Enantioselective iridium-catalyzed hydrogenation of α-arylcinnamic acids and synthesis of (S)-equol

Article abstract of DOI:10.1016/j.tet.2012.03.118

By using iridium catalyst based on chiral spiro phosphine-oxazoline ligands, the hydrogenation of α-arylcinnamic acids was accomplished under ambient pressure and low catalyst loading (as low as 0.01 mol %), providing useful 2,3-diarylpropionic acids in high yields with excellent enantioselectivities (up to 99% ee). A catalytic enantioselective synthesis of (S)-equol with the present hydrogenation reaction as a key step was accomplished starting from commercially available starting materials in six steps with 48.4% overall yield.

Full text of DOI:10.1016/j.tet.2012.03.118

Tetrahedron 68 (2012) 5172e5178
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective iridium-catalyzed hydrogenation of
a
-arylcinnamic acids
and synthesis of (S)-equolq
*
Shuang Yang, Shou-Fei Zhu, Can-Ming Zhang, Song Song, Yan-Bo Yu, Shen Li, Qi-Lin Zhou
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
By using iridium catalyst based on chiral spiro phosphineeoxazoline ligands, the hydrogenation of a-
Received 3 February 2012
Received in revised form 27 March 2012
Accepted 30 March 2012
Available online 7 April 2012
arylcinnamic acids was accomplished under ambient pressure and low catalyst loading (as low as
0.01 mol %), providing useful 2,3-diarylpropionic acids in high yields with excellent enantioselectivities
(up to 99% ee). A catalytic enantioselective synthesis of (S)-equol with the present hydrogenation re-
action as a key step was accomplished starting from commercially available starting materials in six steps
with 48.4% overall yield.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Asymmetric catalysis
Hydrogenation
Chiral spiro ligands
a
-Arylcinnamic acids
(S)-Equol
1. Introduction
developed for asymmetric hydrogenation of a-phenylcinnamic
acids with good to high enantioselectivity.10 Ding and Zhang11
reported an Ir-SpinPHOX-catalyzed asymmetric hydrogenation of
2,3-diphenylacrylic acid with 94% ee at 1 mol % catalyst loading.12
Enantiomerically pure 2,3-diarylpropionic acids and their de-
rivatives are versatile intermediates for the preparation of bi-
ologically active compounds, such as factor Xa inhibitor DX-9065a
and analogues,1 a cannabinoid-1 receptor (CB1R) inverse agonist
MK-0364,2 and a -secretase inhibitor3 (Scheme 1). Since
g a-aryl-
cinnamic acids can be easily obtained through Perkin reaction be-
tween aromatic aldehydes and 2-arylacetic acids, transition metal-
catalyzed asymmetric hydrogenation of a-arylcinnamic acids pro-
vides one of the most efficient approaches for the synthesis of 2,3-
diarylpropionic acids.4 Although many efficient chiral ruthenium,5
rhodium,6 and iridium catalysts7 have been developed for enan-
tioselective hydrogenations of
transition metal-catalyzed asymmetric hydrogenations of
cinnamic acids have been documented. The catalyst Ru-H8-BINAP
was first used to catalyze the asymmetric hydrogenation of
a
-alkylcinnamic acids, only a few
a
-aryl-
a
-
phenylcinnamic acids, however, the enantioselectivity was only
moderate.8 Later on, the enantioselectivity for the same reaction
was improved by using a cluster ruthenium catalyst bearing
a diphosphine ligand.9 Two chiral rhodium-catalysts containing
monodentate phosphoramidite and diphosphine ligands have been
Scheme 1. Biologically active compounds derived from chiral 1,2-diarylpropionic
acids.
q
Congratulations to Prof. Zhang-Jie Shi for being awarded Tetrahedron Young
Investigator Award.
Recently, we developed highly efficient iridium catalysts bearing
chiral spiro phosphineeoxazoline ligand, Ir-SIPHOX (1), for the
* Corresponding author. Tel.: þ86 22 2350 0011; fax: þ86 22 2350 6177; e-mail
address: qlzhou@nankai.edu.cn (Q.-L. Zhou).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.118

S. Yang et al. / Tetrahedron 68 (2012) 5172e5178
5173
asymmetric hydrogenations of
a
excellent enantioselectivity with extremely low catalyst loading.
During the study on the synthesis of natural products and chiral
drugs, which contain 2,3-diarylpropionic acid unit we found that
the catalysts 1 are highly enantioselective for the hydrogenation of
a
-alkyl-,7
a
-alkoxy- and
a
-aryloxy-
a methyl group on the oxazoline ring accomplished the hydroge-
nation in 8 h, while the catalyst (Sa)-1g, which has no substituent
on the oxazoline ring, needed only 0.5 h for complete conversion
(entries 6 and 7). The fact that the catalyst (Sa)-1g gave higher
enantioselectivity (95% ee) means that the axial chirality of the
spiro backbone, instead of the central chiralities on the oxazoline
rings, in the catalysts 1 played a crucial role for controlling the
enantioselectivity of the reaction and the configuration of the
products. The activity of the catalyst (Sa)-1g is so high to furnish the
hydrogenation at S/C of 10,000 within 8 h and afforded the desired
product in a quantitative yield with excellent enantioselectivity
(entry 8). To the best of our knowledge, this is the highest S/C ratio
having ever been reached for asymmetric hydrogention of this type
of substrate.8e11 Moreover, the hydrogenation reaction can also be
carried out under ambient hydrogen pressure without diminishing
enantioselectivity (entry 9). The basic additive is critical for
obtaining high reaction rate and enantioselectivity, with Cs2CO3
and NEt3 being the best choice. Using other bases including K2CO3
and Na2CO3 gave markedly lower conversion and enantioselectivity
under the identical reaction conditions (entries 10 and 11).
,ß-unsaturated acids,13 providing the corresponding chiral acids in
a
-arylcinnamic acids. Here we report the asymmetric iridium-
catalyzed hydrogenation of (E)-2,3-diarylacrylic acids by using
chiral spiro phosphineeoxazoline ligands under ambient pressure,
providing chiral 2,3-diarylpropionic acids in up to 99% ee with very
low catalyst loading (S/C up to 10,000). Using this highly efficient
catalytic hydrogenation as a key step, a concise enantioselective
total synthesis of the natural product (S)-equol was accomplished
in six steps with 48.4% overall yield starting with commercially
available materials.
2. Results and discussion
In the initial study, the hydrogenation of a-phenylcinnamic acid
was performed at 6 atm hydrogen pressure in methanol using
0.25 mol % chiral spiro iridium complexes 1 as catalysts (Table 1).
When catalyst (Sa,S)-1a, which has a benzyl group on the oxazoline
ring, was used, the hydrogenation underwent smoothly to produce
the desired hydrogenation product 2,3-diphenylpropionic acid (3a)
with 93% ee (entry 1). However, the reaction needed relative long
time (12 h) to reach full conversion. To improve the reaction rate as
well as the enantioselectivity of the reaction, the iridium complexes
with other spiro phosphineeoxazoline ligands were evaluated
under the standard reaction conditions. The chiral spiro iridium
catalyst with less bulky P-Ar group, such as 3,5-dimethylphenyl
(1b) and phenyl (1c) showed lower conversion and lower enan-
tioselectivity (entries 2 and 3). The steric hindrance of R group on
oxazoline ring of catalysts 1 also significantly impacted the activity
of catalyst (entries 4e7). For instance, the catalyst (Sa,S)-1f having
Under the optimal reaction conditions, various a-arylcinnamic
acids were investigated in the presence of 0.25 mol % catalyst (Sa)-
1g at ambient pressure. All the tested substrates can be hydroge-
nated to the corresponding 2,3-diarylpropionic acids in high yields
with excellent enantioselectivities (Table 2). The electronic and
steric properties of substituent groups on Ar1 and Ar2 have a neg-
ligible effect on the yield as well as the enantioselectivity of the
reaction. However, the substrates 2f (Ar1¼2-ClC6H4) and 2h
(Ar1¼1-naphthyl) needed longer time (24 h) to complete the re-
action (entries 6 and 8). The highest enantioselectivity (>99% ee)
(entry 4) was obtained in the hydrogenation of (E)-2-phenyl-3-(4-
chlorophenyl)acrylic acid (2d). In addition to the phenyl groups, the
Ar1 of substrate can also be furanyl (2j), giving the hydrogenated
product in 96% yield and 90% ee (entry 10). The hydrogenation of
(E)-2-(3-bromophenyl)-3-(4-chlorophenyl)acrylic acid (2o) was
carried out to prepare 2-(3-bromophenyl)-3-(4-chlorophenyl)
Table 1
Asymmetric hydrogenation of a
-phenylcinnamic acida
Table 2
Asymmetric hydrogenation of
a
-arylcinnamic acid derivativesa
Entry Ar1; Ar2
Product Time (h) Yieldb (%) ee (%)
1
2
3
4
C6H5; C6H5 (2a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
4
4
4
4
4
24
4
24
4
3
4
93
93
96
96
96
95
95
96
96
96
93
94
96
94
96
97
95(R)
95
96(R)
>99(R)
93
95(R)
94
98
97
90
92
93
4-MeC6H4; C6H5 (2b)
4-MeOC6H4; C6H5 (2c)
4-ClC6H4; C6H5 (2d)
3-MeC6H4; C6H5 (2e)
2-ClC6H4; C6H5 (2f)
2-MeOC6H4; C6H5 (2g)
1-Naphthyl; C6H5 (2h)
2-Naphthyl; C6H5 (2i)
Furan-2-yl; C6H5 (2j)
C6H5; 4-MeC6H4 (2k)
C6H5; 4-MeOC6H4 (2l)
C6H5; 4-ClC6H4 (2m)
C6H5; 3-MeC6H4 (2n)
5
Entry
Catalyst
Base
PH (atm)
Time (h)
Convb (%)
eec (%)
2
6
1
2
3
4
5
6
(Sa,S)-1a
(Sa,S)-1b
(Sa,S)-1c
(Sa,S)-1d
(Sa,S)-1e
(Sa,S)-1f
(Sa)-1g
(Sa)-1g
(Sa)-1g
(Sa)-1g
(Sa)-1g
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NEt3
6
6
6
6
6
6
6
12
1
1
12
12
12
12
12
8
0.5
8
4
100
32
56
100
100
100
100
100
100
71
93
74
61
93
93
93
95
93
95
42
47
7c
8
9
10c
11
12
13
14
15d
16d,e
4
4
4
4
7
97(R)
94
97(S)
97(S)
8d
9
Cs2CO3
Na2CO3
K2CO3
4-ClC6H4; 3-BrC6H4 (2o) 3o
4-ClC6H4; 3-BrC6H4 (2o) 3o
10
11
42
47
4
1
88
a
Reaction conditions and analyses of product were the same with those of Table
1, entry 9 except otherwise noted. Full conversions were obtained for all reactions.
a
Reaction conditions: 1/2a/base¼0.00125:0.5:0.25 mmol, S/C¼400, in
2 mL
b
methanol at 45 ꢀC.
Isolated yield.
b
c
Determined by 1H NMR.
Determined by HPLC using a Chiralpak AD-H column.
S/C¼10,000, 5 equiv NEt3 as additive, at 70 ꢀC.
PH ¼6 atm.
2
c
d
Using (Ra)-1g as catalyst.
d
e
S/C¼10,000, PH ¼12 atm, 5 equiv NEt3 as additive, at 70 ꢀC.
2

5174
S. Yang et al. / Tetrahedron 68 (2012) 5172e5178
propionic acid ((S)-3o), a key intermediate for the synthesis of
Merk’s CB1R inverse agonist MK-0364 (Scheme 1).2 By readily
changing the catalyst to (Ra)-1e, the expected acid (S)-3o was
obtained in 96% yield and 97% ee (entry 15). The hydrogenation of
2o can be performed at S/C¼10,000 without diminishing enantio-
selectivity (entry 16).
(S/C¼5000) produced the acid (S)-3p in 97% yield with 98% ee. The
reduction of acid (S)-3p with LiAlH4 at 0 ꢀC gave the alcohol 4 in
94% yield. At last, the alcohol 4 was converted to (S)-equol fol-
lowing the standard procedures.18 Thus, the total synthesis of
(S)-equol was accomplished in 48.4% overall yield. Considering the
easily available starting materials, economic steps, and high yield,
the present catalytic asymmetric total synthesis of (S)-equol rep-
resents a compelling approach to this important natural product.
To further demonstrate the synthetic potential of Ir-SIPHOX-
catalyzed enantioselective hydrogenation of a-arylcinnamic acids,
we conducted the total synthesis of (S)-equol. (S)-Equol is an im-
portant soy isoflavonoids metabolite, which has attracted in-
creasing attention for its phytoestrogenic activity and potential use
in menopausal hormone replacement therapy.14 Although many
syntheses of the racemic isoflavans have been reported,15 so far,
only a few asymmetric syntheses of optically pure isoflavans have
been developed.16 In 2006, Boulanger et al.17 reported the asym-
metric total synthesis of (S)-equol in 9.8% overall yield by using
Evans alkylation as a key step. Recently, Kobayashi et al.18 de-
veloped another approach to the asymmetric total synthesis of (S)-
equol starting with (S)-lactate. The synthesis included fifteen steps
with a copper-mediated allylic substitution as a key step. It is worth
mentioning that those two total syntheses need use of 1 equiv
chiral auxiliary or chiral starting material. The only catalytic
asymmetric synthesis of (S)-equol was accomplished starting with
daidzein, another isoflavonoid,19 by using iridium-catalyzed
asymmetric hydrogenation of dehydroequol as a key step. We en-
visaged that the (S)-equol can be synthesized starting with our
hydrogenation product 3p. As (E)-3-(2,4-dimethoxyphenyl)-2-(4-
methoxyphenyl)acrylic acid 2p is easily prepared from commer-
cially available 2,4-dimethoxyphenylaldehyde and 2-(4-
methoxyphenyl)acetic acid, the total synthesis of (S)-equol can be
as short as six steps (Scheme 2). Firstly, the unsaturated carboxylic
acid 2p was prepared through Perkin reaction in 81% yield. The
hydrogenation of 2p in the presence of 0.02 mol % catalyst (Ra)-1g
3. Conclusion
We have developed a highly efficient iridium-catalyzed asym-
metric hydrogenation of
a-arylcinnamic acids. Under ambient
pressure and low catalyst loading, a wide range of (E)-2,3-
diarylacrylic acids were hydrogenated to 1,2-diarylpropionic acids
in high yields with excellent enantioselectivities. The concise
asymmetric synthesis of (S)-equol by means of Ir-(Ra)-1g catalyst
indicated a high potential for practical use of the present iridium-
catalyzed asymmetric hydrogenation reaction.
4. Experimental section
4.1. General
Unless otherwise noted, all reactions and manipulations were
performed in an argon-filled glovebox (VAC DRI-LAB HE 493) or
using standard Schlenk techniques. Melting points were measured
on a RY-I apparatus and uncorrected. 1H and 13C NMR spectra were
recorded on a Bruker AV 400 spectrometer at 400 MHz (1H NMR)
and 100 MHz (13C NMR) or a Bruker AV 300 spectrometer at
300 MHz (1H NMR) and 75 MHz (13C NMR) in CDCl3 or DMSO-d6.
Chemical shifts were reported in parts per million down field from
internal Me4Si and external 85% H3PO4, respectively. Optical
Scheme 2. Total synthesis of (S)-equol.

S. Yang et al. / Tetrahedron 68 (2012) 5172e5178
5175
rotations were determined using a Perkin Elmer 341 MC polarim-
eter. HRMS were recorded on IonSpec FT-ICR mass spectrometer
with ESI resource. Enantiomeric excesses of the hydrogenation
products were determined by chiral HPLC. HPLC analyses were
performed using a Hewlett Packard Model HP 1100 Series in-
strument. Anhydrous THF were distilled from sodium benzophe-
none ketyl. Anhydrous NEt3 were freshly distilled from calcium
hydride under nitrogen atmosphere. Anhydrous MeOH were dis-
tilled from magnesium under nitrogen atmosphere. Hydrogen gas
(99.999%) was purchased from Boc Gas Inc., Tianjin. The catalysts
1aeg were prepared according to our previous procedure.20 Some
of the spiro phosphineeoxazoline ligands are commercially avail-
able from Strem Chemical Co. or Jiuzhou Pharm. NaBArF was pre-
pared according to the literatures.21
AreH), 3.85 (t, J¼7.6 Hz, 1H, CH), 3.40 (dd, J¼13.6 and 8.4 Hz, 1H,
CH2), 3.03 (dd, J¼14.0 and 7.2 Hz, 1H, CH2).
4.3.2. 2-Phenyl-3-p-tolylpropionic acid (3b).12a White solid, mp
113e114 ꢀC, 93% yield, 95% ee, ½a 2D0
ꢁ100 (c 1.2, acetone), HPLC
ꢂ
condition for corresponding amide: Chiralpak AD-H column
(25ꢃ0.46 cm ID), n-hexane/2-propanol¼70:30,1.0 mL/min, 254 nm
UV detector, tR¼7.67 min (minor) and tR¼8.86 min (major). 1H NMR
(400 MHz, CDCl3)
d
7.31e7.25 (m, 5H, AreH), 7.02 (d, J¼8.0 Hz, 2H,
AreH), 6.99 (d, J¼8.0 Hz, 2H, AreH), 3.83 (dd, J¼8.4 and 7.2 Hz, 1H,
CH), 3.36 (dd, J¼14.0 and 8.4 Hz, 1H, CH2), 2.99 (dd, J¼14.0 and
6.8 Hz, 1H, CH2), 2.28 (s, 3H, CH3).
4.3.3. (R)-3-(4-Methoxyphenyl)-2-phenylpropionic acid (3c).32 White
solid, mp 123e124 ꢀC, 96% yield, 96% ee, ½a 2D0
ꢁ118 (c 1.3, acetone),
ꢂ
HPLC condition for corresponding amide: Chiralcel OD-H column
(25ꢃ0.46 cm ID), n-hexane/2-propanol¼70:30,1.0 mL/min, 254 nm
UV detector, tR¼9.97 min for (S)-enantiomer and tR¼11.65 min for
4.2. Synthesis of (E)-2,3-diarylacrylic acids
(R)-enantiomer. 1H NMR (400 MHz, CDCl3)
d 7.33e7.24 (m, 5H,
The (E)-2,3-diarylacrylic acids were prepared according to lit-
erature procedure starting with aromatic aldehydes and 1-
arylacetic acids in the precence of NEt3.12a The acids 2a,22 2b,23
2c,24 2d,24 2e,12a 2f,25 2g,26 2h,27 2i,28 2j,29 2k,12c 2l,12a 2m,30
2n12a are known compounds.
AreH), 7.01 (d, J¼8.4 Hz, 2H, AreH), 6.75 (d, J¼8.4 Hz, 2H, AreH),
3.80 (t, J¼8.0 Hz, 1H, CH), 3.75 (s, 3H, CH3), 3.34 (dd, J¼14.0 and
8.4 Hz, 1H, CH2), 2.97 (dd, J¼13.6 and 6.8 Hz, 1H, CH2).
4.3.4. (R)-3-(4-Chlorophenyl)-2-phenylpropionic acid (3d).2a White
solid, mp 137e138 ꢀC, 96% yield, >99% ee, ½a 2D0
ꢁ129 (c 1.1, acetone),
ꢂ
4.2.1. E-2-(3-Bromophenyl)-3-(4-chlorophenyl)acrylic acid (2o).
HPLC condition for corresponding amide (the chloride was re-
moved by Pd/C): Chiralpak AD-H column (25ꢃ0.46 cm ID), n-hex-
ane/2-propanol¼70:30, 1.0 mL/min, 254 nm UV detector,
tR¼7.91 min for (S)-enantiomer and tR¼9.43 min for (R)-enantio-
White solid, mp: 255e256 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d 7.80
(s, 1H, ]CH), 7.57 (d, J¼7.6 Hz, 1H, AreH), 7.41 (s, 1H, AreH),
7.37e7.31 (m, 3H, AreH), 7.17 (d, J¼7.6 Hz, 1H, AreH), 7.09 (d,
J¼8.4 Hz, 2H, AreH); 13C NMR (100 MHz, DMSO-d6)
d 167.6, 138.5,
mer. 1H NMR (400 MHz, CDCl3)
d 7.33e7.26 (m, 5H, AreH), 7.18 (d,
138.3, 133.9, 133.0, 132.4, 132.0, 131.8, 130.7, 128.7, 128.5, 121.6.
HRMS (ESI) calcd for [MꢁH, C15H9BrClO2]ꢁ: 334.9480, found
334.9471.
J¼8.4 Hz, 2H, AreH), 7.02 (d, J¼8.4 Hz, 2H, AreH), 3.80 (t, J¼8.0 Hz,
1H, CH), 3.36 (dd, J¼14.0 and 8.4 Hz, 1H, CH2), 3.00 (dd, J¼14.0 and
7.2 Hz, 1H, CH2).
4.3.5. 2-Phenyl-3-m-tolylpropionic acid (3e).12a White solid, mp
4.3. Asymmetric hydrogenation of (E)-2,3-diarylacrylic acids
78e79 ꢀC, 96% yield, 93% ee, ½a 2D0
ꢁ121 (c 1.1, acetone), HPLC con-
ꢂ
dition for corresponding amide: Chiralpak AD-H column
(25ꢃ0.46 cm ID), n-hexane/2-propanol¼70:30,1.0 mL/min, 254 nm
UV detector, tR¼4.94 min (minor) and tR¼5.81 min (major). 1H NMR
To a Schlenk tube was charged with a stirring bar, a-phenyl-
cinnamic acid (2a, 112 mg, 0.5 mmol), catalyst (Sa)-1g (2.4 mg,
0.00125 mmol), Cs2CO3 (82 mg, 0.25 mmol), and 2 mL MeOH at
ambient atmosphere. The air in the Schlenk tube was replaced with
hydrogen for five times. The Schlenk tube was then charged with
hydrogen to 1 atm by a balloon, and the reaction mixture was
stirred at 45 ꢀC for 4 h. After releasing hydrogen, the reaction
mixture was added with 20 mg NaOH and concentrated on a rotator
vapor. The mixture was added 25 mL water and washed with Et2O.
The aqueous layer was acidified with concd HCl, and extracted with
Et2O. The organic layer was dried with Na2SO4. The conversion of
substrate was determined by 1H NMR analysis. The crude product
was purified by a flash chromatography on silica gel column to give
pure product 3a as a white solid. The acid 3a (113 mg, 0.5 mmol)
(400 MHz, CDCl3)
d
7.33e7.26 (m, 5H, AreH), 7.12 (t, J¼7.6 Hz, 1H,
AreH), 6.99 (d, J¼7.2 Hz, 1H, AreH), 6.92 (t, J¼7.6 Hz, 2H, AreH),
3.86 (t, J¼8.0 Hz, 1H, CH), 3.38 (dd, J¼13.6 and 8.8 Hz, 1H, CH2), 3.00
(dd, J¼14.0 and 6.8 Hz, 1H, CH2), 2.28 (s, 3H, CH3).
4.3.6. (R)-3-(2-Chlorophenyl)-2-phenylpropionic acid (3f). White
solid, mp 105e106 ꢀC, 95% yield, 95% ee, ½a 2D0
ꢁ110 (c 1.0, acetone),
ꢂ
HPLC condition for corresponding amide (the chloride was re-
moved by Pd/C): Chiralpak AD-H column (25ꢃ0.46 cm ID), n-hex-
ane/2-propanol¼70:30, 1.0 mL/min, 254 nm UV detector,
tR¼8.15 min for (S)-enantiomer and tR¼9.74 min for (R)-enantio-
mer. 1H NMR (400 MHz, CDCl3)
d 7.34e7.28 (m, 6H, AreH),
was reacted with aniline (50
m
L, 0.55 mmol) in the presence of
7.15e7.05 (m, 3H, AreH), 4.03 (dd, J¼8.4 and 7.2 Hz, 1H, CH), 3.49
DMAP (4 mg, 0.033 mmol) and DCC (110 mg, 0.53 mmol) in 2.0 mL
THF for 30 min. The reaction mixture was filtrated through Celite.
The filtrate was concentrated on a rotator vapor. After a flash
chromatography on Al2O3 column with petroleum ether and ethyl
acetate (PE/EA¼4:1), the amide was determined ee value by HPLC
with a Chiralpak AD-H column. The analysis data for hydrogenation
products were listed as below.
(dd, J¼13.6 and 8.4 Hz, 1H, CH2), 3.14 (dd, J¼13.6 and 6.4 Hz, 1H,
CH2). 13C NMR (100 MHz, CDCl3)
d 179.7, 137.9, 136.2, 134.2, 131.5,
129.6, 128.8, 128.15, 128.07, 127.8, 126.7, 51.1, 37.3. HRMS (ESI) calcd
for [MꢁH, C15H12ClO2]ꢁ: 259.0531, found 259.0529.
4.3.7. 3-(2-Methoxyphenyl)-2-phenylpropionic acid (3g). White
solid, mp 135 ꢀC, 95% yield, 94% ee, ½a 2D0
ꢁ123 (c 0.72, acetone),
ꢂ
HPLC condition for corresponding amide: Chiralpak AD-H column
(25ꢃ0.46 cm ID), n-hexane/2-propanol¼85:15, 1.0 mL/min, 254 nm
UV detector, tR¼32.87 min (minor) and tR¼35.28 min (major). 1H
4.3.1. (R)-2,3-Diphenylpropionic acid (3a).31 White solid, mp
79e81 ꢀC, 93% yield, 95% ee, ½a 2D5
ꢁ126 (c 0.49, acetone), HPLC
ꢂ
condition for corresponding amide: Chiralpak AD-H column
(25ꢃ0.46 cm ID), n-hexane/2-propanol¼70:30, 1.0 mL/min, 254 nm
UV detector, tR¼6.69 min for (S)-enantiomer and tR¼8.07 min for
NMR (400 MHz, CDCl3)
d
7.30e7.24 (m, 5H, AreH), 7.16 (t, J¼8.0 Hz,
1H, AreH), 6.98 (d, J¼7.2 Hz, 1H, AreH), 6.82e6.74 (m, 2H, AreH),
3.98 (t, J¼6.8 Hz, 1H, CH), 3.78 (s, 3H, CH3), 3.36 (dd, J¼13.2 and
8.4 Hz, 1H, CH2), 3.04 (dd, J¼13.6 and 6.4 Hz, 1H, CH2). 13C NMR
(R)-enantiomer. 1H NMR (400 MHz, CDCl3)
d 7.33e7.09 (m, 10H,

5176
S. Yang et al. / Tetrahedron 68 (2012) 5172e5178
(100 MHz, CDCl3)
d
179.9, 157.5, 138.6, 130.8, 128.5, 128.0, 127.8,
J¼6.8 Hz, 2H, AreH), 3.82 (t, J¼7.6 Hz, 1H, CH), 3.37 (dd, J¼13.6 and
8.0 Hz, 1H, CH2), 3.00 (dd, J¼13.6 and 7.6 Hz, 1H, CH2). 13C NMR
127.3,126.9, 120.2, 110.1, 55.1, 51.2, 34.5. HRMS (ESI) calcd for [MꢁH,
C16H15O3]ꢁ: 255.1027, found 255.1026.
(100 MHz, CDCl3) d 179.4, 138.2, 136.2, 133.6, 129.6, 128.9, 128.5,
126.7, 52.9, 39.2. HRMS (ESI) calcd for [MꢁH, C15H12O2]ꢁ: 259.0531,
4.3.8. 3-(Naphthalene-1-yl)-2-phenylpropionic acid (3h). White
found 259.0529.
solid, mp 96e97 ꢀC, 96% yield, 98% ee, ½a 2D0
ꢁ115 (c 1.2, acetone),
ꢂ
HPLC condition for corresponding amide: Chiralpak AD-H column
(25ꢃ0.46 cm ID), n-hexane/2-propanol¼70:30,1.0 mL/min, 254 nm
UV detector, tR¼5.23 min (minor) and tR¼7.32 min (major). 1H NMR
4.3.14. 3-Phenyl-2-m-tolylpropionic acid (3n).12a White solid, mp
93e94 ꢀC, 94% yield, 94% ee, ½a 2D0
ꢁ135 (c 1.0, acetone), HPLC
ꢂ
condition for corresponding amide: Chiralpak AD-H column
(25ꢃ0.46 cm ID), n-hexane/2-propanol¼70:30, 1.0 mL/min, 254 nm
UV detector, tR¼4.40 min (minor) and tR¼6.12 min (major). 1H NMR
(400 MHz, CDCl3)
d
7.98 (d, J¼7.6 Hz, 1H, AreH), 7.82 (d, J¼7.2 Hz,
1H, AreH), 7.68 (d, J¼8.0 Hz, 1H, AreH), 7.49e7.45 (m, 2H, AreH),
7.30e7.23 (m, 6H, AreH), 7.17e7.15 (m, 1H, AreH), 4.05 (t, J¼6.4 Hz,
1H, CH), 3.89 (dd, J¼14.0 and 8.8 Hz, 1H, CH2), 3.45 (dd, J¼13.6 and
(400 MHz, CDCl3)
6.4 Hz, 1H, CH), 3.39 (dd, J¼13.6 and 8.4 Hz, 1H, CH2), 3.01 (dd,
J¼14.0 and 6.8 Hz, 1H, CH2), 2.33 (s, 3H, CH3).
d
7.25e7.07 (m, 9H, AreH), 3.82 (dd, J¼8.4 and
6.0 Hz, 1H, CH2). 13C NMR (100 MHz, CDCl3)
d 179.8, 138.1, 134.4,
133.9, 131.6, 129.0, 128.7, 128.0, 127.6, 127.3, 127.1, 126.1, 125.5, 125.3,
123.2, 52.2, 36.4. HRMS (ESI) calcd for [MꢁH, C19H15O2]ꢁ: 275.1078,
found 275.1075.
4.3.15. (S)-2-(3-Bromophenyl)-3-(4-chlorophenyl)-propionic
acid
(3o).35 White solid, mp 110e111 ꢀC, 96% yield, 97% ee, ½a 2D6
ꢂ
þ74.5 (c
3.0, CHCl3), HPLC condition for corresponding amide: Chiralcel OD-
H column (25ꢃ0.46 cm ID), n-hexane/2-propanol¼80:20, 1.0 mL/
min, 254 nm UV detector, tR¼6.86 min for (S)-enantiomer and
tR¼9.71 min for (R)-enantiomer. 1H NMR (400 MHz, CDCl3)
4.3.9. 3-(Naphthalene-2-yl)-2-phenylpropionic acid (3i).33 White
solid, mp 152e153 ꢀC, 96% yield, 97% ee, ½a 2D0
ꢁ150 (c 0.43, acetone),
ꢂ
HPLC condition for corresponding amide: Chiralpak AD-H column
(25ꢃ0.46 cm ID), n-hexane/2-propanol¼70:30,1.0 mL/min, 254 nm
UV detector, tR¼6.63 min (minor) and tR¼8.22 min (major). 1H NMR
d
7.46e7.41 (m, 2H, AreH), 7.25e7.19 (m, 4H, AreH), 7.01 (d,
J¼8.0 Hz, 2H, AreH), 3.77 (t, J¼7.6 Hz, 1H, CH), 3.34 (dd, J¼13.6 and
(400 MHz, CDCl3)
d 7.79e7.70 (m, 3H, AreH), 7.57 (s, 1H, AreH),
8.4 Hz, 1H, CH2), 2.98 (dd, J¼14.0 and 7.2 Hz, 1H, CH2).
7.44e7.43 (m, 2H, AreH), 7.33e7.23 (m, 6H, AreH), 3.98 (t, J¼6.8 Hz,
1H, CH), 3.57 (dd, J¼13.6 and 8.4 Hz, 1H, CH2), 3.20 (dd, J¼14.0 and
6.8 Hz, 1H, CH2).
4.4. Total synthesis of (S)-equol
4.4.1. Synthesis
of
(E)-3-(2,4-dimethoxyphenyl)-2-(4-methox-
4.3.10. 3-Furan-2-yl-2-phenylpropionic acid (3j). White solid, mp
yphenyl)acrylic acid (2p). To a 50 mL flask was added 3.9 g
(23.5 mmol) 2,4-dimethoxybenzaldehyde, 3.9 g (23.5 mmol) 2-(4-
methoxyphenyl)acetic acid, 4.0 mL NEt3 and 2.6 mL Ac2O. The so-
lution was refluxed for 2 h and then was added 5% aq NaOH and
washed with CH2Cl2. The aqueous layer was acidified with acetic
acid and the pale yellow solid was precipitated. The solid was
recrystallized with ethyl acetate and petroleum ether to afford 2p
as a yellow solid (6.0 g, 81% yield). Mp 224e225 ꢀC. 1H NMR
105e106 ꢀC, 96% yield, 90% ee, ½a 2D0
ꢁ144 (c 1.4, acetone), HPLC
ꢂ
condition for corresponding amide: Chiralpak AD-H column
(25ꢃ0.46 cm ID), n-hexane/2-propanol¼70:30,1.0 mL/min, 254 nm
UV detector, tR¼5.59 min (minor) and tR¼9.73 min (major). 1H NMR
(400 MHz, CDCl3)
d
7.32e7.26 (m, 6H, AreH), 6.21 (dd, J¼3.2 and
2.0 Hz, 1H, AreH), 5.94 (d, J¼2.8 Hz, 1H, AreH), 3.99 (dd, J¼8.4 and
6.4 Hz, 1H, CH), 3.44 (dd, J¼15.2 and 8.4 Hz, 1H, CH2), 3.06 (dd,
J¼15.2 and 6.8 Hz, 1H, CH2). 13C NMR (100 MHz, CDCl3)
d
177.7,
(400 MHz, DMSO-d6)
d
7.94 (s, 1H, ]CH), 7.06 (d, J¼8.4 Hz, 2H,
145.7, 145.3, 135.8, 128.8, 127.9, 127.1, 127.0, 122.6, 51.8, 37.8. HRMS
AreH), 6.90 (d, J¼8.8 Hz, 2H, AreH), 6.58 (d, J¼8.8 Hz, 1H, AreH),
6.55 (d, J¼2.4 Hz, 1H, AreH), 6.25e6.22 (m, 1H, AreH), 3.84 (s, 3H,
CH3), 3.76 (s, 3H, CH3), 3.71 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-
(ESI) calcd for [MꢁH, C13H11O3]ꢁ: 215.0714, found 215.0714.
4.3.11. 3-Phenyl-2-p-tolylpropionic acid (3k).12a White solid, mp
d6) d 168.8, 161.4, 159.3, 158.4, 133.1, 130.9, 130.5, 129.8, 128.7, 115.7,
117e118 ꢀC, 93% yield, 92% ee, ½a 2D0
ꢂ
ꢁ152 (c 1.0, acetone), HPLC
113.8, 105.0, 98.0, 55.6, 55.2, 54.9. HRMS (ESI) calcd for [MꢁH,
condition for corresponding amide: Chiralpak AD-H column
(25ꢃ0.46 cm ID), n-hexane/2-propanol¼70:30,1.0 mL/min, 254 nm
UV detector, tR¼8.21 min (minor) and tR¼11.22 min (major). 1H
C18H17O5]ꢁ: 313.1081, found 313.1078.
4.4.2. Synthesis of (S)-3-(2,4-dimethoxyphenyl)-2-(4-
methoxyphenyl)propionic acid (3p). To a hydrogenation tube was
charged with a stirring bar, (E)-3-(2,4-dimethoxyphenyl)-2-(4-
methoxyphenyl)acrylic acid (2p) (393 mg, 1.25 mmol), catalyst
NMR (400 MHz, CDCl3)
1H, CH), 3.38 (dd, J¼13.6 and 8.4 Hz, 1H, CH2), 3.01 (dd, J¼14.0 and
d
7.26e7.10 (m, 9H, AreH), 3.82 (t, J¼8.0 Hz,
6.8 Hz, 1H, CH2), 2.32 (s, 3H, CH3).
(Ra)-1g (0.48 mg, 0.00025 mmol) in 1 mL MeOH, NEt3 (875
mL,
4.3.12. 2-(4-Methoxyphenyl)-3-phenylpropionic acid (3l).34 White
6.25 mmol) and 3.5 mL MeOH at ambient atmosphere. The hy-
drogenation tube was put into an autoclave. Hydrogen was charged
into the autoclave and released for three times. The autoclave was
then charged with hydrogen to 12 atm, and the reaction mixture
was stirred at 70 ꢀC for 3 days. After releasing hydrogen, the re-
action mixture was added with 50 mg NaOH and concentrated on
a rotator vapor. The mixture was added with 75 mL water and
washed with Et2O. The aqueous layer was acidified with concd HCl,
extracted with Et2O. The extract was dried over anhydrous Na2SO4.
The conversion of substrate was determined by 1H NMR analysis.
The crude product was purified by a flash chromatography on silica
gel column to give pure product as a white solid (382 mg, 97%
solid, mp 108e109 ꢀC, 94% yield, 93% ee, ½a 2D0
ꢁ136 (c 1.1, acetone),
ꢂ
HPLC condition for corresponding amide: Chiralcel OD-H column
(25ꢃ0.46 cm ID), n-hexane/2-propanol¼90:10, 1.0 mL/min, 254 nm
UV detector, tR¼31.23 min (minor) and tR¼32.72 min (major). 1H
NMR (400 MHz, CDCl3)
d
7.24e7.16 (m, 5H, AreH), 7.09 (d, J¼7.2 Hz,
2H, AreH), 6.83 (d, J¼8.8 Hz, 2H, AreH), 3.79 (t, J¼8.0 Hz, 1H, CH),
3.79 (s, 3H, CH3), 3.36 (dd, J¼14.0 and 8.4 Hz, 1H, CH2), 3.00 (dd,
J¼13.6 and 7.2 Hz, 1H, CH2).
4.3.13. (R)-2-(4-Chlorophenyl)-3-phenylpropionic acid (3m). White
solid, mp 120e121 ꢀC, 96% yield, 97% ee, ½a 2D0
ꢁ124 (c 1.2, acetone),
ꢂ
HPLC condition for corresponding amide (the chloride was re-
moved by Pd/C): Chiralpak AD-H column (25ꢃ0.46 cm ID), n-hex-
ane/2-propanol¼70:30, 1.0 mL/min, 400 bar, 254 nm UV detector,
tR¼7.19 min for (S)-enantiomer and tR¼8.55 min for (R)-enantio-
yield). Mp 135e136 ꢀC, ½a D23
ꢂ
þ122 (c 0.29, CHCl3). 1H NMR
(400 MHz, DMSO-d6)
d
7.19 (d, J¼8.4 Hz, 2H, AreH), 6.90e6.84 (m,
3H, AreH), 6.49 (s, 1H, AreH), 6.35 (d, J¼7.6 Hz, 1H, AreH), 3.77 (s,
3H, CH3), 3.71 (s, 3H, CH3), 3.70 (s, 3H, CH3), 3.77e3.70 (m, 1H, CH),
3.11 (dd, J¼13.6 and 8.4 Hz, 1H, CH2), 2.83 (dd, J¼13.6 and 6.8 Hz,
mer. 1H NMR (400 MHz, CDCl3)
d 7.27e7.17 (m, 7H, AreH), 7.06 (d,

S. Yang et al. / Tetrahedron 68 (2012) 5172e5178
5177
1H, CH2). 13C NMR (100 MHz, DMSO-d6)
d
174.6, 159.1, 158.1, 158.0,
(S)-enantiomer. Mp 190e191 ꢀC. 1H NMR (400 MHz, DMSO-d6)
131.4,130.5, 128.7,119.1,113.7,104.1, 98.2, 55.3, 55.0, 54.9, 49.9, 33.2.
d
9.30 (s, 1H, OH), 9.19 (s, 1H, OH), 7.10 (d, J¼8.4 Hz, 2H, AreH), 6.86
HRMS (ESI) calcd for [MꢁH, C18H19O5]ꢁ: 315.1238, found 315.1231.
(d, J¼8.0 Hz, 1H, AreH), 6.72 (d, J¼8.4 Hz, 2H, AreH), 6.29 (dd, J¼8.0
and 2.0 Hz,1H, AreH), 6.19 (d, J¼1.6 Hz,1H, AreH), 4.14 (d, J¼8.0 Hz,
1H, CH2), 3.89 (t, J¼10.4 Hz, 1H, CH2), 3.04e2.97 (m, 1H, CH),
4.4.3. Synthesis of (S)-3-(2,4-dimethoxyphenyl)-2-(4-
methoxyphenyl)propan-1-ol (4).18 To
a
suspension of LiAlH4
2.86e2.73 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6)
d 156.5,
(229 mg, 6.0 mmol) in 5 mL of anhydrous THF was added a solution
of 3p (382 mg,1.2 mmol) in 5 mL THF at 0 ꢀC over a period of 15 min.
The resulting mixture was stirred at room temperature for 2 h, and
quenched with saturated aqueous NaHCO3 solution and 10% aq
NaOH at 0 ꢀC. The mixture was filtered through Celite and washed
thoroughly with ethyl acetate. The organic layer was separated and
the aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with water and brine, dried over an-
hydrous Na2SO4 and concentrated. The residue was purified by
a flash chromatography on silica gel (PE/EA¼4:1) to give alcohol 4
156.1, 154.5, 131.7, 130.1, 128.3, 115.3, 112.6, 108.0, 102.6, 70.3, 37.2,
31.3. HRMS (ESI) calcd for [MꢁH, C15H13O3]ꢁ: 241.0870, found
241.0869.
Acknowledgements
We thank the National Natural Science Foundation of China and
the National Basic Research Program of China (2012CB821600), and
the ‘111’ project (B06005) of the Ministry of Education of China for
financial support.
(341 mg, 94% yield) as a colorless liquid. 98% ee, ½a D23
þ65.4 (c 0.29,
ꢂ
CHCl3), HPLC condition: Chiralpak AD-H column (25ꢃ0.46 cm ID),
n-hexane/2-propanol¼80:20, 1.0 mL/min, 220 nm UV detector,
tR¼11.05 min for (R)-enantiomer and tR¼16.36 min for (S)-enan-
Supplementary data
The NMR spectrums for new compounds and HPLC charts for
hydrogenation products are provided. Supplementary data associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tet.2012.03.118.
tiomer. 1H NMR (400 MHz, CDCl3)
d
7.14 (d, J¼8.8 Hz, 2H, AreH),
6.86e6.83 (m, 3H, AreH), 6.43 (d, J¼2.4 Hz, 1H, AreH), 6.35 (dd,
J¼8.0 and 2.0 Hz, 1H, AreH), 3.79 (s, 3H, CH3), 3.78 (s, 3H, CH3), 3.77
(s, 3H, CH3), 3.69 (t, J¼4.8 Hz, 2H, CH2), 3.06e2.92 (m, 2H, CH2), 2.77
(dd, J¼13.2 and 6.0 Hz, 1H, CH), 1.73 (s, 1H, OH). 13C NMR (100 MHz,
References and notes
CDCl3)
d 159.3, 158.3, 158.2, 134.9, 131.2, 129.0, 120.6, 113.8, 104.0,
98.4, 66.1, 55.4, 55.3, 55.2, 47.9, 32.4.
1. (a) Nagahara, T.; Yokoyama, Y.; Inamura, K.; Katakura, S.; Komoriya, S.; Yama-
guchi, H.; Hara, T.; Iwamoto, M. J. Med. Chem. 1994, 37, 1200e1207; (b) Ko-
moriya, S.; Kanaya, N.; Nagahara, T.; Yokoyama, A.; Inamura, K.; Yokoyama, Y.;
Katakura, S.; Hara, T. Bioorg. Med. Chem. 2004, 12, 2099e2114.
2. (a) Lin, L. S.; Lanza, T. J.; Jewell, J. P.; Liu, P.; Shah, S. K.; Qi, H.; Tong, X.; Wang, J.;
Xu, S. S.; Fong, T. M.; Shen, C.-P.; Lao, J.; Xiao, J. C.; Shearman, L. P.; Stribling, D.
S.; Rosko, K.; Strack, A.; Marsh, D. J.; Feng, Y.; Kumar, S.; Samuel, K.; Yin, W.; Van
der Ploeg, L. H. T.; Goulet, M. T.; Hagmann, W. K. J. Med. Chem. 2006, 49,
7584e7587; (b) Kim, M.; Kim, J. Y.; Song, K.-S.; Kim, J.; Lee, J. Tetrahedron 2007,
63, 12845e12852.
3. Churcher, I.; Ashton, K.; Butcher, J. W.; Clarke, E. E.; Harrison, T.; Lewis, H. D.;
Owens, A. P.; Teall, M. R.; Williams, S.; Wrigley, J. D. J. Bioorg. Med. Chem. Lett.
2003, 13, 179e183.
4. For selected reviews of transition-meal-catalyzed asymmetric hydrogenation
reactions, see: (a) Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; (b) Asymmetric Catalysis on In-
dustrial Scale: Challenges, Approaches and Solutions; Blaser, H.-U., Schmidt, E.,
Eds.; Wiley-VCH: Weinheim, 2004; (c) Tang, W.; Zhang, X. Chem. Rev. 2003, 103,
3029e3069.
4.4.4. Synthesis of (S)-1-(3-bromo-2-(4-methoxyphenyl)propyl)-2,4-
dimethoxybenzene (5).18 To an ice-cooled solution of alcohol 4
(341 mg, 1.1 mmol) and PPh3 (447 mg, 1.7 mmol) in 1 mL CH2Cl2
was added CBr4 (402 mg, 1.23 mmol) in 1 mL CH2Cl2. The mixture
was stirred at room temperature for 3 h and concentrated to afford
an oil, which was purified by chromatography on silica gel (PE/
EA¼10:1) to afford bromide 5 (367 mg, 90% yield) as a white solid.
Mp 94e95 ꢀC. ½a 2D3
ꢂ
þ33.9 (c 0.21, CHCl3). 1H NMR (400 MHz, CDCl3)
d
7.12 (d, J¼7.6 Hz, 2H, AreH), 6.91e6.84 (m, 3H, AreH), 6.43 (s, 1H,
AreH), 6.36 (d, J¼8.0 Hz, 1H, AreH), 3.80 (s, 3H, CH3), 3.78 (s, 3H,
CH3), 3.77 (s, 3H, CH3), 3.64e3.55 (m, 2H, CH2), 3.31e3.25 (m, 1H,
CH), 3.04 (dd, J¼13.6 and 7.6 Hz, 1H, CH2), 2.88 (dd, J¼13.2 and
6.4 Hz, 1H, CH2). 13C NMR (100 MHz, CDCl3)
d 159.5, 158.44, 158.36,
5. Cheng, X.; Zhang, Q.; Xie, J.-H.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed.
2005, 44, 1118e1121 and references therein.
134.7,131.1,128.7,120.0,113.7,103.8, 98.5, 55.4, 55.3, 55.2, 47.0, 38.9,
35.0.
6. (a) Yamada, I.; Yamaguchi, M.; Yamagishi, T. Tetrahedron: Asymmetry 1996, 7,
3339e3342; (b) 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, 4824e4831; (c) Chen, W.; Mc-
Cormack, P. J.; Mohammed, K.; Mbafor, W.; Roberts, S. M.; Whittall, J. Angew.
Chem., Int. Ed. 2007, 46, 4141e4144.
7. Li, S.; Zhu, S.-F.; Zhang, C.-M.; Song, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2008, 130,
8584e8585.
8. Uemura, T.; Zhang, X.; Matsumura, K.; Sayo, N.; Kumobayashi, H.; Ohta, T.;
Nozaki, K.; Takaya, H. J. Org. Chem. 1996, 61, 5510e5516.
4.4.5. Synthesis of (S)-4-(3-bromo-2-(4-hydroxyphenyl)propyl)ben-
zene-1,3-diol (6).18 To a solution of bromide 5 (367 mg, 1.0 mmol) in
CH2Cl2 (4 mL) was added BBr3 (0.35 mL, 3.6 mmol) at ꢁ78 ꢀC. The
mixture was allowed to warm to ambient temperature, stirred for
19 h, and re-cooled to ꢁ50 ꢀC. The reaction was quenched by ad-
dition of H2O (2 mL) and most of the volatile materials were
evaporated. The resulting mixture was diluted with saturated
NH4Cl and was extracted with EtOAc two times. The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated to afford a solid, which was chromatographed on
silica gel (PE/EA¼1:1) to afford phenol 6 (259 mg, 80% yield). The
product is unstable and used immediately in the following step.
9. Moberg, V.; Haukka, M.; Koshevoy, I. O.; Ortiz, R.; Nordlander, E. Organome-
tallics 2007, 26, 4090e4093.
10. (a) 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, 4209e4212; (b) Fox, M. E.; Jackson, M.; Lennon,
I. C.; Klosin, J.; Abboud, K. A. J. Org. Chem. 2008, 73, 775e784.
11. Zhang, Y.; Han, Z.-B.; Li, F.-Y.; Ding, K.-L.; Zhang, A. Chem. Commun. 2010,
156e158.
12. For representative heterogeneous catalytic asymmetric hydrogenation of
a-
arylcinnamic acids, see: (a) Sugimura, T.; Uchida, T.; Watanabe, J.; Kubota, T.;
}
}
Okamoto, Y.; Misaki, T.; Okuyama, T. J. Catal. 2009, 262, 57e64; (b) Szollosi, G.;
4.4.6. Synthesis of (S)-equol.18 A mixture of phenol 6 (259 mg,
0.8 mmol) and K2CO3 (536 mg, 3.88 mmol) in 12 mL acetone was
stirred at 50 ꢀC for 8 h, cooled to room temperature, and filtered
through a pad of Celite. The filtrate was concentrated and the res-
idue was purified by chromatography on silica gel (PE/EA¼3:1) to
ꢀ
€
€ €
ꢀ
Herman, B.; Felfoldi, K.; Fulop, F.; Bartok, M. Adv. Synth. Catal. 2008, 350,
2804e2814; (c) Sugimura, T.; Watanabe, J.; Okuyama, T.; Nitta, Y. Tetrahedron:
Asymmetry 2005, 16, 1573e1575; (d) Jones, M. D.; Raja, R.; Thomas, J. M.;
Johnson, B. F. G.; Lewis, D. W.; Rouzaud, J.; Harris, K. D. M. Angew. Chem., Int. Ed.
2003, 42, 4326e4331.
13. Li, S.; Zhu, S.-F.; Xie, J.-H.; Song, S.; Zhang, C.-M.; Zhou, Q.-L. J. Am. Chem. Soc.
afford (S)-equol (177 mg, 91% yield) as a white solid. 97% ee, ½a D23
ꢂ
2010, 132, 1172e1179.
14. (a) Chang, Y.-C.; Nair, M. G. J. Nat. Prod. 1995, 58, 1892e1896; (b) Morito, K.;
Hirose, T.; Kinjo, J.; Hirakawa, T.; Okawa, M.; Nohara, T.; Ogawa, S.; Inoue, S.;
Muramatsu, M.; Masamune, Y. Biol. Pharm. Bull. 2001, 24, 351e356; (c) Setchell,
K. D. R.; Brown, N. M.; Lydeking-Olsen, E. J. Nutr. 2002, 132, 3577e3584.
ꢁ13.9 (c 0.21, EtOH), HPLC condition: Chiralpak AD-H column
(25ꢃ0.46 cm ID), n-hexane/2-propanol¼80:20, 1.0 mL/min, 254 nm
UV detector, tR¼5.24 min for (R)-enantiomer and tR¼7.22 min for

5178
S. Yang et al. / Tetrahedron 68 (2012) 5172e5178
15. (a) Wessely, F.; Prillinger, F. Chem. Ber. 1939, 72B, 629e633; (b) Lamberton, J. A.;
Suares, H.; Watson, K. G. Aust. J. Chem. 1978, 31, 455e457; (c) Muthyala, R. S.; Ju,
Y. H.; Sheng, S.; Williams, L. D.; Doerge, D. R.; Katzenellenbogen, B. S.; Helferich,
W. G.; Katzenellenbogen, J. A. Bioorg. Med. Chem. 2004, 12, 1559e1567; (d)
Gharpure, S. J.; Sathiyanarayanan, A. M.; Jonnalagadda, P. Tetrahedron Lett.
2008, 49, 2974e2978; (e) Li, S.-R.; Chen, P.-Y.; Chen, L.-Y.; Lo, Y.-F.; Tsai, I.-L.;
Wang, E.-C. Tetrahedron Lett. 2009, 50, 2121e2123; (f) Goto, H.; Terao, Y.; Akai, S.
Chem. Pharm. Bull. 2009, 57, 346e360.
22. Periasamy, M.; Rameshkumar, C.; Radhakrishnan, U.; Brunet, J.-J. J. Org. Chem.
1998, 63, 4930e4935.
23. Chapman, O. L.; Adams, W. R. J. Am. Chem. Soc. 1968, 90, 2333e2342.
24. Bednowitz, A. L.; Brown, R. G.; Donaruma, L. G.; Hamilton, W. C.; Kropf, R. A.;
Southwick, P. L.; Stansfield, R. E. J. Org. Chem. 1974, 39, 3537e3543.
25. Bowden, K.; Parkin, D. C. Can. J. Chem. 1968, 46, 3909e3914.
€
ꢀ
ꢀ
26. Felfoldi, K.; Sutyinszky, M.; Nagy, N.; Palinko, I. Synth. Commun. 2000, 30,
1543e1554.
16. For the asymmetric synthesis of (S)-equol based on bio-catalysis, see: (a) Kim,
M.; Kim, S.-I.; Han, J.; Wang, X.-L.; Song, D.-G.; Kim, S.-U. Appl. Environ. Mi-
crobiol. 2009, 75, 3062e3068; (b) Wang, X.-L.; Hur, H.-G.; Lee, J. H.; Kim, K. T.;
Kim, S.-I. Appl. Environ. Microbiol. 2005, 71, 214e219; (c) Miyazawa M.; Horibe
I.; Araki H. WO2011034126, 2011.
17. Heemstra, J. M.; Kerrigan, S. A.; Doerge, D. R.; Helferich, W. G.; Boulanger, W. A.
Org. Lett. 2006, 8, 5441e5443.
18. Takashima, Y.; Kaneko, Y.; Kobayashi, Y. Tetrahedron 2010, 66, 197e207.
19. Setchell K.D.R.; Sorokin V.D. US20070027329, 2007.
27. Michaelidou, A.; Hadjipavlou-Litina, D. J. Enzym. Inhib. Med. Chem. 2003, 18,
537e544.
28. Summers, J. B.; Mazdiyasni, H.; Holms, J. H.; Ratajczyk, J. D.; Dyer, R. D.; Carter,
G. W. J. Med. Chem. 1987, 30, 574e580.
ꢀ
}
€
ꢀ
ꢀ
29. Forgo, P.; Felfoldi, K.; Palinko, I. J. Mol. Struct. 2005, 744, 273e276.
}
ꢀ
€ €
ꢀ
30. Szollosi, G.; Herman, B.; Szabados, E.; Fulop, F.; Bartok, M. J. Mol. Catal. A: Chem.
2010, 333, 28e36.
ꢀ
€
€
31. Bartok, M.; Wittmann, G.; Gondos, G.; Smith, G. V. J. Org. Chem.1987, 52,1139e1141.
ꢀ
32. Camps, P.; Gimenez, S. Tetrahedron: Asymmetry 1996, 7, 1227e1234.
20. Zhu, S.-F.; Xie, J.-B.; Zhang, Y.-Z.; Li, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128,
12886e12891.
33. Vicario, J.; Walko, M.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128,
5127e5135.
21. (a) Nishida, H.; Takada, N.; Yoshimura, M.; Sonoda, T.; Kobayashi, H. Bull. Chem.
Soc. Jpn. 1984, 57, 2600e2604; (b) Brookhart, M.; Grant, B.; Volpe, A. F., Jr.
Organometallics 1992, 11, 3920e3922.
34. Vaccaro, W.; Amore, C.; Berger, J.; Burrier, R.; Clader, J.; Davis, H.; Domalski, M.;
Fevig, T.; Salisbury, B.; Sher, R. J. Med. Chem. 1996, 39, 1704e1719.
35. Kim, M.; Yun, H.; Kwak, H.; Kim, J.; Lee, J. Tetrahedron 2008, 64, 10802e10809.