ChenPhos: Highly modular P-stereogenic C1-symmetric diphosphine ligands for the efficient asymmetric hydrogenation of α-substituted cinnamic acids

Article abstract of DOI:10.1002/anie.201304472

These cats are purrfectionists: The ChenPhos ligands (see structure) showed dramatically higher catalytic activity in the title reaction than their C ₂-symmetric predecessor with two dimethylaminoethyl-substituted ferrocenyl(phenyl)phosphanyl groups. The ready accessibility, extreme air stability, and high enantioselectivity, activity, and productivity of these ligands make them very promising for a wide range of practical applications. Copyright

Full text of DOI:10.1002/anie.201304472

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DOI: 10.1002/anie.201304472
Ligand Design
ChenPhos: Highly Modular P-Stereogenic C1-Symmetric Diphosphine
Ligands for the Efficient Asymmetric Hydrogenation of a-Substituted
Cinnamic Acids
Weiping Chen,* Felix Spindler, Benoit Pugin, and Ulrike Nettekoven
Over four decades, tremendous effort has been devoted to the
design and synthesis of chiral phosphine ligands that can
provide high enantioselectivity and high reactivity in asym-
metric catalysis.[1] Since the discovery of the diop ligand by
Kagan and Dang in 1971,[2] the concept of C2 symmetry has
been a very popular design motive for chiral diphosphine
ligands (probably as a result of the huge success of ligands
such as dipamp, binap, MeO-biphep, and Duphos, as well as
the ease of synthesis).[3] Indeed, a large number of diphos-
phine ligands with C2 symmetry have been developed for
highly efficient asymmetric hydrogenation reactions of vari-
ous olefins, ketones, and imines.[4] Despite impressive prog-
ress in this field, the design of structurally novel, readily
accessible, operationally convenient, and efficient chiral
phosphine ligands remains a formidable task. The complexity
of most catalytic processes precludes a purely rational
approach based on mechanistic and structural criteria. There-
fore, most new chiral catalysts are still found empirically, with
chance, intuition, and systematic screening all playing impor-
tant roles. Even though, when the mechanism of a certain
reaction, such as rhodium-catalyzed hydrogenation,[5] is well-
established, at most the semirational design of new ligands is
possible. General experience is that small structural alter-
ations can lead to significant, unpredictable changes in
catalysis. For this reason, ideally, a new ligand should be
readily accessible through a synthetic route that allows the
straightforward variation of structural and electronic features
and optimization for a specific application.
Previously, we described the first C2-symmetric diphos-
phine that combines carbon- and phosphorus-centered chir-
ality and planar chirality: TriFer (Scheme 1). Although its
high enantioselectivity in the asymmetric hydrogenation of a-
substituted cinnamic acids was unprecedented,[6] the synthesis
of TriFer was very difficult to scale up because reasonable
diastereoselectivity was only possible under very strict con-
ditions; the catalyst activity and productivity were still
unsatisfactory, since complete conversion was only possible
at a relatively low ratio of substrate to catalyst. Furthermore,
Scheme 1. Comparison of the TriFer and ChenPhos ligands.
the modularity of the TriFer ligand is restricted by the
availability of dichlorophosphines. For practical applications
in industry, not only very high enantioselectivity, but also the
productivity (turnover number, TON) and activity (turnover
frequency, TOF) of catalysts as well as the accessibility and
modularity of ligands are also crucial issues.[7] Herein, we
report a new, very simple and efficient synthesis of ferrocene-
based P-stereogenic phosphines on the basis of thermal
epimerization through pyramidal inversion as the key step, as
well as a novel, readily accessible and highly modular family
of C1-symmetric P-chiral diphosphine ligands, ChenPhos[8]
(Scheme 1), which show extremely high enantioselectivity,
activity, and productivity for the rhodium-catalyzed asym-
metric hydrogenation of a-substituted cinnamic acids.
ChenPhos was designed on the basis of various facts and
hypotheses. According to the plausible mechanism of the
asymmetric hydrogenation of a-substituted cinnamic acids
under the catalysis of a TriFer–Rh complex,[6] we anticipated
that one dimethylamino group may be enough for the
secondary interaction between the catalyst and the substrate.
A current trend in the design of chiral diphosphane ligands is
the differentiation of the electronic and/or the steric proper-
ties of the phosphorus donors.[9] As pointed out by Achiwa
and co-workers,[10] the intermediates in the catalytic cycle of
the asymmetric hydrogenation are nonsymmetrical, and,
consequently, the two phosphino groups interact with
a metal-bound substrate in an electronically and sterically
different manner. Indeed, the presence of nonequivalent
phosphorus centers, in particular the replacement of one of
the diphenylphosphine units in a C2-symmetric diphosphine
with a more electron rich dicyclohexylphosphanyl group,
often results in improved catalyst activity and a significant but
unpredictable change in enantioselectivity.[11,12] Our design of
[*] Dr. W. Chen,[+] Dr. F. Spindler, Dr. B. Pugin, Dr. U. Nettekoven
Solvias AG, WRO-1055.6.68B
Mattenstrasse 22, Postfach, 4002 Basel (Switzerland)
E-mail: wpchen@fmmu.edu.cn
[+] Present address:
School of Pharmacy, Fourth Military Medical University
169 Changle West Road, Xi’an, 710032 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304472.
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the highly modular ChenPhos ligands involves: 1) the 2-(1-
N,N-dimethylaminoethyl)ferrocenyl group on P1 for the
secondary interaction between catalyst and substrate; 2) the
stereogenic phosphorus center P1 for high enantioselectivity;
3) the introduction of bulky and electron-rich R groups on P2
for the enhancement of catalytic activity by the strengthened
d–s* interaction (acceleration of the oxidative addition of
molecular hydrogen), and, possibly, enantioselectivity by the
rigid chelation of rhodium with electron-deficient olefins.
This modification greatly improves the modularity of the
ligand and makes ChenPhos C1-symmetric (Scheme 1).
We previously reported a very simple, highly diastereo-
selective strategy for building up ferrocene ligands with P-
chiral phosphine group(s): the treatment of a dichlorophos-
phine first with a chiral lithiated ferrocene and then with
a second organometallic reagent.[13] This straightforward
method gives almost perfect diastereoselectivity with simple
alkyl and aryl organometallic reagents. However, the diaste-
reoselectivity was variable (often low) when the second
organometallic reagent was derived from another ferrocene
derivative, as in the synthesis of ChenPhos. Fortunately, we
were able to develop another very simple and efficient
synthesis of ferrocene-based P-chiral phosphines for the
preparation of ChenPhos on the basis of thermal epimeriza-
tion through pyramidal inversion as the key step.[14]
1-lithio-1’-bromoferrocene, generated from 1,1’-dibromofer-
rocene by monolithiation with nBuLi in THF (between À25
and À308C, 3 h), to afford a mixture of (RC,SFc,SP)-3 and
(RC,SFc,RP)-3. A solution of the product mixture in toluene
was heated at reflux for 4 h to promote epimerization.
Fortunately, the thermodynamically more stable diastereo-
mer was the desired intermediate (RC,SFc,SP)-3, which could
be isolated as a single diastereomer in 59% yield by
recrystallization from EtOH. Lithiation of (RC,SFc,SP)-3,
followed by treatment with a diaryl or dialkyl chlorophos-
phine, R2PCl, normally gave the desired ChenPhos ligands
1a–n in high yield. ChenPhos 1a was also prepared efficiently
by lithiation of a mixture of (RC,SFc,SP)-3 and (RC,SFc,RP)-3,
treatment with Cy2PCl, and then thermal epimerization.
In route 2, the achiral P2 group, Cy2P, was first introduced
(Scheme 3). Thus, 1,1’-dibromoferrocene (4) was selectively
monolithiated with nBuLi in THF (between À25 and À308C,
3 h) and treated with Cy2PCl (08C, 10 min, then RT, 1.5 h) to
Two synthetic routes were investigated for the preparation
of ChenPhos. In route 1, the chiral P1 group, (RC,SFc,SP)-1-[2-
(1-N,N-dimethylaminoethyl)ferrocen-1-yl]phenylphosphanyl,
was first introduced (Scheme 2). Thus, the Ugi amine (R)-2
was lithiated with sBuLi (08C, 1.5 h) and then treated first
with PhPCl2 (> À358C, 10 min, then RT, 1.5 h) and then with
Scheme 3. Synthesis of ChenPhos (route 2).
give 6 in 85% yield. Lithiation of 6, followed by treatment
with a monochlorophosphine 5, which was prepared by
lithiation of the Ugi amine (R)-2 with sBuLi (08C, 1.5 h)
and then treatment with an aryl or alkyl dichlorophosphine
R’PCl2 (< À358C, 10 min, then RT, 1.5 h), afforded ChenPhos
as a mixture of two diastereomers. The desired ChenPhos
ligands 1o–r were obtained in high yield after thermal
epimerization of the diastereomeric mixtures.
The synthesis of ChenPhos is very economical and simple,
since it can be completed without the purification of
intermediates (“one-pot” synthesis, ca. 60% overall yield)
for both routes (see the Supporting Information). Also, the
synthesis is highly modular; the R and R’ groups can be any
aryl or alkyl group that tolerates lithiation and a Grignard
reaction. The absolute configuration of (RC,SFc,SP)-1a was
Scheme 2. Synthesis of ChenPhos (route 1). o-An=o-anisidyl, Cy=
cyclohexyl, TBME=tert-butyl methyl ether.
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confirmed by single-crystal X-ray diffraction analysis. Impor-
tantly, ChenPhos ligands are extremely insensitive to air
oxidation; for example, the 1H and 31P NMR spectra of ligand
(RC,SFc,SP)-1a remained unchanged when this ligand was
heated as a solid for three days at 758C in air or when it was
stored as a non-degassed solution in EtOAc/EtOH for
6 months at room temperature. Ligand 1a was readily
synthesized on a kilogram scale in a one-pot synthesis.
The efficiency of Rh–ChenPhos complexes as catalysts
was investigated in the enantioselective hydrogenation of (E)-
2-(3-(3-methoxypropoxy)-4-methoxybenzylidene)-3-methyl-
butanoic acid (7): a key step in the production of the renin
inhibitor aliskiren[6,15,16] (Table 1). All ligands with bulky and
electron-rich phosphino group might strengthen the d–s*
interaction and accelerate the oxidative addition of molecular
hydrogen. Considering both enantioselectivity and activity,
1a is the best-performing ChenPhos ligand prepared so far.
ChenPhos was also highly effective in the asymmetric
hydrogenation of 3-aryl 2-alkoxy acrylic acids: a key step in
the synthesis of some PPAR agonists (PPAR = peroxisome
proliferator-activated receptor). For example, in the Rh-
catalyzed hydrogenation of (E)-3-(4-benzyloxyphenyl)-2-
methoxyacrylic acid (9), the use of 1h led to the product 10
with 95.2% ee (Scheme 4).
Table 1: Asymmetric hydrogenation of (E)-2-(3-(3-methoxypropoxy)-4-
methoxybenzylidene)-3-methylbutanoic acid (7).
Scheme 4. Asymmetric hydrogenation of (E)-3-(4-benzyloxyphenyl)-2-
methoxyacrylic acid. Bn=benzyl, nbd=norbornadiene.
As observed for TriFer,[6] the high enantioselectivity of
ligand 1a in the Rh-catalyzed asymmetric hydrogenation of
a-substituted cinnamic acids is due to a secondary electro-
static interaction of the dimethylamino group of the ligand
with the carboxylate unit of the substrate. Ligand 1t (in which
the dimethylamino group present in 1a is replaced with
a methoxy group) was not effective for the Rh-catalyzed
hydrogenation of 7 (8 was formed with 44% ee) owing to the
lack of this secondary interaction, although it is a perfect
ligand for the hydrogenation of the standard substrate methyl
2-acetamidoacrylate (the product was formed with
> 99.9% ee; see the Supporting Information). Furthermore,
all ChenPhos ligands were almost inactive in the Rh-catalyzed
hydrogenation of the corresponding esters of 7 and 9.
Ligand
S/C
8500
2000
5000
12000
8500
12000
12000
p(H2) [bar]
t [h]
Conversion [%]
ee [%]
1a
1b
1c
1h
1p
1a
TriFer
50
50
60
50
60
50
50
5
22
20.5
3.5
20
100
99
100
49.3
99
99.2
87.4
97.5
99.2
21.4
99.0
99.5
3.5
3.5
95
14
electron-rich R groups on P2 showed high enantioselectivity
and activity. Typically, the product 8 was formed with less than
90% ee when R was an aryl group (e.g. 1b, 87.4% ee);
whereas up to > 99% ee was observed when R was a bulky
and electron-rich alkyl group (see the Supporting Informa-
tion).[17] The enantioselectivity of 1a (R = Cy) was slightly
lower than that of TriFer (99.2 versus 99.5% ee); however,
importantly, 1a is much more active and productive. When 7
was hydrogenated with a hydrogen pressure of 50 bar at 358C
in MeOH for 3.5 h with a molar substrate/catalyst ratio (S/C)
of 12000, conversion was 95% with the 1a–Rh complex,
whereas under identical conditions, TriFer gave only 14%
conversion. Interestingly, the product was formed with
99.2% ee when ligand 1h (R = 2-norbornyl) was used, even
though this ligand existed as a mixture of at least four
diastereomers (as confirmed by 31P NMR spectroscopy)
owing to the presence of racemic exo/endo 2-norbornyl
groups. In accord with our design concept, the dramatic
increase in the activity of ligand 1a seems to be due to the
introduction of two nonequivalent phosphorus centers and an
electron-rich dicyclohexylphosphanyl group. Cy-TriFer,
formed by the replacement of both phenyl rings of TriFer
with cyclohexyl groups, indeed showed enhanced activity, but
not to the same extent as ligand 1a. Strangely, ligand 1p, with
two nonequivalent but electron-rich phosphorus centers (with
three cyclohexyl groups), gave a very poor result in the
hydrogenation (21.4% ee). The introduction of a bulky and
Preliminary screening of the scope of application of
ChenPhos indicated that the ligand gives active Rh catalysts
=
=
(for C C hydrogenation), Ru catalysts (for C O hydro-
=
genation), and Ir catalysts (for C N hydrogenation; see the
Supporting Information); however, no optimization efforts
have been made so far.
In conclusion, ChenPhos was designed by replacing one 2-
(1-dimethylaminoethyl)ferrocenyl(phenyl)phosphanyl group
of TriFer with a bulky, electron-rich phosphanyl group. This
change was found to dramatically enhance the catalytic
activity of the corresponding rhodium complexes, the enan-
tioselectivity of which remained high. The synthesis of
ChenPhos on the basis of thermal epimerization through
pyramidal inversion as the key step is economical and simple.
ChenPhos meets all requirements of a ligand of practical
relevance: it is readily accessible, extremely air-stable, and
exhibits very high enantioselectivity, activity, and productivity
in asymmetric catalytic reactions. Furthermore, because of its
high modularity, ChenPhos has the potential for very broad
application.
Received: May 24, 2013
Published online: July 1, 2013
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Org. Lett. 2010, 12, 4400; z) T. Imamoto, K. Tamura, Z. Zhang, Y.
Keywords: asymmetric hydrogenation ·
C1-symmetric diphosphines · P-stereogenic ligands ·
phosphane ligands · pyramidal inversion
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crystallization or chromatography, and crude 1c (ca. 90% purity,
as determined by 31P NMR spectroscopy) was used in the
hydrogenation.
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[16] For the asymmetric hydrogenation of (E)-2-(3-(3-methoxy-
propoxy)-4-methoxybenzylidene)-3-methylbutanoic acid (7),
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Angew. Chem. Int. Ed. 2013, 52, 8652 –8656