Highly efficient asymmetric hydrogenation of cyano-substituted acrylate esters for synthesis of chiral γ-lactams and amino acids

Article abstract of DOI:10.1039/c5ob02422f

A highly efficient and enantioselective synthesis of γ-lactams and γ-amino acids by Rh-catalyzed asymmetric hydrogenation has been developed. Using the Rh-(S,S)-f-spiroPhos complex, under mild conditions a wide range of 3-cyano acrylate esters including both E and Z-isomers and β-cyano-α-aryl-α,β-unsaturated ketones were first hydrogenated with excellent enantioselectivities (up to 98% ee) and high turnover numbers (TON up to 10 000).

Full text of DOI:10.1039/c5ob02422f

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Highly efficient asymmetric hydrogenation of
cyano-substituted acrylate esters for synthesis
Cite this: DOI: 10.1039/c5ob02422f
of chiral γ-lactams and amino acids†
Received 25th November 2015,
Accepted 8th December 2015
Duanyang Kong, Meina Li, Rui Wang, Guofu Zi and Guohua Hou*
DOI: 10.1039/c5ob02422f
www.rsc.org/obc
A highly efficient and enantioselective synthesis of γ-lactams and
γ-amino acids by Rh-catalyzed asymmetric hydrogenation has
been developed. Using the Rh-(S,S)-f-spiroPhos complex, under
mild conditions a wide range of 3-cyano acrylate esters including
both E and Z-isomers and β-cyano-α-aryl-α,β-unsaturated ketones
were first hydrogenated with excellent enantioselectivities (up to
98% ee) and high turnover numbers (TON up to 10 000).
As a privileged structural skeleton, chiral lactams are found in
a broad range of natural and biologically active molecules,1
such as a number of widely employed medicinal agents, peni-
cillins, cephalosporins, carbapenems, monobactams, salino-
sporamide A, rolipram and brivaracetam. Although chiral
β-lactams as the largest subclass of the lactam family are
especially attractive as antibiotics, γ-lactams are also very
important (Fig. 1),2 and widely exist in many natural products
and pharmaceuticals.3 For example, brivaracetam, bearing a
chiral γ-lactam, has an anticonvulsant effect by binding to the
ubiquitous synaptic vesicle glycoprotein 2A (SV2A).4 Particu-
larly, enantiomerically pure γ-lactams, as key intermediates,
are readily converted into pharmacologically important mole-
cules, such as 2,3-disubstituted pyrrolidines.5 Moreover,
γ-lactams can also be easily hydrolyzed to the corresponding
amino acids and their derivatives,6 which are analogues of the
neurotransmitter, γ-aminobutyric acid (GABAs) used for the
treatment of a series of central nervous system disorders.7
Thus, a simple efficient method for the synthesis of optically
active γ-lactams is highly desirable.
Fig. 1 Structures of biologically active compounds involving lactam
moieties.
corresponding γ-lactams and amino acids.6b,10 Recently, we
reported the synthesis of a chiral ferrocenyl diphosphine
ligand, f-spiroPhos, combined with a privileged spirobiindane
skeleton, which was developed by Zhou and co-workers,11 and
proved its high efficiency in the asymmetric hydrogenation of
nitroolefins.12 It is the excellent performance exhibited in pre-
vious work that promts us to evaluate the hydrogenation of
cyano-substituted acrylate esters with the Rh-(S,S)-f-spiroPhos
complex. Herein, we report the first highly efficient and
enantioselective hydrogenation of this kind of substrate, which
provides a new efficient route to optically active γ-lactams as
well as γ-amino acids (Scheme 1).13
Initially, asymmetric hydrogenation of (Z)-methyl 3-cyano-
2-phenylacrylate 1a was investigated by using the complex of
(S,S)-f-spiroPhos and [Rh(COD)2]BF4 as the catalyst under 70 atm
of H2 in CH2Cl2 for 12 h. At room temperature, albeit excellent
enantioselectivity, 98% ee, incomplete conversion was
observed. When we used [Rh(COD)Cl]2 as the metal precursor,
only 9% conversion was achieved. Fortunately, an increase of
the reaction temperature to 40 °C resulted in full conversion
Despite a number of successful examples of asymmetric
hydrogenation of other types of prochiral substrates,8 to the
best of our knowledge, the direct hydrogenation of cyano-sub-
stituted acrylate esters has not yet been reported.9 The result-
ing hydrogenation products can be readily converted into the
Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal
University, No. 19 Xinjiekouwai St., Beijing 100875, China.
E-mail: ghhou@bnu.edu.cn
†Electronic supplementary information (ESI) available: General experimental
procedures, compound characterization data and analysis of enantioselectivities
of hydrogenation products. See DOI: 10.1039/c5ob02422f
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Scheme 1 Rh-catalyzed asymmetric hydrogenation of cyano-substi-
tuted acrylate esters.
Fig. 2 Structures of the ligand screened.
without any loss of the ee value (Table 1, entries 1 and 2). Fur-
thermore, a screening of other chiral phosphorus ligands avail-
able in our lab revealed that most of the ligands including
(S)-BINAP, (S,R)-DuanPhos, (R)-JosiPhos, (S,S)-f-Binaphane,
(R)-DM-SegPhos and (S)-MonoPhos (Fig. 2) exhibited only low
activity and poor enantioselectivity for this reaction (entries
3–8). Subsequently, the solvent effect was investigated and had
However, much lower hydrogen pressure would result in
incomplete conversion.
Encouraged by the promising result obtained in the hydro-
genation of (Z)-methyl 3-cyano-2-phenylacrylate 1a, a variety of
(Z)-3-cyano-2-substituted acrylate esters
1 were examined
under the optimized reaction conditions. As the results illus-
trate in Table 2, the electronic properties of the substituent at
the meta or para-position of the aromatic ring had no obvious
influence on both the reactivity and enantioselectivity, and
full conversions with excellent ee values, 95%–98% ee, were
a
significant influence on the conversion and enantio-
selectivity. Toluene, DME, Et2O and MeOH gave only poor con-
versions and moderate enantioselectivities (entries 9 and
12–14), while THF and dioxane provided full conversions and
slightly lower enantioselectivities (entries 10 and 11). Notably,
under lower hydrogen pressure, 30 atm, the hydrogenation was
complete in 8 h with unchanged enantioselectivity (entry 15).
Table 2 Rh-catalyzed asymmetric hydrogenation of (Z)-3-cyano-2-
substituted acrylate esters 1a
Table 1 Rh-catalyzed asymmetric hydrogenation of (Z)-methyl
3-cyano-2-phenylacrylate 1a, optimizing reaction conditionsa
Entry
R
R′
Product
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
C6H5(1a)
C6H5(1b)
CH3
C2H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
>99(98)
>99(97)
>99(97)
>99(96)
>99(96)
>99(97)
>99(97)
>99(98)
>99(96)
>99(98)
>99(97)
>99(95)
>99(98)
>99(98)
>99(97)
99(95)
98(R)d
96(−)
96(−)
97(−)
97(−)
98(−)
97(−)
97(−)
97(−)
97(−)
95(−)
98(−)
98(−)
97(−)
97(−)
97(−)
4-CH3C6H4(1c)
4-CH3OC6H4(1d)
4-FC6H4(1e)
4-ClC6H4(1f)
4-BrC6H4(1g)
3-CH3C6H4(1h)
3-CH3OC6H4(1i)
3-FC6H4(1j)
2-CH3C6H4(1k)
2-CH3OC6H4(1l)
1-Naphthyl(1m)
2-Naphthyl(1n)
iPr(1o)
Entry Ligands
T (°C) Solvent
Conv.b (%) ee.c(%)
1
2
3
4
5
6
7
8
(S,S)-f-spiroPhos
(S,S)-f-spiroPhos
(S)-BINAP
(S,R)-DuanPhos
(R)-JosiPhos-1
(S,S)-f-Binaphane 40
25
40
40
40
40
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
Dioxane
DME
Et2O
MeOH
CH2Cl2
79
>99
<5
9
29
80
7
65
14
>99
97
31
27
29
>99
98
98
NA
NA
28
58
NA
0
59
93
97
89
12
67
98
9
10
11e
12f
13e
14
15e
16e
(R)-DM-SegPhos
(S)-MonoPhos
40
40
40
40
40
40
40
40
40
9
(S,S)-f-spiroPhos
(S,S)-f-spiroPhos
(S,S)-f-spiroPhos
(S,S)-f-spiroPhos
(S,S)-f-spiroPhos
(S,S)-f-spiroPhos
(S,S)-f-spiroPhos
10
11
12
13
14
15d
Cyclohexyl(1p)
a Unless otherwise mentioned, all reactions were carried out with a
[Rh(COD)2]BF4/(S,S)-f-spiroPhos/substrate ratio of 1 : 1.1 : 100, CH2Cl2,
30 atm H2, 40 °C, 8 h. b Determined by 1H NMR spectroscopy or GC
analysis; data in parentheses are isolated yields. c Determined by HPLC
a Unless otherwise mentioned, all reactions were carried out with a analysis using a chiral stationary phase or chiral GC analysis. d The
Rh(COD)2BF4/phosphine/substrate ratio of 1 : 2.1 : 100, CH2Cl2, 70 atm absolute configuration of (R)-2a was determined by comparison with
H2, 12 h. b Determined by 1H NMR spectroscopy. c Determined by optical rotation data for the reported literature.6b e 12 h. f 50 atm
HPLC analysis using a chiral stationary phase. d 30 atm H2, 8 h.
H2, 24 h.
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achieved (entries 1–10). However, presumably due to steric hin- sions (entries 3–10). Even for the sterically hindered ortho-
drance, substrates with a Me (1k) or MeO group (1l) at the substituted substrates, 1k′ and 1l′, the highest enantio-
ortho-position of the aromatic ring and with a 1-naphthyl selectivity, 98% ee, was achieved (entries 11 and 12). Moreover,
group (1m) required a longer reaction time for full conversion the substrate with an alkyl substituent (iPr and cyclohexyl) also
but without any erosion of enantioselectivity (entries 11–13). afforded the desired products with full conversions and excel-
Gratifyingly, excellent enantioselectivities were also observed lent enantioselectivities (entries 15 and 16).
for the alkyl substrates (iPr and cyclohexyl), albeit with longer
reaction time (entries 15 and 16).
Furthermore, besides 3-cyano acrylate esters, the Rh-(S,S)-f-
spiroPhos catalyst is also very efficient for the asymmetric
Under the optimized conditions, the asymmetric hydro- hydrogenation of β-cyano-α-aryl-α,β-unsaturated ketones.
genation of (E)-methyl 3-cyano-2-phenylacrylate 1a′ was also Under the optimized conditions, (E)-β-cyano-α-aryl-α,β-unsatu-
investigated. However, only moderate enantioselectivity, 73% ee, rated ketones 3 were hydrogenated to the corresponding pro-
was achieved with an opposite configuration, this was because ducts 4 in full conversions with 91–95% ee, which could be
the different olefin geometry often reacted from the opposite further reduced to the desired products 5 in the presence of
enantioface. Inspired by the research of halide effects in NaBH4 with excellent diastereoselectivities, dr > 99 : 1, and
rhodium catalysts by Lautens and Fagnou,14 we replaced the unchanged enantioselectivities (Table 4).
metal precursor with [Rh(COD)Cl]2. To our delight, the ee
More importantly, the hydrogenation could be accom-
value of the hydrogenation product 2a′ dramatically increased plished on the gram scale and with much lower catalyst
to 97% ee with an opposite configuration (Table 3, entry 1), loading. With the Rh-(S,S)-f-spiroPhos catalyst, the hydrogen-
which facilitated the access to the chiral cyano compound with ation of the substrate 1a′ was carried out on the gram scale at
any configuration. Subsequently, a series of (E)-substrates 1′ a catalyst loading of 0.01 mol% under 100 atm of initial H2
were smoothly hydrogenated with comparable results of (Z)- pressure, the desired product 2a′ was obtained in full conver-
substrates. Regardless of the electronic properties or position sion with 97% ee. The results indicated that this catalyst was
of the substituents in the phenyl moiety, no apparent effect on exceptionally highly efficient for the asymmetric hydrogen-
the reactivities and enantioselectivities was observed. For ation of these substrates and showed very high turnover
example, the substrates with a Me, MeO or F, Cl group at the numbers (TON) approaching 10 000 (Scheme 2).
meta- or para-position of the phenyl ring afforded the corres-
In addition, this catalyst system can also be successfully
ponding products with 95%–97% ee values and full conver- applied to the synthesis of important chiral pharmacophore
fragments, γ-lactams and amino acids (Scheme 3).6b The
hydrogenation products were further reduced and sub-
sequently cyclized,6a γ-lactams and γ-amino esters were
obtained in high yields and excellent enantioselectivities.
Table 3 Rh-catalyzed asymmetric hydrogenation of (E)-3-cyano-2-
substituted acrylate esters 1’a
Table 4 Rh-catalyzed asymmetric hydrogenation of (E)-β-cyano-
α-aryl-α,β-unsaturated ketones 3a
Entry
R
R′
Product
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
C6H5(1a′)
C6H5(1b′)
CH3
C2H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
2a′
2b′
2c′
2d′
2e′
2f′
2g′
2h′
2i′
2j′
2k′
2l′
2m′
2n′
2o′
2p′
>99(98)
>99(98)
>99(96)
>99(96)
>99(97)
>99(96)
>99(97)
>99(98)
>99(98)
>99(97)
>99(96)
>99(96)
>99(98)
>99(98)
>99(96)
>99(96)
97(S)d
97(+)
97(+)
97(+)
97(+)
96(+)
96(+)
96(+)
95(+)
96(+)
98(+)
98(+)
95(+)
95(+)
96(+)
94(+)
4-CH3C6H4(1c′)
4-CH3OC6H4(1d′)
4-FC6H4(1e′)
4-ClC6H4(1f′)
4-BrC6H4(1g′)
3-CH3C6H4(1h′)
3-CH3OC6H4(1i′)
3-FC6H4(1j′)
2-CH3C6H4(1k′)
2-CH3OC6H4(1l′)
1-Naphthyl(1m′)
2-Naphthyl(1n′)
iPr(1o′)
Entry
Ar
Product
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
9
C6H5(3a)
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
>99(96)
>99(97)
>99(95)
>99(95)
>99(96)
(92)
(89)
(90)
(89)
(91)
95(+)
96(+)
91(+)
92(+)
2-CH3OC6H4(3b)
3-CH3C6H4(3c)
4-CH3C6H4(3d)
4-CH3OC6H4(3e)
C6H5(4a)
2-CH3OC6H4(4b)
3-CH3C6H4(4c)
4-CH3C6H4(4d)
4-CH3OC6H4(4e)
9
10
11
12
13
14
15
16
94(+)
95(dr > 99 : 1)
96(dr > 99 : 1)
90(dr > 99 : 1)
92(dr > 99 : 1)
94(dr > 99 : 1)
Cyclohexyl(1p′)
10
a Unless otherwise mentioned, all reactions were carried out with a a Unless otherwise mentioned, all asymmetric hydrogenation of
[Rh(COD)Cl]2/(S,S)-f-spiroPhos/substrate ratio of 0.5 : 1.1 : 100, CH2Cl2, 30 reactions were carried out with
a [Rh(COD)Cl]2/(S,S)-f-spiroPhos/
atm H2, 40 °C, 8 h. b Determined by 1H NMR spectroscopy or GC substrate ratio of 0.5 : 1.1 : 100, CH2Cl2, 30 atm H2, 40 °C, 8 h.
analysis; data in parentheses are isolated yields. c Determined by HPLC b Determined by 1H NMR spectroscopy; data in parentheses are
analysis using a chiral stationary phase or chiral GC analysis. d The isolated yields. c Determined by HPLC analysis using
a chiral
absolute configuration of (S)-2a′ was determined by comparison with stationary phase; diastereomeric ratios were determined by 1H NMR of
optical rotation data for the reported literature.6b
crude products.
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Scheme 3 Synthesis of γ-lactams and γ-amino esters.
In conclusion, we have developed a highly efficient and
enantioselective hydrogenation of 3-cyano acrylate esters
including both E and Z-isomers and β-cyano-α-aryl-α,β-unsatu-
rated ketones to produce chiral cyano compounds with excel-
lent enantioselectivities (up to 98% ee) and high turnover
numbers (TON up to 10 000). Moreover, this method provides
a new efficient route to optically active γ-lactams and γ-amino
acids.
We thank the National Natural Science Foundation of China
(Grant No. 21272026, 21172022, 21472013), the Fundamental
Research Funds for the Central Universities, the Specialized
Research Fund for the Doctoral Program of Higher Education of
China, the Program for Changjiang Scholars and Innovative
Research Team in University, and the Beijing Municipal
Commission of Education for generous financial support.
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