Rapid identification of a scalable catalyst for the asymmetric hydrogenation of a sterically demanding aryl enamide

Article abstract of DOI:10.1021/op100011y

High throughput screening was used to find a cost-effective and scalable catalyst for the asymmetric hydrogenation of a sterically demanding enamide as an intermediate towards a new potent melanocortin receptor agonist useful in the treatment of obesity.

Full text of DOI:10.1021/op100011y

Organic Process Research & Development 2010, 14, 568–573
Rapid Identification of a Scalable Catalyst for the Asymmetric Hydrogenation of a
Sterically Demanding Aryl Enamide
Laurent Lefort,* Jeroen A. F. Boogers, Thijs Kuilman,† Robert Jan Vijn,† John Janssen,† Harrie Straatman,†
Johannes G. de Vries, and Andre´ H. M. de Vries
DSM Pharmaceutical Products - P.O. Box 81, 5900 AB Venlo, The Netherlands, and DSM Pharmaceutical Products - InnoVatiVe
Synthesis and Catalysis, P.O. Box 18, 6160 MD Geleen, The Netherlands
Scheme 1. Prochiral substrates for asymmetric
hydrogenation
Abstract:
High throughput screening was used to find a cost-effective and
scalable catalyst for the asymmetric hydrogenation of a sterically
demanding enamide as an intermediate towards a new potent
melanocortin receptor agonist useful in the treatment of obesity.
Lessons drawn from the testing of a first library of 96 chiral
monodentate phosphoramidites led to the design of a second
focused library of 16 chiral ligands, allowing the discovery of a
new efficient catalyst. This catalyst was based on rhodium and a
bulky monodentate phosphite ligand. The catalyst was scaled up
and used in the kilogram production of the desired bulky chiral
amide.
enamides with relatively small ortho substituents (methyl,
halides, methoxy).6
The aryl enamide we needed to hydrogenate, as part of our
customer manufacturing operations, was endowed with a very
bulky ortho substituent, i.e. an N-Boc piperidyl group (Scheme
2, 3). The hydrogenation product of this molecule (Scheme 2,
4) is an intermediate for the preparation of 5, a potent
melanocortin receptor agonist discovered by Merck, and
potentially useful in the treatment of obesity.7 The Merck sci-
entists identified [(S,S)-Me-BPE-Rh(COD)]BF4 (Me-BPE )
(-)-1,2-Bis((2S,5S)-2,5-dimethylphospholano)ethane) as an ef-
ficient hydrogenation catalyst.8 Full conversion and an enan-
tiomeric excess of 87-90% were obtained at S/C ) 500,
provided the bulky aryl enamide was washed twice with
NaHCO3 solution, and recrystallized prior to the asymmetric
hydrogenation.9
Introduction
Since the initial success of Knowles with L-DOPA,1 the Rh-
catalyzed asymmetric hydrogenation of N-acylated R-dehydro
amino acids or esters (Scheme 1, 1) has received a lot of
attention from the scientific community, both academic and
industrial.2 Substrates lacking the acid or ester function, i.e.
simple aryl enamides (Scheme 1, 2), are useful precursors of
chiral amides that can be further converted to chiral amines.3
Although aryl enamides appeared to be more demanding than
the corresponding enamide acids or esters, numerous homoge-
neous catalysts have been developed for their hydrogenation
with high enantiomeric excess.2b,4 The presence of an ortho
substituent R2 (Scheme 1, 2) on the aromatic ring of the
enamide, even as small as Br, can have a detrimental effect on
the enantiomeric excess,5 although consecutive studies reported
active and enantioselective catalysts for a limited set of aryl
Chiral monodentate ligands, such as phosphoramidites
derived from Binol,10 are in general an order of magnitude
cheaper than chiral bisphosphines, and have shown to be capable
of hydrogenating aryl enamides successfully.11 Moreover, to
deal with the severe time constraints imposed on process
(6) (a) Zhang, W.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 5515–
5518. (b) Morimoto, T.; Nakajima, N.; Achiwa, K. Tetrahedron
Asymmetry 1995, 6, 23–26. (c) Teng, X.; Keys, H.; Jeevanandam, A.;
Porco, J. A., Jr.; Degterev, A.; Yuan, J.; Cuny, G. D. Bioorg. Med.
Chem. Lett. 2007, 17, 6836–6840. (d) Stemmler, R. T.; Bolm, C.
Tetrahedron Lett. 2007, 48, 6189–6191. (e) Harrison, P.; Meek, G.
Tetrahedron Lett. 2004, 45, 9277–9280. (f) Huang, H.; Zheng, Z.;
Luo, H.; Bai, C.; Hu, X.; Chen, H. J. Org. Chem. 2004, 69, 2355–
2361. (g) Gridnev, I. D.; Yasutake, M.; Higashi, N.; Imamoto, T. J. Am.
Chem. Soc. 2001, 123, 5268–5276. (h) Li, G.; Antilla, J. C. Org. Lett.
2009, 11, 1075–1078. Le, J. C.-D.; Pagenkopf, B. L. J. Org. Chem.
2004, 69, 4177–4180.
* Author to whom correspondence may be sent. E-mail: Laurent.lefort@
dsm.com.
† DSM Pharmaceutical Products (Venlo).
(1) (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.
(7) (a) Goulet, M. T.; Nargund, R. P.; Ujjainwalla, F.; Walsh, T. F.;
Warner, D. Acylated piperidine derivatives as melanocortin-4 receptor
agonists. (Merck). WO/2002/068388, 2002. (b) Savarin, C. G.; Chung,
J.; Murry, J. A.; Cvetovich, R. J.; McWilliams, C.; Hughes, D.; Amato,
J.; Boice, G.; Conrad, K.; Corley, E.; Reamer, R.; DiMichele, L. In
Process Chemistry in the Pharmaceutical Industry; Gadamasetti, K.,
Braish, T. , Eds.; CRC Press: Boca Raton, FL, 2008; Vol. 2, p 65.
(8) Boice, G. N.; McWilliams, C.; Murry, J. A.; Savarin, C. G. Stereo-
selective preparation of 4-aryl piperidine amide by asymmetric
hydrogenation of a prochiral enamide and intermediates of this process.
(Merck). WO 2006/057904, 2006.
(2) (a) Blaser, H.-U., Schmidt, E., Eds. Asymmetric Catalysis on Industrial
Scale: Challenges, Approaches and Solutions; Wiley-VCH: Weinheim,
2004. (b) de Vries, J. G., Elsevier, C. J., Eds. The Handbook of
Homogeneous Hydrogenation; Wiley-VCH: Weinheim, 2007.
(3) For a review on industrial methods to chiral amines and other chiral
compounds, see: Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.;
Kesseler, M.; Sturmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004,
43, 788–824.
(4) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029–3069.
(5) Burk, M. J.; Wang, M. W.; Lee, J. R. J. Am. Chem. Soc. 1996, 118,
5142–5143.
(9) Shultz, C. S.; Krska, S. W. Acc. Chem. Res. 2007, 40, 1320–1326.
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10.1021/op100011y  2010 American Chemical Society
Published on Web 03/18/2010

Scheme 2. Asymmetric hydrogenation of bulky enamide 3 en route to the drug candidate 5
development in the pharma industry, we have implemented a
high throughput set up for the rapid synthesis of a library of 96
chiral phosphoramidite ligands (and other monodentate ligands
such as phosphites). This library can be tested in parallel in a
custom-made hydrogenation reactor12 and the entire screening
of the 96 ligands is usually completed in less than 2 days.13
This high throughput experimentation (HTE) setup was a key
success factor in the discovery of a new cheap catalyst for the
hydrogenation of a dehydrocinnamic acid derivative, an inter-
mediate for the renin inhibitor aliskiren.14
can be combined with Rh(COD)2BF4 to generate the catalyst.
The library was composed of 64 (R)-Binol-based ligands
(column 1-8), 16 (R)-octahydro-Binol-based ligands (Column
9-10) and 16 (R)-3,3′-dimethyl -Binol-based ligands (Column
11-12). The 64 amines used in combination with Binol and
the 16 amines used in combination with both the octahydro-
and dimethyl-Binol are shown in Figure 1.
As can be seen in Figure 1, the amines used are very diverse
structurally and electronically. About equal numbers of primary
and secondary amines were used. Of these, 11 amines were
used in their enantiomerically pure form. Several amines con-
taining an extra coordinating group such as a thioether (H2),
an amine (A8 or B7), an ether or an acetal (B8, G7 or H7)
were also included, as well as an amide (A4), hydrazines (D8
and E8), and a crown-ether (D7).
In this report, we present the application of this high
throughput screening protocol to bulky enamide 3 leading to
the discovery of a cost-effective hydrogenation catalyst used
for kg production of 4.
The 96 phosphoramidites were reacted with 1/2 equivalent
of Rh(COD)2BF4 in DCM for 15 min to allow formation of
the catalysts, Rh(COD)L2BF4 (L)phosphoramidite ligand) and
the set of the 96 catalysts was tested in parallel in the
asymmetric hydrogenation of 3. Results are given in Figure 2,
following the layout for the ligands as described in Figure 1.
Among the 64 phosphoramidites based on Binol, the
conversion varied from 0 to 72% for the ligand based on
t-BuNH2, D4, which also induced quite a good ee relative to
the whole library, -47%. Among these 64 ligands, several other
ligands based on bulky primary amines with R-branching stood
out both in terms of activity and/or enantioselectivity: i-PrNH2
(F4, 51% conv., -52% ee); rac-2-neo-pentyl-NH2 (A5, 38%
conv., -51% ee); R-(c)-hexyl-ethyl-NH2 (G6, 21% conv.,
-46% ee and H6, 30% conv., -48% ee). The best ee for this
set of ligands was also obtained with a rather bulky primary
amine containing a morpholine group (F7, 29% conv., -59%
ee). As a result of the rather large number of ligands tested,
one can see a trend emerging: Although the substrate is itself
bulky, it seems like a bulky amino part based on primary amines
may be needed for high ee and activity. Looking at the results
obtained with the ligands based on octahydro-Binol, primary
amine based ligands (Column 10) appeared again better than
those with secondary amines (Column 9). The highest conver-
sion among these 16 ligands was obtained using the ligand based
on n-dodecyl amine (D10, 45% conv., -45% ee), but the one
based on i-PrNH2 also induced a relatively good ee (B10, 26%
conv., -44% ee), confirming the previous observation with the
set of ligands based on Binol.
Results and Discussion
Screening for a Phosphoramidite Based Asymmetric
Hydrogenation Catalyst. The first rhodium/phosphoramidite-
catalyzed hydrogenation experiments were performed in the
Endeavor reactor (8 parallel vessels, 0.5 mmol scale in 5 mL
of solvent)15 and were aimed at finding a standard set of
experimental conditions to be used in the parallel screening.
These initial trials indicated that alcohols (MeOH, EtOH,
i-PrOH) were better solvents than toluene, EtOAc, MTBE and
DCM. A sufficient amount of product (>25% conversion) was
obtained within 3 h using 25 bar of H2 at room temperature to
allow measurement of the enantiomeric excess (substrate to
catalyst ratio of 50).
Next, a library of 96 phosphoramidite ligands was prepared
following our high throughput protocol previously described.13
The 96 ligands are synthesized in parallel by reaction between
a chlorophosphite and an amine. The reaction mixtures are
filtered in parallel leading to stock solutions of the ligands that
(10) For the use of phosphoramidites in Rh-catalyzed asymmetric hydro-
genations, see: (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. (c) de Vries, J. G.; Lefort, L. Chem.sEur. J.
2006, 12, 4722. (d) Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de
Vries, J. G. Acc. Chem. Res. 2007, 40, 1267–1277.
(11) Bernsmann, H.; Van Den Berg, M.; Hoen, R.; Minnaard, A. J.; Mehler,
G.; Reetz, M. T.; De Vries, J. G.; Feringa, B. L. J. Org. Chem. 2005,
70 (3), 943–951.
(12) The 96-vial parallel reactor was built by Premex: http://www.premex-
reactorag.ch/index.php?page)464.
The most interesting results, however, were obtained with
ligands based on 3,3′-dimethyl-Binol and primary amines
(column 12) with again a ligand based on an R-branched amine
resulting in the most active catalyst and the highest enantiose-
lection (B12, i-PrNH2, 95% conv., 78% ee). Quite surprisingly,
(13) Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G. Org.
Lett. 2004, 6, 1733.
(14) Boogers, J. A. F.; Felfer, U.; Kotthaus, M.; Lefort, L.; Steinbauer,
G.; de Vries, A. H. M.; de Vries, J. G. Org. Process Res. DeV. 2007,
11, 585–591.
(15) http://www.biotage.com/DynPage.aspx?id)23682.
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Figure 1. Set of amines (yellow ) 1ary amine, white ) 2ary amine, blue ) enantiomerically pure) used to prepare the first library
of 96 phosphoramidite ligands.
Figure 2. Results of the screening of the library of the 96 phosphoramidite ligands (Reaction conditions: Rh(COD)L2BF4, 25 °C, 25
bar H2, [3] ) 0.073 M in dry EtOH, 3/Rh ) 50 mol/mol, reaction time ) 3 h).
catalysts based on the ligands derived from 3,3′-dimethyl-Binol
and secondary amines (column 11) hardly showed any activity.
Interestingly, although in all cases the diol has the (R)-
configuration, ligands based on 3,3′-dimethyl-Binol led pre-
dominantly to formation of the desired (S)-enantiomer of the
product, while the ligands based on Binol and octahydro-Binol
led to the (R)-product. This could indicate a different coordina-
tion behaviour or a different active catalyst configuration when
ligands derived from 3,3′-dimethyl-Binol are used.16
derived from 3,3′-dimethyl-Binol (Figure 3). In addition to the
hits from the first screening, i-PrNH2 and t-BuNH2 (B1 and
A1, respectively) 12 other aliphatic amines were included, 6
of them with an R-alkyl substitution. Since monodentate
phosphites are relatively similar to monodentate phosphora-
midites, particularly the phosphoramidites based on primary
amines, and since Reetz and Mehler have demonstrated that
monodentate Binol-based phosphites are also excellent ligands
in Rh-catalyzed hydrogenations,17 two R-branched aliphatic
alcohols (i-PrOH at C2, and t-BuOH at G2) were included in
this second focused library.18 The ligands obtained from this
secondary library were tested under the same conditions as
before, and the results are presented in Figure 3. As can be
These promising results led us to prepare a second smaller
library of ligands focusing on the hits of the first ones16 ligands
(16) We already demonstrated that phosphoramidites based on 3,3′-
disubstituted biphenol or binaphthol could exhibit quite different
behavior than their corresponding unsubstituted analogues. Giacomina,
F.; Meetsma, A.; Panella, L.; Lefort, L.; de Vries, A. H. M.; de Vries,
J. G. Angew. Chem., Int. Ed. 2007, 46, 1497–1500.
(17) Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889–
3890.
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Figure 3. Set of amines (blue ) enantiomerically pure) and alcohols used to prepare the focused library and results of the screening
of this library of the 16 ligands. (Reaction conditions: Rh(COD)L2BF4, 25 °C, 25 bar H2, [3] ) 0.073 M in dry EtOH, 3/Rh ) 50
mol/mol, reaction time ) 3 h).
seen from the predominance of red- and orange-coloured cells,
the ligands in this second library performed much better than
the ones in the first screening. The good result obtained with
i-PrNH2-based ligand was confirmed (B1, 86% conv., 84% ee),
but gratifyingly, better results were also obtained. Several
phosphoramidite ligands (C1, A2, and G2) led to full conversion
and induced enantioselectivities of ∼85%, whilst the phosphite
Figure 4. Ligands used and results obtained in the Endeavor
reactor. Conditions: 25 °C, 25 bar H2, [3] ) 0.091 M in dry
EtOH, Rh(COD)2BF4, ligand/Rh ) 2 mol/mol, 3/Rh ) 50 mol/
mol, reaction time ) 2 h.
ligand based on t-BuOH gave the best performance (G2, 99%
conv., 93% ee). 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. For example, the
phosphite based on i-PrOH (C2) led to only 43% conv. and
85% ee. Overall, the use of aliphatic amines lacking R-substitu-
tion (D1, D2, and E3) never resulted in ee’s above 65%,
whereas those with an R-alkyl group always led to an ee in
excess of 75% with the exception of H1 which is rather peculiar
due its additional N group.
highly successful ligand in other applications,14 did not convert
enamide 3, confirming again the need to always tune the ligand
to the substrate. Due to its higher activity and enantioselectivity,
the phosphite G2 was chosen as sole candidate to go further
along the validation process.
Gram-scale amounts of G2 were easily prepared using the
so-called reverse synthesis where PCl3 is first reacted with one
equivalent of t-BuOH, followed by the reaction with (R)-3,3′-
dimethyl-Binol. This methodology developed by van Leeuwen
and co-workers was shown to be more efficient for the coupling
of bulky partners (i.e., bulky Binol with bulky amines or alco-
hols) to the phosphorus.19 The catalyst Rh(COD)(G2)2BF4 was
also prepared on gram scale in a straightforward manner by
simply mixing the ligand and the Rh precursor in DCM.
Precipitation of the catalyst was achieved by addition of hep-
tanes. The freshly preformed catalyst was tested in the
Endeavor reactor under a number of different reaction
conditions (Table 1).
Scale-Up of the Hits (G1 and G2). Both ligands were
prepared on a larger scale following a procedure similar to the
one used for the library, i.e. without complete purification/
isolation but a simple filtration to remove the insoluble
Et3N·HCl generated during the condensation reaction. These
ligands (G1, G2) were tested in an Endeavor experiment along
with the pure 3,3′-dimethyl-Binol monophos (Figure 4, L1).
As can be seen in Figure 4, the results obtained in the library
were confirmed by an Endeavor experiment in terms of
enantioselectivity. Since the reaction was run for a shorter time,
we were able to observe a difference of activity between the
phosphoramidite G1 and the phosphite G2, the latter appearing
much more active. Interestingly, the catalyst based on L1, a
A slightly better ee was obtained with the isolated catalyst
(Table 1, entry 1) compared to the previous results. i-PrOH and
(18) When this work was done, DSM had a non-exclusive license from
the Max Planck Institute in Mu¨lheim an den Ruhr, Germany, for
the use of monodentate phosphites in asymmetric hydrogenation
processes.
(19) van Rooy, A.; Burgers, D.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Recl. TraV. Chim. Pays-Bas 1996, 115, 492–498.
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Table 1. Hydrogenation conditions and conversion/
The substrate was divided in two batches and hydrogenated
in a 16 L autoclave using the following conditions: 0.35 mol
% catalyst, 9 wt% substrate, 7.5 L i-PrOH, 6 bar H2, 32 °C.
Both hydrogenations proceeded well, leading to complete
conversion after 20 h. The enantiomeric excess was lower than
the one obtained on lab scale: 89% ee, possibly still due to
remaining Rh or other impurities.21 The two batches were
combined for removal of the N-Boc protecting group and
crystallization as follows: After the hydrogenation, the reaction
mixture was treated with activated carbon, followed by 5 N
HCl in IPA at 50 °C. Upon cooling down, the final product,
i.e. the HCl salt (Scheme 3), was isolated as an off-white solid
(yield: 84%, purity: 96 wt %). The enantiomeric excess
increased to 98.9%, but the amount of residual Rh (83 ppm)
made a rework necessary. After a second treatment with
activated carbon, the solid was crystallized from EtOH/CH3CN
leading to a final product meeting the specifications in terms
of purity (99.6 area %), enantioselectivity (99.9% ee) and Rh
content (3 ppm). Crystallization without charcoal treatment only
lowered the Rh content to 33 ppm.
enantioselectivitya
entry
solvent
P (bar)
T (°C)
conv. %
ee %
1
2
3
4
5
6
EtOH
i-PrOH
EtOAc
EtOH
EtOH
EtOH
25
25
25
5
25
25
25
25
40
60
100
100
100
100
100
100
97
97
99
98
97
95
5
5
a Conditions: [3] ) 0.091, Rh(COD)(G2)2BF4, 3/Rh ) 50 mol/mol, reaction
time ) 2 h, 5 mL of solvent.
EtOAc are equally suitable solvents (entries 2 and 3) although
the enantiomeric excess is a little bit higher in EtOAc. The
reaction proceeds also well under 5 bar of hydrogen (entry 4).
Increasing the temperature does not lead to a significant drop
in the enantioselectivity and consequently high turnover fre-
quencies should be attainable even at a pressure of 5 bar. Prior
to the kilogram production in the pilot plant, a 50-mL autoclave
experiment was performed with a higher S/C ratio to have
an indication of the TOF. The conditions were as follows:
Rh(COD)(G2)2BF4, [3] ) 6.9 wt %, 3/Rh ) 521 mol/mol, 50
mL EtOAc as solvent, 5 bar H2, 50 °C, 700 rpm. After 1.5 h,
the conversion was 82% (97.5% ee) corresponding to an average
TOF around 250 h-1. A second analysis performed after 17 h
showed full conversion and an ee of 97.1%. At this stage, we
considered the catalyst to be validated, and the technology was
transferred to the pilot plant for kilogram-scale production.
Preparation of the Prochiral Substrate 3 and Large-Scale
Hydrogenation. Substrate 3 used for the catalyst screening was
provided by Merck. Whilst looking for a suitable catalyst for
the hydrogenation of 3, we also investigated the scalability of
the route towards 3 for production at kilogram scale. Aryl
enamide 3 can be prepared in two steps starting from a CBZ-
dihydropyridine chlorobenzonitrile 5 (Scheme 3).7b The syn-
thesis involves the hydrogenation of the dihydropyridine
substituent with the Wilkinson catalyst, exchange of the
N-protecting group, and a direct preparation of the enamide by
reaction with MeLi and acetic anhydride. Development work
allowed us to improve the process and make it fit for our 25-L
reactor. Notably, the amount of expensive Wilkinson catalyst
was lowered by a factor of 2.5. Ultimately, starting from 2.2
kg of 5, we were able to obtain around 1.1 kg of enamide 3.
This material was isolated from the reaction mixture as a solid
by crystallization from EtOH/H2O.
Conclusion
High throughput experimentation (HTE) associated with our
automated ligand synthesis of chiral monodentate phosphora-
midites/phosphites were key success factors for the discovery
of an efficient catalyst within the short time frame available
for this project. Scheme 4 represents the progress of the project
versus the time. Both the cumulated number of experiments
and the conversion/enantioselectivity of the best catalytic system
at the moment are plotted on this graph. The project started
with a few experiments to gain an impression of the hydrogena-
tion behavior of the new substrate. A major improvement was
achieved in slightly more than a week thanks to the use of the
high throughput protocol. The last two weeks of the project
were dedicated to preparing the ligand and catalyst at gram
quantities, optimizing its performance, and determining the
activity and enantioselectivity at 50 mL scale. Not surprisingly,
the improvement of the catalytic system was related to the
number of experiments, and it can be concluded that the project
would not have been successful in such a short time span
without the use of HTE. Due to its ease of synthesis, the ligand
was easily produced on gram scale. Although the performance
of the catalyst was not as good on pilot-plant scale as in the
lab, it allowed the synthesis of the desired chiral amide on
kilogram scale.
Since the initial lab tests of the obtained material were not
satisfying20 and analysis showed traces of Rh due to the
Wilkinson hydrogenation (measured to be as high as 1160 ppm),
a recrystallization was carried out by dissolving the crude
substrate in hot ethanol, treating with activated carbon, and
adding H2O to precipitate the solid (recovery yield of 93%).
Scheme 3. Synthetic route towards prochiral enamide 3
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Scheme 4. Progress of the project (activity and ee of the
best catalytic system at the time; cumulated number of
experiments performed) versus time (days)
min. The reaction mixture is then filtered on a glass frit (P4),
the left-over solid are washed with 2 × 15 mL dry toluene.
The filtrates are split in two batches. One batch is kept in the
glovebox. The other is taken out of the glovebox to the vacuum
line where the solvent is evaporated under vacuum from around
50 mL to about 5 mL. 20 mL of pentane is added to the solution,
yielding a small amount of precipitate, which is filtered off.
The filtrate is collected and the solvent is evaporated under
vacuum, yielding a white sticky solid. 1H NMR (toluene-d8) δ:
7.88-7.11 (m, 10H), 2.85 (s, 3H), 2.77 (s, 3H), 1.54 (s, 9H);
31P NMR δ: 155.5.
Synthesis of (COD)Rh(G2)2BF4. In the glovebox,
Rh(COD)2BF4 (2.69 g, 6.62 mmol) is dissolved into 25 mL of
dry DCM. The phosphite G2 (6.04 g, 14.5 mmol, 2.2 equiv/
Rh) dissolved in 25 mL of dry DCM is added dropwise to the
Rh solution over a period of 30 min. The dark-red solution turns
bright orange after addition of all the ligand. The mixture is
stirred for 2 h extra, and heptane is added, leading to the
precipitation of an orange solid (5.99 g, yield ) 80%).
Hydrogenation of Enamide 3 in a 150-mL Autoclave.
Rh(COD)(G2)2BF4 (23 mg, 0.02 mmol) is placed in a Schlenk
tube under N2 and dissolved in 4 mL of dry degassed DCM. A
150-mL Parr autoclave is loaded with 3.98 g of enamide 3 (10.5
mmol). The autoclave is closed and purged with N2. Dry,
degassed EtOAc (50 mL) is added. The mixture is stirred for a
few minute prior to the addition of Rh catalyst solution (S/C )
530). The autoclave is purged with N2 and H2 filling/emptying
cycles. The reactor is pressurized with 5 bar of H2 and heated
to 50 °C. Once this temperature is reached, the reaction
is stirred at 700 rpm The hydrogenation is stopped after
17 h, and analysis is performed using chiral HPLC.
Conversion ) 100%, 97.1% ee.
Experimental Section
General. All laboratory-scale reactions were performed in
a dry nitrogen atmosphere using standard Schlenk techniques
or in the glovebox. Anhydrous solvents over molecular sieve
purchased from Fluka were systematically used. Amines
(generally >99%) were used as provided by Aldrich, Fluka,
Acros. Binol, octahydro-Binol and 3,3′-dimethyl-Binol based
phosphorus chloride were prepared according to a published
procedure.22 Rh(COD)2BF4 was provided by Umicore and
Heraeus.
Synthesis of G2, (R)-3,3′-Dimethylbinapthyl-tert-butoxy-
phosphite. Stock solutions of the different reagents are prepared
as follow: 1.577 g of PCl3 (11.5 mmol) is dissolved in 10 mL
of dry toluene. 0.847 g of tert-butanol (11.5 mmol) is dissolved
in 10 mL of dry toluene. 1.23 g of Et3N (12.2 mmol) is
dissolved in 10 mL of dry toluene. The stock solutions are
brought in the glovebox. The solutions of tert-butanol and Et3N
are mixed together and added slowly to the solution of PCl3.
The reaction mixture is left to stir for 1 h. 3.614 g of (R)-3,3′-
dimethyl-Binol (11.5 mmol) is dissolved in 5 mL of dry toluene,
together with 2.308 g of Et3N (22.85 mmol). The Binol solution
is slowly added to the reaction mixture and left to stir for 45
Acknowledgment
We thank Merck & Co, Rahway, NJ, for allowing us to
publish these results, and I. Maes and J. Andrien for their help
with analytical work.
Supporting Information Available
(20) Purity of the substrate is crucial to have a smooth asymmetric
hydrogenation, as also described by Merck for this substrate, see ref
9. Note that at the time of this investigation the purification work of
enamide 3 was not yet published, nor known to us.
(21) The lower ee value obtained here is caused by a suboptimal purification
of the substrate due to tight deadlines for the delivery of the final
product. However, these results made us feel confident that our process
was fitted for large-scale production since improvements both in terms
of substrate-to-catalyst ratio and enantiomeric excess are common in
successive production campaigns.
Experimental procedure for the preparation and testing of
the libraries of ligands and for the large-scale hydrogenation.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Received for review January 15, 2010.
OP100011Y
(22) de Vries, A. H. M.; Pineschi, M.; Arnold, L. A.; Imbos, R.; Feringa,
B. L. Angew. Chem., Int. Ed. 1997, 36, 2620.
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