Catalytic asymmetric exo′-Selective [3+2] cycloaddition of iminoesters with nitroalkenes

Article abstract of DOI:10.1002/anie.201004098

Under control: A chiral imidazoline-aminophenol/Ni(OAc)₂ complex promotes the first catalytic asymmetric exo′-selective [3+2] cycloaddition of iminoesters and nitroalkenes. Thermodynamic control over the stepwise Michael/Mannich cyclization steps gives the adducts in up to 99% ee.

Full text of DOI:10.1002/anie.201004098

Angewandte
Chemie
DOI: 10.1002/anie.201004098
Cycloaddition
Catalytic Asymmetric exo’-Selective [3+2] Cycloaddition of
Iminoesters with Nitroalkenes**
Takayoshi Arai,* Naota Yokoyama, Asami Mishiro, and Hiroyasu Sato
Highly functionalized complex molecules are key tools for
promoting biochemical research and developing pharmaceut-
ical compounds because the positions of the heteroatoms and
the direction of lone pairs in the molecules are closely linked
to their biological activities. Catalytic asymmetric synthesis is
a fundamental technique to supply these complex compounds
in a stereoselective manner. As a representative example, the
catalytic asymmetric 1,3-dipolar cyclization reaction has been
widely studied for the synthesis of multisubstituted pyrroli-
dines.[1] Azomethine ylides, generated from an iminoester and
a nitroalkene, can be used to introduce an additional nitro
functionality onto the pyrrolidine ring, thus affording four
stereogenic centers and up to eight diastereomers. When a
trans nitroalkene is used, the stereoconjunction between the
3- and 4-positions is fixed in a trans conformation, and four
diastereomers are possible, classified as endo, exo, endo’, and
exo’ isomers (Scheme 1).
also recently succeeded in performing the endo-selective
cyclization using a PyBidine/Cu(OTf)2 catalyst.[6] Success in
the endo-selective cyclization led us to undertake the addi-
tional challenge of obtaining the other diastereomers.[7]
Screening of the metal salts to investigate the exo’ (and/or
endo’) adduct ratio found that nickel salts facilitated the
selective production of the exo’ product.[8] As the basis for
exploring efficient asymmetric catalysts, we prepared a library
of solid-phase imidazoline–aminophenol/metal catalysts
(Table 1)[9] and developed a new high-throughput screening
Table 1: Ligand (L) code.
L
R1,R1
R2
R3
R4
L
R1,R1
R2
R3
R4
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
A
A
A
A
A
A
A
A
A
A
C
C
C
C
C
D
D
D
D
D
H
H
H
Br
Br
H
H
H
Br
Br
H
tBu
Br
Br
NO2
H
tBu
Br
Br
L11
L12
L13
L14
L15
L16
L17
L18
L19
L20
B
B
B
B
B
B
B
B
B
B
C
C
C
C
C
D
D
D
D
D
H
H
H
Br
Br
H
H
H
Br
Br
H
tBu
Br
Br
NO2
H
tBu
Br
Br
NO2
NO2
Scheme 1. Possible diastereomers generated in the pyrrolidine syn-
thesis using an iminoester and a trans nitroalkene.
(HTS) method, in which the reaction mixtures were directly
analyzed following the solid-phase catalysis by circular
dichroism (CD) spectroscopy.[10] Using this “solid-phase
catalysis/CD-HTS” system, appropriate catalysts for the
exo’-selective synthesis were explored using the solid-phase
imidazoline–aminophenol/Ni(OAc)2 catalysts (Figure 1). The
solid-phase L9/Ni(OAc)2 and L10/Ni(OAc)2 catalysts
recorded the highest CD intensities among the 20 solid-
phase catalysts tested. Specifically, the L9/Ni(OAc)2 catalyst
gave the exo’ adduct in 32% yield and 70% ee, whilst L10/
Ni(OAc)2 gave the adduct in 23% yield and 76% ee. With this
fascinating exo’-selective asymmetric catalysts in hand, the
reaction conditions were re-examined in the solution phase
(for optimization, see the Supporting Information).
In 2005, Carretero and co-workers reported an example of
exo-selective pyrrolidine ring construction,[2a,3] and Hou and
co-workers succeeded in switching the endo/exo selectivity by
tuning the electron density of the chiral ligand.[4,5] We have
[*] Prof. Dr. T. Arai, N. Yokoyama, A. Mishiro
Department of Chemistry, Graduate School of Science
Chiba University, Inage, Chiba 263-8522 (Japan)
Fax: (+81)43-290-2889
E-mail: tarai@faculty.chiba-u.jp
Homepage: http://synthesis.chem.chiba-u.jp/
Dr. H. Sato
Application Laboratory, Rigaku Corporation
Akishima, Tokyo 196-8666 (Japan)
Under the optimized condition, the L21 (corresponding to
L9 without the solid support)/Ni(OAc)2 catalysis reaction in
K2CO3 gave the product in 99% yield in acetonitrile at À108C
in a highly exo’-selective manner (exo’/endo/exo/endo’ =
82:16:1:1), and the exo’ adduct was obtained in up to
[**] This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and
Technology (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004098.
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Table 2: L21/Ni(OAc)2-catalyzed exo’-selective [3+2] cycloadditions.[a]
No. Imino- Nitro-
t
[h]
Yield
[%]
exo’/endo/exo/endo’ ee of
ester
alkene
exo’
[%]
Figure 1. Solid-phase catalysis/CD-HTS.
1
2
3
4
5
6
7
8
IE1
IE2
IE3
IE4
IE5
IE6
IE7
IE1
IE1
IE1
IE1
IE1
IE1
IE1
IE1
IE1
NA1
NA1
NA1
NA1
NA1
NA1
NA1
NA2
NA3
NA4
NA5
NA6
NA7
NA8
NA9
NA10
63
43
42
43
57
42
42
57
45
46
57
45
32
45
45
45
99
79
67
84
70
67
70
93
85
86
94
87
78
66
68
64
82:16:1:1
90:10:0:0
89:11:0:0
87:9:0:4
88:10:0:2
85:8:0:7
97
93
96
97
91
91
99
96
97
95
96
96
97
96
92
94
97% ee. For L22 (corresponding to L10 without the solid
support)/Ni(OAc)2, the reaction using Et3N in dioxane at
108C gave the product in a highly exo’-selective manner (exo’/
endo/exo/endo’ = 90:8:0:2), though the ee of the exo’ adduct
was 91%. The scope of the L21/Ni(OAc)2-catalyzed exo’-
selective synthesis of chiral pyrrolidines is summarized in
Table 2.
92:7:0:1
86:13:0:1
85:14:0:1
82:16:0:2
80:17:0:3
88:11:0:1
81:15:1:3
84:14:0:2
68:28:0:4
79:21:0:0
9
10
11
12
13
14
15
16
exo’ Products were obtained from various aromatic
substrates bearing electron-deficient or electron-rich sub-
stituents in good diastereoselectivities and high enantiomeric
excesses (Table 2, entries 1–14). Aliphatic nitroalkenes were
also converted into their corresponding exo’ products in the
L21/Ni(OAc)2 or L22/Ni(OAc)2-catalyzed reactions (Table 2,
entries 15 and 16).
[a] The absolute configuration of the exo’ products was determined by
analogy to the structure examined in entry 2.
The structures of the exo’ products were confirmed by an
nOe experiment for the compound obtained in Table 2,
entry 9 (for details, see the Supporting Information). The
absolute configuration of the exo’ product obtained in
Table 2, entry 2 was unequivocally determined by X-ray
crystallographic analysis after oxidation of the product
(Scheme 2). Because DDQ oxidation of the exo’ product
gave the same compound as oxidation of endo product,[6] the
stereochemistry of exo’ product was attributed to be the 5-
epimer of the endo product.
This synthesis is the first general success in the catalytic
asymmetric exo’-selective reaction of iminoesters and nitro-
alkenes.[11] A plausible mechanism for why the L21/Ni(OAc)2
provides the adduct exo’-selectively is shown in Scheme 3.[12]
The stereochemistry of the exo’ product suggests that the L21/
Ni(OAc)2-catalyzed reaction isn’t a concerted 1,3-dipolar
cyclization of the metal-bound azomethine ylide with the
nitroalkene. We confirmed that no epimerization of the endo
and exo’ adducts occurred under these reaction conditions.
One plausible mechanism could involve an initial nickel-
catalyzed Michael addition of the iminoester to the nitro-
alkene.[13] The nucleophilic addition at the C2 position of the
Scheme 2. Structural determination of the [3+2] cycloadduct.
DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
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added successively at room temperature, and the imino
ester (0.15 mmol) was added at À108C. After being stirred
for the appropriate time (indicated in Table 2), the reaction
mixture was quenched with water. The organic layer was
extracted with ethyl acetate and dried over Na2SO4. After
the solvent had been removed under reduced pressure, the
1
diastereomeric ratio was determined by H NMR spectro-
scopic analysis. The crude mixture was purified by column
chromatography on silica gel to afford the Michael/Mannich
product. The enantiomeric excesses of the products were
determined by HPLC on a chiral stationary phase using a
À
À
À
Daicel Chiralcel OD H, OJ H, Chiralpak AD H, or
À
Chiralpak AS H column.
Received: July 5, 2010
Keywords: asymmetric synthesis ·
.
combinatorial chemistry · cycloaddition · nickel ·
stereoselectivity
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À
mediate. Before the subsequent Mannich reaction, the C N
single bond must rotate to give the exo’ isomer via the most
stable transition state. DFT calculations at the 6-31G/B3LYP
level also suggest that the exo’ adduct is the most stable
among the four possible isomers depicted in Scheme 1.
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Chen, Takemoto, and Gong independently reported the
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In conclusion, we have reported the first successful
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and nitroalkenes using a L21/Ni(OAc)2 catalytic system. A
well-designed stepwise reaction would alleviate the limita-
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