral centers of 4 could be installed via asymmetric
hydrogenation of the enamide, 2. Numerous homogeneous
catalysts have been developed for the hydrogenation of
similar enamides with high enantiomeric excess [
However, the prochiral substrate 2 was endowed with a very
bulky ortho substituent, i.e. an N-Boc piperidyl group, thus
belonging to a class of molecules unexplored in asymmetric
hydrogenation. The catalyst used by the Merck scientists was
(S,S)-Me-BPE-Rh(COD)BF4 (Me-BPE =
(-)-1,2-Bis((2S,5S)2,5-dimethylphospholano)ethane) giving full conversion and
an enantiomeric excess of 87-90% at S/C = 500 [
]. At such
a substrate to catalyst ratio, the contribution of the catalyst
price in the overall cost for production was too high to
consider large scale production. Upon request from Merck,
we applied our high throughput screening protocol to discover
a more cost-effective hydrogenation catalyst for the
production of 3.
In an initial set of experiments using a single rhodium/
phosphoramidite catalyst, we identified alcohols (MeOH,
H2N – Nonyl
EtOH, IPA) as the most suitable solvents and 25 bar of H2 and
room temperature as reaction conditions allowing the formation
of sufficient product to measure the enantiomeric excess
(substrate to catalyst ratio of 50). Next, we prepared a
library of 96 phosphoramidites ligands (Fig. 9) composed of:
– 64 (R)-Binol-based ligands (column 1-8);
– 16 (R)-octahydro-Binol-based ligands (column 9-10);
– 16 (R)-3,3’-dimethyl Binol-based ligands (column 11-12).
The amines used in combination with these 3 different
Binols were chosen as diverse structurally and electronically as
possible to cover a large part of the parameter space.
Reaction of these 96 ligands with Rh(COD)2BF4 led to the
formation of the catalysts, Rh(COD)L2BF4 (L =
phosphoramidite ligand) which were tested in parallel in the asymmetric
hydrogenation of 2. Results are given in Figure 10, following
the layout for the ligands as described in Figure 9.
At first sight, the library appears overall unsuccessful.
The predominant colors are in blue/green tones indicating
conversions and e.e.’s below 50%. Nevertheless, two red
spots stand out in the last column. Indeed, two ligands based
on 3,3’-dimethyl Binol and primary amines with α-branching
(column 12, row B and F) induced conversions above 90%
associated with the highest e.e.’s of this library. The most
active and enantioselective catalyst was the one based on
B12 with i-PrNH2 as amine giving 95% conv., 78% e.e.).
Quite surprisingly, catalysts based on the ligands derived
from 3,3’-dimethyl-Binol and secondary amines (column 11)
hardly showed any activity.
These promising results led us to prepare a second smaller
library of ligands focusing on the structural feature of the hits
of the first one – 16 ligands derived from 3,3’-dimethyl-Binol
in combination with primary amines (Fig. 11). Monodentate
phosphites obtained from the reaction of the chlorophosphite
with an alcohol instead of an amine are relatively similar to
monodentate phosphoramidites [
]. Consequently, two alpha
branched aliphatic alcohols (i-PrOH at C2 and t-BuOH at G2)
were included in this second focused library. The ligands of
this secondary library were tested under the same conditions
as before and the results are presented in Figure 11. The
predominance of red and orange colored cells confirms that we
were on the right track. Most of the ligands in this second
library performed much better than the ones in the first
screening. Several new phosphoramidite ligands (C1, G1 and
A2) led to full conversions and induced enantioselectivities of
~85%, but the best ligand was the phosphite based on t-BuOH
(G2, 99% conv., 93% e.e.). Having a closer look at these
results, it is apparent how sensitive the outcome of the
hydrogenation is to small variations in the structure of the ligand.
The phosphite ligand based on i-PrOH (C2) led to only 43%
conv. and 85% e.e. demonstrating that the absence of a simple
methyl group can have a tremendous effect.
Gram scale amounts of G2 and of the precatalyst Rh(COD)
(G2)2BF4 were easily prepared. The reaction conditions were
further optimized in an additional set of small-scale
experiments. For the kg production, the hydrogenation was performed
in a 16L autoclave using the following conditions: 0.35 mol%
catalyst, 9 wt% substate, 7.5 L IPA, 6 bar H2, 32°C. The
reaction proceeded well, leading to complete conversion after 20 h.
The enantiomeric excess was lower than the one obtained
on lab scale: 89% e.e., possibly still due to impurities in the
starting material. However, the enantiomeric excess was
increased to 98.9% via recrystallization in the follow-up
Since the implementation of our high throughput screening
platform, we have applied it to numerous projects and in
many cases, it appeared to be a key success factor for the
discovery of an efficient catalyst within the short time frame
available. Figure 12 shows the typical profile of a successful
screening project. On this graph, the cumulated number of
experiments and the performance of the best catalytic system
at any given moment are plotted versus the time. In general,
the project starts with a few experiments to get acquainted
with the new substrate. At this stage, the performance of the
catalyst is rather modest. A major improvement is achieved
via the use of HTE. At the end of the project, the best results
obtained using the parallel equipment are confirmed in a
large scale autoclave that resembles the one used for ton
scale production. In general, slightly better performances are
observed due to easier handling of larger amounts of material
and better gas-liquid mixing at higher scale. Not surprisingly,
the improvement of the catalytic system is related to the
number of experiments. Even today, as the world becomes
more and more virtual, chemistry and more specifically
asymmetric hydrogenation remain an experimental science.
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