Asymmetric 1,4-Addition of Arylboronic Acids to β,γ-Unsaturated α-Ketoesters using Heterogeneous Chiral Metal Nanoparticle Systems

Article abstract of DOI:10.1002/adsc.201901294

Asymmetric 1,4-addition reactions with β,γ-unsaturated α-ketoesters are valuable because the resulting chiral ketoester compounds can be converted into various useful species that are often used as chiral building blocks in drug and natural product synthesis. However, β,γ-unsaturated α-ketoesters have two reactive points in terms of nucleophilic additions, which will lead to the 1,4-adduct, the 1,2-adduct and to the combined 1,4- and 1,2-adduct. Therefore, controlling this chemoselectivity is an important factor for the development of these transformations. Here, we developed an asymmetric 1,4-addition of aryl boronic acids to β,γ-unsaturated α-ketoesters by using heterogeneous chiral rhodium nanoparticle systems with a chiral diene ligand bearing a secondary amide moiety. The newly developed polydimethylsilane-immobilized rhodium nanoparticle catalysts showed high activity, high chemoselectivity, and excellent enantioselectivity, and this is the first heterogeneous catalytic system for this asymmetric reaction. Metal nanoparticle catalysts were recovered and reused without loss of activity or leaching of metal. (Figure presented.).

Full text of DOI:10.1002/adsc.201901294

Title: Asymmetric 1,4-Addition of Arylboronic Acids to β,γ-Unsaturated
α-Ketoesters using Heterogeneous Chiral Metal Nanoparticle
Systems
Authors: Hiroyuki Miyamura, Tomohiro Yasukawa, Zhiyuan Zhu, and
Shu Kobayashi
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901294
Link to VoR: http://dx.doi.org/10.1002/adsc.201901294

10.1002/adsc.201901294
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Asymmetric 1,4-Addition of Arylboronic Acids to -
Unsaturated -Ketoesters using Heterogeneous Chiral Metal
Nanoparticle Systems‡
Hiroyuki Miyamura,a# Tomohiro Yasukawa,a# Zhiyuan Zhu,a Shū Kobayashia,*
a Department of Chemistry, School of Science,ꢀ The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
Fax: (+81) 3-5684-0634; E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
# Both authors contributed equally.
‡ Dedicated to Professor Eric N. Jacobsen on the occasion of his 60th birthday
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))
chemoselectivity is an important factor for the
unsaturated -ketoesters are valuable because the resulting development of these transformations.
Abstract: Asymmetric 1,4-addition reactions with -
chiral ketoester compounds can be converted into various
useful species that are often used as chiral building blocks
in drug and natural product synthesis. However, -
unsaturated -ketoesters have two reactive points in terms
of nucleophilic additions, which will lead to the 1,4-adduct,
the 1,2-adduct and to the combined 1,4- and 1,2-adduct.
Therefore, controlling this chemoselectivity is an important
factor for the development of these transformations. Here,
we developed an asymmetric 1,4-addition of aryl boronic
acids to -unsaturated -ketoesters by using
heterogeneous chiral rhodium nanoparticle systems with a
chiral diene ligand bearing a secondary amide moiety. The
newly developed polydimethylsilane-immobilized rhodium
nanoparticle catalysts showed high activity, high
chemoselectivity, and excellent enantioselectivity, and this
is the first heterogeneous catalytic system for this
asymmetric reaction. Metal nanoparticle catalysts were
recovered and reused without loss of activity or leaching of
metal.
Rhodium-catalyzed asymmetric additions of aryl
boronic acid, especially asymmetric conjugate
addition to unsaturated carbonyl compounds, which
were pioneered by Hayashi and Miyaura et al.,[3] are
powerful catalytic systems that can realize both high
yields and high selectivities. In 2008, asymmetric
1,2-addition of aryl boronic acid to -ketoesters using
a chiral rhodium complex with a spirophosphite
ligand was reported by Zhou et al., and 1,2-selectivity
was observed even using -unsaturated -ketoesters
as substrates (Figure 1, a).[4] In 2014, asymmetric 1,4-
addition of aryl boronic acids to -unsaturated -
ketoamides and -unsaturated -ketoesters was
developed by Liao et al. using chiral rhodium
complexes
with sulfinylphosphine
ligands.[5]
However, incorporation of highly bulky amide or
ester groups to substrates was required to obtain
higher enantioselectivities, and substrates with
smaller ester groups, such as ethyl ester, gave 72%
enantiomeric excess (ee) maximum (Figure 1, a).
This is probably because the highly electron-
withdrawing nature of -ketocarbonyl moieties
lowers the energy barrier between the desired and
undesired transition states, and more sophisticated
chiral environments that can differentiate two
transition states for chiral recognition would be
desired for higher enantioselectivities with less bulky
and more common ketoester groups.
Keywords: 1,4-addition; asymmetric reaction; polymer; Rh
nanoparticle; -unsaturated -ketoester
Asymmetric synthesis is crucial for fine chemical
production, such as for the synthesis of drugs,
biologically active compounds, and natural products.
In particular, asymmetric carbon–carbon bond
formation is useful because both chiral centers and
carbon-based skeletons of the target molecules are
constructed simultaneously.[1] Asymmetric 1,4-
addition reactions with -unsaturated -ketoester
are valuable because the resulting chiral ketoester
compounds can be further converted into various
useful species that are often used as chiral building
blocks in drug and natural product synthesis.[2]
However, -unsaturated -ketoesters have two
reactive points in terms of nucleophilic additions,
which will lead to the formation of the 1,4-adduct, the
1,2-adduct and to the combined 1,4- and 1,2-adduct
(Figure
1).
Therefore,
controlling
this
1
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10.1002/adsc.201901294
Advanced Synthesis & Catalysis
reactions of aryl boronic acids with ,-unsaturated
carbonyl compounds, such as ketones, esters, and
amides.[12] In addition, we have recently developed a
chiral diene ligand, including a secondary amide
moiety with bifunctionality, interacting with a metal
nanoparticle through a diene moiety and activating a
substrate by hydrogen bonding.[12c,12f,12g]
In this article, we report the development of
asymmetric 1,4-addition reactions of aryl boronic
acids with -unsaturated -ketoesters that proceed
with high catalytic turnover and excellent
enantioselectivity using heterogeneous metal
nanoparticle systems incorporating a chiral diene
ligand. This is the first heterogeneous system that has
been applied for this asymmetric transformation.
Figure 1. Asymmetric addition of aryl boronic acids to
-unsaturated -ketoesters.
In addition, heterogeneous systems for asymmetric
1,4-addition of aryl boronic acids to -unsaturated
-ketoesters
have
never
been
reported.
Figure 2. Structure of the polymer support.
Table 1. Screening heterogeneous catalysts.
Heterogeneous catalysts have attracted great attention
because of their facile separation from products,
reusability, and application to industrial processes.[6]
As a general strategy to develop heterogeneous metal
catalysts
for
asymmetric
transformations,
immobilized chiral ligands for the formation of chiral
metal complexes have been widely explored.[7]
However, these strategies suffer from complicated
preparation of immobilized ligands, metal leaching
during preparation, and often instability of
immobilized ligands. In addition, immobilized metal
catalysts for organic transformations are generally
less active than the corresponding homogeneous
catalysts, and they often suffer from serious levels of
leaching of metals during reactions and decreased
activity during recovery and reuse.[8] As a strategy to
convert homogeneous catalysis into heterogeneous
catalysis, the use of heterogeneous metal nanoparticle
catalysts is of great interest because of their
reusability, robustness, and high reactivity.[8e,9]
Asymmetric synthesis with heterogeneous metal
nanoparticle systems using chiral ligands as “chiral
modifiers” have been investigated, especially in
asymmetric hydrogenation reactions pioneered by
Orito et al.[7a,10] By contrast, asymmetric C–C bond-
formation reactions using heterogeneous metal
Entry Support Metal
Yield Ee
(%)[a] (%) (%) (%)
7aa 8aa
1
Rh
Rh
Rh
Rh
70
66
97
97
98
4
3
7
–
4
–
8
7
–
–
11
1
1
1
1
1
1
2
2
2
–
2[b]
3[c]
4[d]
5
–
–
–
6
–
[g]
[g]
[g]
94
<10[f]
–
[g]
[g]
[g]
Rh–Ag(1:1) 50
Rh–Ag(1:3) 51
Rh
Rh
97
98
97
97
95
98
[g]
nanoparticle systems are
a
very limited and
6
7
developing field.[11]
56
74
15
2
8[e]
9
In this context, we have developed chirally
modified rhodium and bimetallic nanoparticle
systems based on the polymer-incarcerated strategy,
in which polystyrene derivatives with cross-linking
moieties are used to immobilize metal nanoparticles.
The metal nanoparticles are stabilized with weak but
multiple interactions of benzene rings in the polymer
and physical envelopment. Chirally modified
rhodium-based metal nanoparticle systems thus
developed can be applied to asymmetric 1,4-addition
[g]
[g]
Rh–Pt(1:1) 19
Rh 95
–
–
[h]
10
[a]
[b]
Isolated yield.
Corresponding 4-methylbenzyl ester
[c]
was used as a substrate instead of 4a.
Corresponding
[d]
isopropyl ester was used as a substrate instead of 4a.
Corresponding tert-butyl ester was used as a substrate
instead of 4a. [e] 5a (1.5 equiv) was used. [f] Determined by
[g]
[h]
1H NMR analysis.
Not determined.
Homogeneous
catalyst, [Rh(C2H4)Cl]2 (Rh: 1 mol%) was used.
2
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10.1002/adsc.201901294
Advanced Synthesis & Catalysis
We started our investigation using previously
corresponding homogeneous complex catalyst was
examined (entries 7 vs. 10). Excellent yield was
obtained and side products hardly formed in the
homogeneous conditions. It showed that in spite of
lower yield, the same level of high enantioselectivity
with the homogeneous system was obtained in
heterogeneous catalyst systems.
developed heterogeneous Rh or its bimetallic
nanoparticle catalysts immobilized in a composite
support of polymer with a cross-linking moiety and
commercially available Ketjenblack (1). The ethyl
ester 4a was chosen as a less bulky and common ester
to achieve the catalyst system that can control
selectivities more precisely. These catalysts showed
high reactivity and enantioselectivity in various types
of asymmetric 1,4-addition reactions of aryl boronic
acids. When 1 mol% of Rh nanoparticle catalyst was
used with 2 mol% of chiral diene ligand 3, which
contains a secondary amide moiety for bifunctional
activation of substrate 4a in a previously optimized
solvent system of water and toluene, the desired 1,4-
adduct (6aa) was obtained in good yield and with
very high enantioselectivity; the reaction was
accompanied by the formation of small amounts of
the 1,2-adduct (7aa) and the double adduct (8aa)
(Table 1, entry 1). The use of a substrate containing a
4-methylbenzyl ester moiety gave the similar result
with the reaction with 4a and the 1,4-adduct was
obtained with excellent ee in good yield (entry 2). We
also tested substrates with a bulkier ester group as
controls. Excellent yield and ee were observed in the
reaction with a substrate containing an iso-propyl
ester moiety (entry 3). On the other hand, the reaction
with a substrate containing a tert-butyl ester moiety
hardly gave the desired product in spite of high
conversion of the substrate (entry 4). Probably, too
bulky ester group sterically might inhibit the desired
reaction and the substrate might thermally decompose.
It is remarkable that even the substrate with small
ester group gave good yield and the similar level of
high enantioselectivity with those obtained from the
bulky ester in our catalytic systems. In our previous
studies, bimetallic nanoparticles of Rh and Ag
showed better performance for asymmetric 1,4-
addition reactions and we tested two bimetallic
catalysts with different metal ratios for this reaction.
However, yields were lower than that obtained using
Table 2. Optimization of reaction conditions.
Entry
Solvent
t
Yield Ee
7aa;
(h) (%)[a] (%) 8aa (%)
x
y
1
2
3
4
1.5 2
1.5 2
1.5 1
2.0 1
2.0 1
toluene:H2 18 74
O (1:2)
toluene:Et 12 65
OH (1:1)
toluene:Et 18 73
OH (1:1)
toluene:Et 18 77
OH (1:1)
97
98
97
97
96
7; 2
2; 11
7; 6
7; 10
6; 7
5[b]
toluene:Et 12 82
OH (1:1)
[a]
[b]
Isolated yield. Catalyst was prestirred with 3 and 5a
for 4 h before the addition of 4a.
We further optimized the reaction conditions using
the Rh metal nanoparticle catalyst immobilized on 2
(Table 2). The reaction proceeded smoothly in a
toluene–ethanol solvent system (entry 2) and the
amount of chiral ligand 3 could be reduced to 1 mol% in
this solvent system with a higher yield (entry 3). When
the amount of phenylboronic acid was increased to 2.0
equiv under the reaction conditions based on entry 3, a
slightly higher yield was observed (entry 4). In our
previous investigation, we noted that induction periods
were required to activate metal nanoparticles under
reductive conditions, and these induction periods could
be shortened by prestirring of the heterogeneous
catalysts with chiral ligand and aryl boronic acid as an
activator.[12c,12f] We applied these prestirring conditions
to the current reaction system and were pleased to find
that a higher yield was also observed with shorter
reaction time (entry 5). We, thus, established the
reaction conditions with prestirring to be the optimized
conditions, and recovery and reuse experiments were
conducted in which ligand 3 was externally added in
each run (Scheme 1). From runs one to five, high yields
and excellent enantioselectivities were maintained but
the yield dropped in the sixth run. We suspected the
adsorption of impurities on the nanoparticle surface led
the
Rh nanoparticle
catalyst, while
the
enantioselectivity was almost identical (entries 5 and
6).
Recently, we have developed Rh–Pt bimetallic
nanoparticle catalysts immobilized on a composite
support of polydimethylsilane (DMPSi) with alumina
(2) for arene hydrogenation.[13] Polysilane is a safe
and inexpensive material that undergoes minimal
swelling, thereby facilitating the handling of the
catalysts.[13,14] When this catalyst was tested for the
asymmetric 1,4-addition, high enantioselectivity was
observed but the yield was low (entry 9). We then
prepared a novel Rh single-metal nanoparticle
catalyst using support 2 (Rh/DMPSi–Al2O3). This
catalyst system showed higher activity and excellent
enantioselectivity; however, a significant amount of
double adduct 8aa was formed (entry 7). A higher
yield was obtained while maintaining excellent
enantioselectivity when
a reduced amount of
phenylboronic acid was employed to suppress the
over-reaction (entry 8). The activity of the
3
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10.1002/adsc.201901294
Advanced Synthesis & Catalysis
to diminished catalytic activity. The collected catalyst
was then heated at 100 C for 5 h under air atmosphere
before the seventh run and catalytic activity was revived.
Therefore, the reactivation operation was conducted for
a further three runs and high yields were maintained
with excellent enantioselectivities.
Entry R1, R2 (4) Ar (5) x, y
Yield Ee Byproducts
(mol%) (%)[b] (%) 7–9[c]
1
4-MeO- Ph
C6H4, Et
4-MeO- 4-F-
C6H4, Et C6H4
4-MeO- 4-Ph-
C6H4, Et C6H4
1.0, 1.0 82
1.0, 1.0 90
1.0, 1.0 86
1.5, 1.5 94
96 7 (6%),
8 (7%)
98 not
detected
98 7 (6%)
Scheme 1. Recovery and reuse of the catalyst.
2
We then examined the use of the aliphatic -
unsaturated -carbonyl substrate 4b. When a reaction
was conducted with both 1 mol% of ligand 3 and a
Rh nanoparticle catalyst without prestirring, 1,4-
adduct 6ba was obtained in moderate yield with
excellent enantioselectivity (Table 3, entry 1). In this
reaction, ethanol adduct 9b was obtained as an
undesired byproduct instead of the 1,2-adduct and
double adduct that were obtained with substrate 4a.
In addition, substrate 4b decomposed under the
reaction conditions in the absence of catalyst and 5a.
To enhance the desired reaction before
decomposition of 4b, prestirring, which shortened the
induction period, was effective and a higher yield was
observed (entry 2). The reaction time of 12 h was
sufficient to obtain a good yield by using the
prestirring method (entry 3).
3[d]
4
4-Me-
Ph
99 7 (3%)
99 7 (6%)
99 7 (10%)
C6H4, Et
4-Me-
5
4-MeO- 2.0, 2.0 84
C6H4, Et C6H4
6
2-Me-
3-MeO- 1.0, 2.0 68
C6H4, Et C6H4
7
4-Cl-
Ph
1.0, 1.0 90
1.0, 1.0 46
1.0, 1.0 82
94 not
detected
98 not
detected
97 9 (9%)
C6H4, Et
2-thienyl, Ph
Et
8
9
Me, Et
Ph
10[e] Me, Et
4-MeO- 1.0, 2.0 74
C6H5
78 9 (13%)
92 9 (22%)
94 9 (6%)
11
Me, Et
Me, Et
3-MeO- 1.0, 1.0 73
C6H4
2-MeO- 2.0, 2.0 74
C6H4
Table 3. Optimization of the conditions for aliphatic
substrate.
12
[a]
Catalyst was prestirred with 3 and 5 for 4 h before the
[b]
[c]
addition of 4. Isolated yield. Yields were determined
using 1H NMR analysis. [d] 18 h. [e] 80 C.
The substrate scope of the reaction was then
investigated (Table 4). An aryl boronic acid with an
electron-withdrawing moiety reacted smoothly to
afford the desired product in both excellent yield and
ee (entry 2). Bulky aryl boronic acid also reacted
smoothly with excellent selectivity (entry 3). An
unsaturated ketoester containing a 4-methylphenyl
moiety gave the desired product in excellent yield
with 99% ee, although slightly increased catalytic
loading was required (entry 4). 4-Methoxy
phenylboronic acid gave the desired product in good
yield and with 99% ee with 2 mol% of catalyst and
ligand (entry 5). Unsaturated ketoester containing a
2-methylphenyl moiety gave a moderate yield and a
moderate regioselectivity, probably because of its
greater steric bulk (entry 6). The use of an
unsaturated ketoester containing a 4-chlorophenyl
moiety gave excellent yield and excellent ee (entry 7).
An unsaturated ketoester containing a thienyl moiety
also reacted with excellent ee but in moderate yield
Entry
1
Yield (%)[a]
67
81
Ee (%)
97
97
9b (%)
7
6
9
2[b]
3[b,c]
82
97
[a]
[b]
Isolated yield. Catalyst was prestirred with 3 and 5a
for 4 h before the addition of 4b. [c] 12 h.
Table 4. Substrate scope.[a]
4
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10.1002/adsc.201901294
Advanced Synthesis & Catalysis
The recovered Rh/DMPSi–Al2O3 was washed with ethyl
acetate, toluene, and ethanol, successively. The recovered
catalysts were then dried in vacuo overnight to remove the
remaining solvents. After drying, the weight of the
recovered catalysts was measured, and the next run was
conducted with a reaction scale based on the amount of
recovered catalyst.
(entry 8). In all reactions with aromatic substrates,
high selectivity for 1,4-addition over 1,2-addition was
observed. When electron-rich aryl boronic acids were
used for the aliphatic unsaturated ketoester substrate,
2 mol% of the catalyst and the ligand were required
to obtain a good yield (entries 10 and 12). A 3-
methoxy phenylboronic acid in which an electron-
donating group was located at the less electronically Acknowledgements
interacting position reacted smoothly with excellent
This work was partially supported by a Grant-in-Aid for
ee with 1 mol% catalytic loading (entry 11).
Although the background reaction to afford ethanol
adduct 9b was always competitive in all reactions
with aliphatic substrate 4b, the desired pathway could
proceed in good yield with lower catalyst loading.
In summary, we have developed an asymmetric
1,4-addition reaction of aryl boronic acids to -
unsaturated -ketoesters using heterogeneous chiral
rhodium nanoparticle systems with a chiral diene
ligand bearing a secondary amide moiety. The newly
developed DMPSi immobilized rhodium nanoparticle
catalysts, which is the first heterogeneous catalytic
system for this asymmetric reaction, showed high
activity, high chemoselectivity, and excellent
enantioselectivity. Prestirring of the heterogeneous
catalyst and aryl boronic acid improved the yield. The
metal nanoparticle catalyst was recovered and reused
without loss of activity or leaching of metal. Smaller
ester moieties in the -unsaturated -ketoester, such
as ethyl ester, were compatible with the reaction and
excellent enantioselectivities were achieved. This
Scientific Research from the Japan Society for the Promotion of
Science (JSPS), MEXT Japan, NEDO, and AMED.
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the
previously
developed
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Asymmetric 1,4-addition: Typical procedure (Table 2, entry 5)
Phenylboronic acid 5a (73.2 mg, 0.6 mmol) and
Rh/DMPSi–Al2O3 (36.3 mg with 0.083 mmol/g loading of
Rh, 0.003 mmol) were combined in a CarouselTM tube
equipped with a magnetic stirring bar. Air was then
replaced with argon using Schlenk techniques. Chiral diene
ligand 3 (0.8 mg, 0.003 mmol) was then added as a stock
solution in toluene/ethanol = 1:1 (v/v) (520 L in total) to
the reaction vessel. The mixture was stirred for 4 h at 100
C as prestirring, then ethyl (E)-4-(4-methoxyphenyl)-2-
oxobut-3-enoate (4a) (65.4 mg, 0.3 mmol) was added as a
solution in toluene/ethanol = 1:1 (v/v) (520 L in total).
After the addition, the mixture was stirred for 12 h at 100
C. After cooling to room temperature, the reaction
mixture was diluted and washed with ethyl acetate and the
solid catalysts were filtrated off. The reaction solution was
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1
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NMR analysis of the crude mixture was taken with internal
standard
(1,1,2,2-tetrachloroethane)
to
determine
conversions and yields. The solvent and the internal
standard were then removed in vacuo, and the residue was
purified with preparative TLC to afford ethyl (S)-4-(4-
methoxyphenyl)-2-oxo-4-phenylbutanoate (6aa) in 82%
yield. The ee was determined to be 96% using HPLC with
DAICEL AS-3 column and with hexane/2-PrOH = 9:1
(flow rate = 1.0 mL/min) as eluent.
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Reactivation of recovered catalyst during recovery and reuse
5
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Advanced Synthesis & Catalysis
COMMUNICATION
Asymmetric 1,4-Addition of Aryl Boronic Acid to
-Unsaturated -Ketoesters Using Heterogeneous
Chiral Metal Nanoparticle Systems
Adv. Synth. Catal. Year, Volume, Page – Page
Hiroyuki Miyamura,a# Tomohiro
Yasukawa,a# Zhiyuan Zhu,a Shū
Kobayashia*
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