Rh/DuanPhos-Catalyzed Asymmetric Hydrogenation of β-Acetylamino Vinylsulfides: An Approach to Chiral β-Acetylamino Sulfides

Article abstract of DOI:10.1021/acs.orglett.7b01115

Rh/DuanPhos-catalyzed asymmetric hydrogenation of challenging β-acetylamino vinylsulfides has been developed, affording chiral β-acetylamino sulfides with high yields and excellent ee's (up to 99% ee). This novel methodology provides an efficient and concise synthetic route to chiral β-acetylamino sulfides. The potential utility of this protocol in the synthesis of Apremilast has also been disclosed.

Full text of DOI:10.1021/acs.orglett.7b01115

Letter
pubs.acs.org/OrgLett
Rh/DuanPhos-Catalyzed Asymmetric Hydrogenation of
β‑Acetylamino Vinylsulfides: An Approach to Chiral β‑Acetylamino
Sulfides
Wenchao Gao,† Hui Lv,*,† and Xumu Zhang*,†,§
†College of Chemistry and Molecular Science, Wuhan University, Wuhan, Hubei 430072, China
§Depament of Chemistry, South University of Science and Technology of China, Shenzhen, Guangdong 518055, China
S
* Supporting Information
ABSTRACT: Rh/DuanPhos-catalyzed asymmetric hydroge-
nation of challenging β-acetylamino vinylsulfides has been
developed, affording chiral β-acetylamino sulfides with high
yields and excellent ee’s (up to 99% ee). This novel
methodology provides an efficient and concise synthetic route to chiral β-acetylamino sulfides. The potential utility of this
protocol in the synthesis of Apremilast has also been disclosed.
hiral organosulfur compounds play important roles in
organic chemistry and medicinal chemistry because of
methodology to obtain chiral compounds.4 In this context,
the asymmetric hydrogenation of functionalized alkenes bearing
C, N, O, P, B, or Si substituents have been well explored
(Scheme 1).5 However, the asymmetric hydrogenation of
C
their inherent biological values and potential pharmaceutical
applications (Figure 1).1 Particularly, about 20% of marketed
Scheme 1. Asymmetric Hydrogenation of β-Acetylamino
Vinylsulfides
Figure 1. Chiral pharmaceuticals containing C−S bonds.
alkenes bearing a sulfur substituent is rare.6 The main challenge
lies in the fact that the S atom extremely tends to coordinate
with the transition metal which results in the catalyst
deactivation.6 Our group has been devoted to developing
rigid and electron-rich chiral phosphine ligands which have
been applied in asymmetric hydrogenation to synthesize chiral
amines and chiral alcohols.7 Based on our previous work in
asymmetric hydrogenation, we envisioned that the electron-rich
S atom could be easily solvated by protic solvent. Meanwhile,
the formation of a hydrogen bond between the S atom and
protic solvent would weaken the coordination ability of sulfur.8
With this idea in mind, we wish to solve the issue of asymmetric
hydrogenation of sulfur-functionalized alkenes. Herein, we
pharmaceuticals are organosulfur compounds, with many of the
top selling drugs in 2012 containing at least one C−S bond.2
Therefore, C−S bond formations hold a prominent position in
organic synthesis and have attracted extreme enthusiasm from
organic chemists. To date, significant advancement has been
achieved for the establishment of the C−S bond, which mainly
refers to addition, substitution, and other strategies.3 However,
there are relatively few methods for the synthesis of chiral
organosulfur compounds. Therefore, developing convenient
and efficient methodology for chiral organosulfur compounds is
still in great demand.
In recent decades, transition-metal-catalyzed asymmetric
hydrogenation has been extensively applied in both academic
study and practical production, which has been developed as
one of the most powerful and environmentally friendly
Received: April 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01115
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Organic Letters
Letter
disclosed a new strategy to generate chiral β-acetylamino
sulfides in high yields and excellent enantioselectivities via Rh-
catalyzed asymmetric hydrogenation of β-acetylamino vinyl-
sulfides.
Initially, N-(2-(methylthio)-1-phenylvinyl)acetamide 1a was
prepared from the 2-bromo-1-phenylethan-1-one according to
the literature (see Supporting Information for details), and Rh-
catalyzed asymmetric hydrogenation of the mixture of Z/E
isomers of 1a was chosen as the model reaction to optimize the
reaction conditions. The reaction was initially conducted in
MeOH under 80 atm of H2 at room temperature for 24 h in the
presence of 2 mol % Rh(NBD)2BF4, evaluating a variety of
diphosphine ligands developed in our group and some
commercial available chiral ligands (Figure 2). As shown in
precursors were tested; the high enantioselectivities were
maintained, but the conversion dropped dramatically (Table
1, entries 9−11).
Encouraged by the promising results, further optimization of
reaction conditions were conducted to improve the conversion
of 1a. As shown in Table 2, the solvents played an important
Table 2. Solvent and Concentration Screening for Rh-
a
Catalyzed Asymmetric Hydrogenation of 1a
b
c
entry
solvent
concn (M)
conv (%)
ee (%)
1
MeOH
EtOH
iPrOH
CH2Cl2
THF
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.25
0.025
0.017
0.017
30
83
81
80
68
27
78
51
95
99
99
95
97
98
97
95
98
98
60
98
98
98
2
3
4
5
6
toluene
TFE
iPrOH
iPrOH
iPrOH
iPrOH
7
8
9
10
d
11
a
Figure 2. Structures of the phosphine ligands for hydrogenation of 1a.
Unless otherwise mentioned, 1a was hydrogenated with the
conditions: Rh(NBD)2BF4/(Sc,Rp)-DuanPhos/1a ratio of 1:1.1:50,
in 1 mL of solvent under 80 atm of H2 at room temperature for 24 h.
b
1a is the mixture of Z/E isomers, and the ratio is 2:1. Determinde by
c
1H NMR spectroscopy. Determined by HPLC analysis using a chiral
stationary phase. 1a is the mixture of Z/E isomers, and the ratio is
2.5:1.
Table 1. Ligand and Rh Precursor Screening For
Asymmetric Hydrogenation of 1a
d
a
role in the asymmetric hydrogenation of 1a. The solvent
i
screening revealed PrOH was the best choice (entries 1−7).
We found that both the conversion and enantioselectivity
dropped sharply when the concentration of 1a was increased
(entry 8). In contrast, decreasing the concentration was
beneficial for the improvement of conversion and enantiose-
lectivity (entries 9−10). When the concentration of the
substrate was decreased to 0.017 M, the reaction worked
smoothly, affording the hydrogenated product with full
conversion and excellent ee. The possible reason was that the
low concentration of 1a was helpful for the formation of the
b
c
entry
L
Rh
conv (%)
ee (%)
1
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(COD)2BF4
[Rh(COD)Cl]2
Rh(COD)2SO3CF3
−
−
trace
−
−
−
−
2
3
4
−
−
27
14
30
4
5
−
6
45
20
95
94
95
94
7
i
8
hydrogen bond between PrOH and the S atom of 1a which
9
inhibited the combination of the S atom with the catalyst to
some extent. In addition, when the ratio of the Z/E isomer of
1a was changed, the same ee was obtained, which disclosed that
the Z/E ratio had no influence on the reaction enantiose-
lectivity (for more details, see SI).
With the optimized reaction conditions in hand, a variety of
β-acetylamino vinylsulfides were examined, and the results are
summarized in Table 3. It was found that high yields and
excellent ee’s were achieved in most cases. The substituents of
the R group, whether they are electron-withdrawing or
-donating groups introduced at the ortho-, meta-, or para-
positions of the phenyl group, had little influence on the
reactivity and enantioselectivity, providing the corresponding
compounds in good yields and with excellent enantioselectiv-
ities (entries 1−12). In the case of the heteroaryl substituted
substrate, high yields and ee’s were obtained (entries 14, 15).
However, a 2-naphthyl-substituted substrate was hydrogenated
10
11
15
10
a
Unless otherwise mentioned, 1a was hydrogenated with the
conditions: Rh/ligand/substrate ratio of 1:1.1:50, in 1 mL of MeOH
under 80 atm of H2 at room temperature for 24 h. 1a is the mixture of
b
Z/E isomers, and the ratio is 2:1. Determined by 1H NMR
c
spectroscopy. Determined by HPLC analysis using a chiral stationary
phase.
Table 1, no matter if P-chiral diphosphine ligands, axially chiral
biarylbisphosphorus ligands, or chiral ferrocenyldiphosphine
ligands were employed for this reaction, all of them exhibited
poor activity (Table 1, entries 1−8). To our delight, the desired
product 2a was obtained with excellent enantioselectivity when
(Sc,Rp)-DuanPhos was employed, although the conversion is
low (Table 1, entry 8). Subsequently, several rhodium
B
DOI: 10.1021/acs.orglett.7b01115
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
patients with active psoriatic arthritis, could be synthesized
readily following literature procedures.10 In addition, in order
to determine the absolute configuration of the product, 3a was
prepared by oxidation of 2a11 (Scheme 2, eq 2). The absolute
configuration of 2a was confirmed to be S by comparing the
optical rotation of 3a with the known literature value.12
In summary, we have developed an efficient approach for
asymmetric hydrogenation of β-acetylamino vinylsulfides to
generate chiral β-acetylamino sulfides. Using Rh/(Sc,Rp)-
DuanPhos as a catalyst, a series of β-acetylamino vinylsulfides
could be hydrogenated smoothly to give the desired products in
high yields with excellent ee’s. In addition, an effective and
concise synthetic route to Apremilast was developed. Further
investigations on asymmetric hydrogenation of functionalized
enamides are underway in our laboratory.
Table 3. Rh-Catalyzed Asymmetric Hydrogenation of β-
Acylamino Vinylsulfide 1
a
b
c
entry
R
product
yield (%)
ee (%)
1
2
3
4
5
Ph (1a)
2a
2b
2c
2d
2e
2f
97
93
94
99
96
93
88
98
98
98
96
94
76
99
99
−
98
97
94
86
94
89
98
98
99
97
94
96
92
99
97
−
4-Me-C6H4 (1b)
3-Me-C6H4 (1c)
2-Me-C6H4 (1d)
4-OMe-C6H4 (1e)
4-CF3-C6H4 (1f)
4-F-C6H4 (1g)
4-Cl-C6H4 (1h)
4-Br-C6H4 (1i)
4-I-C6H4 (1j)
de
,
6
7
8
9
2g
2h
2i
d
d
d
ASSOCIATED CONTENT
* Supporting Information
■
10
11
12
13
14
15
16
2j
S
d
d
d
3-F-C6H4 (1k)
2-F-C6H4 (1l)
2-naphthyl (1m)
2-furyl (1n)
2k
2l
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01115.
2m
2n
2o
2p
Experimental details and characterization data (PDF)
2-thienyl (1o)
tBu (1p)
a
AUTHOR INFORMATION
Corresponding Authors
Unless otherwise mentioned, all the substrates 1 were hydrogenated
■
with the conditions: Rh(NBD)2BF4/(Sc,Rp)-DuanPhos/substrate ratio
i
of 1:1.1:50, in 3 mL of PrOH under 80 atm of H2 at room
*E-mail: huilv@whu.edu.cn.
*E-mail: xumu@whu.edu.cn.
ORCID
b
c
temperature for 24 h. Isolated yields. Determined by HPLC analysis
d
using a chiral stationary phase. The reaction conditions: 5 mol %
catalyst, under 100 atm of H2 at 30 °C for 30 h. When the catalyst
loading was 2 mol %, the conversion was low and the ee was only 48%.
e
Hui Lv: 0000-0003-1378-1945
Xumu Zhang: 0000-0001-5700-0608
Notes
with excellent ee but only moderate conversion (entry 13).
When alkyl substituted substrate 1p was examined for this
reaction, it did not work for this transformation (entry 16).
To explore the potential synthetic utility of this method-
ology, further derivatization and applications were carried out.
As shown in Scheme 2, eq 1, Rh-catalyzed asymmetric
hydrogenation of 1q proceeds smoothly to give the
corresponding product 2q in high yield with excellent ee.
Then 2q was oxidized by H2O2 in the presence of TaCl5,
affording β-acetylamino sulfone 3q in moderate yield without
any loss of enantiomeric excess. Starting from 3q, Apremilast,9
a drug approved by the FDA in 2014 for treatment of adults
The authors declare no competing financial interest.
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), and the “111” Project of the
Ministry of Education of China.
Scheme 2. Synthetic Transformations
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DOI: 10.1021/acs.orglett.7b01115
Org. Lett. XXXX, XXX, XXX−XXX