Iridium/f-Amphox-Catalyzed Asymmetric Hydrogenation of Styrylglyoxylamides

Article abstract of DOI:10.1055/s-0037-1609623

We report an iridium-catalyzed asymmetric hydrogenation reaction for the preparation of chiral homophenylalanine derivatives. Catalyzed by an iridium/f-amphox complex, the asymmetric hydrogenation of styrylglyoxylamides was conducted smoothly with turnover numbers of up to 10,000 and up to 98% ee. This method was successfully applied in a synthesis of a fragment of benazepril, a drug used for the treatment of high blood pressure.

Full text of DOI:10.1055/s-0037-1609623

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
en
A
S. Wang et al.
Letter
Synlett
Iridium/f-Amphox-Catalyzed Asymmetric Hydrogenation of
Styrylglyoxylamides
Simin Wanga
Yuena Yua
Jialin Wen*a,b
OH
O
[Ir(COD)Cl]2 (0.05 mol%)
H
H
N
R1
N
R1
R2
L1 (0.11 mol%)
R2
0
0
0
0
0-
0
0
3
3-
3
2
8
3-
2
6
5
O
O
DCE, KOH
Xumu Zhang*a,c
H2 (20 atm)
TON up to 10000
r.t., 12 h
a Department of Chemistry, Southern University of Science and Technolo-
gy, 1088 Xueyuan Road, Shenzhen, 518055, P. R. of China
wenjl@sustc.edu.cn
COOH
H
N
16 examples
96–99% yield
94–98% ee
O
O
N
zhangxm@sustc.edu.cn
N Ph2P
b Academy for Interdisciplinary Studies, Southern University of Science and
Technology, 1088 Xueyuan Road, Shenzhen, 518055, P. R. of China
c Shenzhen Grubbs Institute, Southern University of Science and Technolo-
gy, 1088 Xueyuan Road, Shenzhen, 518055, P. R. of China
NH
O
Fe
O
L1
f-amphox
benzazepril
Received: 28.04.2018
O
O
O
O
Accepted after revision: 30.07.2018
Published online: 20.08.2018
O
N
H
N
O
O
DOI: 10.1055/s-0037-1609623; Art ID: st-2018-u0271-l
N
H
O
H
OH
N
Abstract We report an iridium-catalyzed asymmetric hydrogenation
reaction for the preparation of chiral homophenylalanine derivatives.
Catalyzed by an iridium/f-amphox complex, the asymmetric hydroge-
nation of styrylglyoxylamides was conducted smoothly with turnover
numbers of up to 10,000 and up to 98% ee. This method was success-
fully applied in a synthesis of a fragment of benazepril, a drug used for
the treatment of high blood pressure.
OH
H
ramipril
O
O
moexipril hydrochloride
O
OH
O
N
Key words homophenylalanines, asymmetric catalysis, iridium cataly-
sis, hydrogenation, benazepril
S
S
NH⋅HCl
O
O
NH
N
O
temocapril hydrochloride
The last two decades have witnessed the widespread
application of inhibitors of angiotensin-converting enzyme
(ACE).1 Most ACE inhibitors with therapeutic significance
contain a common unit: L-homophenylalanine. This family
of building blocks is found in numerous chiral bioactive
molecules (Figure 1),2 including some successful drugs such
as ramipril and benazepril. Many efforts have been made to
develop a reliable and economical method for preparing op-
tically pure homophenylalanine and its derivatives.3 Com-
pared with heterogeneous systems,4 which have advantages
in terms of catalyst cost and robustness, homogeneous cat-
alytic hydrogenation have other advantages, such as a high
turnover efficiency and a high enantioselectivity (>95% ee).
Although chiral amino acids are readily prepared by using
the Wilkinson–Osborn Rh/bisphosphine system, cases with
a high turnover number (TON) in excess of 10,000 are rare.5
To develop an efficient approach to optically pure ho-
mophenylalanine derivatives, new synthetic methods are
still in demand.
S
O
O
H
N
O
O
O
OH
N
HN
O
N3
KNI-694
O
⋅HCl
O
O
HO
H
N
OH
O
N
O
O
O
N
NH
O
O
benazepril
delapril hydrochloride
Figure 1 Bioactive molecules containing a homophenylalanine unit
As part of our continuing interest in applying transi-
tion-metal-catalyzed asymmetric hydrogenation (AH) in
the preparation of chiral molecules, we attempted to design
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
S. Wang et al.
Letter
Synlett
condensation. The resulting chiral alcohols can be trans-
formed into the desired amino acids in two steps with in-
version of the chiral center. The challenges in the hydroge-
nation step lies in both its chemoselectivity and its enanti-
oselectivity: selective 1,2-reduction of conjugated ketone
and differentiation between the vinyl and the carboxy
group must be achieved in a single step.
O
O
CHO
X
AH
X
R1
+
R1
O
key step
O
X = NR2 or OR
OH
OH
MsCl
Pd/C
H2
X
X
*
*
R1
R1
NHR2
O
O
We recently developed a series of ferrocene-based tri-
dentate ligand for Ir-catalyzed AH: f-amphox (L1),6 f-am-
phol (L2),7 and f-ampha (L3).8 This family of ligands showed
excellent reactivities and stereoselectivities in AH of simple
and functionalized ketones. In these successful examples of
ketone reduction reactions, an NH effect was proposed to
be responsible for the high TON with such polarized double
bonds as carbonyl.9 We surmised that the polar C=O bond in
a styrylglyoxylamide might be reduced in the presence of
an iridium complex, with retention of the C=C bond.
NR2
*
X
R1
O
chiral homophenylalanine derivatives
Scheme 1 Synthetic route to chiral homophenylalanine derivatives
a practical synthetic route to chiral homophenylalanine de-
rivatives (Scheme 1). As hydrogenation substrates, styryl-
glyoxylic acid derivatives can be readily obtained by aldol
Table 1 Optimization of the Asymmetric Hydrogenation of 1aa
OH
H
O
H
N
[Ir(COD)Cl]2/Ligand
N
base, H2, r.t.
S/C = 1000
O
O
1a
2a
H
N
H
H
N
N
O
Ph2P
O
N
Ar2P
Fe
OH
Ar2P
OH
Fe
Fe
Ar = 3,5-(tBu)2C6H3
(RC, SC, SC, RFC)-f-amphol
Ar = 3,5-(tBu)2C6H3
(SC, SC, RFC)-f-ampha
L3
(SC, SC, RFC)-f-amphox
L1
L2
Entry
Ligand
Solvent
Base
Conversionb (%)
eec (%)
1
L1
L2
L3
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
i-PrOH
i-PrOH
i-PrOH
toluene
CH2Cl2
THF
t-BuOK
99
92
NDd
ND
89
82
85
ND
83
94
79
92
91
94
90
94
2
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
MeONa
Cs2CO3
KOH
trace
trace
99
3
4
5
99
6
99
NRe
7
F3CCH2OH
EtOH
DCE
8
55
9
99
10
11
12
13
14
15f
DCE
99
DCE
77
DCE
81
DCE
99
DCE
MeOK
91
DCE
KOH
99
a Reaction conditions: 1a (0.1 mmol), [Ir(COD)Cl]2 (0.05 mol%), ligand (0.11 mol%), solvent (1 mL), H2 (50 atm), 12 h.
b Determined by 1H NMR analysis.
c Determined by HPLC analysis.
d ND = not determined.
e NR = no reaction.
f 20 atm.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
S. Wang et al.
Letter
Synlett
We commenced our study by testing the reactivity of
these tridentate ligands in Ir-catalyzed AH of N-benzyl-2-
hydroxy-4-phenylbut-3-enamide (1a). The reaction was
carried out at room temperature in i-PrOH in the presence
t-BuOK and an iridium catalyst generated in situ by mixing
[Ir(COD)Cl]2 with L1–L3 [substrate/catalyst ratio (S/C) = 1000]
(Table 1). Although iridium complexes of these three li-
gands are all excellent catalysts for AH of acetophenone,
their performances in this case were totally different. It was
interesting to find that f-amphol and f-ampha lacked activi-
ty (Table 1, entries 2 and 3), whereas f-amphox showed a
high enantioselectivity (92% ee) with full conversion in the
AH of the model substrate (entry 1). Careful screening of
the solvent revealed that this reaction proceeded smoothly
in DCE with a high conversion and high enantioselectivity
(entries 4–9). Further evaluation of various bases were car-
ried out in an attempt to improve the enantioinduction
with L1 as the ligand. Whereas sodium and cesium bases
produced slightly lower enantioselectivities, potassium
bases (t-BuOK and KOH) emerged as better choices (entries
10 and 14), providing higher enantioselectivities (94% ee)
and conversions (99%). When we reduced the hydrogena-
tion pressure from 50 to 20 atm (entry 15), no significant
change occurred in the conversion or the ee.
With the optimal reaction conditions (Table 1, entry 15)
in hand, we investigated the substrate scope of this asym-
metric hydrogenation of styrylglyoxylamides. A wide range
of substrates were investigated. In general, the AH reactions
proceeded smoothly to afford the desired chiral -hydroxy
-enamides in excellent yields and high enantiomeric ex-
O
OH
H
[Ir(COD)Cl]2 (0.05 mol%)
f-amphox (0.11 mol%)
R1
N
H
R1
N
R2
R2
DCE/iPrOH = 22.2:1
O
O
KOH, H2 (20 atm), r.t., 12 h
1
2
OH
OH
H
OH
OH
H
N
H
N
H
N
N
O
O
O
O
2a
2b
2c
2d
98% yield, 94% ee
96% yield, 94% ee
99% yield, 98% ee
98% yield, 94% ee
OH
H
OH
H
OH
N
N
N
O
O
Br
Cl
O
2e
nr
2f
2g
98% yield, 95% ee
98% yield, 96% ee
OH
OH
H
OH
H
F
OH
H
H
Br
N
N
N
N
O
O
O
O
F3C
2h
2i
2j
2k
96% yield, 97% ee
97% yield, 98% ee
96% yield, 95% ee
99% yield, 98% ee
OH
OH
H
H
OH
OH
H
MeO
N
H
N
F
N
N
O
O
O
S
O
F
2l
2m
2n
2o
98% yield, 98% ee
99% yield,98% ee
97% yield, 96% ee
98% yield, 97% ee
OH
H
OH
H
OH
H
OH
H
N
N
N
N
O
O
O
O
O
N
2p
2q
2r
nr
2s
nr
99% yield, 98% ee
97% yield, 96% ee
Scheme 2 Scope study for the asymmetric hydrogenation of -keto amides 1 with Ir/f-amphox Reaction conditions: 1 (0.2 mmol), [Ir(COD)Cl]2 (0.05
mol%), ligand L1 (0.11 mol%), DCE (2 mL), i-PrOH (90 L), r.t., 12 h. Isolated yields are reported, and the ee values were determined by HPLC analysis.
The absolute configuration of 2c was determined by comparing its optical rotation with that reported in the literature.10 The structure of 2g was con-
firmed by single-crystal X-ray diffraction analysis.11
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
S. Wang et al.
Letter
Synlett
cesses (Scheme 2). Various secondary amides 1a–d were in-
vestigated, and the tert-butyl amide 1c was found to give
the corresponding chiral alcohol 2c with excellent selectivi-
ty (99% yield, 98% ee). Tertiary amide 1e, however, was not
hydrogenated under these conditions. Substrates contain-
ing para-, ortho-, or meta-substituents with various elec-
tronic effects on the benzene ring provided hydrogenated
products with satisfactory yields and enantioselectivities.
Gratifyingly, substrates containing heterocycles such as
thiophene or furan also reacted smoothly (2o: 98% yield,
97% ee; 2p: 99% yield, 98% ee). Regrettably, pyridylvinyl and
alkyl substrates did not react smoothly under these condi-
tions (2r and 2s).
To demonstrate a synthetic application of this method, a
scaled-up reaction of 1c was conducted and 2c was ob-
tained in 96% yield and 95% ee (Scheme 3). In accordance
with the high efficiency in the previously reported Ir/f-am-
phox catalyzed AH of ketones, the turnover number in the
case was up to 10,000 with a low loading of base (1 mol%
KOH) under 50 atm of H2 at 25 °C.
(5c), with retention of the chirality at the C-2 position.
Benazepril can be readily prepared from the -hydroxy es-
ter 5c by a known method12 (Scheme 2).
In summary, we have developed a straightforward
method for preparing chiral 2-hydroxy-4-phenylbutanoic
acid derivatives by using an AH strategy.13 Styrylglyoxyl-
amides can be efficiently hydrogenated with high chemose-
lectivity and high enantioselectivity in the presence of an
Ir/f-amphox complex catalyst. We believe that this method
will benefit the synthesis community in facilitating the
preparation of chiral homophenylalanine derivatives. The
presence of the homophenylalanine unit in many drugs,
such as benazepril and ramipril, highlights the potential in-
dustrial applications of this method.
Funding Information
We thank the Shenzhen Basic Research Free Exploration Fund
(JCYJ20170817104853520)
and
Shenzhen
Peacock
Plan
(KQTD2015071710315717) from the Shenzhen Commission of Sci-
ence, Technology and Innovation.
)(
OH
O
Ir/f-amphox
KOH (1 mol%)
H
H
N
N
Acknowledgment
O
DCE, H2 (50 atm)
r.t., 12 h
S/C = 10000
O
2c
1c
46.2 mg
We thank Mr. Jiong Yang for the single-crystal x-ray diffraction analysis.
99% yield, 97% ee
96% yield, 95% ee
0.6 g
OH
O
Supporting Information
H
H
N
(1) Ir/f-amphox
(S/C= 10000)
KOH, H2
N
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609623.
O
O
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
3c
1c
0.3 g
(2) 5% Pd/C
(5 wt%)
MeOH, H2
86% yield
99% ee after recrystallization
References and Notes
OH
O
(1) HBr/H2O
120 °C, 12 h
H2N
(1) Parmley, W. W. Am. J. Med. 1998, 105, 27S.
N
O
(2) (a) Hou, F. F.; Zhang, X.; Zhang, G. H.; Xie, D.; Chen, P. Y.; Zhang,
W. R.; Jiang, J. P.; Liang, M.; Wang, G. B.; Liu, Z. R.; Geng, R. W. N.
Engl. J. Med. 2006, 354, 131. (b) Frampton, J. E.; Peters, D. H.
Drugs 1995, 49, 440. (c) Chrysant, S. G.; Chrysant, G. S. Expert
Rev. Cardiovasc. Ther. 2003, 1, 345. (d) Yasunari, K.; Maeda, K.;
Nakamura, M.; Watanabe, T.; Yoshikawa, J.; Asada, A. Cardio-
vasc. Drug Rev. 2004, 22, 189. (e) McCormack, P. L.; Keating, G.
M. Drugs 2006, 66, 961.
O
O
(2) 10% H2SO4/EtOH
r.t., 24 h
5c
O
55% yield for two steps
99% ee
ref. 9
HO
O
O
N
NH
(3) Ahmad, A. L.; Oh, P. C.; Abd Shukor, S. R. Biotechnol. Adv. 2009,
27, 286.
(4) (a) Blaser, H.-U.; Jalett, H. P.; Wiehl, J. J. Mol. Catal. 1991, 68,
215. (b) Blaser, U.-H.; Jalett, H.-P.; Spindler, F. J. Mol. Catal. A:
Chem. 1996, 107, 85. (c) Blaser, H.-U.; Studer, M. Acc. Chem. Res.
2007, 40, 1348.
O
O
benazepril
Scheme 3 Scaled-up AH of a styrylglyoxylamide and a practical syn-
thetic route to benazepril
(5) The Handbook of Homogeneous Hydrogenation; de Vries, J. G.;
Elsevier, C. J., Ed.; Wiley-VCH: Weinheim, 2008.
(6) Wu, W.; Liu, S.; Duan, M.; Tan, X.; Chen, C.; Xie, Y.; Lan, Y.; Dong,
X.-Q.; Zhang, X. Org. Lett. 2016, 18, 2938.
(7) Yu, J.; Long, J.; Yang, Y.; Wu, W.; Xue, P.; Chung, L. W.; Dong,
X.-Q.; Zhang, X. Org. Lett. 2017, 19, 690.
(8) Yu, J.; Duan, M.; Wu, W.; Qi, X.; Xue, P.; Lan, Y.; Dong, X.-Q.;
Zhang, X. Chem. Eur. J. 2017, 23, 970.
Transformations of the chiral alcohol 2c were per-
formed. A Pd/C-catalyzed reduction of the C=C double bond
was conducted with the crude AH reaction mixture to give
chiral -hydroxybutamide 3c in 86% yield and 99% ee after
crystallization. Hydrolysis with aqueous HBr and sequential
esterification gave ethyl (2S)-2-hydroxy-4-phenylbutanoate
(9) Zhao, B.; Han, Z.; Ding, K. Angew. Chem. Int. Ed. 2013, 52, 4744.
(10) Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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S. Wang et al.
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(11) CCDC 1862847 contains the supplementary crystallographic
data for compound 2g. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
mixture was stirred at r.t. for 12 h. The hydrogen gas was
released slowly in a well-ventilated hood, and the solution was
passed through a short column of silica gel to remove the metal
1
complex. The product was analyzed by H NMR for conversion,
(12) Thaper, R. K.; Kumar, Y.; De, S.; Kumar, D. S. M. WO 02076375,
2002.
(13) Asymmetric Hydrogenation of Styrylglyoxylamides 1a–r;
General Procedure
and the ee was determined by HPLC.
(14) (S,3E)-N-(tert-Butyl)-2-hydroxy-4-phenylbut-3-enamide (2c)
White solid; yield: 46 mg (99%; conversion: 99%; 98% ee); mp
24
71–74 °C; []D –7.8 (c 0.5, MeOH). HPLC: Chiracel AD-3
In an argon-filled glove box, a 10 mL vial was charged with
[Ir(COD)Cl]2 (4.0 mg, 5.9 ×10–3 mmol), f-amphox (7.3 mg, 13.1 ×
10–3 mmol), and anhyd i-PrOH (3 mL). The mixture was stirred
for 2 h at 25 °C to give an orange-red solution. The resulting
solution (50 L, c = 4 × 10–3 mmol/mL) and a solution of KOH in
i-PrOH (40 L, c = 0.05 mmol/mL) were transferred by a syringe
into a 5 mL vial charged with the appropriate -keto -enamide
(0.2 mmol) in DCE (2 mL). The vial was transferred to an auto-
clave, which was then charged with 20 atm of H2 and the
column [254 nm, 25 °C, hexane–i-PrOH (80:20); flow: 1.0
mL/min]; tR1 = 4.0 min, tR2 = 4.4 min. 1H NMR (400 MHz, CDCl3):
 = 7.36–7.29 (m, 2 H), 7.25 (dd, J = 9.9, 4.7 Hz, 2 H), 7.21–7.15
(m, 1 H), 6.65 (d, J = 15.9 Hz, 1 H), 6.18 (dd, J = 15.9, 7.0 Hz, 1 H),
5.97 (s, 1 H), 4.51 (d, J = 6.9 Hz, 1 H), 3.52 (s, 1 H), 1.29 (s, 9 H).
13C NMR (101 MHz, CDCl3):  = 171.5, 136.3, 132.6, 128.6, 128.0,
127.4, 126.8, 73.0, 51.4, 28.8. HRMS-ESI: m/z [M + Na]+ calcd for
C
14H19NNaO2: 256.1305; Found: 256.1308.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E