Nickel-catalyzed enantioselective hydrogenation of β-(acylamino)acrylates: Synthesis of chiral β-amino acid derivatives

Article abstract of DOI:10.1021/acs.orglett.7b02417

The nickel-catalyzed asymmetric hydrogenation of β-(acylamino)acrylates has been developed, affording chiral β-amino acid derivatives with excellent yields (95-99% yield) and enantioselectivities (97-99% ee). With the Ni-Binapine system, high enantioselectivities (98-99% ee) have also been obtained in the hydrogenation of Z/E isomeric mixtures of β-alkyl and β-aryl β-(acylamino)acrylates. The synthesis of chiral β-amino acid derivatives on a gram scale has also been achieved with 0.2 mol % catalyst loading.

Full text of DOI:10.1021/acs.orglett.7b02417

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Enantioselective Hydrogenation of
β‑(Acylamino)acrylates: Synthesis of Chiral β‑Amino Acid Derivatives
†
†
†
,†,‡
,†,§
Xiuxiu Li, Cai You, Shuailong Li, Hui Lv,*
and Xumu Zhang*
†Key Laboratory of Biomedical Polymers, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan, Hubei 430072, China
‡
Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular
Sciences, Wuhan University, Wuhan, Hubei 430072, China
§
Department of Chemistry, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
*
S Supporting Information
ABSTRACT: The nickel-catalyzed asymmetric hydrogenation of β-(acylamino)acrylates has been developed, affording chiral β-
amino acid derivatives with excellent yields (95−99% yield) and enantioselectivities (97−99% ee). With the Ni−Binapine
system, high enantioselectivities (98−99% ee) have also been obtained in the hydrogenation of Z/E isomeric mixtures of β-alkyl
and β-aryl β-(acylamino)acrylates. The synthesis of chiral β-amino acid derivatives on a gram scale has also been achieved with
0.2 mol % catalyst loading.
symmetric hydrogenation of alkenes is one of the most
dominant and well-established methods for the synthesis
easy task in asymmetric hydrogenation, even if the precious
metals are employed. To date, there are only a handful of
7
A
of enantiopure compounds. It has found multiple applications
in many pharmaceuticals and biologically active molecules.
catalytic systems can work well for the asymmetric hydro-
1
genation of Z/E isomeric mixtures of β-(acylamino)acrylates
7a−h
Typically, these asymmetric hydrogenation methods rely on
precious metal compounds based on rhodium, ruthenium, or
iridium. Excellent stereoselectivity can be achieved by a
(Scheme 1a).
In the first-row metal-catalyzed asymmetric
(transfer) hydrogenation, the catalytic systems that can
complete this task have not appeared. Herein, we report the
first nickel-catalyzed asymmetric hydrogenation of Z/E mixture
of β-(acylamino)acrylates with excellent yields (95−99% yield)
and enantioselectivities (97−99% ee, Scheme 1b).
2
judicious choice of suitable phosphorus ligands, and the catalyst
loading can be lowered for an industrial scale. However, these
heavy metal compounds are seriously contaminating the
environment, and their reserves in the Earth’s crust are
exhausted. By contrast, catalysts containing first-row transition
elements offer potential advantages in cost and sustainability.
Recently, replacing these expensive and toxic elements with
more abundant and environmentally compatible metals such a3s
iron, cobalt, and nickel has drawn a great deal of attention.
Scheme 1. Asymmetric Hydrogenation of Z/E Isomeric
Mixtures of β-(Acylamino)acrylates
4
5
Although some examples of iron-, cobalt- and nickel-
6
catalyzed asymmetric (transfer) hydrogenation of CC,
CO, and CN bonds were reported, the hydrogenation
of Z/E isomeric mixtures of olefins, an important reflection of
catalytic systems’ compatibility, has never been studied.
Since both (Z)- and (E)-isomeric substrates are formed
simultaneously in most synthetic protocols, the development of
a catalytic system that can tolerate both isomeric substrates is
essential. This is especially important in the situation where the
(Z)- and (E)-substrates cannot be easily separated and only
their mixture can be employed as the starting material. The
Received: August 5, 2017
tolerance of both isomers of β-(acylamino)acrylates is not an
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02417
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We began the initial investigation with the asymmetric
hydrogenation of methyl (Z)-3-acetamido-3-phenyl acrylate 1a
to optimize the reaction conditions. Without any additives, a
variety of diphosphine ligands (Figure 1) developed by our
enantioselectivities and bad conversions were obtained (Table
1, entries 5−8).
Inspired by these promising results, we investigated the
solvent effects in the presence of a 5 mol % Ni(OAc) /(S)-
2
Binapine complex, as summarized in Table 2. Solvent screening
Table 2. Solvent Screening for Ni-Catalyzed Asymmetric
a
Hydrogenation of (Z)-1a
b
c
entry
solvent
MeOH
CF CH OH
conv (%)
ee (%)
1
2
3
4
5
6
93
>99
92
99
3
2
CH Cl2
trace
trace
trace
trace
>99
2
toluene
1,4-dioxane
THF
d
7
CF CH OH
99
3
2
a
Unless otherwise mentioned, all reactions were carried out with a
Ni(OAc) /(S)-Binapine/substrate ratio of 1:1.1:20, in 1 mL of solvent,
2
b
1
at 50 °C, under hydrogen (50 atm) for 24 h. Determined by H
NMR spectroscopy. Determined by HPLC analysis using a chiral
stationary phase. Carried out with a Ni(OAc) /(S)-Binapine/
c
Figure 1. Structures of the phosphine ligands for hydrogenation of
d
2
(Z)-1a.
substrate ratio of 1:1.1:100.
group and some commercially available chiral ligands were
examined, as summarized in Table 1. The evaluation of ligands
showed that this reaction proceeded smoothly in alcoholic
solvents (entries 1 and 2), and CF CH OH was found to give
3
2
full conversion with 99% ee. However, when nonprotonic
solvents were used, only trace conversions were detected
Table 1. Ligand Screening for Ni-Catalyzed Asymmetric
Hydrogenation of (Z)-1a
a
(
entries 3−6). Full conversion with unchanged ee value was
also obtained when the reaction was carried out in CF CH OH
3
2
with 1 mol % catalyst loading (entry 7).
With an optimized set of conditions in hand, we explored the
substrate scope and generality of this catalytic reaction (Scheme
b
c
entry
ligand
conv (%)
ee (%)
2
). First, the substituent on the ester group was changed from
1
2
3
4
5
6
7
8
(S)-Binapine
(Rc,Sp)-DuanPhos
(S,S)-Me-DuPhos
(R,R)-QuinoxP*
(S)-BINAP
93
18
92
methyl to ethyl. However, the result indicated that this change
of the substrate has almost no impact on this reaction (2b).
Many functional groups, such as methyl (2c), methoxy (2d),
halides (2e−g), and trifluoromethyl (2h), at the para position
of the phenyl group are compatible with this transformation.
Substrates with meta- or ortho-substitution on the phenyl group
are also tolerated, and excellent ee values were obtained (2i and
2j). Moreover, good yields and excellent enantioselectivities
were obtained with substrates containing other aromatic
fragments, including thiophenes, furans, and naphthalenes
(2k−n). Notably, when the aryl substituent was changed to
an alkyl group, such as methyl, excellent enantioselectivity (98%
ee) was also achieved (2o).
Since both Z and E isomeric substrates are formed
simultaneously and it is difficult to obtain a single isomer in
most cases, asymmetric hydrogenation of their Z/E mixtures is
crucial for the synthesis of chiral β-amino acid derivatives.
Based on this idea, we used the Z/E isomeric mixture as the
substrate directly to investigate the compatibility of this
catalytic system, as summarized in Scheme 3. To our delight,
when the hydrogenation of the 1:1 Z/E isomeric mixture (1a)
was conducted, the results were almost the same as that of pure
(Z)-1a. Next, substrates bearing heterocyclic rings and alkyl
groups were also tested, and excellent yields (96−98%) with
excellent enantioselectivities (98−99% ee) were obtained.
These results declare that this nickel-catalyzed system can
53
trace
19
73
11
33
(S)-SegPhos
JosiPhos
trace
25
−9
rac
WalPhos
23
a
All reactions were carried out with a Ni(OAc) /ligand/substrate ratio
2
of 1:1.1:20, in 1 mL of methanol, at 50 °C, under hydrogen (50 atm)
b
1
c
for 24 h. Determined 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 (R)-3-acetamido-3-phenyl-
propanoate, with that reported in the literature; see ref 6b.
revealed (S)-Binapine to be superior to all others tested, and it
is notable that the Ni−(S)-Binapine catalytic system is efficient
for the asymmetric hydrogenation of the Z isomer of 1a (Table
, entry 1, 93% conversion and 92% ee). The use of (Rc,Sp)-
DuanPhos, (S,S)-DuPhos, and (R,R)-QunioxP* showed low
conversions with poor to moderate enantioselectivities (Table
, entries 2−4). Chiral biarylbisphosphorus ligands with axial
chirality or chiral ferrocenyl structures, such as (S)-BINAP, (S)-
SegPhos, JosiPhos and WalPhos, were also investigated, but low
1
1
B
DOI: 10.1021/acs.orglett.7b02417
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Ni-Catalyzed Asymmetric Hydrogenation of (Z)-
β-(Acylamino)acrylates.
Scheme 4. Gram-Scale Reaction for the Nickel-Catalyzed
Asymmetric Hydrogenation of 1b
a
method provides a concise route to the synthesis of β-amino
acids, which are versatile precursors in chemical synthesis. More
importantly, with this Ni−Binapine system, high enantiose-
lectivities (98−99% ee) have also been obtained in the
hydrogenation of Z/E isomeric mixtures of β-alkyl and β-aryl
β-(acylamino)acrylates. Further investigation on asymmetric
hydrogenation of alkenes bearing unprotected NH is underway
2
in our laboratory.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02417.
Experimental details and characterization data (PDF)
a
Unless otherwise mentioned, all reactions were carried out with a
AUTHOR INFORMATION
Corresponding Authors
Ni(OAc) /(S)-Binapine/substrate ratio of 1:1.1:100, in 1 mL of
■
*
*
2
b
CF CH OH, at 50 °C, under hydrogen (50 atm) for 24 h. Yield of
3
2
c
the isolated product. Determined by HPLC analysis using a chiral
stationary phase.
E-mail: huilv@whu.edu.cn.
E-mail: zhangxm@sustc.edu.cn.
ORCID
Scheme 3. Ni-Catalyzed Asymmetric Hydrogenation of Z/E
Isomeric Mixtures of β-(Acylamino)acrylates
a
Hui Lv: 0000-0003-1378-1945
Xumu Zhang: 0000-0001-5700-0608
Notes
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,
■
2
1432007, and 21372179), the Youth Chen-Guang Science
and Technology Project of Wuhan City (2015071704011640),
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.
a
Unless otherwise mentioned, all reactions were carried out with a
Ni(OAc) /(S)-Binapine/substrate ratio of 1:1.1:100, in 1 mL of
2
CF CH OH, at 50 °C, under hydrogen (50 atm) for 24 h.
3
2
b
1
c
Determined by H NMR spectroscopy. Yield of the isolated
product. Determined by HPLC analysis using a chiral stationary
d
phase.
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Organic Letters
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DOI: 10.1021/acs.orglett.7b02417
Org. Lett. XXXX, XXX, XXX−XXX