Enantioselective hydrogenation of α-aryloxy and α-alkoxy α,β-unsaturated carboxylic acids catalyzed by chiral spiro iridium/phosphino-oxazoline complexes

Article abstract of DOI:10.1021/ja909810k

The iridium-catalyzed highly enantioselective hydrogenation of α-aryloxy and α-alkoxy-substituted α,β-unsaturated carboxylic acids was developed. By using chiral spiro phosphino-oxazoline ligands, the hydrogenation proceeded smoothly to produce various α-aryloxy- and α-alkoxy-substituted carboxylic acids with extremely high enantioselectivities (ee up to 99.8%) and reactivities (TON up to 10 000) under mild conditions. The hydrogenation of R-benzyloxy-substituted α,β-unsaturated acids provided an efficient alternative for the synthesis of chiral R-hydroxy acids after an easy deprotection. A mechanism involving a catalytic cycle between IrI and IrIII was proposed on the basis of the coordination model of the unsaturated acids with the iridium metal center. The rationality of the catalytic cycle, with an olefin dihydride complex as the key intermediate, was supported by the deuterium-labeling studies. The X-ray diffraction analysis of the single crystal of catalyst revealed that the rigid and sterically hindered chiral environment created by the spiro phosphino-oxazoline ligands is the essential factor that permits the catalyst to obtain excellent chiral discrimination. A chiral induction model was suggested on the basis of the catalyst structure and the product configuration.

Full text of DOI:10.1021/ja909810k

Published on Web 01/04/2010
Enantioselective Hydrogenation of r-Aryloxy and r-Alkoxy
r,ꢀ-Unsaturated Carboxylic Acids Catalyzed by Chiral Spiro
Iridium/Phosphino-Oxazoline Complexes
Shen Li, Shou-Fei Zhu, Jian-Hua Xie, Song Song, Can-Ming Zhang, and
Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai UniVersity,
Tianjin 300071, China
Received November 19, 2009; E-mail: qlzhou@nankai.edu.cn
Abstract: The iridium-catalyzed highly enantioselective hydrogenation of R-aryloxy and R-alkoxy-substituted
R,ꢀ-unsaturated carboxylic acids was developed. By using chiral spiro phosphino-oxazoline ligands, the
hydrogenation proceeded smoothly to produce various R-aryloxy- and R-alkoxy-substituted carboxylic acids
with extremely high enantioselectivities (ee up to 99.8%) and reactivities (TON up to 10 000) under mild
conditions. The hydrogenation of R-benzyloxy-substituted R,ꢀ-unsaturated acids provided an efficient
alternative for the synthesis of chiral R-hydroxy acids after an easy deprotection. A mechanism involving
a catalytic cycle between IrI and IrIII was proposed on the basis of the coordination model of the unsaturated
acids with the iridium metal center. The rationality of the catalytic cycle, with an olefin dihydride complex
as the key intermediate, was supported by the deuterium-labeling studies. The X-ray diffraction analysis of
the single crystal of catalyst revealed that the rigid and sterically hindered chiral environment created by
the spiro phosphino-oxazoline ligands is the essential factor that permits the catalyst to obtain excellent
chiral discrimination. A chiral induction model was suggested on the basis of the catalyst structure and the
product configuration.
Introduction
inhibitors. Figure 1 shows selected examples of bioactive
compounds containing chiral R-oxy-functionalized carboxylic
Optically active R-oxy-functionalized carboxylic acids are an
important class of building blocks for asymmetric synthesis in
pharmaceutical and agrochemical industries and for total
synthesis of natural products.1 For example, the R-aryloxy
propionic acids exhibit significant biological properties as crop
protection reagents.2 (R)-R-(p-Chlorophenoxy)butyric acids pos-
sess antiplatelet activities.3 Many R-aryloxy and R-alkoxy
dihydrocinnamic acid derivatives, including Ertiprotafib, Tesa-
glitazar, and Aleglitazar, have attracted considerable attention
as potential agonists against peroxisome proliferator-activated
receptors (PPARs) in the treatment of type 2 diabetes and
dyslipidemia,4 and several compounds of this class are now in
various stages of development. The chiral ꢀ-phenyllactic acid
derivatives, such as Aeruginosins,5 are important parts of
bioactive peptides, which have been shown to be potent protease
acids.
Transition metal-catalyzed asymmetric hydrogenation of
R-aryloxy- or R-alkoxy-substituted R,ꢀ-unsaturated acids, which
are easily prepared from readily available starting materials,
represents one of the most atom-economic and efficient methods
for the synthesis of chiral R-oxy-functionalized carboxylic acids.
Over the past decades, significant progress has been achieved
in the catalytic asymmetric hydrogenation of a wide range of
unsaturated substrates.6 A variety of efficient chiral rhodium
and ruthenium complexes have been developed for the hydro-
genation of R-aryl- or R-alkyl-substituted R,ꢀ-unsaturated acids
with excellent activities and enantioselectivities.7 However,
highly efficient catalysts for the asymmetric hydrogenation of
R-aryloxy- or R-alkoxy-substituted R,ꢀ-unsaturated acids, a
(4) (a) Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B. R.
J. Med. Chem. 2000, 43, 527–550. (b) Liu, K. G.; Smith, J. S.; Ayscue,
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J.-G. WO2005108352, 2005. (e) Shrestha, S.; Bhattarai, B. R.; Cho,
H.; Choi, J.-K.; Cho, H. Bioorg. Med. Chem. Lett. 2007, 17, 2728–
2730.
(1) (a) Hanessian, S. Total Synthesis of Natural Products: The Chiron
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H. F. a-Hydroxy Acids in EnantioselectiVe Syntheses; John Wiley &
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Catalysis on Industrial Scale: Challenges, Approaches and Solutions;
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Warrant, G. W. Weed Technol. 1991, 5, 826–833. (c) Kikuo, A.;
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1172 J. AM. CHEM. SOC. 2010, 132, 1172–1179
10.1021/ja909810k  2010 American Chemical Society

R-Aryloxy and R-Alkoxy R,ꢀ-Unsaturated Carboxylic Acids
A R T I C L E S
Figure 1. Selected bioactive compounds derived from chiral R-aryloxy or alkoxy carboxylic acids.
Scheme 1
reaction which has great potential for wide application in organic
synthesis, are limited. In 2004, Maligres and Krska8 reported
the first highly enantioselective hydrogenation of R-aryloxy
crotonic acids using ruthenium-BINAP complexes as catalysts.
However, this reaction required high catalyst loading for some
substrates. Shortly thereafter, we demonstrated that the ruthe-
nium diacetate complexes ligated by chiral spiro diphosphine
ligands SFDP were highly efficient catalysts for the hydrogena-
tion of R-aryloxy crotonic acid derivatives.9 The R-aryloxy
saturated acids were obtained in up to 95% ee at a mole ratio
of substrate to catalyst (S/C) of 200. However, when this
procedure was extended to the hydrogenation of R-methoxy
cinnamic acids, this catalyst only afforded a moderate enanti-
oselectivity. Houpis and co-workers10 screened more than 250
catalysts and conditions in the asymmetric hydrogenation of
R-ethoxy cinnamic acid, and finally obtained 92% ee by using
Rh-Walphos catalyst. Puentener et al.11 reported that the chiral
Rh-catalyzed hydrogenation of R-ethoxy cinnamic acids. Wol-
tering et al.13 also investigated the asymmetric hydrogenation
of R-alkoxy cinnamic acids by using rhodium, ruthenium, and
iridium complexes of diphosphine ligands as catalysts; however,
the catalyst activity and enantioselectivity (e90% ee) were
unsatisfactory. Although tremendous efforts have been devoted
in this field, none of the present chiral catalysts gave acceptable
results for the asymmetric hydrogenations of both R-aryloxy-
and R-alkyloxy-substituted R,ꢀ-unsaturated acids. Moreover, the
catalytic asymmetric hydrogenation of R-aryloxy-substituted
cinnamic acids has not been documented yet.
ruthenium/diphosphine complex ((S)-TMBTP)Ru(OAc)2 was an
efficient catalyst for the hydrogenation of R-methoxy cinnamic
acid with high enantioselectivities (up to 94% ee). Chen and
McCormack and colleagues12 used a new ferrocene-based
diphosphine ligand Trifer and obtained up to 98% ee in the
(7) For representative examples, see: (a) Ohta, T.; Takaya, H.; Kitamura,
M.; Nagai, K.; Noyori, R. J. Org. Chem. 1987, 52, 3174–3176. (b)
Uemura, T.; Zhang, X.; Matsumura, K.; Sayo, N.; Kumobayashi, H.;
Ohta, T.; Nozaki, K.; Takaya, H. J. Org. Chem. 1996, 61, 5510–5516.
(c) Yamada, I.; Yamaguchi, M.; Yamagishi, T. Tetrahedron: Asym-
metry 1996, 7, 3339–3342. (d) Benincori, T.; Cesarotti, E.; Piccolo,
O.; Sannicolo`, F. J. Org. Chem. 2000, 65, 2043–2047. (e) Pai, C.-C.;
Lin, C.-W.; Lin, C.-C.; Chen, C.-C.; Chan, A. S. C.; Wong, W. T.
J. Am. Chem. Soc. 2000, 122, 11513–11514. (f) Sturm, T.; Weissen-
steiner, W.; Spindler, F. AdV. Synth. Catal. 2003, 345, 160–164. (g)
Cheng, X.; Zhang, Q.; Xie, J.-H.; Wang, L.-X.; Zhou, Q.-L. Angew.
Chem., Int. Ed. 2005, 44, 1118–1121. (h) Co, T. T.; Shim, S. C.; Cho,
C. S.; Kim, T.-J.; Kang, S. O.; Han, W.-S.; Ko, J.; Kim, C.-K.
Organometallics 2005, 24, 4824–4831. (i) 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, 4209–4212. (j) Scrivanti, A.; Bovo, S.;
Ciappa, A.; Matteoli, U. Tetrahedron Lett. 2006, 47, 9261–9265. (k)
Qiu, L.; Li, Y.-M.; Kwong, F. Y.; Yu, W.-Y.; Fan, Q.-H.; Chan,
A. S. C. AdV. Synth. Catal. 2007, 349, 517–520.
Since Pfaltz and co-workers14 developed chiral analogues of
Crabtree’s catalyst (abbreviated as Ir-PHOX, Scheme 1), such
cationic iridium catalysts have been extensively studied in the
asymmetric hydrogenations of unfunctionalized olefins, imines,
and heteroaromatic compounds,15 although they were long
neglected in the hydrogenation of functionalized olefins.16 Very
recently, we reported a highly enantioselective hydrogenation
of R-alkyl R,ꢀ-unsaturated carboxylic acids catalyzed by Ir/chiral
spiro phosphino-oxazoline (abbreviated as Ir-SIPHOX, Scheme
1, 1a-f) cationic complexes.17 The extremely high activities,
(8) Maligres, P. E.; Krska, S. W.; Humphrey, G. R. Org. Lett. 2004, 6,
3147–3150.
(13) Woltering, M.; Bunlaksananusorn, T.; Gerlach, A. EP1801093,
2007.
(9) Cheng, X.; Xie, J.-H.; Li, S.; Zhou, Q.-L. AdV. Synth. Catal. 2006,
348, 1271–1276.
(14) Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402–1411.
(15) (a) Blaser, H.-U. AdV. Synth. Catal. 2002, 344, 17–31. (b) Cui, X.;
Burgess, K. Chem. ReV. 2005, 105, 3272–3296. (c) Zhou, Y.-G. Acc.
Chem. Res. 2007, 40, 1357–1366. (d) Church, T. L.; Andersson, P. G.
Coord. Chem. ReV. 2008, 252, 513–531. (e) Zhu, S.-F.; Xie, J.-B.;
Zhang, Y.-Z.; Li, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128, 12886–
12891.
(10) Houpis, I. N.; Patterson, L. E.; Alt, C. A.; Rizzo, J. R.; Zhang, T. Y.;
Haurez, M. Org. Lett. 2005, 7, 1947–1950.
(11) Puentener, K.; Scalone, M. US 2005070714, 2005.
(12) Chen, W.; McCormack, P. J.; Mohammed, K.; Mbafor, W.; Roberts,
S. M.; Whittall, J. Angew. Chem., Int. Ed. 2007, 46, 4141–4144.
9
J. AM. CHEM. SOC. VOL. 132, NO. 3, 2010 1173

A R T I C L E S
Li et al.
Scheme 2
Table 1. Asymmetric Hydrogenation of R-Phenoxy Crotonic Acid
with Iridium Complexesa
enantioselectivities, broad substrate scope, and mild reaction
conditions demonstrated that Ir-SIPHOXs were excellent
catalysts for the hydrogenations of R,ꢀ-unsaturated carboxylic
acids. Therefore, we envisioned that the introduction of various
R-aryloxy and R-alkoxy substituents into R,ꢀ-unsaturated acids
would extend the scope of this practically useful hydrogenation.
In this article, we report a detailed investigation on the
asymmetric hydrogenation of R-aryloxy- and R-alkoxy-substi-
tuted R,ꢀ-unsaturated acids using Ir-SIPHOX catalysts. Under
very mild conditions, a broad range of R-aryloxy- and R-alkoxy-
substituted R,ꢀ-unsaturated acids were hydrogenated with
unprecedented enantioselectivities (up to 99.8% ee) at high
reactivities (TON up to 10 000). This procedure provided a facile
access to a variety of optically active R-oxy-functionalized
carboxylic acids.
entry
[Ir]
additive
time (h)
conv (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
(Sa,S)-1a
(Ra,S)-1a
(Sa,S)-1b
(Sa,S)-1c
(Sa,S)-1d
(Sa,S)-1e
(Sa)-1f
Ir-PHOX
(Ra)-2
(Sa,S)-1c
(Sa,S)-1c
(Sa,S)-1c
(Sa,S)-1c
(Sa,S)-1c
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
24
24
24
24
24
24
24
24
24
10
24
24
24
24
25
0
79
30
95
100
90
75
0
15
100
<5
15
65
60
64
98
89
98
95
79
99.2 (S)
10d
11d
12d
13d
14d
Results and Discussion
NEt3
Na2CO3
K2CO3
95
97
96
Synthesis of the r,ꢀ-Unsaturated Carboxylic Acids. The
R-aryloxy- or R-alkoxy-substituted crotonic acid derivatives
3a-j8,9 and 7p-q18 were prepared in good yields according to
the literature procedures. The R-oxy-functionalized cinnamic
acids 5a-p, 7a-o, and 9a-j were prepared by using the aldol
reaction of 2-aryloxy or 2-alkoxy acetates with appropriate
aldehydes, followed by dehydroxylation with benzenesulfonyl
chloride and triethylamine. The hydrolysis of the resulting
unsaturated esters afforded unsaturated acids as (Z)-isomers in
moderate to good yields (Scheme 2). So as not to introduce
impurity to the catalytic hydrogenation reaction, the unsaturated
acids were further purified by recrystallization from petroleum
ether/ethyl acetate (unoptimized solvent) until 99% pure.
Asymmetric Hydrogenation of r-Aryloxy Crotonic Acid
Derivatives. To examine the catalytic capability of Ir-SIPHOX
complexes (1) in the hydrogenation of R-oxy-functionalized
unsaturated acids, we chose R-phenoxy crotonic acid (3a) as
the model substrate. The hydrogenation was initially performed
a Reaction conditions: 0.5 mmol scale, [substrate] ) 0.25 mol L-1 in
MeOH, S/C ) 200, 0.5 equiv of Cs2CO3 as additive, PH2 ) 6 atm, room
b
temperature. Determined by H NMR analysis. c Determined by HPLC
1
analysis of the respective anilide with
a chiral column (see the
Supporting Information); absolute configuration was determined by
comparison of optical rotation with literature date.8 d Carried out at 40
°C.
at a substrate to catalyst mole ratio (S/C) of 200 in MeOH under
6 atm of H2 at room temperature for 24 h, with 0.5 equiv of
Cs2CO3 as an additive. By using catalyst (Sa,S)-1a, the reaction
proceeded with 25% conversion, afforded the hydrogenation
product in 79% ee (Table 1, entry 1). The inefficiency of catalyst
(Ra,S)-1a (entry 2) revealed that it has mismatched configura-
tions. Next, we studied the catalysts with various substituent
groups on the P-phenyl rings of the catalysts and found that
only the catalysts with 3,5-di-tert-butyl substituents afforded
both high activity and high enantioselectivity (Table 1, entries
4-7). This result implied that the sterically hindered P-aryl
group is a necessary factor for achieving good results. Further
comparison of the substituents on the oxazoline ring of the
catalyst showed that the (Sa,S)-1c was the most efficient catalyst,
providing the hydrogenation product 4a in 98% ee (Table 1,
entry 4). In contrast, other types of P,N-ligated chiral Ir
complexes, such as Ir-PHOX and (Ra)-2, were incapable of
this hydrogenation reaction (conversion e15%). Interestingly,
increasing the reaction temperature from room temperature to
40 °C significantly accelerated the hydrogenation rate, leading
(16) The asymmetric hydrogenation of 2-phenethylacrylic acid catalyzed
by Ir-PHOX has been tried with moderate enantioselectivity. See:
Scrivanti, A.; Bovo, S.; Ciappa, A.; Matteoli, U. Tetrahedron Lett.
2006, 47, 9261–9265. The iridium-catalyzed asymmetric hydrogenation
of tiglic acid was also reported with modest enantioselectivity. See:
Zhou, J.; Ogle, J. W.; Fan, Y.; Banphavichit, V.; Zhu, Y.; Burgess,
K. Chem.-Eur. J. 2007, 13, 7162–7170.
(17) Li, S.; Zhu, S.-F.; Zhang, C.-M.; Song, S.; Zhou, Q.-L. J. Am. Chem.
Soc. 2008, 130, 8584–8585.
(18) (a) Pfister, K.; Robinson, C. A.; Tishler, M. J. Am. Chem. Soc. 1945,
67, 2269. (b) Seifert, P.; Vogel, E.; Rossi, A.; Schinz, H. HelV. Chim.
Acta 1950, 33, 725–736.
9
1174 J. AM. CHEM. SOC. VOL. 132, NO. 3, 2010

R-Aryloxy and R-Alkoxy R,ꢀ-Unsaturated Carboxylic Acids
A R T I C L E S
Table 2. Asymmetric Hydrogenation of R-Aryloxy Crotonic Acidsa
Table 3. Asymmetric Hydrogenation of R-Aryloxy Cinnamic Acidsa
entry substrate
R
Ar
S/C time (h) yield (%)
ee (%)
entry substrate
Ar1
Ar2
time (h) yield (%)
ee (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
Me C6H5
200
200
100
100
200
10
18
24
24
10
18
4
18
18
24
95
93
91
88
92
94
93
92
94
95
99.2 (S)
98 (S)
96 (S)
89 (S)
99.5 (S)
97 (S)
99.7
98 (S)
97 (S)
83 (S)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
C6H5
C6H5
C6H5
C6H5
C6H5
8
18
15
8
95
89
92
91
94
93
93
91
94
96
91
92
93
98
92
94
99.6
Me 3-CH3C6H4
Me 3-BrC6H4
Me 3,5-F2C6H3
Me 4-CH3C6H4
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
99.5
99.5
99.5
99.8 (S)
99.1 (S)
99.8
99.7
99.8
99.6
99.4
99.7
99
4-CH3OC6H4 C6H5
8
Me 4-tert-BuC6H4 200
4-ClC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
18
24
8
10
14
16
1
1
18
2
Me 4-MeOC6H4
Me 4-ClC6H4
Me 2-naphthyl
200
100
200
200
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
3-CH3OC6H4
4-CH3OC6H4
3-CF3C6H4
9
10b
3j
H
C6H5
a Reaction conditions and analysis are the same as those in Table 1,
entry 10. Full conversions were obtained for all reactions. b By using
catalyst (Sa)-1f.
4-CF3C6H4
naphthalen-1-yl
naphthalen-2-yl
furan-2-yl
99.4
99.2
99
to a complete reaction within 10 h and a higher enantioselectivity
using catalyst (Sa,S)-1c (99.2% ee, Table 1, entry 10). Because
no racemization of the hydrogenation product was observed
under the reaction conditions, we believe that the relative high
temperature shorted the reaction time, and thus reduced the
chance of the catalyst decomposition, which may enhance
enantioselectivity of reaction. It is worth mentioning that without
adding basic additives the hydrogenation could hardly occur
(Table 1, entry 11). A comparison of different basic additives
under the optimal conditions established that Cs2CO3 was the
most suitable base for achieving high conversion and high
enantioselectivity.
Under the optimal reaction conditions, the hydrogenations
of different R-aryloxy crotonic acids 3a-i were examined, and
good to excellent enantioselectivities were obtained. Both steric
and electronic properties of the aryl groups of the substrates
have a great impact on the reactivity (Table 2). When a
substituent existed at the ortho position of the phenyl ring, the
substrate could not be completely hydrogenated, even using 2
mol % catalyst (S/C ) 50, data not shown). Conversely, all of
the substrates having meta or para substituents on the phenyl
rings gave full conversions within 24 h. A higher catalyst loading
(1 mol %) was needed when an electron-withdrawing group
was introduced into the phenyl ring, but it did not have an
obvious influence on enantioselectivity (Table 2, entries 3 and
8). An exceptional example was the substrate 3d having two
meta-fluoro groups on the phenyl ring, which provided a lower
enantioselectivity (89% ee, Table 2, entry 4). The hydrogenation
of R-aryloxy acrylic acid (3j) was also investigated by using
catalyst (Sa)-1f; the corresponding product was obtained in 83%
ee. Increasing the size of ꢀ-substituent to ethyl (R ) Et)
seriously inhibited the reaction and led to only a trace amount
of hydrogenation product (data not shown).
10
a Reaction conditions and analysis are the same as those in Table 1,
entry 10. Full conversions were obtained for all reactions.
(Table 3). Similarly, the substrates with ortho substituents on
Ar1 or Ar2 needed a longer reaction time in the hydrogenation
of R-aryloxy cinnamic acid derivatives (Table 3, entries 2 and
7). It is interesting that the electronic effects of substituents were
opposite for Ar1 and Ar2. When an electron-withdrawing group
was introduced into Ar1, the hydrogenation became slower
(Table 3, entry 6), while an electron-withdrawing group on Ar2
accelerated the reaction (Table 3, entries 12 and 13). The
unsaturated acids with a naphthyl or furanyl at the ꢀ-position
(5n-5p) were also suitable substrates for the hydrogenation,
affording the corresponding saturated carboxylic acids in high
yields and excellent enantioselectivities (Table 3, entries 14-16).
Asymmetric Hydrogenation of r-Alkoxy r,ꢀ-Unsaturated
Carboxylic Acids. Chiral R-alkoxy carboxylic acid derivatives
have received increasing attention due to their successful utility
as starting materials for the asymmetric synthesis of a series of
PPARs agonists.4 Mild and practical methods for the preparation
of these compounds are still highly sought after.19 When we
applied our Ir-SIPHOXs catalysts in the hydrogenation of
R-alkoxy cinnamic acid derivatives, we found all of the catalysts
(Sa,S)-1c-1f bearing 3,5-di-tert-butylphenyl groups on the P
atom, but with different substituents on the oxazoline rings,
showed essentially the same catalytic capabilities. Under the
optimal reaction conditions, all of these catalysts afforded
excellent enantioselectivities (97-99.3% ee) at 0.25 mol %
catalyst loading (S/C ) 400) (Table 4). Among the tested
catalysts, (Sa,S)-1e containing a methyl group on the oxazoline
ring gave the best results in terms of activity and enantioselec-
tivity (Table 4, entry 5).
Asymmetric Hydrogenation of r-Aryloxy Cinnamic Acids.
Encouraged by the successful hydrogenation of R-aryloxy
crotonic acids 3, we then applied catalyst (Sa,S)-1c to the
hydrogenation of R-aryloxy cinnamic acid derivatives. Although
chiral R-aryloxy dihydrocinnamic acid derivatives are important
chiral building blocks in organic synthesis, the asymmetric
hydrogenation of related prochiral R,ꢀ-unsaturated acids remains
undeveloped. We observed that the hydrogenation of R-aryloxy
cinnamic acid derivatives 5 proceeded smoothly under the
standard conditions. Full conversions were achieved at S/C ratio
of 200 with extremely high enantioselectivities (99-99.8% ee)
A variety of R-methoxy cinnamic acid derivatives 7a-o can
be hydrogenated by catalyst (Sa,S)-1e with full conversions and
excellent enantioselectivities (>99% ee) regardless of the steric
and electronic properties of the substituents on the phenyl ring
(19) (a) Deussen, H.-J.; Zundel, M.; Valdois, M.; Lehmann, S. V.; Weil,
W.; Hjort, C. M.; Østergaard, P. R.; Marcussen, E.; Ebdrup, S. Org.
Process Res. DeV. 2003, 7, 82–88. (b) Linderberg, M. T.; Moge, M.;
Sivadasan, S. Org. Process Res. DeV. 2004, 8, 838–845. (c) Aikins,
J. A.; Haurez, M.; Rizzo, J. R.; Van Hoeck, J.-P.; Brione, W.;
Kestemont, J.-P.; Stevens, C.; Lemair, X.; Stephenson, G. A.; Marlot,
E.; Forst, M.; Houpis, I. N. J. Org. Chem. 2005, 70, 4695–4705.
9
J. AM. CHEM. SOC. VOL. 132, NO. 3, 2010 1175

A R T I C L E S
Table 4. Asymmetric Hydrogenation of R-Alkoxy Cinnamic Acidsa b
Li et al.
,
for their synthesis are highly desired. On the basis of the success
in the hydrogenation of R-alkoxyl cinnamic acids, we envisioned
that the asymmetric hydrogenation of R-benzyloxy cinnamic
acids, followed by readily deprotection of the benzyl group,
would afford an efficient approach to the synthesis of chiral
R-hydroxy dihydrocinnamic acids. This strategy should be an
important complement to the asymmetric hydrogenation of
3-aryl-2-oxapropionic acids or esters21 and 2-acyloxy-3-ary-
lacrylate esters,22 which met the challenges of the substrate
availability, hydrogenation reactivity, as well as enantioselec-
tivity from the practical point of view. Thus, we performed the
hydrogenation of R-benzyloxy cinnamic acids under the optimal
conditions determined above. Fortunately, 9a was smoothly
hydrogenated to 10a with 99.7% ee in the presence of 0.25 mol
% of catalyst (Sa,S)-1e and 0.5 equiv of Cs2CO3 in methanol
under 6 atm H2 pressure at room temperature (Table 5, entry
1). The product 10a was easily deprotected by Pd/C under a
hydrogen atmosphere to generate R-hydroxy dihydrocinnamic
acid quantitatively without diminishing the optically purity (see
the Supporting Information for details). This methodology is
rather flexible and worked well with a broad scope of substrates
(Table 5, entries 1-10). Excellent enantioselectivities of higher
than 98% ee were achieved for all substrates, indicating a high
tolerance of the current reaction toward the pattern and electronic
properties of the substituents on the phenyl ring of the substrates.
As compared to other methods that led to R-hydroxy dihydro-
cinnamates such as asymmetric hydrogenation of R-ketoesters,21,23
this method has the advantages of substrate accessibility, high
activity and enantioselectivity, and mild reaction conditions.
(R)-3-(4-Fluorophenyl)-2-hydroxy propionic acid 11 is one
of the fragments of rupintrivir, a rhinovirus protease inhibitor
currently in human clinical trials to treat the common cold, and
is a basis for the design of anticoronaviral drugs.24 However,
only a few methods have been described for the synthesis of
this compound, and most of them are not suitable for a large-
scale preparation.23 To demonstrate the practical potential of
our strategy for the enantioselective synthesis of R-hydroxy
dihydrocinnamic acid derivatives, the asymmetric synthesis of
11 was studied with catalytic hydrogenation (Scheme 3). In the
hydrogenation of compound 9k, the catalyst (Ra)-1f was
employed to fit the configuration of the product. Impressively,
the saturated acid 10k was attained in 97% yield with over 99%
ee at a catalyst loading of 0.01 mol % (S/C ) 10 000).20 After
deprotection, (R)-3-(4-fluorophenyl)-2-hydroxy propionic acid
(11) was obtained in quantitative yield with no defluorination.
entry subst
R1
R2
[Ir]
time (h) yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
7a
7a
7a
7a
7a
7a
7b
7c
7d
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3 (Sa,S)-1a
CH3 (Sa,S)-1b
CH3 (Sa,S)-1c
CH3 (Sa,S)-1d
CH3 (Sa,S)-1e
CH3 (Sa)-1f
24
24
6
10
6
12
10
6
24
10
10
24
8
27c
27c
95
96
95
93
93
94
97
91
92
95
91
91
94
95
96
93
92
93
94
91
97
33 (S)
13 (S)
99.1 (S)
99 (S)
99.3 (S)
97 (S)
99.7
99.6
99.2
99.6
99.7
99.4
99.8
99.5
99.6
99.2
99.7
99.8
99.7
2-CH3C6H4
4-CH3C6H4
2-CH3OC6H4 CH3 (Sa,S)-1e
3-CH3OC6H4 CH3 (Sa,S)-1e
4-CH3OC6H4 CH3 (Sa,S)-1e
2-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-CF3C6H4
4-NO2C6H4
CH3 (Sa,S)-1e
CH3 (Sa,S)-1e
10 7e
11 7f
12 7g
13 7h
14 7i
15 7j
16 7k
17 7l
CH3 (Sa,S)-1e
CH3 (Sa,S)-1e
CH3 (Sa,S)-1e
CH3 (Sa,S)-1e
CH3 (Sa,S)-1e
CH3 (Sa,S)-1e
CH3 (Sa,S)-1e
C2H5 (Sa,S)-1e
C2H5 (Sa,S)-1e
C2H5 (Sa)-1f
24
6
6
4
18 7m 2-naphthyl
10
10
16
18
6
19 7n
20 7o
21d 7o
22 7p
23e 7q
C6H5
4-BnOC6H4
4-BnOC6H4
CH3
99.5 (S)
99.2 (S)
99
CH3 (Sa,S)-1e
CH3 (Sa,S)-1e
C2H5
20
95
a Reaction conditions: 0.5 mmol scale, [substrate] ) 0.25 mol L-1 in
MeOH, S/C ) 400, 0.5 equiv of Cs2CO3 as additive, PH2 ) 6 atm, room
temperature. b Analysis is the same as that in Table 1, entry 10. Full
conversions were obtained for all cases except entries
1 and 2.
c Conversion. d S/C ) 6000, 2 equiv of NEt3 as additive, 90 °C. e S/C )
50.
of the substrates (Table 4, entries 7-20). The catalyst (Sa,S)-1e
was also sensitive to the ortho-substituent on the phenyl rings
of substrates 7, as indicated by the lowered reaction rate (Table
4, entries 7, 9, 12, and 14). Changing the alkoxy group from
methoxy to ethoxy did not affect the activity and enantioselec-
tivity (Table 4, entry 19 vs entry 5). Encouraged by this
promising result, we investigated the enantioselective hydro-
genation of R-ethoxy cinnamic acid derivative 7o. The product
of this reaction is a key intermediate in the synthesis of potential
PPARs agonist for the treatment of type 2 diabetes and
dyslipidemia.10 Gratifyingly, (Sa,S)-1e showed a good catalytic
efficiency in the asymmetric hydrogenation of 7o and gave the
desired product 8o in 93% yield with an unprecedented 99.5%
ee (Table 4, entry 20). Further investigation indicated that the
catalysts Ir-SIPHOX allowed the reaction to be performed at
a very low catalyst loading (S/C ) 6000) without compromising
the enantioselectivity.20 This result represents the highest levels
of enantioselectivity and efficiency in the asymmetric hydro-
genation of R-alkoxy cinnamic acid derivatives so far reported
(Table 4, entry 21).10-13 Catalyst (Sa,S)-1e was also found to
be the suitable catalyst for asymmetric hydrogenation of
R-methoxy crotonic acid 7p and its homologue 7q. In both cases,
the corresponding saturated acids were obtained in high enan-
tioselectivities (Table 4, entries 22 and 23), although a much
higher catalyst loading was needed when a bulkier ethyl group
was introduced into the ꢀ-position of substrate.
Mechanism Consideration. The mechanism of hydrogenation
of unfunctionalized olefins by Crabtree’s catalyst and chiral
(20) In this reaction with high substrate concentration, the addition of 2
equiv of NEt3 can increase the solubility of unsaturated carboxylic
acids, besides act as a basic additive, while Cs2CO3 has no such effect.
(21) (a) Boaz, N. W.; Debenham, S. D. WO0226750, 2002. (b) Boaz, N. W.;
Mackenzie, E. B.; Debenham, S. D.; Large, S. E.; Ponasik, J. A. J.
Org. Chem. 2005, 70, 1872–1880. (c) Fujiwara, T.; Yokozawa, T.
US20070073065, 2007. (d) Amano, S.; Fujii, A.; Yamamoto, S.;
Mitsuda, M. WO 2008018520, 2008.
(22) (a) Burk, M. J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem. Soc. 1998,
120, 4345–4353. (b) Liu, Y.; Sandoval, C. A.; Yamaguchi, Y.; Zhang,
X.; Wang, Z.; Kato, K.; Ding, K. J. Am. Chem. Soc. 2006, 128, 14212–
14213.
(23) Tao, J.; McGee, K. Org. Process Res. DeV. 2002, 6, 520–524, and
references therein.
Asymmetric Hydrogenation of r-Benzyloxy Cinnamic Acid
Derivatives: An Alternative Route for Chiral r-Hydroxy Di-
hydrocinnamic Acids. Optically pure R-hydroxy dihydrocin-
namic acid derivatives are important intermediates in medicinal,
biological, and synthetic chemistry, and thus effective methods
(24) (a) Dragovich, P. S.; et al. J. Med. Chem. 1999, 42, 1213–1224. (b)
Zalman, L. S.; Brothers, M. A.; Dragovich, P. S.; Zhou, R.; Prins,
T. J.; Worland, S. T.; Patick, A. K. Antimicrob. Agents Chemother.
2000, 44, 1236–1241. (c) Anand, K.; Ziebuhr, J.; Wadhwani, P.;
Mesters, J. R.; Hilgenfeld, R. Science 2003, 300, 1763–1767.
9
1176 J. AM. CHEM. SOC. VOL. 132, NO. 3, 2010

R-Aryloxy and R-Alkoxy R,ꢀ-Unsaturated Carboxylic Acids
A R T I C L E S
Scheme 3
Table 5. Asymmetric Hydrogenation of R-Benzyloxy Cinnamic
Scheme 4
Acidsa
coordination of the acid group to the metal center of the catalyst
triggered the subsequent hydrogenation steps.
entry
substrate
Ar
time (h)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
9a
9b
9c
9d
9e
9f
9g
9h
9i
C6H5
4
10
6
6
12
3
5
2
2
6
96
93
90
93
91
96
95
95
93
92
99.7 (S)
99.7
99.6
99.8
99.2
99.5
99.4
98
On the basis of the results presented above, a mechanism
involving a catalytic cycling between IrI and IrIII was proposed
for Ir-SIPHOX-catalyzed hydrogenation of R,ꢀ-unsaturated
acids (Figure 2). Because the reactions cannot be completed
without basic additives (see Table 1, entry 11 and ref 17), we
speculated that the addition of base formed the carboxy anion,
which chelates to the iridium center of catalyst more easily than
the acid itself. The active catalyst is generated with the oxidative
addition of hydrogen to the catalyst precursor 1 to generate the
IrIII intermediate A, which undergoes the coordination by the
olefinic carboxy anion to form the complex B. The intramo-
lecular rearrangement of B gives the key olefin dihydride
intermediate C, which is the chiral discriminating step. Next,
the migratory insertion of hydride from the metal of the catalyst
to the double bond of the substrate leads to an alkyl hydride D.
Subsequently, the reductive elimination of the alkyl and the
hydride releases the product and yields the IrI complex E, which
then undergoes the oxidative addition with hydrogen to regener-
ate the IrIII intermediate A and accomplishes the catalytic cycle.
However, the Ir(III)/Ir(V) mechanism, although less likely,
cannot be completely excluded at this stage.
We also conducted a deuterium-labeling study to obtain
further information about the reaction mechanism. When
substrate 7a was treated with D2 in methanol catalyzed by (Sa,S)-
1e, deuterium atoms were detected at both R and ꢀ positions of
product in a similar ratio (54% and 58% respectively, Scheme
5, equation a). This trend was also observed in the reaction using
H2 in CD3OD (Scheme 5, equation b), indicating the existence
of H/D exchange between Ir-H and methanol.28 The similar
distribution of deuterium atoms at both R and ꢀ positions in
product clearly showed that an olefin dihydride intermediate
must be involved in the catalytic cycle. This distribution of
deuterium atoms also strongly supports a hydrogenolysis
mechanism, instead of a protonolysis mechanism in the product-
yielding step (Figure 2, from D to E). An analogous experiment
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
2-CH3OC6H4
3-CH3OC6H4
4-CH3OC6H4
3-CF3C6H4
4-CF3C6H4
2-naphthyl
99.5
99.8
10
9j
a Reaction conditions are the same as those for Table 4, entry 5. Full
conversions were obtained for all reactions.
analogues has been investigated for many years.25 Two different
catalytic cycles, IrI-IrIII and IrIII-IrV,27 have been proposed
26
on the basis of experimental and computational results. Both
cycles involved a key olefin dihydride complex, containing P,N-
ligands, two hydrides, and an olefin. The vacant site of the
complex can be coordinated with solvent or molecular H2, thus
generating two different catalytic cycles. If the prochiral olefin
contains an additional coordination group, six orbitals of the
iridium will be fully occupied, and thus the hydrogenation most
likely passes through the IrI-IrIII catalytic cycle. To learn more
details about the hydrogenation of unsaturated acids, we needed
to clarify whether the acid group, the part which is essentially
different from the unfunctionalized olefins, coordinates with
iridium during the catalytic cycle. As shown in Scheme 4, (Z)-
methyl 2-methoxy-3-phenylacrylate (12), a structural analogue
of 7a, was not able to undergo the hydrogenation under the
standard reaction conditions. This outcome implied that the acid
group plays a crucial role in the catalytic cycle and the
(25) For a review, see: Roseblade, S. J.; Pfaltz, A. C. R. Chimie 2007, 10,
178–187.
(26) (a) Crabtree, R. H.; Demou, P. C.; Eden, D.; Mihelic, J. M.; Parnell,
C. A.; Quirk, J. M.; Morris, G. E. J. Am. Chem. Soc. 1982, 104, 6994–
7001. (b) Mazet, C.; Smidt, S. P.; Meuwly, M.; Pfaltz, A. J. Am. Chem.
Soc. 2004, 126, 14176–14181. (c) Dietiker, R.; Chen, P. Angew. Chem.,
Int. Ed. 2004, 43, 5513–5516.
(27) (a) Brandt, P.; Hedberg, C.; Andersson, P. G. Chem. -Eur. J. 2003, 9,
339–347. (b) Fan, Y.; Cui, X.; Burgess, K.; Hall, M. B. J. Am. Chem.
Soc. 2004, 126, 16688–16689. (c) Cui, X.; Fan, Y.; Hall, M. B.;
Burgess, K. Chem.-Eur. J. 2005, 11, 6859–6868.
(28) (a) Albeniz, A. C.; Heinekey, D. M.; Crabtree, R. H. Inorg. Chem.
1991, 30, 3632–3635. (b) Jessop, P. G.; Morris, R. H. Coord. Chem.
ReV. 1992, 121, 155–284.
9
J. AM. CHEM. SOC. VOL. 132, NO. 3, 2010 1177

A R T I C L E S
Li et al.
Figure 2. Plausible mechanism for the Ir-SIPHOXs-catalyzed hydrogenation of R,ꢀ-unsaturated acids.
Figure 3. The crystal structure and model of catalyst (Sa,S)-1c (the hydrogen atoms, anion BArF-, and COD have been omitted for clarity).
with D2 in CD3OD was performed and stopped at 75%
conversion (Scheme 5, equation c). The product was quantita-
tively deuterium-labeled in the positions where double bonds
localized, and no deuterium was detected in the recovered
starting material. This result suggests that the migratory insertion
step in the catalytic cycle is irreversible (Figure 2, from C to
D).
Scheme 5. Deuterium-Labeling Studies
Enantiocontrol Model. To understand the chiral induction
model and stereochemistry in the asymmetric hydrogenation of
R,ꢀ-unsaturated carboxylic acids catalyzed by Ir-SIPHOX
complexes 1, we grew a single crystal of (Sa,S)-1c and performed
X-ray diffraction analysis.29 As shown in Figure 3, spiro
phosphino-oxazoline ligand created a rigid and sterically
hindered chiral environment (“chiral pocket”) around the iridium
center. The crowded “chiral pocket” efficiently minimized the
number of possible transition states in the reaction and facilitated
chiral discrimination. For easy understanding, the space in the
front of iridium center was modeled into four quadrants. A part
of spirobiindane backbone of SIPHOX ligand, which is strongly
rigid and sterically hindered, occupied the quadrant 2. One
P-phenyl and one of the tert-butyl groups on another P-phenyl
hindered the quadrants 1 and 4, respectively. Only the quadrant
3 is relatively open, which could be accessed by the most
sterically demanding part of the substrate.
According to this model, the olefin double bond of R,ꢀ-
unsaturated acid will prefer to coordinate to catalyst (Sa,S)-1c
by its Re face, leading to the saturated carboxylic acid product
with S configuration, which is consistent with the experimental
results (Figure 4).
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1178 J. AM. CHEM. SOC. VOL. 132, NO. 3, 2010

R-Aryloxy and R-Alkoxy R,ꢀ-Unsaturated Carboxylic Acids
A R T I C L E S
7 mL (50 mmol) of diisopropylamine in 60 mL of dry THF. After
being stirred for 30 min at the same temperature, a solution of 40
mmol of 2-aryloxy or 2-alkoxy acetate in 20 mL of THF was added
dropwise. The mixture was stirred for 20 min at -78 °C, allowed
to warm to -30 °C, and then a solution of 35 mmol of aromatic
aldehyde in 20 mL of THF was added dropwise at this temperature.
Next, 45 mmol of benzenesulfonyl chloride was added, and the
resulting mixture was allowed to warm to room temperature and
was stirred overnight.
The reaction was quenched with brine and extracted with EtOAc.
The combined organic layers were dried over Na2SO4 and concen-
trated under vacuum. The residue was mixed with 20 mL of
triethylamine and heated under reflux in an oil bath for 3 h. After
being cooled to room temperature, the mixture was concentrated,
and 3 M HCl was added. The layers were separated, and the aqueous
layer was extracted with EtOAc. The combined organic layers were
dried over Na2SO4 and concentrated under vacuum. The crude
product was purified by flash column chromatography to yield the
unsaturated carboxylic ester.
Figure 4. Coordination model of unsaturated acid with catalyst (Sa,S)-1c.
With this model, we can readily understand why the catalyst
favors the Z-isomer of unsaturated acids over its E counterpart.
For example, the hydrogenation of (E)-5a gave a very low
conversion, as well as a low enantioselectivity (Scheme 6).
Scheme 6. Asymmetric Hydrogenation of
(E)-2-Phenoxy-3-phenylacrylic Acid
To a stirred solution of carboxylic ester in 25 mL of EtOH was
added 25 mL of 3 M NaOH. The mixture was stirred for 2 h under
reflux. The reaction mixture was cooled and concentrated, and ether
(100 mL) and 3 M HCl (50 mL) were added at 0 °C. The organic
phase was separated, and the aqueous phase was extracted twice
with ether. The combined organic layers were dried over Na2SO4
and concentrated in vacuum. The crude product was purified by
recrystallization from petroleum ether/ethyl acetate.
Conclusions
General Procedure for the Asymmetric Hydrogenation. To
a hydrogenation tube equipped with a stir bar were added R,ꢀ-
unsaturated carboxylic acids, catalyst, Cs2CO3, and MeOH at
ambient atmosphere. The hydrogenation tube was then put into an
autoclave. The air in the autoclave was replaced with hydrogen
five times. The autoclave was then charged with hydrogen to 6
atm, and the reaction mixture was stirred at the appropriate
temperature for a certain time. After releasing the hydrogen, the
reaction mixture was acidified with 3 M HCl and extracted with
ether. The extract was dried over Na2SO4 and concentrated on a
rotary evaporator. The conversion of substrate was determined by
1H NMR analysis. The crude product was purified by flash
chromatography on silica gel column to give the pure product. The
product was reacted with aniline (1.1 equiv) in the presence of
DMAP and DCC in THF for 30 min to afford the corresponding
amide. After flash chromatography on a neutral Al2O3 column, the
desired amide was obtained and analyzed on SFC with a chiral
column to determine the ee value.
In conclusion, we have demonstrated that the Ir/chiral spiro
phosphino-oxazoline (Ir-SIPHOX) cationic complexes are
highly efficient catalysts for the enantioselective hydrogenation
of R-aryloxy- and R-alkoxy-substituted R,ꢀ-unsaturated car-
boxylic acids, producing a variety of optically active R-oxy-
functionalized carboxylic acids in extremely high enantioselec-
tivities under mild reaction conditions. Among them, the
hydrogenation of R-benzyloxy-substituted R,ꢀ-unsaturated acids
provided a convenient methodology for the synthesis of chiral
R-hydroxy acids. A mechanism involving a catalytic cycle
between IrI and IrIII was proposed on the basis of the
experimental results. The rationality of the catalytic cycle, with
an olefin dihydride complex as the key intermediate, was
supported by the deuterium-labeling studies. The X-ray diffrac-
tion analysis of the single crystal structure of the iridium catalyst
revealed that the rigid and sterically hindered spiro phosphino-
oxazoline ligands created an efficient chiral environment around
the metal of the catalyst, which accounts for the high level of
enantioselectivity of the reaction.
Acknowledgment. We thank the National Natural Science
Foundation of China, the Major Basic Research Development
Program (Grant No. 2006CB806106), and the “111” project
(B06005) of the Ministry of Education of China.
Experimental Section
General Procedure for the Synthesis of Unsaturated
Carboxylic Acids 5a-p, 7a-o, and 9a-j. At -78 °C, 24 mL
(48 mmol) of nBuLi (2.0 M in hexane) was added to a solution of
Supporting Information Available: Details of experimental
procedures, the synthesis and analysis data of substrates, and
the analysis data of ee values of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(29) For original data of the crystal structure of the iridium complex (Sa,S)-
1c, see the Supporting Information.
JA909810K
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J. AM. CHEM. SOC. VOL. 132, NO. 3, 2010 1179