A mixed-ligand approach enables the asymmetric hydrogenation of an α-isopropylcinnamic acid en route to the renin inhibitor aliskiren

Article abstract of DOI:10.1021/op0602369

An asymmetric hydrogenation process for the α-isopropyl dihydrocinnamic acid derivative 2, an intermediate for the renin inhibitor aliskiren (4), has been developed using a rhodium catalyst ligated with a chiral monodentate phosphoramidite and a nonchiral phosphine. Whereas catalysts based on two equivalents of monodentate phosphoramidites gave promising results, the rate of hydrogenation and ee of the product could be improved spectacularly by the addition of monodentate non-chiral triarylphosphines to these catalysts. This remarkable mixed-ligand catalyst has been identified using high-throughput experimentation. With the best catalysts turnover numbers >5000 mol mol ^-1, turnover frequencies >1000 mol mol^-1 h ^-1, and ee's up to 95% have been achieved.

Full text of DOI:10.1021/op0602369

Organic Process Research & Development 2007, 11, 585−591
A Mixed-Ligand Approach Enables the Asymmetric Hydrogenation of an
r-Isopropylcinnamic Acid en Route to the Renin Inhibitor Aliskiren
Jeroen A. F. Boogers,† Ulfried Felfer,‡ Martina Kotthaus,‡ Laurent Lefort,† Gerhard Steinbauer,‡
Andre´ H. M. de Vries,† and Johannes G. de Vries*,†
DSM Pharmaceutical Products - AdVanced Synthesis, Catalysis & DeVelopment, P.O. Box 18, 6160 MD Geleen, The
Netherlands, and DSM Fine Chemicals, Austria Nfg GmbH & Co. KG, St.-Peter-Strasse 25, A-4021 Linz, Austria
Abstract:
ceutical entities are the most important ones. In the mean
time, we have come a long way towards solving these two
major hurdles by the development of cost-effective and
modular synthesized monodentate ligands (MonoPhos)sin
collaboration with the group of Feringa and Minnaard5s
and implementation of high-throughput experimentation
(HTE) techniques,4,6 including the development of methodol-
ogy for automated parallel synthesis of these ligands.6,7 This
parallel protocol, in which 96 new ligands are synthesized
and tested within 2 days, is now routinely used by DSM
Pharmaceutical Products for the screening of customer
requests.
An asymmetric hydrogenation process for the r-isopropyl
dihydrocinnamic acid derivative 2, an intermediate for the renin
inhibitor aliskiren (4), has been developed using a rhodium
catalyst ligated with a chiral monodentate phosphoramidite and
a nonchiral phosphine. Whereas catalysts based on two equiva-
lents of monodentate phosphoramidites gave promising results,
the rate of hydrogenation and ee of the product could be
improved spectacularly by the addition of monodentate non-
chiral triarylphosphines to these catalysts. This remarkable
mixed-ligand catalyst has been identified using high-throughput
experimentation. With the best catalysts turnover numbers
>5000 mol mol-1, turnover frequencies >1000 mol mol-1 h-1
,
During the development of this automated protocol we
were faced with the challenge to find a more cost-effective
catalyst for the asymmetric hydrogenation of the R-isopro-
pylcinnamic acid derivative (1), which is an intermediate in
Novartis’ new blood pressure-lowering agent aliskiren (4),
the first oral renin inhibitor (Scheme 1).8,9 This route to
synthon A (3) with the key asymmetric hydrogenation step
has been developed recently.10 The catalyst is based on a
ferrocene-based bisphosphine ligand called Walphos,11 which
is prepared in five steps from the Ugi amine.10a Although
and ee’s up to 95% have been achieved.
Introduction
Asymmetric hydrogenation is one of the early success
stories of the application of homogeneous catalysis in fine
chemicals production.1 The L-DOPA process that earned
Knowles his Nobel Prize was developed in the early 1970s.2
Yet, in the years after, not many other asymmetric hydro-
genation processes were implemented.3 We and others have
analysed the obstacles that stood between this wonderful
technology and its use in production.3,4 There are several
critical issues involved with asymmetric hydrogenation of
which (i) the overall costs for the catalytic transformations
mainly the metal and the ligand but also the substrate which
may need to be highly puresand (ii) the time-to-market
pressure in the development of processes for new pharma-
(5) (a) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de
Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000,
122, 11539. (b) van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman,
M.; Schudde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.;
Maljaars, C. E. P.; Willans, C. E.; Hyett, D.; Boogers, J. A. F.; Henderickx,
H. J. W.; de Vries, J. G. AdV. Synth. Catal. 2003, 345, 308.
(6) (a) de Vries, J. G.; Lefort, L. Chem. Eur. J. 2006, 12, 4722. (b) For a recent
review on high-throughput and parallel screening methods in asymmetric
hydrogenation, see: Ja¨kel, C.; Paciello, R. Chem. ReV. 2006, 106, 2912.
(c) For a review on ligand libraries, see: Gennari C.; Piarulli, U. Chem.
ReV. 2003, 103, 3071.
* To whom correspondence should be addressed. E-mail: Hans-JG.Vries-
de@dsm.com.
† DSM Pharmaceutical Products - Advanced Synthesis, Catalysis & Develop-
ment.
(7) (a) Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G. Org.
Lett. 2004, 6, 1733. (b) Duursma, A.; Lefort, L.; Boogers, J. A. F.; de Vries,
A. H. M.; de Vries, J. G.; Minnaard, A. J.; Feringa, B. L. Org. Biomol.
Chem. 2004, 2, 1682.
‡ DSM Fine Chemicals, Austria Nfg GmbH & Co. KG.
(1) (a) Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and
Solutions: Blaser, H.-U., Schmidt, E., Eds.; Wiley-VCH: Weinheim, 2004.
(b) de Vries, J. G., Elsevier, C. J., Eds. The Handbook of Homogeneous
Hydrogenation; Wiley-VCH: Weinheim, 2007; Vol. 1-3. (c) Blaser, H.-
U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. AdV. Synth.
Catal. 2003, 345, 103.
(8) (a) Wood, J. M.; Maibaum, J.; Rahuel, J.; Grutter, M. G.; Cohen, N. C.;
Rasetti, V.; Ruger, H.; Go¨schke, R.; Stutz, S.; Fuhrer, W.; Schilling, W.;
Rigollier, P.; Yamaguchi, Y.; Cumin, F.; Baum, H. P.; Schnell, C. R.; Herold,
P.; Mah, R.; Jensen, C.; O’Brien, E.; Stanton, A.; Bedigian, M. P. Biochem.
Biophys. Res. Commun. 2003, 308, 698. (b) Herold, P.; Stutz, S.; Spindler,
F. WO 02/02508, 2002. (c) Herold, P.; Stutz, S. WO 02/08172, 2002. (d)
Go¨schke, R.; Maibaum, J. K.; Schilling, W.; Stutz, S.; Rigollier, P.;
Yamaguchi, Y.; Cohen, N. C.; Herold, P. U.S. Patent 97/5,654,445, 1997.
(9) For other synthesis approaches to aliskiren, see for example: Lindsay, K.
B.; Skrydstrup, T. J. Org. Chem. 2006, 71, 4766 and references therein.
(10) (a) Sturm, T.; Weissensteiner, W.; Spindler, F. AdV. Synth. Catal. 2003,
345, 160. (b) See also: Herold, P.; Stutz, S. WO 02/02500, 2002. (c) Blaser,
H.-U.; Spindler, F.; Thommen, M. In The Handbook of Homogeneous
Hydrogenation; de Vries, J. G., Elsevier, C. J., Eds.; Wiley-VCH: Wein-
heim, 2007; Vol. 3, p 1279.
(2) (a) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.;
Weinkauff, O. J. J. Am. Chem. Soc. 1977, 99, 5946. (b) Knowles, W. S.
Acc. Chem. Res. 1983, 16, 106. (c) Knowles, W. S. Angew. Chem., Int. Ed.
2002, 41, 1998.
(3) (a) Blaser, H.-U.; Pugin, B.; Spindler, F. J. Mol. Catal. A: Chem. 2005,
231, 1. (b) Blaser, H.-U. Chem. Commun. 2003, 293. (c) de Vries, J. G. In
Encyclopedia of Catalysis; Horvath, I. T., Ed.; Wiley: New York, 2003;
Vol. 3, p 295. (d) Blaser, H.-U.; Spindler, H.; Studer, M. Appl. Catal., A
2001, 221, 119.
(4) (a) de Vries, J. G.; de Vries, A. H. M. Eur. J. Org. Chem. 2003, 799. (b)
Hawkins, J. M.; Watson, T. J. N. Angew. Chem., Int. Ed. 2004, 43, 3224.
(11) Weissensteiner, W.; Sturm, T.; Spindler, F. WO 02/02578, 2002.
10.1021/op0602369 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/10/2007
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Scheme 1. Asymmetric hydrogenation in the synthesis of aliskiren
the reaction effectively produces the product with 95% ee
at a substrate/catalyst ratio (S/C) of 5000, we felt that the
use of a monodentate phosphoramidite ligand could lead to
substantial cost savings.
the reverse. Fortunately, ligand 5e also induces the highest
enantioselectivity.
The relatively low rate of the reaction is related to the
fact that phosphoramidite ligands, although good π-acceptors,
are poor σ-donors. Since oxidative addition of hydrogen is
the putative rate-determining step, ligands that donate charge
will accelerate the transition of Rh(I) to Rh(III). Fortunately,
the use of monodentate ligands creates the opportunity to
screen for additives or ligands, which could conceivably
donate more electrons to the Rh-phosphoramidite complex,
and hence make it more active. In Figure 3 the results are
shown of a rather random screening of phosphines, bispho-
sphines, and several types of nitrogen-containing ligands that
were added to the rhodium/MonoPhos precursor. This
screening was carried out using a liquid dispensing robot in
the glovebox to prepare the solutions containing catalysts,
additives, and substrates. The actual hydrogenation was
carried out in the Premex 96, an autoclave capable of
handling 96 vials at the same time.
These results immediately confirm the power of the high-
throughput experimentation approach: only a few of these
experiments gave interesting results, which would not have
been found easily in a one-experiment-at-a-time approach.
Addition of triphenylphosphine, tri-p-tolylphosphine or tri-
p-anisylphosphine (all relatively electron rich) led to a
remarkable acceleration (full conversion) and ee’s of a
promising level,13 whereas addition of triarylphosphines
substituted with halogens are less accelerating and moreover
give rise to racemic product. Most of the tested bisphosphines
also accelerate, but here the low ee’s suggest that maybe
the monodentate phosphoramidites have been replaced by
the nonchiral or racemic bisphosphines. Nitrogen-based
additives were uniformly ineffective.
Part of the work described in this paper has been
communicated earlier as part of a concept article.6a
High-Throughput Screening Approach. Since most
successful asymmetric hydrogenations of R,â-unsaturated
carboxylic acids are described with catalysts derived from
ruthenium12 and in view of the above results,11 we started
our screenings with both [Ru(cymene)Cl2]2 and RuCl3 and
[Rh(COD)2]BF4 as catalyst precursors using the parent
MonoPhos and eight other phosphoramidites as ligands
(Figure 1, 5a-g, 6, and 7). The best results from this
preliminary screening were obtained with rhodium catalysts,
at 20 bar hydrogen pressure in isopropanol at 85 °C (Figure
2).
Although the enantioselectivities obtained in these experi-
ments were not as good as the published results, we were
confident, on the basis of past experience, that further
optimisation using the “instant ligand library” protocol would
allow us to find a ligand that induces sufficiently high
enantioselectivity. What worried us more was the rate of the
reaction, which needed to be improved rather drastically to
achieve a cost-effective process.
Upon looking for trends in Figure 2 we found that the
positive effect of the 3,3′-disubstitution pattern (ligands 5e
and 5f) on the rate is clearly discernible. Whereas the
rhodium catalyst based on ligand 5e was relatively slow for
the hydrogenation of methyl 2-acetamidocinnamate as com-
pared to the MonoPhos-based catalyst,5b here we see just
Since these results were obtained with the parent Mono-
Phos ligand, we decided to test the effect of the added
phosphine for other Rh catalysts based on other phosphora-
midite ligands, in particular the 3,3′-disubstituted ones.
The results of this run depicted in Figure 4 confirm that
the positive effect of added triphenylphosphine on the rate
and enantioselectivity is universal for the tested phosphora-
midites. Again, the 3,3′-disubstituted ligands gave the most
(12) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; Chapter 1, p 21.
(13) These experiments are the first instance in which we have used a mixed-
ligand catalyst (July 2002). The usefulness of this approach is quite general
and has also independently been shown by Reetz and coworkers: (a) Reetz,
M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. Angew. Chem., Int. Ed. 2003,
42, 790. (b) Reetz, M. T.; Mehler, G. Tetrahedron. Lett. 2003, 44, 4593.
(c) Pen˜a, D.; Minnaard, A. J.; Boogers, J. A. F.; de Vries, A. H. M.; de
Vries, J. G.; Feringa, B. L. Org. Biomol. Chem. 2003, 1, 1087.
Figure 1. MonoPhos ligands.
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Figure 2. Initial screening of phosphoramidite ligands in the Rh-catalysed hydrogenation of 1.
Figure 3. Screening of 31 additives in the Rh/MonoPhos-catalysed hydrogenation of 1.
interesting results: 75% ee for the 3,3′-diphenyl-substituted
ligand mixed with PPh3 (racemic without PPh3!) and 80%
ee for ligand 5e (3,3′-dimethyl ligand). The scope of the
mixed-ligand hydrogenation of R-alkylated cinnamates and
acrylates has been further explored in collaboration with
Feringa/Minnaard.14
in turn evokes the question of the stoichiometry. If we assume
that only two ligands can be bound to rhodium in its active
state, the following complexes may be formed (PA )
phosphoramidite; TPP ) triphenylphosphine):
[Rh(PA)2]+ h [Rh(PA)TPP]+ h [Rh(TPP)2]+
The triphenylphosphine effect can be explained by as-
suming the phosphine is bound to the metal complex. This
The increased rate and enantioselectivity can only result
from the formation of the mixed complex. Thus, formation
of this complex needs to be optimised. In the next experi-
ments we have systematically varied the Rh/PA/TPP ratio.
Results are depicted in Table 1.
(14) Hoen, R.; Boogers, J. A. F.; Bernsmann, H.; Minnaard, A. J.; Meetsma,
A.; Tiemersma-Wegman, T. D.; de Vries, A. H. M.; de Vries, J. G.; Feringa,
B. L. Angew. Chem., Int. Ed. 2005, 44, 4209.
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Table 2. Effect of water/i-PrOH on the Rh-catalysed
cinnamate hydrogenationa
entry
vol % water in i-PrOH
conv. (%)
ee (%)
1
2
3
4
5
6
0
20
30
40
50
50
86b
62
67
85
93
94
94
92
95
67
100b
55
Figure 4. Asymmetric hydrogenation of 1 with [Rh(COD)2]-
BF4/2L/1PPh3.
a Conditions: substrate/rhodium ratio of 100, 3,3′-dimethyl-MonoPhos/
rhodium ratio of 2, TPP/rhodium ratio of 1, 20 bar of hydrogen, 4 h reaction
time at 25 °C unless stated otherwise. b Only measured after 18 h of reaction
time.
Table 1. Effect of phosphoramidite/triphenylphosphine ratio
entry
PA/Rh
TPP/Rh
conv. (%)
ee (%)
Scheme 2. Validation of screenings results in 150-mL
autoclave
1
2
3
4
5
6
7
8
9
3.6
2
2
2
2
1
1
1
2
1
1
2
3
5
3
2
1
63
100
100
100
100
100b
100b
100b
100b
76
80
78
76
75
59
66
76
80
0.4
a Conditions: substrate/rhodium ratio of 100, solvent is i-PrOH, 20 bar of
hydrogen, 2 h reaction time at 85 °C unless stated otherwise. b Only measured
after 18 h of reaction time.
Validation and Pilot-Plant Run. After this screening
exercise and the identification of a highly promising catalyst,
we wanted to validate these results at a larger scale
(autoclaves between 150 and 450 mL) using scaleable
conditions. The most important parameters for large-scale
application are the concentration, turnover number (TON),
and activity (TOF), all related with the cost-determining
“space-time-yield” factor. Since higher hydrogen pressure
and higher temperature are advantageous for the activity, but
disadvantageous for the enantioselectivity, we decided to use
As can be seen from the results, any presence of TPP in
the catalyst mixture enhances the activity and enantioselec-
tivity compared with the Rh(PA)2 complex; however, the
enantioselectivity is the highest if the ratio between PA and
TPP is 2 or larger. With a Rh/PA/TPP ratio of 1:2:1 the
formation of the non-enantioselective, but active, Rh(TPP)2
complex is prevented.15
At this stage we were all excited about the positive
nonchiral phosphine effect, but the enantioselectivity was
still not high enough for application. Fortunately, a second
important breakthrough was found when the reaction condi-
tions, solvent and temperature, were optimised using the
mixed-ligand system. As in the initial screening the results
obtained with non-protic solvents, e.g., dichloromethane,
were disappointing; however, adding water to isopropanol
(20-60 v/v%) enhanced the enantioselectivity up to a
staggering 95% at 25 °C (Table 2). The ee is nearly
independent of the water concentration, in contrast to the
activity. It decreases drastically at water concentrations above
40 v/v%, due to solubility problems of the substrate. The
exact role of water is not clear at this stage, but we assume
it may have a positive effect in association and dissociation
of the substrate and product, respectively.
(15) Confirmed by 31P NMR, see: (a) Hoen, R. New Approaches in Asymmetric
Rhodium-Catalyzed Hydrogenations with Monodentate Phosphoramidites.
Ph.D. thesis, University of Groningen, 2006. The optimal ratio in this mixed-
ligand approach needs to be determined for every new substrate and every
new ligand. For a discussion and a mathematical model see: (b) Gennari,
C.; Monti, C.; Piarulli, U.; de Vries, J. G.; de Vries, A. H. M.; Lefort, L.
Chem. Eur. J. 2005, 11, 6701.
Figure 5. Schematic drawing of a Venturi loop reactor.
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Figure 6. Screening of monodentate phosphoramidite ligands based on 3,3′-BINOL in the Rh-catalysed hydrogenation of 1 with
TPP as additive. (Conditions: 55 °C, 25 bar H2, in i-PrOH, [Rh(COD)2]BF4, 1/Rh ) 100, ligand/Rh ) 2, TPP/Rh ) 1.)
the compromise conditions depicted in Scheme 2, furnishing
the product with 90% ee (at 55 °C and 80 bar of hydrogen).
The next items to be developed were the scale-up of the
chiral ligand synthesis, and the optimisation of the catalyst
formulation and addition. Whereas the first item was tackled
quite straightforwardly, some special requirements were
needed for the catalyst formulation and addition. Unfortu-
nately, these cannot be disclosed at this stage of the project.16
Interestingly, by using this chiral ligand derived from
3,3′dimethyl-BINOL an impurity in the product was observed
by using HPLC in, at first sight, alarming high amounts
(based on area %). After a moment of disappointment, the
source of the problem was rapidly identified as being caused
by the enormous high response factor of the BINOL
fragment, formed in tiny amounts by hydrolysis of the chiral
ligand.
(16) Due to confidentiality reasons full data on the scaled-up process could not
be presented.
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Scheme 3. Catalyst system for the asymmetric
hydrogenation of 1
hydrogenation than the ones derived from primary amines
(columns 6-12).
(c) Almost all ligands induced a medium-to-high ee,
indicating that the 3,3′-dimethyl-BINOL part is the determin-
ing moiety for enantioselectivity.
(d) Most ligands prepared in this screen led to better
results as obtained with the ligand used above (A1, not in
situ prepared but added as such). Note that these results were
obtained without addition of water.
The five best ligands in terms of enantioselectivity and
activity (encircled in Figure 6), (together with the ligand used
earlier) were tested with 16 triarylphosphines (experiments
and results are not shown). Although the highest ee’s were
found with tri-o-anisylphosphine combined with several of
the phosphoramidites derived from secondary amines, the
best performance (combination of activity and enantioselec-
tivity) was found for the 3,3′-dimethyl-PipPhos ligand (5i)
mixed with tri-m-tolylphosphine. This final result of this
screening effort was again validated as shown in Scheme 3.
Compared with that of the catalyst used in the pilot plant
the activity is more than 4 times as high.
Validations. The excellent performance of the catalyst
prepared from 3,3′-dimethyl-PipPhos (5i) and a nonchiral
phosphine was also seen at larger scale. As can be seen from
Figure 7,17 the rate of asymmetric hydrogenation is first order
in rhodium concentration at relative high rhodium concentra-
tions. At lower amounts of rhodium the reaction times are
longer than one would expect for a linear relation, most likely
due to catalyst deactivation caused by a minor impurity in
the starting material. However, even at a substrate/Rh-catalyst
ratio >10,000 a full conversion has been obtained after a
reasonable reaction time (Figure 8.). From these data it is
also clear that in all cases the process was stable and is not
suffering from substrate or product inhibition.
The actual pilot-plant run was performed in a loop reactor
and proceeded satisfactorily, furnishing the product within
specs. A loop reactor is different from a stirred tank reactor
(CSTR) in that part of the liquid is pumped up continuously
and sprayed though a nozzle (Venturi loop) together with
the hydrogen gas, ensuring optimal mass transfer from the
gas to the liquid phase. For a schematic picture, see Figure
5. However, the observed activity (full conversion after ca.
18 h at S/C ratio of 3000) should be better in order to reach
an overall improved throughput (“space-time-yield”). There-
fore, a second screening, now with the automated ligand
synthesis protocol, was initiated.
“Instant Ligand Library” Screening. Since the 3,3,′-
dimethyl-BINOL moiety of the chiral ligand was crucial for
high ee and activity, we decided to screen a library of 96
different phosphoramidite ligands all based on this diol. The
conditions used for this screening (see Figure 6) were slightly
different from the optimal ones used above since water was,
at that time, not tolerated in our automated ligand library
setup.
As can be seen, a wide variety of primary and secondary
amine-derived ligands were tested, giving a wealth of
information. A few conclusions can be drawn:
(a) 10-15% of the ligands are not formed, due to steric
hindrance and/or impurities (confirmed by 31P NMR).
(b) In general the ligands derived from secondary amines
(columns 1-5) lead to higher yields in this specific
Conclusion
In conclusion we have developed a scaleable asymmetric
hydrogenation process based on a mixed monodentate ligand
approach by using a bulky phosphoramidite and triarylphos-
Figure 7. Hydrogenation times required to reach full conversion at different Rh-catalyst/substrate ratios.17
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Figure 8. Hydrogenation times required to reach full conversion at different substrate/Rh ratios.
phine. The identification and development of this unique
catalyst has been accelerated by using HTE techniques,
including automated parallel ligand synthesis and parallel
screening. We have proven that this approach with a virtual
unlimited ligand library delivers scaleable asymmetric hy-
drogenations and are confident that we can disclose other
examples in the near future.
(R)-3-[4-Methoxy-3-(3-methoxypropoxy)phenyl]-2-(1-
methylethyl)propanoic Acid. In a 450-mL autoclave, 50 g
(178.35 mmol) of E-3-[4-methoxy-3-(3-methoxyproxy)-
phenyl]-2-(1-methylethyl)propanoic acid, 100 mg (0.234
mmol) of 3,3′-dimethyl-PipPhos, 47.6 mg (0.1172 mmol)
of [Rh(COD)2]BF4 and 30.8 mg (0.117 mmol) of triph-
enylphosphine were suspended in 160 mL of isopropanol/
H2O (4:1). The autoclave was purged 5× with N2 and heated
to 55 °C. Next it was purged 3× with H2 and subsequently
pressurised to 80 bar with H2 without stirring. The hydro-
genation was continued at this temperature and pressure
while stirring at 100 rpm. After 18 h the autoclave was
allowed to come to room temperature and depressurized. The
product was isolated (50 g, 97%) and the enantiomeric excess
determined by HPLC; ee ) 90%
Experimental Section
Screening experiments in the Endeavor were performed
on a 5-mL scale. For this all the solid substances were
weighed in the glass insert tubes in air, which were then
placed in the apparatus. The apparatus was closed and flushed
10× with 3 bar N2. Then degassed solvent (3 vacuum/N2
cycles) was added through the injection valve. The apparatus
was flushed again with 3 bar N2 without stirring (10×), 5×
with stirring, and 10× with 30 bar H2 without stirring.
Thereafter, the Endeavor was simultaneously pressurized to
the desired H2 pressure (normally 20 bar) and heated to the
desired temperature under stirring at 500 rpm. The following
amounts were used: 2 mM [Rh(COD)2]BF4, IPA (5 mL),
ligand/Rh ) 2 mol/mol, 1/Rh ) 100.
Acknowledgment
We thank the Feringa/Minaard group from the University
of Groningen for the long-lasting and highly successful
collaboration on asymmetric catalysis, in particular, hydro-
genation.
The screening procedure in the Premex96 is described in
reference 7a.
Received for review November 14, 2006.
OP0602369
(17) The spread in the middle data points is related to operator judgement of
what constitutes full conversion and error due to late or early sampling as
a result of shift changes.
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