Ir-catalyzed Asymmetric Hydrogenation of α-Imino Esters with Chiral Ferrocenylphosphine-Phosphoramidite Ligands

Article abstract of DOI:10.1002/adsc.201900888

An Ir-catalyzed asymmetric hydrogenation of α-imino esters with unsymmetrical hybrid chiral ferrocenylphosphine-phosphoramidite ligands for the synthesis of optically active α-aryl glycines has been described. The result indicated that the presence of the iodo-substitutent at the 3/3’-position of the binaphthyl unit of ligand could significantly improve the catalytic performance. This method features high asymmetric induction and reasonable functional group tolerance, thus providing a concise and efficient approach toward chiral α-aryl glycine derivatives with up to 96% ee.

Full text of DOI:10.1002/adsc.201900888

Title: Ir-catalyzed Asymmetric Hydrogenation of α-Imino Esters with
Chiral Ferrocenylphosphine-Phosphoramidite Ligands
Authors: Xin-Hu Hu and Xiang-Ping Hu
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10.1002/adsc.201900888
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Ir-catalyzed Asymmetric Hydrogenation of α-Imino Esters with
Chiral Ferrocenylphosphine-Phosphoramidite Ligands
Xin-Hu Hu,a,b and Xiang-Ping Hua*
a
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
Fax:(+86)-411-84684746; Phone: (+86)-411-84379206; E-mail: xiangping@dicp.ac.cn
University of Chinese Academy of Sciences, Beijing 100049, China
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
antibacterial
agents,
-lactam
antibiotics,
Abstract. An Ir-catalyzed asymmetric hydrogenation of -
imino esters with unsymmetrical hybrid chiral glycopeptides antibiotics and cardiovascular drugs
(Figure 1).[9]
ferrocenylphosphine-phosphoramidite ligands for the
synthesis of optically active -aryl glycines has been
described. The result indicated that the presence of the
iodo-substitutent at the 3/3’-position of the binaphthyl unit
of ligand could significantly improve the catalytic
performance. This method features high asymmetric
induction and reasonable functional group tolerance, thus
providing a concise and efficient approach toward chiral -
aryl glycine derivatives with up to 96% ee.
Keywords: hydrogenation; asymmetric catalysis; iridium;
-iminoester; chiral phosphine-phosphoramidite ligand
Enantiomerically enriched -amino acids and their
derivatives are vitally important intermediates for
chemical, pharmaceutical and biological syntheses,[1,2]
which play crucial roles in modern protein and
peptide research.[3] To satisfy the enormous demand
for various optically active amino acid compounds,
some highly efficient asymmetric catalytic methods[4-
8]have been developed, including the catalytic
enantioselective Strecker reaction,[4h,4k-l] Sharpless
asymmetric amino-hydroxylation of aryl alkenes,[4j]
asymmetric amination of enolate intermediates,[4m]
dynamic kinetic resolution,[4n-q] asymmetric reduction
of -dehydroamino acid derivatives or -imino
esters,[5-6] asymmetric biomimetic transamination of
-keto acid derivatives,[7] and others.[8]
Among these methods, the most convenient and
straightforward pathway to optically pure -amino
acid derivatives is the catalytic asymmetric
hydrogenation of corresponding -dehydroamino
acid derivatives or -imino esters. In the past decades,
asymmetric hydrogenation of -dehydroamino acid
derivatives has been widely investigated,[5] affording
broad ranges of -alkyl amino acids and their
derivatives in high optical purity. However, as an
important category of -amino acids, the catalytic
asymmetric synthesis of chiral -aryl glycines via the
hydrogenation remains less investigated, although
they have been found wide applications in the
synthesis of some significant drugs such as
Figure 1. Practical chiral -aryl glycine derivatives.
Owing to the lack of the -hydrogen atom, the
synthesis of these compounds via asymmetric
hydrogenation of the corresponding -dehydroamino
acid derivatives is therefore impossible. An
alternative access to -aryl glycines should be the
hydrogenation or transfer hydrogenation of -imino
esters with metal-based catalysts or organocatalysts.
In recent years, some progress has been made in the
area of organocatalysis.[6a-g] In contrast, the transition
metal-catalyzed asymmetric hydrogenation of -
imino esters to prepare such compounds is still far
from satisfactory (Scheme 1), presumably due to the
presence of the E/Z isomers and the poor reactivity of
-imino ester substrates.[6j,6m-n] To the best of our
knowledge, only two efficient catalytic systems have
been developed for the asymmetric hydrogenation of
-imino esters so far. Amii and co-workers[6j]
documented the enantioselective hydrogenation of -
fluorinated imino esters in 2001, but only a limited
range of substrates were hydrogenated successfully.
Notably, in 2006, Zhang et al.[6m] reported a highly
asymmetric hydrogenation of -aryl imino esters via
1
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10.1002/adsc.201900888
Advanced Synthesis & Catalysis
the Rh-tangphos catalyst, affording -aryl amino
esters with high ees up to 95%. In addition, Kadyrov
and Börner et al. have developed a Rh-catalyzed
asymmetric reductive amination of -keto acids with
benzylamine, giving chiral -amino acids with up to
98% ee.[6k] However, only a limited number of
substrates were suitable to the reaction. Therefore, the
development of an efficient catalytic system that can
work well for the hydrogenation of -imino esters is
highly desirable and remains a challenging task.
hydrogenatrion of -aryl imino esters. As a result,
herein we described the first successful iridium-
catalyzed enantioselective hydrogenation of -imino
esters
with
unsymmetrical
hybrid
chiral
ferrocenylphosphine-phosphoramidite
developed within our group (Figure 2).
ligands
Table 1. Optimization of reaction conditions for the
asymmetric hydrogenation of 1a.[a]
Entry L*
Solvent Additive Conv
(%)[b]
ee
(%)[c]
1
2
3
4
5
6
7
8
9
10
11
12
THF
THF
THF
THF
THF
THF
DCM
DCE
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
63
57
51
74
51
83
69
67
83
77
-
67
91
-
91
92
L1
L2
L3
＞99
95
＞99
＞99
43
＞99
＞99
93
95
94
＜10
53
＞99
L4a
L4b
L4c
L4c
L4c
L4c
L4c
L4c
L4c
L4c
L4c
L4c
L4c
Dioxane NIS
Toluene NIS
THF
THF
THF
THF
THF
THF
NCS
NBS
I2
none
I2
13
Scheme 1. Catalytic asymmetric synthesis of chiral aryl
glycine derivatives.
14
＜10
97
＞99
15[d]
16[d][e]
I2
[a]
Reaction conditions unless otherwise noted: 1a (0.4
mmol), [Ir(COD)Cl]2 (2 μmol), L* (4.8 μmol), H2 (50 bar),
solvent (2.0 mL), additives (5 mol%), 24 h, 25 ℃.
[b] Determined by GC.
[c] Determined by chiral HPLC.
[d] The reaction was carried out at 0 ℃.
[e]
The reaction was performed with 1a (0.2 mmol) and I2
(10 mol%).
NIS = N-iodosuccinimide, NCS = N-chlorosuccinimide,
NBS = N-bromosuccinimide.
The initial attempt used N-p-methoxyphenyl
(PMP)-protected methyl imino ester 1a as the model
substrate, and the hydrogenation was conducted in
THF under 50 bar of H2 pressure at 25 ℃ with 1
mol% [Ir(COD)Cl]2/L1 as the catalyst and 5 mol% of
NIS as the additive. To our delight, the reaction
proceeded smoothly, giving the corresponding
hydrogenation product 2a in full conversion albeit
with moderate enantioselectivity (63% ee, Table 1,
entry 1). Subsequent ligand screening disclosed that
the presence of an N-H proton in the ligand structure
was not tolerated, leading to the inferior conversion
and enantioselectivity (Table 1, entry 2). H8-
binaphthyl derived ligand L3 was also tested but gave
Figure
2.
Unsymmetrical
hybrid
chiral
ferrocenylphosphine-phosphoramidite ligands.
Inspired by our recent success in the use of
unsymmetrical hybrid chiral phosphine-
phosphoramidite ligands for various asymmetric
hydrogenations,[10]
in particular Ir-catalyzed
asymmetric hydrogenation of sterically hindered N-
arylimines,[10e] we envisioned that this kind of ligands
may also be efficient to the Ir-catalyzed asymmetric
2
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10.1002/adsc.201900888
Advanced Synthesis & Catalysis
the moderate enantioselectivity of 51% ee (Table 1,
entry 3). To further improve the catalytic
performance, the modification of ligand skeleton via
the introduction of the substituent into the 3/3’-
position of the binaphthyl unit was performed.[10a,11]
To our delight, the introduction of the methyl
substituent (L4a) significantly promoted the
enantioselectivity to 74% ee (Table 1, entry 4).
However, the presence of the phenyl substituent
proved to be detrimental to the hydrogenation,
affording 43% conversion and 51% ee (Table 1, entry
5). The best result was achieved with the iodine-
optical rotation with the reported value in the
literature.[6d,6m]
Having established the optimal hydrogenation
conditions, we then examined the generality of the
Ir/L4c catalytic system in the hydrogenation of -
iminoesters. As shown in Table 2, good to excellent
yields with ee values ranging from 77% to 96% were
obtained for all substrates tested. The position of the
substituent on the phenyl ring obviously affected the
enantioselectivity but showed less effect in the
reactivity (Table 2, entries 2-4). The ortho-substituted
substrate 1b led to much lower enantioselectivity in
comparison with its meta- and para-analogues (1c
and 1d), presumably due to the steric hindrance of the
ortho-substituent. The reaction was not sensitive to
the electronic character of the para-substituent on the
phenyl ring. All imino esters1d-i bearing the para-
substituent gave the corresponding hydrogenation
products 2d-i in high yields (92-98%) and with
excellent enantioselectivities (92-95% ee), regardless
of the electronic property of the substituent (Table 2,
entries 4-9). 2-Naphthyl derivative 1j was suitable to
the hydrogenation although the hydrogenation
product 2j was obtained in not so satisfactory
enantioselectivity (Table 2, entry 10). A series of
different esters 1k and 1l were submitted to the
hydrogenation, and high yield and excellent
enantioselectivity were obtained in both cases (Table
2, entries 11 and 12). N-Phenyl iminoester 1m also
proved to be a suitable substrate, affording the
corresponding hydrogenation product 2m in 95%
yield and with 90% ee (Table 2, entry 13). Aliphatic
substrate was also tolerated with the present catalytic
system. For an example, high yield and
modified
ligand
L4c,
with
which
an
enantioselectivity of 83% ee was obtained (Table 1,
entry 6). With the optimal ligand in hand, the effect
of solvent, additive and temperature were then
examined (Table 1, entries 7-16). Initially, the
influence of the solvent on the conversion and
enantioselectivity were examined, and an obvious
solvent dependence on the enantioselectivity and
reactivity was observed with THF chosen as the best
one (Table 1, entries 7-10). Next, the effect of the
additive was studied by use of various halogen
sources (Table 1, entries 11-14). Halogen-additives
were crucial to the hydrogenation as very low
conversion was observed in its absence. It was found
that the use of iodine additive could significantly
increase the enantioselectivity to 91% ee (Table 1,
entry 13). Better result obtained with iodine additive
are presumably caused by elevating the valence state
of the metal center (IrI to IrIII).[12] Lowering the
reaction temperature and increasing the catalyst
loading could further improve the catalytic
performance, giving the enantioselectivity of up to
92% ee (Table 1, entries15-16). The absolute
stereochemistry of the resulting phenylglycine methyl
ester was determined to be S by the comparison of the
enantioselectivity
were
obtained
for
the
hydrogenation of substrate 1n with a methyl group
(Table 2, entry 14).
Table 2. Ir-catalyzed asymmetric hydrogenation of -iminoesters 1.[a]
Entry Substrate R1
R2
R3
Product Yield (%)[b] Ee (%)[c] Configuration
1
2
3
4
5
6
7
8
C6H5
4-MeOC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
96
93
95
97
96
92
98
97
97
94
94
96
95
90
92
77
87
95
93
93
93
93
92
80
93
96
90
90
(S)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(R)
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2-MeOC6H4 4-MeOC6H4
3-MeOC6H4 4-MeOC6H4
4-MeOC6H4 4-MeOC6H4
4-CH3C6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
2-naphthyl
C6H5
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
C6H5
9
10
11
12
13
14
C6H5
C6H5
Me
i-Pr
Me
Me
2,6-diMeC6H3
3
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10.1002/adsc.201900888
Advanced Synthesis & Catalysis
[a] Reaction conditions: 1 (0.2 mmol), [Ir(COD)Cl]2 (2 μmol), (Sc,Rp,Sa)-L4c (4.8 μmol), H2 (50 bar), THF (2.0 mL), I2 (10
mol%), 24 h, 0 oC.
[b] Isolated yields.
[c] Determined by chiral HPLC.
catalytic
asymmetric
hydrogenation
with
unsymmetrical hybrid phosphine-phosphoramidite
ligands is ongoing in our laboratory.
Experimental Section
In a nitrogen-filled glovebox, a mixture of [Ir(COD)Cl]2
(1.3 mg, 2 μmol) and L4c (4.4 mg, 4.8 μmol) were
dissolved in 1 mL of degassed tetrahydrofuran in a Schlenk
tube under N2. After stirring at room temperature for 1 h,
-iminoester 1 (0.2 mmol) and I2 (5.1 mg, 20 μmol) in 1
mL of THF was added to the catalyst solution and the
resulting mixture was transferred to an autoclave, which
was then charged with H2 (50 bar). The hydrogenation was
performed at 0 °C for 24 h. After carefully releasing the
hydrogen gas, the solvent was removed under reduced
pressure. The crude product was purified through a silica
gel plug (eluting with a mixture of hexanes/EtOAc = 10/1)
to afford the corresponding glycines 2. The enantiomeric
excess was determined by chiral HPLC.
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (21572226 and 21772196)
and Dalian Science and Technology Innovation Project
(2018J12GX054).
Scheme 2. Gram-scale synthesis and synthetic utility.
To demonstrate the practicality of our method to
the synthesis of aryl glycine derivatives, the
asymmetric hydrogenation of 1a was carried out on
gram scale, and the desired product 2a was achieved
in nearly quantitative yield and with 90% ee. The N-
protected group of 2a could be readily removed by
use of cerium ammonium nitrate (CAN) to give
primary amine 3 in high yield and without significant
loss of enantioselectivity.[6m] A practical utility of this
method as the key step for the enantioselective
synthesis of chiral fungicide (R)-metalaxyl is shown
in Scheme 2.[13]
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In summary, we have realized an efficient Ir-
catalyzed asymmetric hydrogenation of -imino
esters by the employment of an unsymmetrical hybrid
chiral ferrocenylphosphine-phosphoramidite ligand
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10.1002/adsc.201900888
Advanced Synthesis & Catalysis
UPDATE
Ir-catalyzed Asymmetric Hydrogenation of α-
Imino Esters with Chiral Ferrocenylphosphine-
Phosphoramidite Ligands
Adv. Synth. Catal. Year, Volume, Page – Page
Xin-Hu Hu, and Xiang-Ping Hu*
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