Nickel(II)-Catalyzed Enantioselective 1,3-Dipolar Cycloaddition of Nitrones with α,β-Unsaturated Acylcarboxylates

Article abstract of DOI:10.1002/ejoc.201601540

The highly enantioselective 1,3-dipolar cycloaddition of nitrones with α,β-unsaturated acylcarboxylates was realized for the first time by using a chiral bis(indano-oxazoline)-based Ni complex. The reaction proceeded smoothly under mild conditions and provided isoxazolidines with three contiguous stereocenters in high yields with excellent diastereoselectivities (>20:1 dr) and enantioselectivities (up to 99 % ee). The reaction was scaled up to the gram scale, and the products were readily transformed into γ-amino alcohols and other potentially bioactive compounds.

Full text of DOI:10.1002/ejoc.201601540

A Journal of
Accepted Article
Title: Ni(II)-Catalyzed Enantioselective 1, 3-Dipolar Cycloaddition of
Nitrones with α, β-Unsaturated Acyl Carboxylates
Authors: bin fu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601540
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European Journal of Organic Chemistry
10.1002/ejoc.201601540
COMMUNICATION
Ni(II)-Catalyzed Enantioselective 1, 3-Dipolar Cycloaddition of
Nitrones with α, β-Unsaturated Acyl Carboxylates
Lei Xie, Xuan Yu, Jiaqi Li, Zhenhua Zhang, Zhaohai Qin and Bin Fu*
Abstract: A highly enantioselective 1, 3-dipolar cycloaddition of
nitrone with α, β-unsaturated acyl carboxylate was realized for the
first time by a chiral Ni complex of indane-bis(oxazoline). The
reaction can proceed smoothly under mild condition, providing
isoxazolidines with three contiguous stereocenters in high yields with
excellent diastereo-(>20:1 dr) and enantioselectivities (up to 99%
ee). The reaction could be scaled up to gram scale, and the products
were readily transformed into γ-amino alcohol or other potential
bioactive compounds.
bearing 1, 2-dicarbonyl unit as dipolarphiles for the cycloaddition
of nitrones, which is rarely reported, highly valuable and
desirable (Figure1, B).
M
M
O
O
O
O
X
N
R X = O or S
R'
R
A: 1, 5-Coordination
B: 1, 4-Coordination
Figure 1. Different coordination pattern with metal salt.
Introduction
In a continuation of our ongoing efforts in the development
Over the past two decades, the asymmetric 1,3-dipolar
cycloaddition (1,3-DC) reactions have become one of the most
important approaches to enantiomerically enriched heterocyclic
compounds which maybe serve as therapeutic agents,
[14]
of new and efficient catalytic asymmetric methods,
we found
that unsaturated acyl carboxylate were successfully employed to
[15]
the enantioselective Michael addition with indoles. Inspired by
[16]
[1]
this finding and some reports of cycloaddition reaction,
envisioned that α, β-unsaturated acyl carboxylate as
we
a
agrochemicals or the key intermediates of natural products. So
far a variety of Lewis acid-catalyzed and organocatalyzed
methods have been successfully developed for this type of
dipolarophile could be successfully applied in the asymmetric 1,
-dipolar cycloaddition reaction. To our knowledge, there is only
one report involving unsaturated acyl carboxylate as
dipolarophile in 1, 3-DC reaction documented by Gong’s
[2]
3
reaction. Among various 1, 3-dipoles reported in the literatures,
nitrone is undoubtedly the most widely studied one due to its
stability and easy preparation. In addition, the resulting
isoxazolidine products can be converted to biologically active β-
a
[17]
group.
in which the reaction with isocyanoester produced
[3]
optically active dihydropyrrole derivatives by a chiral Ag(I)
catalyst. Herein we report our studies on the asymmetric
cycloaddition of unsaturated acyl carboxylates with nitrones
catalyzed by indane-bisoxazoline-Ni(II) complexes, affording the
isoxazolidines in high yields with excellent diastereo- (>20:1 dr)
and enantioselectivities (up to >99% ee).
amino acids, β-lactams, amino alcohols and alkaloids.
On the other hand, the dipolarophiles of 1, 3-DC reaction
are mainly electron-deficient alkenes or alkynes which easily
form 1, 5-metal-coordinated species (Figure 1, A) in the Lewis
acid-catalyzed process, such as N-enoyl derivatives of
[
4]
[5]
[6]
oxazolidinone,
thiazolidinethione,
pyrrolidinone,
and
[7]
[8]
pyrazolidinone, as well as alkylidene malonate, and pyridinyl
[9]
N-oxide. However, few substrates introducing 1, 4-metal-
coordination pattern in this reaction were reported (Figure 1, B). Results and Discussion
[10]
In 2005, Palomo et al. explored the addition of nitrone with α′-
hydroxy enones in BOX-Cu(II)-catalyzed reactions to obtain the
endo adducts in excellent enantioselectivity. In 2006, Evans et
Initially, we screened the optimal condition by investigating
the cycloaddition between methyl unsaturated acyl carboxylate
[11]
[18, 9]
al. reported the nitrone cycloadditions of α,β-unsaturated acyl
imidazoles using pybox-cerium(IV) complex, giving the products
in high endo/exo selectivity and excellent enantioselectivity. In
1a and nitrone 2a (Scheme 1).
The results are listed in table
Cl at room
temperature for 12 hours in the presence of different metal
complexes of ligand L1, most of Lewis acids including Cu(OTf)
Cu(ClO , Mg(ClO and Ni(acac) didn’t work or showed very
sluggish in the reaction (Entries 1~4). However, we were
pleased to find that Ni(ClO ·6H O-L1 afforded the desired
1. When the reaction was carried out in CH
2
2
[12]
2
010, Ishihara et al. reported a chiral copper(II) complex of 3-
2
,
(
2-naphthyl)-L-alanine amide successfully catalyzed the
4
)
2
4
)
2
2
enantioselective 1, 3-dipolar cycloaddition of nitrones with
propioloylpyrazole and acryloylpyrazole derivatives, providing
endo-cycloadducts with high enantioselectivities. Despite these
advances, studies on the 1, 4-metal-coordination pattern are
less explored in contrast to a number of reports of 1, 5-metal-
coordination pattern in the Lewis acid-catalyzed 1, 3-DC reaction
4
)
2
2
product 3aa in high yield (87%) with exclusive regioselectivity
1
and excellent diastereoselectivity (endo/exo >20:1, by H NMR)
regardless of very poor enantioselectivity (Entry 5).
Subsequently, a series of bisoxazoline (BOX) were examined,
and fortunately indane-BOX ligand L4 gave rise to product 3aa
in 92% yield with 89% ee value (Entry 11). A survey of reaction
solvents revealed that THF afforded the best results (93% yield
and 94% ee, entry 17). Furthermore, the reaction temperature
and the catalyst loading were tested. As expected, the
enantioselectivity could be improved to 97% ee value when the
[13]
of nitrones. A straightforward strategy is to utilize the alkenes
[a]
Department of Applied Chemistry, China Agricultural University,
Yuanmingyuan xilu, Beijing, 100193, China
E-mail: fubinchem@cau.edu.cn
http://www2003.cau.edu.cn/sci/index.php?do=teashow&id=74
Supporting information for this article is given via a link at the end
of the document.((Please delete this text if not appropriate))
o
reaction proceeded at 0 C (Entry 18). Lowering the catalyst
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COMMUNICATION
O
Ph
O
-
O
Ph
N
Ph
Ligand-metal
Solvent
+
N
CO2Me
substituents on β-phenyl unsaturated acyl carboxylates were
examined. All reactions proceeded smoothly to provide the
corresponding isoxazolidine products in high yields and, most
notably, with excellent diastereo- and enantioselectivities (Table
Ph
MeO2C
O
Ph
2a
1a
3aa
2
, entries 1~11, 75~95% yield, >20:1 dr and 94~99% ee),
O
O
O
O
a. R = i-Pr
b. R = Ph
c. R = Bn
R
d. R = t-Bu
indicating that whatever an electron-donating or electron-
withdrawing substituents at various positions on the phenyl ring
had a minimal influence on the diastereo- and enantioselectivity
of the reaction, except for different impacts on the reactivity
Ph
Ph
O
O
Ph
N
N
N
N
N
N
O
N
Ph
R
Ph
Ph
L1
L3
L2
(
24~72 hours). It should be explained that, product 3fa could be
O
O
O
N
converted to the corresponding alkene 4fa by Wittig reaction and
followed determination by HPLC (Entry 5). Moreover, β-2-
naphthyl unsaturated acyl carboxylate was also a suitable
substrate, giving the same high reactivity and selectivity (75%
yield and 95% ee, entry 12). To our delight, the reaction was
successfully extended to β-alkyl group substituted substrates.
Excellent enantioselectivities were observed in the reactions of
β-cyclohexyl or -tert-butyl group unsaturated acyl carboxylate
N
N
N
L4
L5
Scheme 1. The model reaction for optimization and screened bis(oxazoline)
ligands.
(
97% and 98% ee, respectively, entries 13 and 14). Even if
[a]
Table 1. Optimization of the reaction condition.
using n-hexyl substituted substrate, the reaction also furnished
the product 3pa in 86% yield with 88% ee value (Table 2, entry
15). It is noteworthy that the reaction could be accomplished
within 3 hours for β-alkyl group unsaturated acyl carboxylates,
demonstrating higher reaction activity than β-aryl group
substituted substrates.
3
[b]
[c]
Entry
R
Metal salts
Solvent
Yield (%)
Ee (%)
1
2
3
4
5
6
7
L1
L1
Cu(OTf)
2
CH
CH
CH
CH
CH
CH
CH
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
-
-
-
-
Cu(ClO ·6H
4
)
2
2
O
-
L1
Mg(ClO
Ni(acac)
·6H
·6H
·6H
4
)
2
·6H
2
O
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
-
[a]
Table 2. The scope of unsaturated acyl carboxylate esters 1
L1
2
20
87
93
92
88
46
-
0
O
R1
Ph
N
O
R1
Ph
L1
Ni(ClO
Ni(ClO
Ni(ClO
Ni(ClO
Ni(ClO
Ni(ClO
Ni(ClO
Ni(ClO
Ni(ClO
Ni(ClO
Ni(ClO
Ni(ClO
Ni(ClO
Ni(ClO
Ni(ClO
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
)
2
2
O
10
45
43
12
12
-
O
O
Ph
Ni(ClO4)2. 6H2O(10 mol %)
N
N
R1
CO2R2
L4 (11 mol %)
Ph
O
Ph
L2a
L2b
)
2
2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Ph
THF, 0 o
C
2
2
R O C
CO2Et
R O2C
2
)
2
2
1
2a
3
4
8
9
L2c
L2d
L3
L4
L5
L4
L4
L4
L4
L4
L4
L4
)
2
·6H
2
CH
CH
CH
CH
CH
Cl
Cl
Cl
Cl
Cl
1
2
[b]
[c]
)
2
·6H
2
Entry
R
R
T (h)
Yield (%)
Ee (%)
10
11
12
13
14
15
16
17
)
2
·6H
·6H
·6H
2
1
2
3
4
5
6
4-MeC
6
H
4
Me
Me
Me
Me
Me
Me
24
48
24
24
48
24
88(3ba)
75(3ca)
94(3da)
95(3ea)
78(3fa)
80(3ga)
98
98
)
2
2
92
91
-
89
37
-
4-MeOC
6
H
4
)
2
2
4-FC
6
H
4
94
)
2
·6H
·6H
·6H
2
MeOH
Toluene
EtOAc
4-ClC
6
H
4
96
)
2
2
55
90
93
93
93
68
91
90
91
94
97
97
4-NO
2
C
6
H
4
94(4fa)
96
)
2
2
3-MeC
6
H
4
)
2
·6H
2
CHCl
THF
THF
THF
3
7
8
9
3-FC
6
H
4
Me
Me
Me
Me
Me
Me
Et
24
24
24
24
24
72
3
85(3ha)
88(3ia)
86(3ja)
90(3ka)
95(3la)
75(3ma)
88(3na)
92(3oa)
86(3pa)
96
96
97
97
99
95
97
98
88
)
2
·6H
2
6 4
3-BrC H
d
1
8
)
2
·6H
2
6 4
2-MeOC H
e
1
9
)
2
·6H
2
10
2-BrC
6 4
H
[a] The reaction conditions: 11 mol% of ligand and 10 mol % of metal (1.1:1),
11
12
13
2,4-di-ClC H
6 4
solvent (2.0 mL), 1a (0.25 mmol) and 2a (0.3 mmol) for 12 h at rt. [b] Isolated
1
2-Naphthyl
Cyclohexyl
t-Bu
yield. [c] Unless otherwise stated, dr >20:1, determined by H NMR analysis
o
and chiral HPLC. [d] The reaction at 0 C for 24 h. [e]
5 mol% L4-
o
4 2
Ni(ClO )2·6H O, at 0 C for 24 h.
1
4
5
Et
3
1
n-hexyl
Et
3
loading to 5 mol% led to a decreased yield of 68% but with the
remained ee value (Entry 19).
[
a] All reactions were conducted in THF (2 mL) under nitrogen using 10
o
mol% of L4-Ni(ClO
stated, dr >20:1, determined by H NMR analysis and chiral HPLC.
4 2 2
) ·6H O at 0 C. [b] Isolated yield. [c] Unless otherwise
1
Under the optimized conditions (Table 1, entry18, 10 mol %
4 2 2
L4-Ni(ClO ) ·6H O, THF as solvent, and 0 °C), we first
investigated the scope of unsaturated acyl carboxylate in this
reaction. The results are summarized in Table 2. The effect of
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COMMUNICATION
[a]
Table 3. The scope of nitrones 2 in the reaction
which was also confirmed by the fact that, isoxazolidine products
3ar, 3as and 4at bearing different substituents were achieved
R4
O
R4
O
via the reaction of the corresponding unsaturated acyl
carboxylates with nitrones in different yields and ee values
(Figure 2).
O
R4
Ni(ClO4)2. 6H2O
(10 mol %)
N
Ph
O
N
R1
O
N
L4 (11 mol %)
Ph
CO2Me
R3
R3
R3
THF, 0 o
C
R2O2C
2
CO2Et
R O2C
1a
2
3
4
3
4
[b]
[c]
Entry
R
R
T(h)
24
48
24
48
72
24
24
24
24
24
24
48
24
24
72
72
Yield (%)
Ee (%)
98
Br
O
O
O
1
2
3
4
5
6
7
8
9
4-MeC
6
H
4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Bn
91(3ab)
81(3ac)
80(3ad )
72(3ae)
78(3af)
93(3ag)
90(3ah)
70(3ai)
84(3aj)
83(3ak)
81(3al)
71(3am)
93(3an)
86(3ao)
-(3ap)
N
N
N
CO2Me
CO2Et
Ph
EtO C
4-MeOC
6
H
4
96
O
CO2Et
O
2
4-ClC
4-BrC
6
6
H
4
97(4ad)
Br
3as, 86% yield and 94% ee
3ar, 80% yield and 96% ee
4at, 61% yield and 54% ee
H
4
97
Figure 2. Several cycloadducts with various substituents.
4-NO
3-MeC
3-MeOC
3-CF
2-MeC
2-MeOC
2-FC
2-ClC
2
C
6
H
4
93(4af)
6
H
4
97
The absolute configuration of the cycloadduct
3 was
6
H
4
98(4ah)
determined after conversion to the corresponding isoxazolidine
nitro alcohol 5. Treatment of product 3as with nitromethane in
the presence of triethylamine led to a couple of diastereomers
3
C
6
H
4
98
94
88
94
92
98
96
-
6
H
4
5a
and 5b, whose single crystals were cultivated, and
determined by X-ray diffraction analysis. As illustrated in Figure
1
0
1
2
3
4
5
6
6 4
H
[19]
3,
both diastereomers interact with each other through
1
1
1
1
1
1
6 4
H
intermolecular hydrogen bonding between OH and C=O group.
Obviously three contiguous chiral centers on the isoxazolidine
ring of product 5a and 5b have endo relative configuration and
(3S, 4R, 5R) absolute configuration. By analogy the absolute
configuration of 3as and other cycloadducts were also assigned
to be (3S, 4R, 5R).
6
H
4
2-Naphthyl
Cyclohexyl
Ph
Br
Ph
-(3aq)
-
Br
O
O
CH3NO2
3
N
N
[
a] All reactions were conducted in THF (2 mL) under nitrogen using 10
3as
NO2
+
NO2
o
Et N, rt
4 2 2
mol% of L4-Ni(ClO ) ·6H O at 0 C. [b] Isolated yield. [c] Unless otherwise
1
stated, dr >20:1, determined by H NMR analysis and chiral HPLC.
CO2Me
CO Me
HO
2
HO
Br
Br
5
a
5 b
Next, the substrate scope was further extended by variation
of nitrones, as summarized in Table 3. Initially, when N-phenyl
o
substituted nitrone 2 was reacted with 1a at 0 C for 24~72 h,
giving the desired cycloadducts 3ab~3am in 70~93% yields with
O
O
p-Br-Ph
O
88~98% ee values, in which exhibited good reactivity and high
N
-
N
enantioselectivity regardless of the electronic nature and
position of substituent at phenyl group of nitrone 2 (Table 3,
entries 1~12). Moreover, 2-naphthyl or cyclohexyl substituted
nitrone was also very amenable substrates in this reaction,
affording high yields and excellent ee values (98% and 96% ee,
entries 13 and 14). Unfortunately, in the case of N-methyl or -
benzyl group nitrone, the reaction became inert, and no desired
products were yielded even after increasing the reaction
temperature to room temperature (entries 15 and 16). Among
cycloadducts 3ab~3ao, some of them were transformed into the
corresponding isoxazolidine alkenes 4 by Wittig reaction, whose
enantiomeric excesses were readily determined by chiral HPLC.
These results demonstrate that N-phenyl substitution in nitrone
is critical for the reactivity and enantioselectivity of the reaction,
Ni
O
Ph
N
+
C
O
C
Ph-Br-p
Re-face favored
OMe
Figure 3. The determination of absolute configuration and possible
asymmetric induction mode.
Based on the observed stereochemistry in this study we
believe that the dipolarophile (unsaturated carbonyl carboxylate)
coordinates to the Ni(II)-BOX complex through
coordinated pattern and is hence activated, as illustrated in
Figure 3. Subsequently nitrone preferentially approaches the
dipolarophile from the Re-face of the double bond due to the Si-
a 1, 4-
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COMMUNICATION
face steric hindrance from the bulky indane moiety of ligand, Experimental Section
leading to the major (3S, 4R, 5R)-configured isoxazolidine
[
20]
product. According to some reports in the literature, the anion
ClO
Typical procedure for the asymmetric 1,3-dipolar cycloaddition of
unsaturated acyl carboxylate to nitrone: To a dry Schlenk tube,
Ni(ClO4)2·6H2O (0.025 mmol) was added, followed by ligand L4 (0.0275
mmol) in a solvent of THF (1.0 mL) under nitrogen atmosphere. After the
solution was stirred for 1 hour at room temperature, a solution of
unsaturated acyl carboxylate (0.25 mmol) in THF (1.0 mL) was added.
-
4
may coordinate to the Ni(II) center, and form complex
intermediates in a solution. The detailed mechanism remains to
be further studied.
o
The resulting mixture was stirred for 15 min, cooled to 0 С and stirred for
another 15 min before the nitrone (0.3 mmol) was added. After the
o
reaction was completed at 0 С (monitored by TLC), the solution was
directly purified by flash column chromatography on silica gel (ethyl
acetate/petroleum ether, 1/50, v/v and dichloromethane/petroleum ether,
2
5
1
=
/1, v/v) to afford the desired product 3aa as a yellow oil; 93% yield; [α]
D
1
–40.8 (c 1.13, CH2Cl2); H NMR (300 MHz, CDCl3) δ 7.59–7.51 (m, 2H),
7.48–7.41 (m, 2H), 7.41–7.33 (m, 5H), 7.32–7.19 (m, 3H), 7.08–6.93 (m,
3
H), 5.43 (d, J =7.8 Hz, 1H), 5.26 (d, J=6.2 Hz, 1H), 4.43 (dd, J=7.8, 6.3
1
3
Hz, 1H), 3.60 (s, 3H); C NMR (75 MHz, CDCl3) δ 190.29, 160.71,
1
1
50.34, 140.37, 136.33, 128.77, 128.74, 128.64, 128.47, 127.73, 126.67,
26.37, 122.03, 114.32, 81.99, 72.33, 69.30, 52.72; HRMS: Calcd for
+
+
C24H22NO4 ([M+H ]): 402.1700; Found: 402.1697. HPLC analysis
Chiralcel AD-H, n-hexane/i-PrOH 80:20, 1.0 mL/min, tr (major)=8.78 min,
(
Scheme 2. The synthetic utility of the catalyst system.
tr (minor) =10.22 min, 97% ee).
To show the synthetic utility of the catalyst system, the
synthesis of the cycloadduct 3aa was expanded to a gram scale.
As shown in Scheme 2 (a), treatment of 0.95 g of 1a (5.0 mmol)
with 1.08g of 2a (5.5 mmol) in the presence of 5mol% of catalyst
Acknowledgements
We appreciate the National Natural Sciences Foundation of
China (Nos. 21172255) and the Ministry of Science and
Technology of China (No.2015BAK45B01) for financial support.
L4- Ni(ClO
4
)
2
·6H
8) afforded 1.78 g (92% yield) of the desired product 3aa in
7% ee value. In addition, the resulting isoxazolidine could be
2
O under the optimal condition (Table 1, entry
1
9
further transformed into useful compounds. For example, 3aa
97% ee) was reacted with phosphorus ylide to form the
Keywords: 1, 3-Dipolar cycloaddition • Nickel • Nitrone •
Isoxazolidine • α, β-Unsaturated acyl carboxylate
(
[21]
corresponding alkene 4aa in almost quantitative yield, which
o
was subsequently hydrogenated by Pd/C in MeOH at -10 C to
[1]
a) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products (Eds: A. Padwa, W. H.
Pearson), Wiley, New York, 2002. b) B. Engels, M. Christl, Angew.
Chem. Int. Ed. 2009, 48, 7968–7970; c) M. Baunach, C. Hertweck,
Angew. Chem. Int. Ed. 2015, 54, 12550–12552; d) S. Hassana, T. J. J.
Müller, Adv. Synth. Catal. 2015, 357, 617–666; e) C. R. Pitts, T. Lectka,
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give chiral γ-amino alcohol 6 bearing maleate subunit in 75%
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[22]
(
Scheme 2 (b)).
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ee). A variety of unsaturated acyl carboxylates are compatible
with the reaction, and for nitrone dipole N-phenyl substitution is
important for the stereoselectivity and reactivity of the reaction.
The present method shows some advantages including
excellent endo/exo selectivity and enantioselectivity, simple and
cheap catalyst, mild conditions and wide scopes. Therefore, this
method provides a valuable and reliable pathway for the
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Entry for the Table of Contents
COMMUNICATION
Key Topic*
Lei Xie, Xuan Yu, Jiaqi Li, Zhenhua
Zhang, Zhaohai Qin and Bin Fu*
Page No. – Page No.
Text for Table of Contents
Ni(II)-Catalyzed Enantioselective 1, 3-
Dipolar Cycloaddition of Nitrones
with
α,
β-Unsaturated
Acyl
Carboxylates
1, 3-Dipolar Cycloaddition
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