Synthesis of chiral α-benzyl-β2-hydroxy carboxylic acids through iridium-catalyzed asymmetric hydrogenation of α- oxymethylcinnamic acids

Article abstract of DOI:10.1002/cjoc.201400361

An asymmetric hydrogenation of α-oxymethylcinnamic acids was developed by using chiral spiro phosphine-oxazoline/iridium complexes as catalysts to prepare β²-hydroxycarboxylic acids with high reactivity (TON up to 2000) and excellent enantioselectivity (up to 99.5% ee). By using this highly efficient asymmetric hydrogenation as a key step, a concise total synthesis of natural product homoisoflavone (S)-(+)-4 was accomplished. An asymmetric hydrogenation of α-oxymethylcinnamic acids was developed to prepare β²-hydroxycarboxylic acids with high reactivity (TON up to 2000) and excellent enantioselectivity (up to 99.5% ee), which was applied to a concise total synthesis of a natural product homoisoflavone. Copyright

Full text of DOI:10.1002/cjoc.201400361

FULL PAPER
DOI: 10.1002/cjoc.201400361
Synthesis of Chiral α-Benzyl-β2-hydroxy Carboxylic Acids
through Iridium-Catalyzed Asymmetric Hydrogenation of
α-Oxymethylcinnamic Acids†
Ze-Yu Li, Song Song, Shou-Fei Zhu,* Na Guo, Li-Xin Wang, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin)
An asymmetric hydrogenation of α-oxymethylcinnamic acids was developed by using chiral spiro phosphine-
oxazoline/iridium complexes as catalysts to prepare β2-hydroxycarboxylic acids with high reactivity (TON up to
2000) and excellent enantioselectivity (up to 99.5% ee). By using this highly efficient asymmetric hydrogenation as
a key step, a concise total synthesis of natural product homoisoflavone (S)-(＋)-4 was accomplished.
Keywords asymmetric hydrogenation, chiral spiro ligands, iridium catalysts, α-oxymethylcinnamic acids,
α-benzyl-β2-hydroxy carboxylic acids
Introduction
with 59% overall yield.
Optically active α-benzyl-β2-hydroxycarboxylic ac-
ids are ubiquitous building blocks in the syntheses of
pharmaceuticals and natural products (Scheme 1).[1]
Traditional methods for the preparation of chiral
α-benzyl-β2-hydroxy carboxylic acids largely depend on
multistep transformations from chiral materials,[2] chiral
auxiliary,[3] or through resolution.[4] The catalytic enan-
tioselective accesses, which are undoubtedly more effi-
cient than the traditional methods, have been rarely re-
ported.[5] Considering the high efficiency and reliability,
transition-metal-catalyzed asymmetric hydrogenation of
α-oxymethylcinnamic acids (e.g. compound 2) provides
a straightforward access to chiral α-benzyl-β2-hydroxy
carboxylic acids. However, although a number of chiral
catalysts based on ruthenium, rhodium, and iridium
have been developed for the hydrogenations of diverse
α,β-unsaturated carboxylic acids, and excellent reactiv-
ity and enantioselectivity were achieved,[6] the reported
catalysts for the asymmetric hydrogenation of α-oxy-
methylcinnamic acids showed only low to moderate
enantioselectivity or low yield.[7] We here report an
asymmetric hydrogenation of α-oxymethylcinnamic
acids catalyzed by iridium complexes of chiral spiro
phosphine-oxazoline ligands 3[8] with high reactivity
(turnover number, TON up to 2000) and excellent enan-
tioselectivity (96%－99.5% ee) under mild conditions.
Adopting this efficient catalytic hydrogenation as a key
step, a concise enantioselective total synthesis of natural
product homoisoflavone was accomplished in 7 steps
Results and Discussion
We initially studied the hydrogenation of α-phe-
noxymethylcinnamic acid (2a) with iridium complexes
of chiral spiro phosphine-oxazoline ligands (3) as cata-
lysts (Table 1). The hydrogenation was performed at a
substrate to catalyst mole ratio (S/C) of 200 in MeOH
under 6 atm of H2 at 45 ℃, with 0.5 equiv. of Et3N as
an additive. All the tested chiral spiro iridium catalysts 3
can promote the hydrogenation to afford the desired
hydrogenation product 1a in excellent yields (95%－
99% yield) and enantioselectivity (93%－99% ee, En-
tries 1－3). The catalyst (Sa)-3a having no substituent
group at oxazoline ring gave the best results (99% yield
and 99% ee, Entry 1). The base additive was a crucial
factor for the reaction. In addition to organic base Et3N,
the inorganic base Cs2CO3 also provided high yield and
enantioselectivity (Entry 4). However, the hydrogena-
tion was fully prohibited in the absence of the basic ad-
ditive (Entry 5). The catalyst loading of (Sa)-3a can be
reduced to 0.1 mol% compromising neither reactivity
nor enantioselectivity (Entry 6).
A variety of α-aryloxymethylcinnamic acids (2)
were hydrogenated by using catalyst (Sa)-3a. All the
tested substrates provided excellent yields (＞98%) and
enantioselectivities (98%－99.3% ee). The properties of
the substituents Ar and R of substrates exhibited negli-
gible effect on both reactivity and enantioselectivity of
*
E-mail: sfzhu@nankai.edu.cn; qlzhou@nankai.edu.cn; Tel. 0086-022-23504087; Fax: 0086-022-23506177
Received June 3, 2014; accepted August 7, 2014; published online August 25, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400361 or from the author.
Dedicated to Professor Chengye Yuan and Professor Li-Xin Dai on the occasion of their 90th birthdays.
†
Chin. J. Chem. 2014, 32, 783—787
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
783

Li et al.
FULL PAPER
Scheme 1 Bioactive compounds synthesized from chiral α-oxymethylcinnamic acids
O
Ph
O
Ph
HO
OH
O
H
H
O
Me
S
N
N
O
H
NH
S
N
O
O
Ph
O
O
Me
HIV-1 protease inhibitor
(S,S)-Fasidotril
ref [1a]
ref [1c]
?
O
O
asymmetric
COOH hydrogenation
COOH
OR
*
Ar
ref [1d]
N
Ar
N
N
OH
H
OH
O
OR
1
Ph
2
vasopeptidase inhibitor
ref [1e]
ref [1b]
Me
Me
O
OH
Ph
H
H
O
S
N
N
N
N
N
O2N
H
COOH
O
O
Me
Me
renin inhibitor
O
Me
Me
carboxypeptidase A inhibitor
ance of the reaction undoubtedly facilitates its applica-
tions.
Table 1 Iridium-catalyzed asymmetric hydrogenation of 2a:
optimization of the reaction conditionsa
Natural homoisoflavones possess remarkably abun-
0.5 mol% 3
COOH
COOH
OPh
*
Ph
Ph
+ H2 (6 atm)
0.5 equiv. base
MeOH, 45 oC, 12 h
Table 2 Iridium-catalyzed asymmetric hydrogenation of α-aryl-
oxymethylcinnamic acidsa
OPh
2a
1a
0.5 mol% (Sa)-3a
COOH
COOH
OR
*
Ar
Ar
O
N
+ H2 (6 atm)
0.5 equiv. NEt3
MeOH, 45 oC
R
OR
(Sa)-3a
R = H
-
1
BArF
2
(Sa,S)-3b
(Sa,S)-3c
R = Bn
R = i-Pr
Ir
P
Entry
Ar/R
Time/h Product ee/%
Ar
Ar
1
2
3
4
5
6
7
8
9
C6H5/C6H5 (2a)
12
12
12
12
12
12
12
1a
1b
1c
1d
1e
1f
99
Ar = 3,5-tBu2C6H3
C6H5/2-MeC6H4 (2b)
C6H5/3-MeC6H4 (2c)
C6H5/4-MeC6H4 (2d)
C6H5/2-ClC6H4 (2e)
C6H5/3-ClC6H4 (2f)
C6H5/4-ClC6H4 (2g)
99.1
98
Entry Catalyst
Base
NEt3
Conv.b/%
Yieldc/% eed/%
99
1
2
3
4
5
6f
(Sa)-3a
100
100
100
99
97
95
96
nde
96
99
97
93
96
nde
98
99.1
99.2
99
(Sa,S)-3b NEt3
(Sa,S)-3c NEt3
1g
1h
1j
(Sa)-3a
(Sa)-3a
(Sa)-3a
Cs2CO3 100
4-MeOC6H4/3,5-(MeO)2C6H3 (2h) 12
99.3
99
none
NEt3
0
C6H5/Me (2j)
0.5
2
100
10 C6H5/Bn (2k)
11b C6H5/Bn (2k)
1k
1k
1l
99
a Reaction conditions: 0.5 mmol scale, [substrate]＝0.25 mol/L,
−
12
2
96
3/2/base＝0.0025∶0.5∶0.25, pH2＝6 atm, at 45 ℃, 12 h. BArF
is tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. b Determined by
12 4-MeC6H4/Bn (2l)
13 3,4-(OCH2O)C6H3/Bn (2m)
14 3-MeO-4-BnOC6H3/Bn (2n)
15 3,4-(MeO)2C6H3/Bn (2o)
16 C6H5/H (2p)
a Reaction conditions and analysis were the same as those of Ta-
ble 1, Entry 1. Full conversion and over 98% yields were obtained
in all cases. b Using 0.05 mol% catalyst.
99
c
d
1H NMR. Isolated yield. Determined by chiral supercritical
2
1m
1n
1o
1p
99
e
fluid chromatography (SFC). Not detected. f Using 0.1 mol%
2
99
catalyst, 24 h.
2
99
12
99
the reaction (Table 2). It is worthy to mention that the
unprotected α-hydroxymethylcinnamic acid 2p can also
be hydrogenated with high yield and excellent enantio-
selectivity (Entry 16). The high functional group toler-
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 783—787

Synthesis of Chiral α-Benzyl-β2-hydroxy Carboxylic Acids
dant biological activities.[9] Isolation of new homoiso-
flavones arouses great interest from phytochemists,[10]
while the asymmetric synthesis of homoisoflavones re-
mains undeveloped. The homoisoflavone (S)-( ＋ )-4
(Scheme 2) separated from Chlorophytum Inornatum
bears stereogenic center at C3 position and possesses
significant antibacterial activity.[11] Recently, Oudeyer
and Levacher et al.[12] accomplished the asymmetric
synthesis of (S)-(＋)-4 in 12 steps with 7% yield and
81% ee by using an organocatalyzed enantioselective
protonation reaction as a key step.
To demonstrate the utility of the current asymmetric
hydrogenation, we conducted the total synthesis of
(S)-(＋)-4 by using catalyst (Ra)-3a (Scheme 2). First,
α-aryloxymethylcinnamic acid (2i) was prepared from
commercially available 4-methoxybenzaldehyde through
a Perkin condensation, an esterification, a bromination
with NBS, a Williamson etherification with appropriate
phenols, and a basic hydrolysis with high yield. The
hydrogenation of 2i was performed using catalyst
(Ra)-3a to produce (S)-1i with quantitative yield and
extremely high enantioselectivity (99.5% ee). Finally, a
Brønsted acid-catalyzed Friedel-Crafts acylation of
(S)-1i produced the target molecule (S)-(＋)-4 in 98%
yield with 97% ee. The low temperature and solvent free
condition in the Friedel-Crafts acylation reaction are key
factors for resisting the epimerization. Thus the asym-
metric total synthesis of highly optically pure (S)-(＋)-4
was achieved in high yield (59%) from readily accessi-
ble starting materials with 7 easy-handling steps. This
catalytic asymmetric hydrogenation significantly ad-
vances the efficiency of the total synthesis of natural
homoisoflavones.
ium-catalyzed asymmetric hydrogenation of α-oxymeth-
ylcinnamic acids, which provides a readily approach to
the optically active β2-hydroxycarboxylic acids. The use
of iridium-catalyzed asymmetric hydrogenation of
α-oxymethylcinnamic acids provided a concise total
synthesis of natural product homoisoflavone (S)-(＋)-4.
Experimental
General
All the air or moisture sensitive reactions and ma-
nipulations were performed under a nitrogen atmosphere
by using standard Schlenk techniques and a Vacuum
Atmospheres Drybox (VAC DRI-LAB HE 493). Melt-
ing points were measured on a RY-I apparatus and un-
13
corrected. 1H, and C NMR spectra were recorded on a
Bruker AV 400 spectrometer at 400 MHz (1H NMR)
and 100 MHz (13C NMR). Chemical shifts were re-
ported in ppm down field from internal Me4Si and ex-
ternal 85% H3PO4, respectively. Mass spectra were re-
corded on IonSpec FT-ICR mass spectrometer with ESI.
Enantiomeric excesses of the asymmetric hydrogenation
products were determined by chiral HPLC or SFC.
HPLC analyses were performed using a Hewlett Pack-
ard Model HP 1100 Series instruments. SFC analyses
were performed using a Mettler-Toledo Model Analytix
SFC. The spiro ligands are commercially available from
Strem Co. and Jiuzhou Pharm. Anhydrous Et2O and
THF were distilled from sodium benzophenoneketyl.
Anhydrous CH2Cl2 and NEt3 were freshly distilled from
calcium hydride under nitrogen atmosphere. Anhydrous
MeOH was distilled from magnesium under nitrogen
atmosphere. Hydrogen gas (99.999%) was purchased
from Boc Gas Inc., Tianjin. All commercially available
chemicals were used as received unless otherwise noted.
Conclusions
In summary, we developed a highly efficient irid-
Scheme 2 Enantioselective total synthesis of (S)-(＋)-homoisoflavone 4 (NBS＝N-bromosuccinimide; AIBN＝2,2'-azobisisobutyro-
nitrile)
(C2H5CO)2O
COOMe
Me
CHO
COOH
Me
CH3I, K2CO3
NBS, AIBN
C2H5COONa
MeO
DMF
99%
CCl4
95%
MeO
76%
E/Z > 20:1
MeO
O
O
COOMe
COOH
O
H2 (6 atm)
COOMe
Br
HO
NaOH, H2O
0.5 mol% (Ra)-3a
MeO
O
MeO
MeOH
99%
0.5 equiv. NEt3
MeOH, 45 oC, 12 h
99%
MeO
acetone
96%
O
O
O
(87% after recryl.)
O
2i
COOH
O
O
O
TFA, TFAA
98%
MeO
OMe
O
O
O
O
(S)-(+)-homoisoflavone (4)
97% ee
1i
99.5% ee
Chin. J. Chem. 2014, 32, 783—787
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
785

Li et al.
FULL PAPER
General procedure of hydrogenation
of China, the National Basic Research Program of China
(No. 2012CB821600), and the “111” Project (No.
B06005) of the Ministry of Education of China for fi-
nancial support.
A hydrogenation tube was charged with a stir bar,
substrate 2a (0.5 mmol), and catalyst (Sa)-3a (0.0025
mmol). MeOH (2 mL) and Et3N (0.25 mmol) were in-
jected into the hydrogenation tube with a syringe while
stirring. The hydrogenation tube was put into an auto-
clave. The air in the autoclave was replaced with hy-
drogen for five times and finally charged with hydrogen
to 6 atm. The reaction mixture was stirred at 45 ℃ for
12 h. After releasing hydrogen, the reaction solution was
treated with 5% NaOH (10 mL). The aqueous layer was
washed with Et2O (10 mL). The aqueous layer was
acidified with 3 mol/L HCl (pH 1) and extracted with
Et2O (10 mL×3). The combined extracts were washed
with saturated brine, dried over MgSO4, and evaporated
in vacuo to produce the hydrogenation product 1a.[13]
After a flash chromatography on silica gel column with
petroleum ether/ethyl acetate＝1∶1 (V∶V), the desired
chiral acid was obtained as a white solid, 99% yield.
m.p. 104 － 106 ℃ . 99% ee. [α]2D3 –34.6 (c 1.0,
chloroform). SFC conditions: Chiralpak AD-3 column
(25 cm×0.46 cm ID), scCO2/2-propanol＝80∶20, flow
rate＝2.0 mL/min, column backpressure＝100 bar, 220
nm UV detector, tR＝6.08 min for major isomer and tR
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CDCl3) δ: 7.23－6.96 (m, 7H), 6.95 (t, J＝7.2 Hz, 1H),
6.87 (d, J＝8.1 Hz, 2H), 4.09 (dt, J＝13.4, 9.1 Hz, 2H),
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47.0, 34.1.
Synthesis of (S)-7-(4-methoxybenzyl)-7,8-dihydro-
6H-[1,3]dioxolo[4,5-h]chromen-6-one (4)
A mixture of the hydrogenation product (S)-1i (40
mg, 0.121 mmol), trifluoroacetic acid (300 μL), and
trifluoroacetic anhydride (900 μL) was stirred at −10 ℃
for 6 h. The mixture was evaporated in vacuo and puri-
fied by column chromatography (silica gel, EtOAc/pe-
troleum ether, 1∶5, V∶V) to give the product 4 as a
white solid (37 mg, 98%).[14] m.p. 103－105 ℃. 97%
ee. [α]D23＋59.8 (c 1.0, chloroform). SFC conditions:
Lux 5uCellulose-3 OJ-H column (25 cm×0.46 cm ID),
scCO2/2-propanol＝70∶30, flow rate＝2.0 mL/min,
column backpressure＝100 bar, 220 nm UV detector, tR
1
＝5.23 min (R) and tR＝7.72 min (S). H NMR (400
MHz, CDCl3) δ: 7.59 (d, J＝8.4 Hz, 1H), 7.16 (d, J＝
8.5 Hz, 2H), 6.86 (d, J＝8.6 Hz, 2H), 6.61 (d, J＝8.4 Hz,
1H), 6.08 (s, 2H), 4.41 (dd, J＝11.5, 4.0 Hz, 1H), 4.24
(dd, J＝11.4, 7.1 Hz, 1H), 3.80 (s, 3H), 3.17 (dd, J＝
13.9, 4.4 Hz, 1H), 2.88－2.81 (m, 1H), 2.74－2.68 (m,
1H); 13C NMR (101 MHz, CDCl3) δ: 192.1, 158.3,
153.9, 145.4, 134.3, 130.1, 130.0, 123.0, 117.2, 114.0,
103.4, 102.6, 70.0, 55.2, 48.1, 31.8.
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We thank the National Natural Science Foundation
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 783—787

Synthesis of Chiral α-Benzyl-β2-hydroxy Carboxylic Acids
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(Cheng, F.)
Chin. J. Chem. 2014, 32, 783—787
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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