Achiral ligands dramatically enhance rate and enantioselectivity in the Rh/phosphoramidite-catalyzed hydrogenation of α,β-disubstituted unsaturated acids

Article abstract of DOI:10.1002/anie.200500784

(Chemical Equation Presented) Mixing it up: A catalytic system based on a mixed-ligand approach has been developed for the rhodium-catalyzed asymmetric hydrogenation of cinnamic acid derivatives (see scheme, cod = cycloocta-1,5-diene). It is the first time that a catalyst complex based on a heterocombination of a chiral and an achiral monodentate ligand gives dramatically higher enantioselectivity (up to 99%) than any of the corresponding homocomplexes.

Full text of DOI:10.1002/anie.200500784

Angewandte
Chemie
Asymmetric Catalysis
Achiral Ligands Dramatically Enhance Rate and
Enantioselectivity in the Rh/Phosphoramidite-
Catalyzed Hydrogenation of a,b-Disubstituted
Unsaturated Acids**
Rob Hoen, Jeroen A. F. Boogers, Heiko Bernsmann,
Adriaan J. Minnaard,* Auke Meetsma,
Theodora D. Tiemersma-Wegman,
Andrꢀ H. M. de Vries, Johannes G. de Vries,* and
Ben L. Feringa*
In 2000, three research groups demonstrated that the widely
held view that chiral bidentate ligands are necessary to
achieve high enantioselectivity in rhodium-catalyzed hydro-
genations needs revision. Monodentate phosphonites,[1a]
phosphites[1b] and phosphoramidites[1c] proved to be highly
versatile ligands for this important transformation and
afforded excellent enantioselectivities for a broad range of
substrates.
[*] R. Hoen, Dr. H. Bernsmann, Dr. A. J. Minnaard, A. Meetsma,
T. D. Tiemersma-Wegman, Prof. Dr. B. L. Feringa
Department of Organic Chemistry
Stratingh Institute
University of Groningen
Nijenborgh 4, 9747 AG Groningen (The Netherlands)
Fax: (+31)50-363-4296
E-mail: a.j.minnaard@rug.nl
b.l.feringa@rug.nl
Dr. J. A. F. Boogers, Dr. A. H. M. de Vries, Prof. Dr. J. G. de Vries
DSM Pharma Chemicals-Advanced Synthesis
Catalysis and Development
P.O. Box 18, 6160 Geleen (The Netherlands)
Fax: (+31)46-476-7604
E-mail: hans-jg.vries-de@dsm.com
[**] We thank A. Kiewiet for carrying out the mass spectrometric
analysis. Financial support from the NRSC-C, NWO-CW, EU
Combicat Program, and EET is gratefully acknowledged.
Supporting information for this article (results of ligand screening
and general experimental methods) is available on the WWW under
http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 4209 –4212
DOI: 10.1002/anie.200500784
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Communications
Table 1: Screening of phosphoramidites in the rhodium-catalyzed asymmetric
hydrogenation of a-methylcinnamic acid (1)[a,b]
Recently it has been shown that mixtures of chiral
monodentate ligands improve the enantioselectivity and
reactivity in several cases.[2] This new strategy has been
employed in rhodium-catalyzed asymmetric hydrogena-
tions[2,3] and in rhodium-catalyzed additions of boronic
acid.[4] By using this mixed-ligand approach and exploit-
ing the fact that the structure of monodentate ligands can
be varied easily enables a large number of different
catalytic complexes to be screened for a variety of
reactions. Reetz and co-workers have also introduced a
variation of this mixed-ligand approach using a combi-
nation of chiral and achiral ligands.[3a] So far, however,
beneficial influences observed for mixed-ligand systems
are limited to a mixture of two chiral monodentate
ligands.
Herein, we report a mixed-ligand approach in which a
combination of a chiral monodentate phosphoramidite
and an achiral monodentate phosphine ligand gives for
the first time drastic improvement resulting in high, and
in some cases unprecedented, enantioselectivities com-
pared to known bidentate ligands and (combinations of)
chiral monodentate ligands in the rhodium-catalyzed
hydrogenation of disubstituted acrylic acids.
Entry
Ligand
Conversion [%]
ee[c,d] [%]
1
L1a
43
8
2
3
L1a+PPh3
L1b
100
72
43
0
4
5
L1b+PPh3
L1c
100
76
55
0
6
7
L1c+PPh3
L1d
100
91
63
0
8
9
L1d+PPh3
L2a
L2a+PPh3
L2b
L2b+PPh3
L2c
L2c+PPh3
L2d
100
91
100
82
100
81
100
86
37
10
80
3
80
2
85
16
76
10
11
12
13
14
15
16
Our efforts focused on chiral dihydrocinnamic acid
derivatives, which are key intermediates in the synthesis
of several bioactive compounds, including renin inhib-
itors,[5] g-secretase inhibitors,[6] enkephalinase inhibi-
tors,[7] endothelin receptor antagonists,[8] and opioid
antagonists.[9]
L2d+PPh3
100
[a] Reaction conditions: 1 mmol substrate in 4 mL solvent with 0.01 mmol
[Rh(cod)2]BF4 (cod=cycloocta-1,5-diene), 0.02 mmol phosphoramidite and
0.01 mmol PPh3. [b] Reactions were carried out for 5 h. [c] ee values were
determined by GC on a chiral stationary phase (see Supporting Information).
[d] In all cases the R enantiomer of the ligand gave the S enantiomer of the
product.
An initial screening of several mixtures of mono-
dentate phosphoramidites and other phosphorus ligands
in the rhodium-catalyzed asymmetric hydrogenation of
a-methylcinnamic acid (1) showed that the heterocombi-
nation of a chiral phosphoramidite with an achiral
triphenylphosphine gave a dramatic increase in conver-
sion and in enantioselectivity, compared to the corresponding
homocomplexes (Table 1).
Table 2: Screening of achiral phosphines in the rhodium-catalyzed
asymmetric hydrogenation of a-methylcinnamic acid (1)[a,b]
For example the use of L1c in combination with
triphenylphosphine resulted in an enhancement of the con-
version from 76 to 100% and the ee value from 0 to 63%
(entries 5 and 6). It was observed that phosphoramidites
based on 3,3’-dimethyl-2,2’-dihydroxy-1,1’-binaphthyl (3,3’-
dimethylbinol) gave distinctly higher ee values than the
phosphoramidites based on binol (entries 1–8 versus 9–16,
Table 1). Piperidine-based phosphoramidite L2c[10] further
improved the enantioselectivities. The addition of triphenyl-
phosphine in the presence of the catalyst based on L2c
resulted in a remarkable increase in the ee value from 2 to
85% (entries 13 and 14).
A screening of different phosphines was performed after
further optimization of the solvent, temperature, pressure,
and ligand ratio.[11] A variety of achiral alkyl phosphines and
substituted aryl phosphines were tested in the rhodium-
catalyzed asymmetric hydrogenation of a-methylcinnamic
acid (1) using L2c (Table 2).
Entry
R
ee[c,d] [%]
TOF [molmolÀ1 hÀ1
]
1
2
3
4
5
6
7
8
–
16[e]
88
97
87
2
Ph (P1)
46
33
69
61
92
3
46
18
28
17
2
o-tolyl (P2)
m-tolyl (P3)
p-tolyl (P4)
xylyl (P5)
mesityl (P6)
m-ClPh (P7)
p-ClPh (P8)
cyclohexyl (P9)
n-butyl (P10)
tert-butyl (P11)
86
89
33[f]
89
9
90
87
10
11
12
67
13[g]
[a] Reaction conditions: 1 mmol substrate in 4 mL solvent with
0.01 mmol [Rh(cod)2]BF4, 0.02 mmol phosphoramidite and 0.01 mmol
PR3. [b] Reactions were carried out for 16 h. [c] ee values were determined
by GC on a chiral stationary phase (see Supporting Information), full
conversion. [d] In all cases the R enantiomer of the ligand gave the
S enantiomer of the product. [e] 34% conversion. [f] 55% conversion.
[g] 39% conversion.
Substitution at the ortho position of triphenylphosphine
increased the ee value significantly (entries 2 and 3), whereas
substitution at the meta or para position had hardly any
influence on the enantioselectivity (compare entries 2, 4, 5, 8,
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Angewandte
Chemie
and 9). Linear or branched alkyl phosphines resulted in a
decrease in the rate and enantioselectivity compared to
tricyclohexylphosphine P9 (entries 10–12). Electron-donating
or -withdrawing substituents on the aryl phosphines had no
influence on the ee value (compare entries 2 with 4 and 5 as
well as 8 and 9). While reactions were in general complete
after 2 h, incomplete conversions were obtained with the
sterically hindered phosphines P6 and P11 after 16 h
(entries 7 and 12). In these cases, not only did the rate of
the hydrogenations decrease, but the enantioselectivities also
dropped dramatically.
catalyzed and ruthenium-catalyzed hydrogenations using
chiral bidentate ligands.[5a,12,13] With the exception of five
Ru complexes based on bidentate phosphine ligands, which
hydrogenate substrate 3 with ꢀ 95% ee,[12f,13b,13c,14] the pres-
ent system belongs to the most selective so far reported.
In conclusion, a new catalytic system, based on a mixed-
ligand approach, has been developed for the rhodium-
catalyzed asymmetric hydrogenation of cinnamic acid deriv-
atives with ee values up to 99%. Easy variation of the chiral
and achiral monodentate ligands makes it possible to screen a
variety of catalytic systems in a short time. It has been shown
for the first time that a catalyst complex based on a
heterocombination of a chiral and an achiral monodentate
ligand gives dramatically higher
Next the hydrogenation of a number of disubstituted
acrylic acids was studied (Table 3). In all cases, full conversion
Table 3: Rhodium-catalyzed asymmetric hydrogenation of substituted acrylic acids[a],[b]
enantioselectivity than any of the
corresponding homocomplexes.
Received: March 3, 2005
Published online: June 1, 2005
Keywords: asymmetric catalysis ·
.
hydrogenation · ligand effects ·
phosphines · rhodium
Entry
Substrate
Product
Ligand
Phosphine
ee[c,d] [%]
[1] a) C. Claver, E. Fernandez, A.
Gillon, K. Heslop, D. J. Hyett, A.
1
2
3
3
4
5
6
7
8
9
10
11
12
L2b
L2c
L2c
L2c
L2c
P3
P2
P1
P3
P2
87
99[e]
92
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gle, Chem. Commun. 2000, 961;
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95
95
5[f]
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A. H. M. de Vries, J. G. de Vries,
B. L. Feringa, J. Am. Chem. Soc.
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[a] Reaction conditions: 1 mmol substrate in 4 mL solvent with 0.01 mmol [Rh(cod)2]BF4, 0.02 mmol
phosphoramidite and 0.01 mmol PPh3. [b] Reactions were carried out for 16 h. [c] ee values were
determined by GC or HPLC on chiral stationary phases, full conversion was obtained unless indicated
otherwise. [d] In all cases the S enantiomer of the ligand gave the S enantiomer of the product.[15]
[e] Conversion 98%. [f] Reaction was performed at 608C.
[2] a) M. T. Reetz, T. Sell, A. Meis-
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of the substrates was obtained with high to excellent ee values.
The enantioselectivity is higher when R1 is an aromatic group
than when R1 is an alkyl group, as in tiglic acid (3, compare
entry 3 of Table 2 with entry 1 of Table 3). Electron-donating
as well as electron-withdrawing substituents at the aromatic
moiety had little effect on the enantioselectivity (entry 3
versus 4, Table 3). The size of R2 also has little influence on
the enantioselectivities. Enantiomeric excesses of ꢀ 97% for
2 and 9 could be obtained by fine-tuning of the phosphine–
phosphoramidite combination (entry 3 of Table 2 and entry 2
of Table 3).
On the basis of preliminary NMR experiments it can be
concluded that the formation of a heterocomplex comprising
one chiral phosphoramidite and one achiral phosphine bound
to the Rh center is the predominant factor for the remarkable
selectivity enhancement and high activity. The formation of a
homocomplex comprising two achiral phosphines bound to
the Rh center causes a non-asymmetric catalytic reaction.
Using a 2:1 ratio of phosphoramidite:phosphine suppresses
the formation of the latter homocomplex.
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12 exceed or are comparable to reported values for rhodium-
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Angew. Chem. Int. Ed. 2005, 44, 4209 –4212
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
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[11] Optimized conditions for high enantioselectivities are: solvent,
iPrOH/H2O (20%,) 25 bar H2 pressure, 308C, and a 2:1 ratio of
phosphoramidite and phosphine.
[12] For compound 2 see: a) I. Yamada, M. Ohkouchi, M. Yamagu-
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[15] The absolute configuration of 11 was confirmed by X-ray
analysis of the corresponding a-methylbenzylamine derivative.
The absolute configurations of 9 and 10 were assigned by
analogy (see Supporting Information).
4212
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