Synthesis of Chiral β-Borylated Carboxylic Esters via Nickel-Catalyzed Asymmetric Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.9b00994

The highly efficient Ni-catalyzed asymmetric hydrogenation of β-boronic ester substituted-α,β-unsaturated carboxylic esters was successfully developed using (S,S)-Ph-BPE as the ligand. A series of chiral β-borylated carboxylic esters were obtained with high yields (94%-99% yields) and excellent enantioselectivities (89%-99% ee). The gram-scale asymmetric hydrogenation with a low catalyst loading (0.25 mol %) and synthetic transformation of hydrogenation product demonstrated the great synthetic utility of this methodology.

Full text of DOI:10.1021/acs.orglett.9b00994

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Chiral β‑Borylated Carboxylic Esters via Nickel-
Catalyzed Asymmetric Hydrogenation
Zhengyu Han,†,§ Gang Liu,†,§ Xianghe Zhang,† Anqi Li,† 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, P. R. China
‡Department of Chemistry, Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, Guangdong
518055, P. R. China
S
* Supporting Information
ABSTRACT: The highly efficient Ni-catalyzed asymmetric hydro-
genation of β-boronic ester substituted-α,β-unsaturated carboxylic
esters was successfully developed using (S,S)-Ph-BPE as the ligand. A
series of chiral β-borylated carboxylic esters were obtained with high
yields (94%−99% yields) and excellent enantioselectivities (89%−
99% ee). The gram-scale asymmetric hydrogenation with a low
catalyst loading (0.25 mol %) and synthetic transformation of
hydrogenation product demonstrated the great synthetic utility of this methodology.
hiral organoboron compounds have been regarded as an
neboronic ester. The pioneering work of nickel-catalyzed
Cimportant class of synthetic precursors for the con- reduction reported by Hamada,8 Zhou,9 Chirik,10 and our
group11 mainly focused on the reduction of amino ketones,
struction of complicated chiral molecules, which went through
α,β-unsaturated carboxylic esters, hydrazones, ketimines, and
enamines. To the best of our knowledge, the nickel-catalyzed
asymmetric hydrogenation of β-boronic ester substituted α,β-
unsaturated carboxylic esters is still unexplored. In continu-
ation of our studies, we herein successfully developed nickel-
catalyzed asymmetric hydrogenation of β-boronic ester
substituted α,β-unsaturated carboxylic esters with up to 99%
yield and 99% ee (Scheme 1). The possible reaction
mechanism was revealed according to deuteration experiment
results.
the efficient formation of the C−Y (Y = C, N, O, etc.) bond
from the carbon−boron bond.1,2 Increasing effort has been
devoted to the efficient synthesis of chiral organoboron
compounds. Some important methods including hydrobora-
tion reactions of alkenes,3 metal-catalyzed or metal-free
boration reactions of electron-deficient alkenes,4 have been
well established to construct the chiral α-boron compounds.
Some other synthetic strategies such as lithiation−borylation,5
kinetic resulotion of borylated carboxylic esters,6 and
asymmetric hydrogenation7 were also developed. Although
some progress has been made, it is still necessary to develop a
new and efficient method to synthesize these useful chiral
organoboron compounds with high optimal purity.
Among the above synthetic strategies, transition-metal-
catalyzed asymmetric hydrogenation is a powerful and
important method for the synthesis of chiral boronic
compounds,7 which always exhibited excellent stereoselectivity
and high efficiency with the potential of industrialization.
However, the asymmetric hydrogenation was mainly focused
on the precious transition metal catalysts based on
rhodium7a−c,i and iridium,7d−g which could address the
difficulties of high costs and limited resources in nature.
Cheap and earth-abundant transition-metal-catalyzed asym-
metric hydrogenation of alkenylboronates has always been a
goal for chemists to pursue. In 2017, Lu and co-workers
reported the cobalt-catalyzed sequential hydroboration/hydro-
genation of internal alkynes to obtain chiral boronates, which
was a great breakthrough in this field.7h Based on our long-
standing research in this field of asymmetric hydrogenation,
therefore, we are devoted to developing a cheap first-row
transition-metal-catalyzed asymmetric hydrogenation of alke-
Scheme 1. Ni-Catalyzed Asymmetric Hydrogenation of β-
Boronic Ester Substituted α,β-Unsaturated Carboxylic
Esters
In our initial study, we utilized ethyl (Z)-3-phenyl-3-
(4,4,5,5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) acrylate 1a as
the model substrate to investigate bisphosphine ligands (Figure
1) in this nickel-catalyzed asymmetric hydrogenation. In order
to achieve good solubility of the Ni(OAc)2/diphosphine ligand
catalytic system, the catalyst was generated in stiu by mixing
Ni(OAc)2/diphosphine ligand in MeOH. As shown in Table 1,
Received: March 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Screening Solvents for Ni-Catalyzed Asymmetric
Hydrogenation of Ethyl (Z)-3-Phenyl-3-(4,4,5,5-
a
tetramethyl-1,3,2-dioxaborolan-2-yl) acrylate 1a
b
c
entry
solvent
conv (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
MeOH
Trace
Trace
45
NA
NA
75
EtOH/MeOH = 10:1
TFE/MeOH = 10:1
HFIP/MeOH = 10:1
toluene/MeOH = 10:1
hexane/MeOH = 10:1
CHCl3/MeOH = 10:1
TFE/MeOH = 40:1
HFIP/MeOH = 40:1
HFIP
33
83
NR
NR
NR
62
66
71
NA
NA
NA
93
94
95
Figure 1. Structures of chiral bisphosphine ligands.
Table 1. Screening Ligands for Ni-Catalyzed Asymmetric
Hydrogenation of Ethyl (Z)-3-Phenyl-3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl) Acrylate 1a
a
d
11
HFIP
>99
95
a
Reaction condition: 0.1 mmol 1a in 1.0 mL solvent, 1.0 mol %
b
1
Ni(OAc)2/(S, S)-Ph-BPE, 80 atm H2, 80 °C. Determined by H
NMR analysis. Determined by HPLC analysis using a chiral
stationary phase. Reaction time is 48 h. HFIP is hexafluoroisopro-
c
d
b
c
panol. NR = no reaction. NA = not available.
entry
ligand
conv (%)
ee (%)
1
2
3
4
5
6
7
(S)-Bianpine
(S)-BINAP
(Rc,Sp)-Duanphos
tBu-Josiphos
10
Trace
14
54
NA
31
conversions, 93%−94% ee, Table 2, entries 8−9 vs entries
3−4). In order to obtain a better result, the ratio of methanol
was further decreased, and 71% conversion and 95% ee were
obtained in pure hexafluoroisoporpanol (Table 2, entry 10).
When the reaction time was prolonged to 48 h, this
hydrogenation was fully finished (>99% conversion, 95% ee,
Table 2, entry 11).
13
60
(S,S)-Me-Duphos
(S,S)-Ph-BPE
(S)-Segphos
Trace
45
10
NA
75
65
a
Reaction conditions: 0.1 mmol of 1a in 1.0 mL of TFE, S/C = 100,
With the optimized reaction conditions in hand, we focused
on the exploration of the substrate generality of this Ni/(S,S)-
Ph-BPE-catalyzed asymmetric hydrogenation of β-boronic
ester substituted α,β-unsaturated carboxylic esters. These
reaction results were summarized in Scheme 2. When the
carboxylic ester group was changed from ethyl ester (1a) to
methyl ester (1b), n-propyl ester (1c), or isopropyl ester (1d),
these reactions proceeded smoothly to prepare the correspond-
ing hydrogenation products (2a−2d) with full conversion, 99%
yield, 94%−97% ee. These results indicated that the size of the
carboxylic ester group has a slight impact on this asymmetric
hydrogenation. A series of β-aryl-β-boronic ester substituted
α,β-unsaturated esters were then investigated. The substrates
bearing an electron-withdrawing (1e−1g), electron-donating
(1h−1i, 1k), or electron-neutral (1j) group on the phenyl ring
were hydrogenated well to give hydrogenation products (2e−
2k) with excellent results (>99% conversion, 94%−99% yields,
91%−99% ee). We found that the position of the substituted
group on the phenyl ring has little influence on the reactivity
and enantioselectivity. To our delight, the alkyl substrate (1l)
can be smoothly converted to the hydrogenation product (2l)
with >99% conversion, 94% yield, and 89% ee.
To further investigate the mechanism of this Ni/(S,S)-Ph-
BPE-catalyzed asymmetric hydrogenation, deuterium labeling
experiments were carried out. As shown in Scheme 3, the
asymmetric hydrogenation of methyl (Z)-3-phenyl-3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl) acrylate 1b was explored
in (CF3)2CDOD (D-HFIP) solvent. The hydrogenation
product 2b-D was obtained with 61% deuteration at the α-
position of the methyl ester group. This hydrogenation was
conducted in the presence of 75 atm of D2 and HFIP; the
80 atm of H2, 80 °C, 24 h. The catalyst was precomplexed in MeOH
b
1
(0.1 mL for each reaction vial). Determined by H NMR analysis.
c
Determined by HPLC analysis using a chiral stationary phase. TFE is
trifluoroethanol. NA = not available.
t
(S)-Binapine, (Rc,Sp)-Duanphos, Bu-Josiphos, and (S)-Seg-
phos gave very poor conversion and poor to moderate
enantioselectivities (10%−14% conversions, 31%−65% ee,
Table 1, entries 1, 3−4, 7). (S)-BINAP and (S,S)-Me-Duphos
almost did not promote this hydrogenation, and only trace
product was detected (Table 1, entries 2, 5). To our delight,
(S,S)-Ph-BPE provided an inspiring result that included
moderate conversion and enantioselectivity being achieved
(45% conversion, 75% ee, Table 1, entry 6). Compared to
other bisphosphine ligands mentioned above, both the
reactivity and enantioselectivity were greatly improved.
Having found the optimal ligand (S,S)-Ph-BPE, we started
to investigate the solvent effect of this Ni-catalyzed asymmetric
hydrogenation of model substrate 1a (Table 2). The protic
solvents, such as methanol or ethanol, led to trace conversion
(Table 2, entries 1−2). This asymmetric transformation did
not occur in toluene, CHCl3, and hexane (Table 2, entries 5−
7). When the strong protic solvent hexafluoroisopropanol
(HFIP) was applied, better enantioselectivity than that using
trifluoroethanol (TFE) was provided (Table 2, entry 4 vs entry
3). We noticed that methanol is an unfavorable solvent for this
hydrogenation (Table 2, entry 1). We began to reduce the
ratio of methanol in the reaction system, and higher
conversions and excellent enantioselectivities were obtained
in trifluoroethanol and hexafluoroisoporpanol (62%−66%
B
DOI: 10.1021/acs.orglett.9b00994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope Study for the Asymmetric Hydrogenation
Scheme 4. Asymmetric Hydrogenation of (E)-1a
of (Z)-β-Boronic Ester Substituted α,β-Unsaturated
a
Carboxylic Esters
Scheme 5. Gram-Scale Ni-Catalyzed Hydrogenation of (Z)-
1b and Synthetic Transformation of Product 2b
high conversion and excellent enantioselectivity (92% con-
version, 95% ee). As shown in Scheme 5b, synthetic
transformation of product 2b was conducted to further
demonstrate the synthetic utility. The chiral lactone 3 was
easily available through three steps with 67% overall yield and
without any loss of ee value.12 Moreover, compound 3 can be
efficiently converted to chiral γ-butyrolactone 4,12 which is
widely distributed in natural products.13
a
Reaction conditions: 0.1 mmol substrate 1, 1.0 mL HFIP, 1.0 mol %
Ni(OAc)2/(S, S)-Ph-BPE, 80 atm H2, 80 °C, 48 h. Conversion was
determined by 1H NMR analysis. Ee was determined by HPLC
b
analysis using a chiral stationary phase. S/C = 50.
In conclusion, the Ni/(S,S)-Ph-BPE-catalyzed asymmetric
hydrogenation of β-boronic ester substituted α,β-unsaturated
carboxylic esters was successfully developed; various chiral β-
borylated carboxylic esters can be obtained with excellent
results (94%−99% yields, 89%−99% ee). The gram-scale
asymmetric hydrogenation was performed well in the presence
of only a 0.25 mol % catalyst loading. Furthermore, the
important intermediate can be easily obtained through this
asymmetric catalytic methodology. Further investigations on
nickel-catalyzed asymmetric hydrogenation are in progress in
our lab.
Scheme 3. Deuterium Labeling Experiments of Asymmetric
Hydrogenation of 1b
ASSOCIATED CONTENT
* Supporting Information
■
S
product 2b-D′ was obtained with >95% deuteration at the β-
position and 16% deuteration at the α-position of the methyl
ester group. These results showed that our hydrogenation
process should be consistent with the proposed mechanism
reported by Chirik.10
In addition, the Ni-catalyzed asymmetric hydrogenation of
ethyl (E)-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl) acrylate (E)-1a was investigated, affording product 2a
with the same configuration and similar enantioselectivity as
(Z)-substrate 1a (Scheme 4, 52% conversion, 93% ee). This
reaction result illustrated that the Z/E isomeric mixture can be
used as the substrate directly.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00994.
Experimental procedures, NMR and HPLC spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhangxm@sustc.edu.cn.
*E-mail: xiuqindong@whu.edu.cn.
ORCID
To explore the synthetic potential of this Ni-catalyzed
hydrogenation, a gram-scale experiment proceeded under 80
atm of H2 and at 80 °C with only a 0.25 mol % catalyst loading
(Scheme 5a). This transformation proceeded smoothly with
Xiu-Qin Dong: 0000-0002-5045-1198
Xumu Zhang: 0000-0001-5700-0608
C
DOI: 10.1021/acs.orglett.9b00994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
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B.; Shen, X.; Lu, Z. J. Am. Chem. Soc. 2017, 139, 15316−15319.
(i) Liu, G.; Li, A.; Qin, X.; Han, Z.; Dong, X.-Q.; Zhang, X.; Adv.
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We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21432007,
21502145), Wuhan Morning Light Plan of Youth Science
and Technology (Grant No. 2017050304010307), the
Fundamental Research Funds for and the Central Universities
(Grant No. 2042018kf0202), Shenzhen Nobel Prize Scientists
Laboratory Project (Grant No. C17783101), and Science and
Technology Innovation Committee of Shenzhen (Grant No.
KQTD20150717103157174, JSGG 20170821140353405, and
JSGG 20160608140847864). The Program of Introducing
Talents of Discipline to Universities of China (111 Project) is
also appreciated.
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DOI: 10.1021/acs.orglett.9b00994
Org. Lett. XXXX, XXX, XXX−XXX