Iridium-Catalyzed Asymmetric Hydrogenation of Tetrasubstituted α-Fluoro-β-enamino Esters: Efficient Access to Chiral α-Fluoro-β-amino Esters with Two Adjacent Tertiary Stereocenters

Article abstract of DOI:10.1021/acs.orglett.8b02503

An iridium-catalyzed highly efficient asymmetric hydrogenation of challenging tetrasubstituted α-fluoro-β-enamino esters was successfully developed using bisphosphine-thiourea (ZhaoPhos) as the ligand, which prepared a series of chiral α-fluoro-β-amino esters containing two adjacent tertiary stereocenters with high yields and excellent diastereoselectivities/enantioselectivities (73%-99% yields, >25:1 dr, 91%>99% ee, and turnover number (TON) values up to 8600), and no defluorinate byproduct was detected.

Full text of DOI:10.1021/acs.orglett.8b02503

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iridium-Catalyzed Asymmetric Hydrogenation of Tetrasubstituted
α‑Fluoro-β-enamino Esters: Efficient Access to Chiral α‑Fluoro-β-
amino Esters with Two Adjacent Tertiary Stereocenters
Zhengyu Han,† Yu-Qing Guan,† Gang Liu,† Rui Wang,† Xuguang Yin,† Qingyang Zhao,§
Hengjiang Cong,† Xiu-Qin Dong,*,† and Xumu Zhang*,‡,†
†Key Laboratory of Biomedical Polymers, Engineering Research Center of Organosilicon Compounds & Materials, Ministry of
Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, People’s Republic of China
‡Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, Guangdong
518000, People’s Republic of China
§Key Laboratory of Synthetic and Natural Functional Molecule, Chemistry of Ministry of Education, College of Chemistry and
Materials Science, Northwest University, Xi’an, People’s Republic of China
S
* Supporting Information
ABSTRACT: An iridium-catalyzed highly efficient asymmet-
ric hydrogenation of challenging tetrasubstituted α-fluoro-β-
enamino esters was successfully developed using bisphos-
phine−thiourea (ZhaoPhos) as the ligand, which prepared a
series of chiral α-fluoro-β-amino esters containing two
adjacent tertiary stereocenters with high yields and excellent
diastereoselectivities/enantioselectivities (73%−99% yields,
>25:1 dr, 91%−>99% ee, and turnover number (TON)
values up to 8600), and no defluorinate byproduct was
detected.
he organofluorine compounds always exhibit distinctive
hindrance.11,12 To the best of our knowledge, there is seldom
Tproperties from their parent compounds, because of the an asymmetric catalytic reduction of tetrasubstituted α-fluoro-
β-enamino esters to prepare chiral α-fluoro-β-amino esters.12
Since our privileged bisphosphine-thiourea (ZhaoPhos) ligand
unique characters of the F atom, including high electro-
negativity, small steric size, and C−F bond strength.1 The
has proven to be highly efficient in Rh-catalyzed asymmetric
hydrogenations of prochiral disubstituted and trisubstituted
unsaturated functionalized compounds,13 we were convinced
that this challenging asymmetric hydrogenation of tetrasub-
stituted α-fluoro-β-enamino esters could be achieved through
this unique thiourea motif-assisted catalytic system. Indeed, we
herein successfully realized a highly efficient Ir/bisphosphine-
thiourea (ZhaoPhos)-catalyzed asymmetric hydrogenation of
tetrasubstituted α-fluoro-β-enamino esters; various chiral α-
fluoro-β-amino esters containing two adjacent tertiary stereo-
centers were prepared with high yields and excellent
diastereoselectivities/enantioselectivities (Scheme 1; 73%−
99% yields, >25:1 diastereomeric ratio (dr), and 91%−>99%
enantiomeric excess (ee), turnover number (TON) values up
to 8600), and no defluorinate byproduct was detected in this
catalytic system.
chemistry of chiral organofluorine compounds is a fast-
developing research area and has attracted great attention,
because of their wide range of applications in some important
fields, such as agriculturals, pharmaceuticals, and materi-
als.1d,2,3a,c For example, fluorination of drug molecules may
modify metabolic stability, biological activity, and protein−
drug interactions.1d,3 Fluorinated amino acids and peptides
have wide application in bioorganic and medical fields, such as
biological tracers, enzyme inhibitors, mechanistic probes.3b,4,5
Compared with other chiral fluorinated amino acids and
derivatives, there are a limited number of synthetic methods
for the construction of highly stereoselective chiral α-fluoro-β-
amino acids and derivatives.6−8 Most synthetic methodologies
for the construction of chiral α-fluoro-β-amino acids and
derivatives have been well-established through asymmetric α-
fluorination of carbonyl compounds or nucleophilic addition of
fluorinated ketoesters.8
We started our initial research of the asymmetric hydro-
genation of tetrasubstituted α-fluoro-β-enamino esters using
compound 1a12 as a model substrate to investigate metal
precursors at room temperature. Trace conversion and messy
Asymmetric reduction of prochiral functionalized enamides
is regarded as one of the most powerful and important
approaches to chiral amine derivatives, but it is mainly
restricted to disubstituted and trisubstituted enamides.9,10 It
is challenging to realize the asymmetric hydrogenation of
tetrasubstituted enamides, because of their unfavorable steric
Received: August 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02503
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Ir-Catalyzed Asymmetric Hydrogenation of α-
Fluoro-β-enamino Esters
Table 2. Screening Ligands for Asymmetric Hydrogenation
of Ethyl (E)-2-Fluoro-3-phenyl-3-(phenylamino)acrylate
a
1a
b
conversion
(%)
diastereomeric
enantiomeric
c
b
entry
ligand
ratio, dr
excess, ee (%)
1
2
3
4
5
ZhaoPhos L1
>99
49
>25:1
>25:1
98
76
reaction system were observed using Rh(NBD)2BF4, Rh-
(COD)2BF4, and [Rh(COD)Cl]2 as metal precursors (Table
1, entries 1−3). Full conversion, >25:1 dr, and 98% ee were
obtained in the presence of [Ir(COD)Cl]2 (Table 1, entry 4).
This Ir-catalyzed asymmetric hydrogenation was then
performed in different solvents to examine the effect of
solvent. High conversions, excellent diastereoselectivities/
enantioselectivities can be obtained in 1,2-dichloroethane
(DCE) and CHCl3 (97%−99% conversions, >25:1 dr, and
93%−96% ee; Table 1, entries 6 and 9). No desired
hydrogenation products were detected when other usual
solvents were tested, such as tetrahydrofuran (THF), toluene,
1,4-dioxane, MeOH (Table 1, entries 5, 7, 8, 10). When this
asymmetric hydrogenation was conducted under 10 atm H2,
moderate conversion was obtained (77% conversion; Table 1,
entry 11). In addition, this hydrogenation can be finished
within 12 h (>99% conversion, >25:1 dr, and 98% ee; Table 1,
entry 12), and there is no defluorinate byproduct in the
reaction system.
L2
L3
L4
L5
d
d
<5
NA
NA
e
d
d
NR
NR
NA
NA
e
d
d
NA
NA
a
Reaction conditions: 0.05 mmol 1a in 1.0 mL CH2Cl2, S/C = 100,
b
50 atm H2, room temperature, 12 h. Determined by 1H NMR
c
analysis. Determined by HPLC analysis using a chiral stationary
phase. NA = not available. NR = no reaction.
d
e
Several bisphosphine−(thio)urea ligands were then applied
into the iridium-catalyzed asymmetric hydrogenation of
tetrasubstituted α-fluoro-β-enamino ester 1a. As shown in
Table 2, high reactivity and excellent diastereoselectivity/
enantioselectivity can be obtained in the presence of ZhaoPhos
L1 (>99% conversion, 98% ee, >25:1 dr; Table 2, entry 1).
The N-methylation of ZhaoPhos L2 provided poor conversion
and moderate enantioselectivity (49% conversion, 76% ee,
>25:1 dr; Table 2, entry 2). The ligand L3 without two
trifluoromethyl groups on the phenyl ring displayed very poor
reactivity, and <5% conversion was observed (Table 2, entry
3). The ligand L4 bearing a urea motif and L5 without a
Table 1. Optimization of Reaction Conditions for Asymmetric Hydrogenation of Ethyl (E)-2-Fluoro-3-phenyl-3-
a
(phenylamino)acrylate 1a
b
b
c
entry
metal precursor
solvent
conversion (%)
diastereomeric ratio, dr
enaniomeric excess, ee (%)
d
d
1
2
3
4
5
6
7
8
9
Rh(NBD)2BF4
Rh(COD)2BF4
[Rh(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
<5
<5
<5
NA
NA
NA
NA
d
d
NA
d
d
NA
>99
NR
>25:1
98
e
d
d
NA
NA
DCE
97
>25:1
93
e
d
d
toluene
1,4-dioxane
CHCl3
MeOH
CH2Cl2
CH2Cl2
NR
NA
NA
e
d
d
NR
NA
NA
99
NR
>25:1
96
e
d
d
10
11
12
NA
NA
f
77
>99
>25:1
>25:1
98
98
g
a
Reaction conditions: 0.05 mmol 1a, 1.0 mL solvent, 50 atm H2, room temperature, 24 h. For entries 4−12: the catalyst was precomplexed with
b
1
0.05 mmol [Ir(COD)Cl]2 and 0.011 mmol ligand L1 in 1.0 mL CH2Cl2 (50 μL for each reaction vial). Determined by H NMR analysis.
c
d
e
f
g
Determined by HPLC analysis using a chiral stationary phase. NA = not available. NR = no reaction. 10 atm H2. Reaction time is 12 h.
B
DOI: 10.1021/acs.orglett.8b02503
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
thiourea motif did not promote this asymmetric hydrogenation
successfully (Table 2, entries 4 and 5).
results (73%−99% yields, 91%−>99% ee, >25:1 dr). The N-
phenyl amine-derived α-fluoro-β-enamino ethyl ester sub-
strates (1a−1e) with an R group that is either an electron-rich
or electron-poor group proceeded well with full conversion,
excellent enantioselectivities, and high diastereoselectivities
(94%−98% yields, 95%−99% ee, >25:1 dr). In addition, the Ir-
catalyzed asymmetric hydrogenation of tetrasubstituted α-
fluoro-β-enamino ethyl ester substrates with different sub-
stituted groups on the phenyl ring of the aniline motif was also
performed, the hydrogenation products chiral α-fluoro-β-
amino ethyl esters (2f−2j) were afforded with good to
excellent results (80%−>99% conversions, 73%−98% yields,
91%−>99% ee, >25:1 dr). When the ethyl ester group was
changed to a methyl ester group, the substrates (1k−1m) also
worked well in this transformation, and excellent results were
achieved (>99% conversion, 93%−99% yields, 97%−99% ee,
>25:1 dr).
With the optimized reaction conditions in hand, we turned
our attention to investigating the substrate generality of this Ir/
ZhaoPhos-catalyzed asymmetric hydrogenation of tetrasub-
stituted α-fluoro-β-enamino esters. The results are summarized
in Scheme 2. A wide range of tetrasubstituted α-fluoro-β-
enamino ethyl esters substrates with different substituents on
the phenyl ring were hydrogenated smoothly with excellent
Scheme 2. Substrate Scope Study for Asymmetric
Hydrogenation of Tetrasubstituted α-Fluoro-β-enamino
a
Esters
To our delight, the Ir-catalyzed asymmetric hydrogenation
of model substrate tetrasubstituted α-fluoro-β-enamino ethyl
ester 1a could be performed with very low catalyst loading.
When the catalyst loading was gradually decreased from 1.0
mol % (S/C = 100) to 0.2 mol % (S/C = 500) and 0.1 mol %
(S/C = 1000), the hydrogenation product 2a could be still
obtained with excellent results (full conversion, >25:1 dr, and
98% ee; Table 3, entries 1−3). This asymmetric hydrogenation
Table 3. TON Experiments for the Iridium-Catalyzed
Asymmetric Hydrogenation of Ethyl (E)-2-Fluoro-3-phenyl-
a
3-(phenylamino)acrylate 1a
b
c
temperature
H2
(atm)
time
(h)
conversion
(%)
ee
entry
S/C
100
500
1000
5000
10000
(°C)
(%)
1
2
3
4
5
25
25
45
45
45
50
70
80
80
80
12
24
48
60
60
>99
>99
>99
>99
86
98
98
98
98
98
a
Unless otherwise noted, all reactions were performed with a
b
[Ir(COD)Cl]2/ZhaoPhos L1 = 0.5:1.1 in CH2Cl2. Determined by
c
1H NMR analysis. Determined by HPLC analysis using a chiral
stationary phase.
also proceeded smoothly with only 0.02 mol % catalyst (S/C =
5000), full conversion, and excellent diastereoselectivity/
enantioselectivity was achieved (>99% conversion, >25:1 dr,
and 98% ee; Table 3, entry 4). Good conversion and excellent
diastereoselectivity/enantioselectivity was obtained even with
0.01 mol % catalyst (S/C = 10000) (86% conversion, TON =
8600, >25:1 dr, and 98% ee; Table 3, entry 5). These results
indicate that our Ir/ZhaoPhos L1 catalytic system possessed
high activity in this asymmetric hydrogenation.
As shown in Scheme 3, it is possible that the equilibration of
the enamine 1h and the imine 1h′ exists in the reaction system,
and they may participate in this asymmetric hydrogenation. In
order to investigate the reaction mechanism, this asymmetric
hydrogenation of the enamine 1h in the presence of D2 was
conducted under the optimizated reaction conditions. We
found that the product was extensively deuterated at both the
a
Reaction conditions: 0.05 mmol substrate 1 in 1.0 mL CH2Cl2, S/C
= 100, 50 atm H2, room temperature, 12 h. Conversion and dr was
determined by 1H NMR analysis; ee was determined by HPLC
analysis using a chiral stationary phase. bS/C = 50, reaction time is 36
c
h. S/C = 50.
C
DOI: 10.1021/acs.orglett.8b02503
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Organic Letters
Letter
Scheme 3. Deuterium-Labeling Experiment
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.8b02503.
Optimization reaction conditions; procedures; NMR
and HPLC spectra (PDF)
Accession Codes
CCDC 1844417 (for product 2d) and 1844690 (for substrate
1g) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
α- and β-positions. These observations suggest that the
enamine 1h was involved in this asymmetric hydrogenation
and the imine 1h′ was much less likely.
The hydrogenation products 2 containing two adjacent
tertiary stereogenic centers can be readily converted to other
synthetic useful compounds, as exemplified in Scheme 4. The
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xiuqindong@whu.edu.cn (X.-Q. Dong).
*E-mail: zhangxm@sustc.edu.cn (X. Zhang).
ORCID
Scheme 4. Synthetic Transformations of Hydrogenation
Product 2
Hengjiang Cong: 0000-0002-9225-0095
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. 21432007 and
21502145), the Natural Science Foundation of Hubei Province
(Grant No. 2016CFB449), the Wuhan Morning Light Plan of
Youth Science and Technology (Grant No.
2017050304010307), Shenzhen Nobel Prize Scientists Labo-
ratory Project (Grant No. C17213101) and the Fundamental
Research Funds for the Central Universities (Grant No.
2042018kf0202). The Program of Introducing Talents of
Discipline to Universities of China (111 Project) is also
appreciated.
hydrogenation product 2a was efficiently reduced by lithium
aluminum hydride (LiAlH4) to afford chiral β-fluoro-γ-amino
alcohol 3 without loss of stereoselectivity (92% yield, >25:1 dr,
98% ee).14 Hydrolysis of compound 2a provided chiral α-
fluoro-β-amino acid 4 with 85% yield, >25:1 dr, and 98% ee.15
The chiral unprotected α-fluoro-β-amino ester 5 can be easily
obtained from compound 2h in the presence of ceric
ammonium nitrate (CAN) with 71% yield, >25:1 dr, and
99% ee.16
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