Catalytic enantioselective 1,3-dipolar cycloadditions of nitrones with propioloylpyrazoles and acryloylpyrazoles induced by chiral π-cation catalysts

Article abstract of DOI:10.1021/ja1081603

A chiral copper(II) complex of 3-(2-naphthyl)-l-alanine amide successfully catalyzes the enantioselective 1,3-dipolar cycloaddition reaction of nitrones with propioloylpyrazole and acryloylpyrazole derivatives. The asymmetric environment created by intram

Full text of DOI:10.1021/ja1081603

Published on Web 10/19/2010
Catalytic Enantioselective 1,3-Dipolar Cycloadditions of Nitrones with
Propioloylpyrazoles and Acryloylpyrazoles Induced by Chiral π-Cation
Catalysts
Akira Sakakura,† Masahiro Hori,‡ Makoto Fushimi,‡ and Kazuaki Ishihara*,‡,§
EcoTopia Science Institute, Graduate School of Engineering and JST, CREST, Nagoya UniVersity,
Furo-cho, Chikusa, Nagoya, 464-8603, Japan
Received September 10, 2010; E-mail: Ishihara@cc.nagoya-u.ac.jp
Table 1. Enantioselective [3 + 2] Nitrone Cycloaddition with 2aa
Abstract: A chiral copper(II) complex of 3-(2-naphthyl)-L-alanine
amide successfully catalyzes the enantioselective 1,3-dipolar
cycloaddition reaction of nitrones with propioloylpyrazole and
acryloylpyrazole derivatives. The asymmetric environment created
by intramolecular π-cation interaction gives the corresponding
adducts in high yields with excellent enantioselectivity. This is
the first successful method for the catalytic enantioselective 1,3-
dipolar cycloaddition of nitrones with acetylene derivatives. The
1
(mol %)
T (°C),
t (h)
yield
(%)
ee
(%)
entry
solvent
1,3-dipolar cycloadducts can be stereoselectively converted to
ꢀ-lactams via reductive cleavage of the N-O bond using SmI2.
1
2
1a, 5
1b, 5
s
1a, 1
1a, 10
1a, 10
1a, 10
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtNO2
MeCN
toluene
-40, 5
-40, 6
-40, 10
-40, 48
-20, 1
-20, 2
-20, 23
94
96
95
97
95
96
88
87 [R]
84 [R]
s
87 [R]
70 [R]
48 [R]
81 [R]
3
4b
5
Despite recent advances with high-performance catalysts for use
in asymmetric cycloaddition reactions, only a few successful examples
of the catalytic enantioselective Diels-Alder reaction with acetylenic
dienophiles have been reported.1b,2 In general, acetylene derivatives
with a linear sp-sp bond make asymmetric induction with a chiral
Lewis acid difficult because the alkynyl moiety is far from the acidic
metal center. Recently, we reported that Cu(II) complexes of 3-aryl-
L-alanine amides (1a and 1b, Chart 1) effectively promote the
enantioselective Diels-Alder and [2 + 2] cycloaddition reactions with
propioloylpyrazole derivatives 2 and acryloylpyrazole derivatives 3.1
Intramolecular π-cation attractive interaction between the electron-
rich aromatic ring of 1 and the Cu(II) center creates an asymmetric
environment to induce the enantioselective reaction. There have been
no previous reports of the asymmetric 1,3-dipolar cycloaddition of
nitrones with acetylene derivatives, although some achiral reactions
have been reported.3,4 The asymmetric 1,3-dipolar cycloaddition of
nitrones has become one of the most prominent organic transforma-
tions.5-7 We report here the first example of the catalytic and highly
enantioselective 1,3-dipolar cycloaddition reactions of nitrones with 2
promoted by 1•Cu(II) and the subsequent one-step transformation to
anti-2,3-difunctionalized ꢀ-lactams.
6
7
a The reaction of a nitrone (1.1 equiv) with 2a (0.3 mmol) was
conducted in the presence of 1•Cu(NTf2)2 (1-10 mol %) and MS 4 Å
(100 mg) in solvent (1.2 mL). b The reaction of nitrone (1.1 equiv) with
2a (1.5 mmol) was conducted in the presence of 1a•Cu(NTf2)2 (1 mol
%) and MS 4 Å (100 mg) in CH2Cl2 (6 mL).
the presence of 1•Cu(NTf2)2 (5 mol %) and MS 4 Å8 in CH2Cl2
(Table 1). As expected, 1a•Cu(NTf2)2 effectively promoted the
reaction at -40 °C and gave the corresponding adduct 4a with high
enantioselectivity (87% ee, entry 1). Complex 1b•Cu(NTf2)2, which
is also an effective catalyst for the Diels-Alder reaction with 2a,
showed slightly low enantioselectivity (84% ee, entry 2). The
absolute configuration of the major enantiomer of 4a was deter-
mined to be (3R).9 Interestingly, the catalytic activity of
1a•Cu(NTf2)2 was significantly higher than that of Cu(NTf2)2 itself
(entry 1 versus entry 3). Only 1 mol % of 1a•Cu(NTf2)2 successfully
promoted the reaction to give 4a in 97% yield with 87% ee (entry
4). The use of EtNO2, MeCN, and toluene as solvents decreased
the reactivity and enantioselectivity (entries 5-7).
Chart 1. Chiral Lewis Acid Catalysts 1•CuX2
To explore the scope and limitation of the present enantioselec-
tive cycloaddition reaction, several nitrones were examined under
the optimized conditions (Table 2). The nitrone bearing a 1-naph-
thylmethyl (1-NpCH2) group as an N-substituent (R1) showed
slightly higher enantioselectivity than those bearing benzyl and 3,4-
dimethoxybenzyl (DMPM) groups (entries 3 and 4). In contrast,
the use of methyl and phenyl groups as an R1 group decreased the
enantioselectivity (entries 1 and 2). C-(2-Naphthyl)-substituted
nitrones gave the corresponding adducts 9a-c with excellent
enantioselectivities (entries 5, 8, and 10). Adduct 10 with a
3-methylfuran-2-yl (3-Me-furyl) group was obtained in 96% yield
with 84% ee (entry 6). The ee of the adduct 10 could be upgraded
to >99% ee by recrystallization from hexane-Et2O. 3-Chlorobut-
We began our studies by examining the 1,3-dipolar cycloaddition
of N-benzylidenebenzylamine N-oxide with but-2-ynamide 2a in
† EcoTopia Science Institute.
‡ Graduate School of Engineering.
§ JST, CREST.
9
15550 J. AM. CHEM. SOC. 2010, 132, 15550–15552
10.1021/ja1081603  2010 American Chemical Society

C O M M U N I C A T I O N S
2-ynamide 2c was also converted to the corresponding adducts
bearing chloromethyl groups in high enantioselectivities (entries 9
and 10).
1a•Cu(NTf2)2 with high enantioselectivity (Table 3). The reaction
of N-benzylnitrones with crotonamide 3a, acrylamide 3b, and
fumarylamide 3c gave the corresponding endo-adducts 15a-f with
high enantioselectivity (83-94% ee). The absolute configuration
of the major enantiomer of 15a was determined to be (3S,4R,5S).9
Table 2. Enantioselective 1,3-Dipolar Cycloaddition of Nitrones
with Propioloylpyrazoles 2a
Table 3. Enantioselective 1,3-Dipolar Cycloaddition of Nitrones
with Acryloylpyrazoles 3a
T (°C),
t (h)
yield
(%)
ee
(%)
entry
R1
R2
R3 (2)
T (°C),
t (h)
15, yield
(%)
endo/
exo
ee
(%)
1
2
3
4
5
6
7
8
9
Me
Ph
Ph
Ph
Ph
Ph
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
-20, 1.5
-20, 28
-40, 1
-40, 48
-40, 19
-30, 61
5, 81 74
6, 39 80
7, 82 87
8, 91 91
9a, 97 94
10, 96 84
entry
R2
R3 (3)
DMPMb
1-NpCH2
Bn
1
2
3
4
5
6
Ph
Ph
Ph
Me (3a)
H (3b)
CO2Et (3c)
Me (3a)
H (3b)
0, 7
-20, 3.5
rt, 49
0, 13.5 15d, 82 >99:1
-20, 1
-10, 89
15a, 78
15b, 71
15c, 41
98:2
97:3
73:27 83
92
94
c
2-Npd
2-Npb
2-Npb
93
92
Bn
Bn
Bn
Bn
3-Me-furyle Me (2a)
15e, 81
15f, 79
95:5
85:15 91
Ph
H (2b)
H (2b)
-40, 21 4b, 89 92
-40, 2
3-Me-furylc H (3b)
2-Npd
Ph
9b, 80 94
4c, 79 89
ClCH2 (2c) -40, 2
ClCH2 (2c) -40, 3.5 9c, 70 94
a The reaction of nitrone (1.1 equiv) with
conducted in the presence of 1a•Cu(NTf2)2 (10 mol %) and MS 4 Å
(100 mg) in CH2Cl2 (1.2 mL). b 2-Np ) 2-naphthyl. c 3-Me-furyl )
3-methylfran-2-yl.
3
(0.3 mmol) was
10 Bn
2-Npd
a The reaction of nitrone (1.1 equiv) with
conducted in the presence of 1a•Cu(NTf2)2 (10 mol %) and MS 4 Å
2 (0.3 mmol) was
(100 mg) in CH2Cl2 (1.2 mL). b DMPM
) 3,4-dimethoxybenzyl.
c 1-NpCH2 ) 1-naphthylmethyl. d 2-Np ) 2-naphthyl. e 3-Me-furyl )
3-methylfran-2-yl.
Scheme 1. Conversion of Cycloadducts 4a and 10
Figure 1. Proposed endo- and exo-transition-state assemblies for the 1,3-
dipolar cycloaddition with 2a.
Based on the previous results, the following reaction mechanism
was proposed for the present nitrone cycloaddition: 2 and 3 would
be predominantly trans-chelated with 1a•Cu(NTf2)2, and the
carbonyl re face of 2 and 3 would be shielded by the 2-naphthyl
group in 1a (Figure 1).1 To avoid steric hindrance between the
N-cyclopentyl group of 1a and the phenyl group of nitrones in the
exo-transition state (TS), nitrones would approach the si face of 2
and 3 via the endo-TS.13 The finding that bulky C-(2-naphthyl)-
substituted nitrones gave the adducts with excellent enantioselec-
tivities can also be explained by these transition-state models.
In conclusion, we have developed catalytic enantioselective 1,3-
dipolar cycloadditions of nitrones with propioloylpyrazole and
acryloylpyrazole derivatives using chiral π-cation catalysts.14 The
cycloadducts of propioloylpyrazole derivatives could be stereose-
lectively converted to anti-2,3-difunctionalized ꢀ-lactams.
The 1,3-dipolar cycloadducts 4a and 10 could be diastereose-
lectively converted to ꢀ-lactams 11 and 12 via reductive cleavage
of the N-O bond using SmI210 and subsequent cyclization without
any loss of enantiomeric excess (Scheme 1). Diastereoselective
reduction of the methylketone in 12 with L-Selectride11 gave
secondary alcohol 13 (87% yield, dr 9:1). The three-step transfor-
mation of 13 (acetylation of the hydroxy group, oxidative cleavage
of the 3-methylfuran-2-yl group using NaIO4 and RuCl3,12 and
methyl esterification with CH2N2) gave methyl ester 14 (75% yield,
3 steps).
The 1,3-dipolar cycloaddition reaction of nitrones with acry-
loylpyrazole derivatives 3 was also effectively promoted by
9
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C O M M U N I C A T I O N S
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(9) See Supporting Information for details.
Acknowledgment. Financial support for this project was
provided by JSPS.KAKENHI (20245022) and the Global COE
Program of MEXT. The authors thank Ube Industries, Ltd. for their
generous donation of N-(tert-butoxycarbonyl)-3-(2-naphthyl)-L-
alanine.
Supporting Information Available: Experimental procedures, full
characterization of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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