Rhodium-catalyzed asymmetric hydrogenation of β-cyanocinnamic esters with the assistance of a single hydrogen bond in a precise position

Article abstract of DOI:10.1039/c7sc04639a

With the assistance of hydrogen bonds, the first asymmetric hydrogenation of β-cyanocinnamic esters is developed, affording chiral β-cyano esters with excellent enantioselectivities (up to 99% ee). This novel methodology provides an efficient and concise synthetic route to chiral GABA-derivatives such as (S)-Pregabalin, (R)-Phenibut, (R)-Baclofen. Interestingly, in this system, the catalyst with a single H-bond donor performs better than that with double H-bond donors, which is a novel discovery in the metalorganocatalysis area.

Full text of DOI:10.1039/c7sc04639a

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Pleas eC dh oe mn oi ct a al dS jcui es tn mc eargins
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DOI: 10.1039/C7SC04639A
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Rhodium-catalyzed asymmetric hydrogenation of β-
cyanocinnamic esters with the assistance of a single hydrogen
bond in a precise position
Received 00th January 20xx,
Accepted 00th January 20xx
+
a
+a
a
b
a
b
b
DOI: 10.1039/x0xx00000x
Xiuxiu Li, Cai You, Yusheng Yang, Yuhong Yang, Pan Li, Guoxian Gu, Lung Wa Chung, Hui
a, c
a, b
Lv,* and Xumu Zhang*
www.rsc.org/
With the assistance of hydrogen bonds, the first asymmetric discovery provides a new insight for the catalyst design in both
hydrogenation of β-cyanocinnamic esters has been developed, organocatalysis and metalorganocatalysis area.
affording chiral β-cyano esters with excellent enantioselectivities
(
up to 99% ee). This novel methodology provides an efficient and
concise synthetic route to chiral GABA-derivatives, such as (S)-
Pregabalin, (R)-Phenibut, (R)-Baclofen. Interestingly, in this system,
the catalyst with single H-bond donor performed better than that
with double H-bond donors, which is a novel discovery in the
metalorganocatalysis area.
Hydrogen bonding, an important noncovalent interaction, plays
a crucial role in biosystem and enzyme catalysis. Inspired by the
enzyme catalysis, the strategy of hydrogen bonding has been
elaborated and successfully applied in numerous cases of
organocatalysis in the past two decades, which provide the synthetic
Figure 1. Chiral GABA derivatives in pharmaceuticals.
1
community with many solutions for organic synthesis. Among these
Chiral γ-aminobutyric acids (GABA) are an essential class of
4
successful catalysts, thiourea is a special motif for hydrogen bonding.
As a double hydrogen donor, thiourea could activate carbonyl
compounds in neuroscience, and many of them are drugs or have
potential biological activities in the area of neurotransmitters and
2
5
6
7
8
compounds by lowering their LUMO energy. Effective bonding with
brain science, such as Pregabalin, Phenibut, Baclofen (Figure 1). In
addition, many chiral GABA derivatives are common motifs in many
neutral functional groups, potent binding affinity, and high tunability
make thiourea catalysts versatile for many kinds of organic
9
10
11
drugs, such as Rolipram, Brivaracetam,
Vernakalant
and
3
1
2
reactions. Herein, with our ferrocene-thiourea chiral bisphosphine
Enablex (Figure 1). Thus, the synthesis of chiral GABA and their
derivatives has attracted a great deal of interest, but very limited
approaches have been developed. These synthetic methods include
ligands (ZhaoPhos series) which are cooperation of transition metal
catalysis and organocatalysis, we focused on whether both two
hydrogen bonds of the thiourea group are essential in the
transformation. When the asymmetric hydrogenation of β-
cyanocinnamic esters, very challenging substrates in this area, were
carried out, the catalyst (L1) with only one H-bond donor in a precise
position performed better than ZhaoPhos (possesses two H-bond
donors) on both reactivity and enantioselectivity. This novel
1
3
the following: enzymatic kinetic resolution, biocatalytic asymmetric
1
4
reduction,
asymmetric
conjugate
reduction
with
1
5
polymethylhydrosiloxane (PMHS)
and asymmetric Michael
1
6
addition. However, asymmetric hydrogenation of β-cyanocinnamic
esters, the most straightforward access to synthesize chiral GABA
derivatives, has never been reported.
Over the past decades, transition metal catalyzed asymmetric
hydrogenation of functionalized olefins has emerged as a powerful
and environmentally friendly approach to generate chiral
1
7
compounds. With the rapid development of catalytic systems,
18
many types of olefins bearing functional groups such as carbonyl,
1
9
20
21
sulfonyl, cyano group and nitryl, were hydrogenated in high
ee’s and activities. However, asymmetric hydrogenation of β-
cyanocinnamic esters has not been reported, which can be explained
by two reasons: (1) The electron-withdrawing ester group and nitrile
‡
Electronic supplementary information (ESI) available: Experimental procedures, NMR
spectra of compounds. See DOI: 10.1039/x0xx00000x
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group that can sharply reduce the electron density of C=C bond are
In order to obtain optimal reaction conditions, a serious of
very unbeneficial for the C=C bond’s coordination to the metal solvents were screened (summarized in SI). When the reaction was
center, which leads to the low reactivity of these substrates; (2) The carried out with 50 atm H
2
gas at 35 °C in CF
3
CH
2
OH, full conversion
linearity of the nitrile group, which is not suitable for the assistant was attained with 95% ee.
coordination between the C=C bond and metal catalyst, makes it
2
0a,b
a
very difficult to achieve high enantioselectivities.
As a result of Table 2. Evaluation of a series of bisphosphine-thiourea Ligands
these factors, it is a very difficult task to achieve satisfactory results
of the β- cyanocinnamic esters asymmetric hydrogenation with the
classical bidentate diphosphine/Rh system as summarized in Table 1.
Methyl
Table 1. Ligand screening for the Rh-catalyzed asymmetric
a
hydrogenation of 1a
[b]
[c]
Entry
Ligand
Conv. [%]
ee [%]
1
2
3
4
5
6
7
8
9
(Rc,Sp)-DuanPhos
(S)-Binapine
19
trace
trace
23
rac
-
[
b]
[c]
Entry
Ligand
Conv. [%]
ee [%]
(S,S)-Me-DuPhos
(R,R)-QuinoxP*
(S)-BINAP
-
1
2
3
4
ZhaoPhos
99
99
95
98
-
rac
-
L1
L2
L3
trace
trace
trace
25
trace
5
(S)-SegPhos
-
7
(S)-DTBM-SegPhos
(R,S)-tBu-JosiPhos
(R)-TaniaPhos
(R)-WalPhos
-
a
All
reactions
]BF
were
carried
out
with
1
a
rac
-7
-
[Rh(NBD)
2
4
/ligand/substrate ratio of 1:1.1:100, in
mL of
35
trifluoroethanol, at 35 °C, under hydrogen (50 atm) for 18 h.
Determined by H NMR spectroscopy. Determined by HPLC analysis
b
1
c
1
1
0
1
trace
28
using a chiral stationary phase.
ZhaoPhos
84
To obtain insight into this catalytic system, another three chiral
ligands L1-L3 were employed and the results were summarized in
table 2. To our surprise, the N methylation of ZhaoPhos led to a
a
All
reactions
]BF
were
carried
out
with
1
a
[
Rh(NBD)
2
4
/ligand/substrate ratio of 1:1.1:100, in
mL of
b
methanol, at 20 °C, under hydrogen (30 atm) for 18 h. Determined
increase of the enantioselectivity (entry 2, 98% ee), which is quite
1
c
by H NMR spectroscopy. Determined by HPLC analysis using a chiral
stationary phase. The absolute configuration was assigned by
comparing the sign of the optical rotation of the product 2a, methyl
18f, 23
different from the previous results we reported.
In comparison,
when both N-H were replaced, almost no conversion was detected
entry 3), which indicated the importance of hydrogen bonds in this
(
(
R)-3-cyano-3-phenylpropanoate, with that reported in the literature;
reaction. In addition, the ligand L3 without thiourea group showed
very low activity and enantioselectivity (entry 4). These results
displayed that the thiourea motif efficiently activated the carbonyl
group through hydrogen-bonding interaction and worked as an
excellent directing role. Moreover, L1 is superior to ZhaoPhos, which
indicates that one hydrogen bond in a precise position is better than
two in this asymmetric transformation.
see Ref 14c.
(
Z)-3-cyano-3-phenylacrylate as
bidentate diphosphine ligands including P-chiral diphosphine ligands
entries 1-4), ligands having axial chirality (entries 5-7) and ferrocenyl
a model substrate, a series of
(
chiral bisphosphorus ligands (entries 8-10) were tested, giving low to
even trace conversions and almost racemic products, which
disclosed that the classical catalyst systems cannot complete this
task. Recently, substrate orientation by hydrogen bonds as a strategy
in asymmetric hydrogenation has been studied and some progress
With an optimized set of conditions in hand, we explored the
substrate scope and generality of this catalytic reaction. To confirm
the universality of the phenomenon that L1 is superior to ZhaoPhos,
almost each substrate has been compared (Scheme 1). We thought
that enhancement of the steric hindrance of the ester would
influence this transformation, however, the results indicated that
these changes of the substrate have a slight impact on the reaction
2
2
have been made. Therefore, from another perspective, we tried to
utilize the ester group whose carbonyl is a very good H-bond
acceptor to improve the reactivity of the electron-deficient substrate
by employing the ZhaoPhos bearing H-bond donors. Although the
preliminary result was moderate (entry 11, 28% conversion with 84%
ee), it inspired us to a further exploration.
(2a-2c). Many functional groups, such as methyl (2d), methoxy (2e),
phenyl (2f), trifluoromethyl (2g), and halides (2h, 2i and 2j), at the
2
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Pleas Ce hd eom ni oc at la Sd cj iue sn tc me argins
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DOI: 10.1039/C7SC04639A
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para position of the phenyl group are compatible with this much lower reactivity and enantioselectivity were obtained, but the
transformation. Using L1, substrates with meta- or ortho- configuration of 2u can support our viewpoint that the
substitution on the phenyl group are also tolerated and 97% ee and enantioselectivity is inducted by the ester group of the substrates.
9
9% ee values were obtained (2k and 2l). Constantly, polyfluorinated
2
4
a
compounds exist in drug molecules, so a series of polyfluorinated Table 3. The comparison of ZhaoPhos and L1
substrates were examined. Substrates with 3,4-difluoro and 3,5-
difluoro on the phenyl group were tested, and good yields with
excellent enantioselectivities were achieved (2m and 2n). In
comparison, when the 3,4,5-trifluoro compound 1o was employed,
T(°C)
20
the adduct 2o was produced slightly
Ligand
0
35
60
∆
G
HB
-13.4
-12.2
-11.4
-10.0
(
(
kcal/mol)
ZhaoPhos
[
b]
[c]
)
ee
97 (20
95(94) 95(99) 92(99)
-15.3 -14.5 -13.2
∆G
HB
kcal/mol)
-16.4
L1
ee
99(60)
98(99) 98(99) 93(99)
]BF /L/substrate
a
All reactions were carried out with a [Rh(NBD)
2
4
ratio of 1:1.1:100, in 1 mL of trifluoroethanol, under hydrogen (50
b
atm) for 18 h. Ee values were determined by HPLC analysis using a
c
1
chiral stationary phase. Conversions were determined by H NMR
spectroscopy.
a)
32b)
1
00
9
8
7
6
5
0
0
0
0
0
30
28
2
2
6
4
e
e
40
22
20
18
3
2
1
0
0
0
0
y = 0.95x + 1.77
2
R
= 0.99
1
1
6
4
0
10
20
30
40
50
60
70
80
90
100
0.2
0.3
0.4
0.5
Job Plot
0.6
0.7
0.8
ee of L1 (%)
CF3
c)
CN
F3C
COOMe
S
(
R)
N
H
N
O
O
MeO
NC
H
MeO
NC
P
Fe
Rh
S
Scheme 1. Substrate scope. Condition A: L = L1, 20 °C. Condition B: L
H
Ph
H
P
a
=
ZhaoPhos, 35 °C. All reactions were carried out with
a
Ph
BF4
S = solvent
[
Rh(NBD) ]BF /L/substrate ratio of 1:1.1:100, in
1
mL of
2
4
b
Figure 2. a) Hydrogenation of 1a using L1 of varying ee, the line
trifluoroethanol, under hydrogen (50 atm) for 18 h. Determined by
c
d
corresponds to a least-squares linear regression of the data with
HPLC analysis using a chiral stationary phase. Isolated yield. (E)-1a
2
e
1
slope = 0.95, intercept = 1.77, and r = 0.99; b) Job plot, x =
was used. Determined by H NMR spectroscopy.
4
c(L1)/[c(L1)+c(1a)],
y
=
Δδ*10 *c(L1)/[c(L1)+c(1a)]; c) Proposed
compromised ee values, which may be due to the electron-poor hydrogen bonding between the reactive Rh species and 1a.
property of 1o as discussed above. Other disubstituted substrates
could also be accommodated, as exemplified by 2p and 2q.
To gain a better understanding of the performance of ZhaoPhos
Moreover, good yields and excellent enantioselectivities were and L1, free energies (kcal/mol) for hydrogen bonds between
obtained with substrates containing other aromatic fragments, different substrates with the ligand (∆GHB) were evaluated by B3LYP-
2
5
including naphthalenes and thiophenes (2r and 2s). To our delight, GD3BJ /6-31G** method, as summarized in table 3. To our
when the aryl substituent was changed to an alkyl group, such as supprise, the free energy for the hydrogen bond between 1a and
isobutyl, the product 2t which can be readily converted to (S)- ZhaoPhos is smaller than that between 1a and L1, even at different
Pregabalin was produced with 98% ee. All the results reflect a fact temperature, which can explain the experimental results very well.
that L1 bearing a single H-bond donor is more suitable than These results indicate that one H-bond can perfom better than two
ZhaoPhos to this reaction. Moreover, when (E)-1a was employed, ones in this reaction, thus we proposed that the stronger hydrogen
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bond is important in making L1 a more selective catalyst. Both L1 can be used in the synthesis of NK1 antagonists directly, was
system and ZhaoPhos system are sensitive to the reaction produced (Scheme 2c). Scheme 2d exhibited an efficient approach to
temperature due to their weaker hydrogen-bonding interaction with the establishment of chiral pyrrolidines. The asymmetric
substrates at higher temperature.
2 4
hydrogenation product 2a was reduced by NiCl /NaBH in MeOH and
To verify the accuracy of the catalytic model we assumed, the afforded the corresponding lactam 3 in high yield without any loss in
reduction of 1a was performed using L1 of varying ee. As shown in the enantioselectivity. By treating the lactam with lithium aluminium
2
8
figure 2a, a linear correlation between the ee of the ligand and that hydride (LAH) in THF, the chiral pyrrolidine can be readily obtained.
of the product was observed, indicating that a 1:1 ratio of ligand to
2
6
metal is present in the catalytic complex. Moreover, Job plot was
drawn and the curve suggested a 1:1 binding pattern between L1
and 1a (figure 2b), and a 1:1 binding pattern between ZhaoPhos and
Conclusions
In conclusion, the first asymmetric hydrogenation of β-
cyanocinnamic esters has been reported, which provides an efficient
approach for synthesizing chiral GABA derivatives. This
transformation exhibits excellent enantioselectivities (up to 99% ee)
under mild reaction conditions with low catalyst loading. This
method provides a concise route to the synthesis of (S)-Pregabalin,
1
a was also suggested (summarized in SI). These experimental data
validate our hypothesis, and the catalytic model was sketched out as
shown in figure 2c.
(R)-Phenibut, (R)-Baclofen, chiral δ-amino alcohols, chiral γ-lactam
and chiral pyrrolidines, demonstrating the high synthetic utility of
the current methodology. Notably, in our ferrocene-thiourea chiral
bisphosphine ligands (ZhaoPhos series) system, the catalyst with a
single H-bond donor in a precise position performed better than that
with double H-bond donors, which is a novel discovery in the
metalorganocatalysis area. This novel discovery provides a new way
to design catalysts. Further investigations on the detailed
mechanistic studies on the proposed key hydrogen bonds and the
applications of the asymmetric hydrogenation strategy in organic
synthesis are in progress in our lab.
Acknowledgments
We are grateful for financial support from the National Natural
Science Foundation of China (Grant Nos. 21402145, 21432007, and
21372179), the Youth Chen-Guang Science and Technology Project
of Wuhan City (2015071704011640), the Natural Science Foundation
of Hubei Province (2014CFB181), the Fundamental Research Funds
for Central Universities (2042017kf0177), the Important Sci-Tech
Innovative Project of Hubei Province (2015ACA058) and the “111”
Project of the Ministry of Education of China.
Notes and references
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(a) P. M. Pihko, Hydrogen Bonding in Organic Synthesis; Wiley,
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5
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Scheme 2. Synthetic transformations.
In order to further demonstrate the synthetic utility of this
methodology, several gram-scale transformations were achieved, as
summarized in Scheme 2. Firstly, upon decreasing the catalyst
loading to 0.05 mol%, the asymmetric reaction was conducted on a
gram scale, and 97% conversion (TON = 1940) with unchanged
enantioselectivity was obtained (Scheme 2a). Then, a high-efficiency
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13b
14a
synthetic route for (S)-Pregabalin, (R)-Phenibut and (R)-Baclofen
was developed. As shown in Scheme 2b, upon 0.1-0.125 mol%
catalyst loading, three key intermediates were obtained on a gram
scale with high yields (97-98% yield) and excellent ee values (97-98%
ee). So far, this may be the most concise way to synthesize chiral
Pregabalin, Phenibut and Baclofen. Next, a gram-scale 2p, which can
be readily converted to a chiral δ-amino alcohol whose enantiomer
3
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Chemical Science
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DOI: 10.1039/C7SC04639A
The first asymmetric hydrogenation of β-cyanoacrylate esters has been developed to furnish chiral β-cyano esters with excellent
yields and excellent enantioselectivities (up to 99% yield, up to 99% ee), which provides an efficient approach to (S)-Pregabalin, (R)-
Phenibut and (R)-Baclofen, chiral -amino alcohols, chiral -lactam and chiral pyrrolidines. Notably, the catalyst with a single H-bond
donor in a precise position performed better than that with double H-bond donors. This novel discovery provides a new vision for the
catalyst design.