Rhodium(I)-catalyzed enantioselective hydrogenation of substituted acrylic acids with sterically similar β,β-diaryls

Article abstract of DOI:10.1002/anie.201302349

Distinct differentiation: β,β-Disubstituted acrylic acids with sterically similar geminal diaryl groups can be hydrogenated with excellent enantioselectivities in the presence of a Rh^I complex formed in situ with two-component ligands, a chiral secondary phosphine oxide (SPO) and an achiral phosphine (Ph₃P). The sense of asymmetric induction was found to be controlled by the substrate configuration, thus allowing access to both enantiomers of the product with the same catalyst. Copyright

Full text of DOI:10.1002/anie.201302349

Angewandte
Chemie
Communications
Asymmetric Hydrogenation
Y. Li, K. Dong, Z. Wang,
K. Ding*
&&&& — &&&&
Rhodium(I)-Catalyzed Enantioselective
Hydrogenation of Substituted Acrylic
Acids with Sterically Similar b,b-Diaryls
Distinct differentiation: b,b-Disubsti-
tuted acrylic acids with sterically similar
geminal diaryl groups can be hydrogen-
ated with excellent enantioselectivities in
the presence of a RhI complex formed
in situ with two-component ligands,
a chiral secondary phosphine oxide (SPO)
and an achiral phosphine (Ph3P). The
sense of asymmetric induction was found
to be controlled by the substrate config-
uration, thus allowing access to both
enantiomers of the product with the same
catalyst.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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DOI: 10.1002/anie.201302349
Asymmetric Hydrogenation
Rhodium(I)-Catalyzed Enantioselective Hydrogenation of Substituted
Acrylic Acids with Sterically Similar b,b-Diaryls**
Yang Li, Kaiwu Dong, Zheng Wang, and Kuiling Ding*
Dedicated to Professor Guo-Qiang Lin on the occasion of his 70th birthday
Optically active b,b-diarylpropionic acids are a class of
important building blocks for the asymmetric synthesis of
chiral diarylmethine compounds,[1] which are structural moi-
eties that are found in many pharmaceuticals and bioactive
compounds, including the therapeutically important mole-
cules tolterodine,[1a–b] sertraline,[1c] indatraline,[1d] and natural
products, such as cherylline.[1e]
(100 bar). Herein, we present the results of the development
of an efficient asymmetric hydrogenation of b,b-diarylacrylic
acids in the presence of a Rh complex based on the
heterocombination of a chiral monodentate secondary phos-
phine oxide (SPO) preligand and an achiral monodentate
phosphine ligand as the catalyst to afford a wide variety of the
corresponding b,b-diarylpropionic acids with biological
importance in excellent optical purities.
The most challenging issue associated with the control of
stereochemistry in the asymmetric hydrogenation of b,b-
diarylacrylic acids is the differentiation of a stereogenic center
with two sterically similar aryl groups at the b-position of
acrylic acids.[3–8] Very recently, we disclosed that RhI catalysts
generated in situ by interaction with SPO preligands demon-
strated excellent performance in the asymmetric hydrogena-
tion of a-substituted ethenylphosphonic acids.[9] The salient
features of SPO ligands, including ready accessibility, good air
and moisture stability, and the potentially H-bonding OH
group in the ligand,[9,10] prompted us to explore the catalytic
potential of RhI/SPO systems in the asymmetric hydrogena-
tion of challenging b,b-diarylacrylic acid substrates. As shown
in Table 1, chiral monodentate SPO preligands L1–L7 were
evaluated in the rhodium-catalyzed asymmetric hydrogena-
tion of (E)-3-phenyl-3-(p-tolyl) acrylic acid ((E)-1a). How-
ever, an initial screening of the catalysts generated in situ by
mixing [Rh(cod)2]BF4 (cod = 1,5-cyclooctadiene) and L1–L7
in a 1:2 molar ratio resulted in only poor conversions under
the conditions tested (entries 1–9), which indicates that the
Rh complexes of L1–L7 alone are not active enough for
catalysis. Inspired by the fact that mixtures of chiral mono-
dentate ligands (or chiral and achiral) can often improve the
enantioselectivity and reactivity in many transition-metal-
catalyzed reactions,[11] as evidenced by the elegant studies of
several groups,[12–17] we moved to employ this mixed-ligand
strategy in the present reaction. Gratifyingly, use of L3 in
combination with achiral triphenylphosphine indeed resulted
in a dramatic enhancement in the conversion (from 15% to
> 99%) and ee values (from 38% to 95%) under otherwise
identical conditions (entries 10 vs. 3). Notably, further modi-
fication of the RhI catalyst system by varying the relative
amounts of L3 and PPh3 was found to have a profound
influence on the reaction (entries 11 and 13–15). For example,
reducing the molar ratio of Rh/L3/PPh3 to 1:1:1 resulted in
a slight decrease in the product ee value (from 95% to 92%;
entries 10 and 11), presumably as a result of the background
reaction catalyzed by the achiral Rh/PPh3 species (entry 12).
On the other hand, changing the Rh/L3/PPh3 ratio from 1:2:1
to 1:1:2 or 1:3:1 also led to a substantial change in the
Thus far, methods for the asymmetric synthesis of chiral
b,b-diarylpropionic acids often involve a multistep sequence
and/or stoichiometric transformation using chiral auxilia-
ries,[2] only a few examples of catalytic asymmetric methods,
including RhI- or CuII-catalyzed reduction of b,b-diaryl
unsaturated acrylates[3,4] or nitriles[5] using either polymethyl-
hydrosiloxanes or diethoxymethylsilane as the reductants,
and RhI-catalyzed 1,4-addition of organoboron reagents to
arylidene Meldrumꢀs acids,[6] have been reported to provide
the corresponding b,b-diaryl propanoates or propanenitriles
with good to high enantioselectivities. In terms of atom
economy and environmental concerns, asymmetric hydro-
genation of b,b-diarylacrylates with molecular H2 is more
advantageous. In this respect, IrI- or RhI-catalyzed asymmet-
ric hydrogenation of trisubstituted olefins for the formation of
diarylmethine stereogenic centers seems feasible.[7] However,
reactions involving 3,3-diarylacrylates (especially free acids)
proved to be challenging, as only moderate enantioselectiv-
ities were obtained, in most cases under high pressure
[*] Y. Li, K. Dong, Dr. Z. Wang, Prof. Dr. K. Ding
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P. R. China)
E-mail: kding@mail.sioc.ac.cn
[**] We are grateful for the financial support of this work from the Major
Basic Research Development Program of China (2010CB833300),
the National Natural Science Foundation of China (21121062 and
21232009), the Chinese Academy of Sciences, and the Science and
Technology Commission of Shanghai Municipality.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302349.
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Table 1: Dramatic synergistic effect of achiral triphenylphosphine on the
RhI-catalyzed enantioselective hydrogenation of (E)-1a in the presence of
chiral SPO preligands L1–L7.[a]
stantial diversity, thus obviating the need for tedious synthesis
of a chiral bidentate ligand.[11–17] The synergistic effect of
ligand mixtures has also been observed in a variety of catalytic
asymmetric reactions.[18] With these in mind, we shifted our
attention to the screening of a combinatorial library of Rh
catalysts for hydrogenation of the model substrate (E)-1a.
The catalyst library was generated in situ by combining
[Rh(cod)2]BF4, an SPO preligand (L1–L7), and an achiral
tertiary phosphine (P1–P7) in a molar ratio of 1:2:1. The
reactions were conducted under the above optimized con-
ditions, and the results are shown in Table 2. Remarkably, in
most cases the heterocombinations resulted in a considerable
improvement in both conversion and enantioselectivity, as
compared to the cases using the corresponding chiral SPO
alone (P1 and P3–P7 vs. None). These results demonstrated
that the heterocomplexes were generally more reactive and
steroselective than the homocomplexes, which suggests that
the use of different P donors with distinct electronic features
(a s-donating phosphine and a p-accepting phosphorous acid
diester ligand) is favorable for the reaction. An exception was
found in cases using P2, wherein the substrate conversions
remain similar to those obtained using the chiral ligands
alone, probably owing to the steric bulk of tri(o-tolyl)phos-
phine (P2), which prevents the effective formation of the
corresponding heterocomplexes or blocks substrate approach
to the catalyst. It was also found that catalysts with
phosphines bearing electron-donating para substituents on
the aryl groups (P4 and P5) usually afforded better results
than those with electron-withdrawing para substituents (P6),
but the correlation between reactivity and the electronic
properties of the tertiary phosphines is still elusive in the case
of P7. The combinatorial search revealed that several SPO/P
heterocombination ligand systems, for example, L2/P1, L2/
P4, L3/P1, L3/P5, are optimal for RhI-catalyzed hydrogena-
Entry
L (mol%)
PPh3 [mol%]
Conv. [%][b]
ee [%][c]
1
2
3
4
5
6
7
L1 (2)
L2 (2)
L3 (2)
L4 (2)
L5 (2)
L6 (2)
L7 (2)
L3 (2)
L3 (2)
L3 (2)
L3 (1)
none
none
none
none
none
none
none
none
none
none
1
10
16
15
<5
<5
<5
<5
3
82
65
38
–
–
–
–
–
–
95
92
rac
77
95
–
8[d]
9[e]
10
11
12
13
14
15
2
>99
>99
35
18
90
1
2
2
1
L3 (1)
L3 (3)
L3 (2)
2
trace
[a] Reaction conditions: [Rh(cod)2]BF4 (1 mol%), substrate (0.083m),
1
morpholine (10 mol%). [b] Determined by H NMR spectroscopy.
[c] Determined by HPLC analysis on a chiral stationary phase after the
acids were transformed into their corresponding methyl esters with
CH2N2. [d] CH2Cl2 solvent, morpholine (50 mol%). [e] THF solvent,
morpholine (50 mol%). cod=1,5-cyclooctadiene.
Table 2: Screening of catalyst libraries of [Rh(cod)2]BF4/L/Px in the asymmetric hydrogenation of (E)-
conversion and/or ee values 1a.[a]
(entries 13 and 14), which suggests
that subtle equilibria exist among
the Rh(L3)x(PPh3)y species in the
system. Finally, the system with
a Rh/L3/PPh3 ratio of 1:2:2 was
found to be virtually inactive
(entry 15), probably owing to cata-
lyst inhibition caused by coordina-
tive saturation of the Rh centers by
excessive P ligands. Further optimi-
zation of the reaction conditions
(see the Supporting Information)
revealed that the hydrogenation of
(E)-1a catalyzed by Rh/L3/PPh3
(1:2:1) was best performed in iso-
propanol/water (5:1) solvent with
morpholine as the base.
L/P
None[b,c]
P1[b]
P2[b]
P3[b]
P4[b]
P5[b]
P6[b]
P7[b]
L1
L2
L3
L4
L5
L6
L7
10(82)
16(65)
15(38)
<5[d]
86(79)
>99(95)
>99(95)
44(93)
92(17)
>99(80)
>99(81)
14(80)
22(68)
22(31)
<5[d]
80(71)
>99(91)
19(38)
38(79)
98(21)
62(74)
>99(95)
>99(94)
35(82)
96(18)
86(67)
75(80)
>99(94)
>99(95)
62(81)
92(10)
59(62)
56(54)
95(80)
75(93)
88(90)
40(30)
83(38)
98(56)
88(82)
>99(85)
27(56)
80(83)
90(26)
83(72)
96(68)
<5[d]
<5[d]
<5[d]
8(86)
15(75)
93(81)
>99(82)
<5[d]
>99(75)
>99(73)
[a] Reaction conditions: [Rh(cod)2]BF4/L/Px (1:2:1, 1 mol%), morpholine (10 mol%), (E)-1a
(0.25 mmol), iPrOH/H2O (3 mL, 5:1). [b] Data shown is for conversions [%]. Data in parentheses are ee
values [%]. Conversion was determined by H NMR spectroscopy, and the ee value of 2a was
determined by HPLC analysis on a chiral stationary phase after esterification with CH2N2. [c] No
A salient advantage of using the
mixed-ligand approach is that it
allows for rapid generation of
1
a chiral catalyst library with sub- phosphine was used. [d] The ee values were not determined.
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Table 3: Rh-catalyzed asymmetric hydrogenation of b,b-diarylacrylic
acids 1a–v.[a]
group in the para position of the aryl substituent, was also
amenable to the method, smoothly giving 2c with an ee value
of 94% (entry 3). In some cases, extra THF and/or morpho-
line was used to increase the solubility of the substrates
(entries 15 and 18). For the sterically more hindered sub-
strates, including (E)-1l, (Z)-1s, and polysubstituted (Z)-1t,
the reactions also ran smoothly to afford the corresponding
hydrogenation products with high ee values (94–96%), albeit
at an elevated catalyst loading (2 mol%) and/or higher
hydrogen pressure (50 atm) for full conversion of substrates
(entries 12, 19, and 20). The asymmetric hydrogenation of
substrates with a heteroaryl (2-furyl, 1u) or alkyl (methyl, 1v)
group were also successful, affording the corresponding
products, 2u and 2v, respectively, with excellent ee values
(entries 21 and 22). Under otherwise identical conditions,
both E and Z substrates can be hydrogenated with full
conversion. Importantly, the (E) and (Z) isomers of 1a, 1i,
and 1j give products with similar ee values, but enriched in
opposite enantiomers (entries 1 vs. 23, 9 vs. 24, 10 vs. 25). It
seems most likely that the substrate binds to the Rh center in
a chelating fashion, so that the catalyst can differentiate the
enantiotopic faces of the alkene on the basis of the orientation
of the carboxylic group.[8] In this way, both enantiomers of the
chiral b,b-diarylpropionic acids can be easily accessed in high
optical purity by hydrogenating the E or Z substrates using
the same catalyst. Finally, the asymmetric hydrogenation of
(E)-1p proceeded smoothly at a reduced catalyst loading
(0.2 mol% Rh) to afford the corresponding product 2p, a key
intermediate for the synthesis of bioactive (+)-indatraline,[19]
in excellent yield (98%) with high enantioselectivity (93%
ee) after 24 h (entry 26).
Entry Substrate Ar1
Ar2
Product ee [%]
1
2
3
4
5
6
7
(E)-1a
(E)-1b
(E)-1c
(E)-1d
(E)-1e
(E)-1 f
(E)-1g
(E)-1h
(E)-1i
4-MeC6H4
4-MeOC6H4
4-OHC6H4
4-FC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
95(+)
96(+)
94(+)
94(+)
94(+)
94(R)
94(+)
94(+)
91(R)
85(R)
92(R)
95(+)
94(R)
93(+)
4-ClC6H4
4-BrC6H4
4-CF3C6H4
3-FC6H4
2-FC6H4
2-ClC6H4
2-MeOC6H4
2-BnOC6H4
2,4-(MeO)2C6H3 Ph
2-MeO-5-
MeC6H4
3,4-
8
9[b]
10[b] (E)-1j
11[b] (E)-1k
12[c] (E)-1l
13[b] (E)-1m
14[b] (E)-1n
Ph
15[d] (E)-1o
Ph
2o
96(+)
(OCH2O)C6H3
3,4-Cl2C6H3
3,5-F2C6H3
2-naphthyl
4-BnOC6H4
16
17
(E)-1p
(E)-1q
Ph
Ph
Ph
3-MeO-4-
BnOC6H3
3,4,5-
2p
2q
2r
93(R)
92(+)
95(À)
94(+)
18[d] (E)-1r
19[c] (Z)-1s
2s
20[e] (Z)-1t
4-MeOC6H4
2t
96(+)
(MeO)3C6H2
2-furyl
Me
4-MeC6H4
2-FC6H4
2-ClC6H4
Ph
21
22
23
(Z)-1u
(E)-1v
(Z)-1a
Ph
Ph
Ph
Ph
2u
2v
2a
2i
2j
2p
92(+)
91(S)
95(À)
96(S)
96(S)
93(R)
24[b] (Z)-1i
25[b] (Z)-1j
26[f] (E)-1p
Ph
3,4-Cl2C6H3
The synthetic utility of the present method was further
demonstrated in the asymmetric synthesis of intermediates
for the natural products (R)-(+)-4-methoxydalbergione[20]
and (S)-cherylline,[1d] as well as an anti-viral (smallpox)
agent (À)-6,[21] with the hydrogenation products (R)-2m,
(S)-2s, and (+)-2t, respectively, as the starting materials
(Scheme 1). Reduction of (R)-2m with LiAlH4 at room
[a] Reaction conditions: [Rh(cod)2]BF4/L/Px (1:2:1, 1 mol%), morpho-
line (10 mol%), (E)-1a (0.25 mmol), iPrOH/H2O (3 mL, 5:1). The
conversion was >99% for all substrates. The ee values of the products
were determined by HPLC analysis on a chiral stationary phase after
esterification with CH2N2. [b] Morpholine (20 mol%). [c] An additional
THF (2.5 mL), catalyst (2 mol%), and morpholine (100 mol%) and H2
(50 atm) were added. [d] An additional THF (0.5 mL) and morpholine
(100 mol%) were added. [e] An additional THF (0.5 mL), morpholine
(100 mol%), and H2 (50 atm) were added. [f] Conditions: (E)-1p
(0.17m, 0.2 mol%), H2 (50 atm), 24 h. 2p was isolated in 98% yield.
Bn=benzyl.
tion of (E)-1a in terms of reactivity and enantioselectivity. As
L3 was found to be more resistant to water hydrolysis than L2,
the hetercombination of L3 and P1 was chosen as the ligand
system for the further study.
With these results in hand, the hydrogenation of various
b,b-diarylacrylic acids (1a–1v) was studied using [Rh-
(cod)2]BF4/L3/PPh3 (1:2:1) as the catalyst and morpholine
as the base (Table 3). The catalyst system proved to be quite
versatile; the reactions of all substrates, irrespective of their
configurations or the stereoelectronic nature of the 3,3-
substituents, proceeded smoothly to afford full conversions of
substrates, and the enantioselectivities were generally excel-
lent (91–96% ee). The only exception was the reaction
involving (E)-1j, wherein a slightly lower ee value (85%) was
obtained (entry 10). Notably, substrate (E)-1c, with a free OH
Scheme 1. Asymmetric syntheses of a) (R)-(+)-4-methoxydalbergione,
b) (S)-cherylline, and c) anti-viral agent (À)-6 starting from the hydro-
genation products (R)-2m, (S)-2s, and (+)-2t. AIBN=azobisisobutyr-
onitrile, Bn=benzyl, Boc=tert-butoxycarbonyl, DMAP=dimethylami-
nopyridine, DPPA=diphenylphosphoryl azide.
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temperature gave (R)-3 in 76% yield with 92% ee, which has
been used as a key intermediate for the preparation of (R)-
(+)-4-methoxydalbergione (Scheme 1a).[22] Treatment of (S)-
2s with diphenylphosphoryl azide (DPPA) in the presence of
triethylamine, followed by cyclization/reductive amination
using aqueous formaldehyde and formic acid in one pot,
afforded a good yield of highly enantioenriched (S)-4, which
can be readily transformed into (S)-cherylline after debenzy-
lation (Scheme 1b).[23] Finally, esterification of (+)-2t with
benzotriazine 5 and subsequent decarboxylation with tribu-
tylstannane led to the formation of (À)-6 in 47% overall yield
without loss of optical purity (95% ee) (Scheme 1c).
To shed some light on the mechanism of the hydro-
genation reaction, a deuterium-labeling study was performed
for the [Rh(cod)2]BF4/L3/PPh3 (1:2:1) catalyzed reaction of
(E)-1a, using D2 in iPrOH/H2O (5:1) or H2 in
[D8]isopropanol/D2O (5:1) (Scheme 2a and b). In both
diarylpropionic acids can be accessed in high enantiopurity
using the same catalyst by simply switching the E and
Z substrates for hydrogenation. This method has provided
a facile approach for the concise synthesis of a variety of
biologically important natural and non-natural products.
Further studies to explore the mechanism of this asymmetric
reaction, and extend the method to other catalytic reactions
are undergoing in this lab.
Received: March 20, 2013
Published online: && &&, &&&&
Keywords: asymmetric catalysis · combinatorial chemistry ·
.
hydrogenation · rhodium · secondary phosphine oxides
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Scheme 2. Deuterium-labeling studies.
cases, deuterium atoms were found to be partially incorpo-
rated into both the a and b positions of the product in similar
ratios, respectively, indicating the existence of H/D exchange
À
À
between the Rh H (Rh D) species and the solvent, in which
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À
a heterolytic cleavage of the O D bond of the solvent with
the assistance of the OH group of the ligand might be
involved.[24] Such a deuterium distribution pattern also
strongly supports a hydrogenolysis mechanism instead of
a protonlysis mechanism in the product-yielding step. Fur-
thermore, preliminary 31P NMR studies (Supporting Infor-
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mation, Figure S4) indicated the exclusive formation of
a homo-ligand [Rh(L3)2] species (d = 121.3 ppm, JRh-P
1
=
253.6 Hz) in the original Rh/L3 (1:1 or 1:2) system that,
upon the introduction of PPh3 and water, partially evolved
into a minor amount of hetero-ligand species [Rh(L3)(PPh3)],
which might be responsible for the catalysis. Finally, a trial
using a phosphite analogue of L3 (methyl-capped OH group;
Figure S5) for the hydrogenation of (E)-1a under the other-
wise identical conditions as above yielded significantly
inferior results (63% conversion and 44% ee), which suggests
that the free OH group in the ligand should be favorable for
the reaction.
In conclusion, we have developed a highly versatile and
enantioselective RhI-catalyzed asymmetric hydrogenation of
b,b-diarylacrylic acids with sterically similar diaryl groups at
the stereogenic center using a mixed-ligand approach that
affords a variety of enantioenriched b,b-diarylpropionic acids
in high optical purities. Both enantiomers of the chiral b,b-
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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