Endo-selective asymmetric inverse electron-demand 1,3-dipolar cycloaddition reaction of nitrones

Article abstract of DOI:10.3987/COM-06-10791

In the presence of a catalytic amount of the optically active cobalt(III) hexafluoroantimonate, the inverse electron-demand 1,3-dipolar cycloaddition reaction of dihydrofuran with nitrones bearing an electron-withdrawing group effectively proceeded to aff

Full text of DOI:10.3987/COM-06-10791

HETEROCYCLES, Vol. 68, No. 9, 2006
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HETEROCYCLES, Vol. 68, No. 9, 2006, pp. 1801 - 1810. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd May, 2006, Accepted, 14th July, 2006, Published online, 18th July, 2006. COM-06-10791
ENDO-SELECTIVE
ASYMMETRIC
INVERSE
ELECTRON-DEMAND 1,3-DIPOLAR CYCLOADDITION
REACTION OF NITRONES
Tomoko Ashizawa, Natsuki Ohtsuki, Tomoyuki Miura, Makoto
Ohya, Takaomi Shinozaki, Taketo Ikeno, and Tohru Yamada*
Department of Chemistry, Faculty of Science and Technology, Keio
University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
e-mail: yamada@chem.keio.ac.jp
Abstract - In the presence of a catalytic amount of the optically
active
cobalt(III)
hexafluoroantimonate,
the
inverse
electron-demand 1,3-dipolar cycloaddition reaction of dihydrofuran
with nitrones bearing an electron-withdrawing group effectively
proceeded to afford the corresponding adducts with excellent
endo-selectivity.
The catalytic enantioselective 1,3-dipolar cycloaddition reaction of nitrones is one of the most
practical methods for the construction of enantiomerically pure isoxazolidines, which are then
employed as key intermediates in transformation into ꢀ-amino alcohols under mild reducing
conditions, and as useful synthons for the preparation of various biologically active
compounds, such as alkaloids, ꢀ-lactams, and ꢀ-amino acids.1 Several groups have recently
reported the catalytic enantioselective 1,3-dipolar cycloaddition reactions of nitrones with
alkenoyl oxazolidinones, electron-deficient alkenes2 favorable for the bidentate coordination
of a Lewis acid catalyst. However, monodentate alkenals have also been applied3 to the
enantioselective 1,3-dipolar cycloaddition reaction.
It was found that cationic
3-oxobutylideneaminatocobalt(III) complexes could be employed as effective Lewis acid
catalysts for the enantioselective 1,3-dipolar cycloaddition reaction of alkenals even in the
4
presence of electron-donating nitrones.
In these catalytic systems, the
HOMO(nitrone)-LUMO(alkene) interaction is assumed to dominate the reactivity and
selectivity, but the alternative HOMO(alkene)-LUMO(nitrone) interaction is also expected
due to the lowering of the LUMO level through the coordination of the electron-donating
nitrone to the Lewis acid catalyst and the raised HOMO level of the electron-rich alkenes

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HETEROCYCLES, Vol. 68, No. 9, 2006
used, such as vinyl ethers.5 The inverse electron-demand 1,3-dipolar cycloaddition reaction
catalyzed by Lewis acids was first reported by Kanemasa. During the reaction of
N-phenyl-C-benzoylnitrone and an allyl alcohol, it was found that the diastereoselectivity was
improved along with the reaction rate by the coordination of a Lewis acid, such as
MgBr2•Et2O, ZnBr2, TiCl2(i-PrO)2, or BF3•Et2O.6 The first report of the enantioselective
version was published by Scheeren7 using chiral metal complex catalysts. They employed
the oxazaborolidines derived from amino acids as the Lewis acid, achieving a moderate
enantioselectivity but in low yield. Jørgensen reported that the BINOL derived aluminum
complexes8 and the bisoxazoline-copper(II) complexes9 could be employed as the efficient
catalysts for enantioselective 1,3-dipolar cycloaddition reaction of the glyoxylate derived
nitrones with vinyl ethers to achieve a >99% enantioselectivity. In these two pioneering
studies on the asymmetric inverse electron-demand 1,3-dipolar cycloaddition reaction, exo
products only were obtained with high enantioselectivity. The endo-selective inverse
electron-demand 1,3-dipolar cycloaddition reaction of nitrones has been predicted on the basis
10
of a theoretical analysis
of the reaction between the nitrones bearing an
electron-withdrawing group and vinyl ethers,11 nevertheless, the catalytic enantioselective
version of the endo-selective reaction has not yet appeared. We now report the first endo-
and enantioselective inverse electron-demand 1,3-dipolar cycloaddition of nitrones using
cationic 3-oxobutylideneaminatocobalt(III) complexes as efficient Lewis acid catalysts.
Study of the enantioselective reactions using the optically active ketoiminatocobalt(II)
complexes as the Lewis acid catalyst, including the hetero Diels-Alder reaction,12 the
carbonyl-ene reaction,13 and the 1,3-dipolar cycloaddition of nitrones has indicated that the
enantioselectivity as well as the reactivity are affected by the counter anions of the cationic
cobalt complexes. Various counter anions of the cationic cobalt(III) complexes were
examined as catalysts for the inverse electron-demand 1,3-dipolar cycloaddition reaction of
N-phenyl-C-benzoylnitrone with 2,3-dihydrofuran (Table 1). When the cobalt(II) complex
was employed, the reaction did not proceed (Entry 1). The iodo cobalt(III) complex
catalyzed the reaction at -20 °C to provide the corresponding isoxazolidine in moderate yield
and endo-selectivity, but with a low enantioselectivity (Entry 2), whereas use of cationic
cobalt(III) complexes with appropriate anions led to an improved reaction rate and the
endo-selectivity (Entries 3-6). In particular, the triflimide and hexafluoroantimonate anions
of the cationic cobalt(III) complex afforded the corresponding cycloadducts with high
endo-selectivity and moderate enantioselectivity (Entries 7-9).14
To improve the enantioselectivity of the endo product, the ligand structures of the cationic
cobalt(III) hexafluoroantimonate complexes were examined in the catalytic inverse

HETEROCYCLES, Vol. 68, No. 9, 2006
1803
electron-demand 1,3-dipolar cycloaddition reaction of N-phenyl-C-benzoylnitrone with
2,3-dihydrofuran (Table 2).
When the complexes (1i) and (1j), bearing
1,2-diaminocyclohexane and 1,2-dimethylethylenediamine as the chiral diamine were
employed as catalysts, the corresponding isoxazolidine was obtained in 87% and 73% yield
with 36% ee and 38% ee, respectively (Entries 1 and 2). The cationic cobalt(III) complexes
with the optically active 1,2-diphenylethylenediamine (1h) afforded the cycloadduct in good
yield with a 90% endo-selectivity and 47% ee (Entry 3), while the sterically demanding
complexes (1k) derived from 1,2-bis(3,5-dimethylphenyl)ethylenediamine afforded the
cycloadduct with a high endo-selectivity, but only 31% ee (Entry 4). For the reaction
catalyzed by the most sterically demanding cobalt(III) complex (1l), derived from
1,2-bis(2,4,6-trimethylphenyl)ethylenediamine, the endo-selectivity decreased (Entry 5).
The side chains of the ketoiminato ligand were also examined. Employing the complexes
(1m) and (1n) bearing the acetyl and tert-butyl ester side chains, gave maintained
endo-selectivities, but decreased enantioselectivities for the cycloadducts, 6% and 19%,
respectively (Entries 6 and 7).
Table 1. Various counter anions of the cationic cobalt complex catalysts
5mol%
Ph
Ph
N
O
N
O
Co
X
Ph
Ph
H
O
O
O
O
O
N
N
O
1
O
Ph
Ph
CH2Cl2, -20 °C, MS4A
O
3
4a
2a
Entrya)
X
Time / h
Yield / %b)
Endo / Exoc)
Ee (Endo) / %eed)
1
2
Co(II)
Iodide
OTs
(1a)
(1b)
(1c)
(1d)
(1e)
(1f)
(1g)
Trace
65
87
11
5
79 / 21
83 / 17
87 / 13
91 / 9
10
16
21
25
24
46
47
54
3
70
4
BF4
55
5
OTf
5
55
6
PF6
11
2
63
91 / 9
7
NTf2
66
>99 / 1
90 / 10
89 / 11
8
9e)
8
76
SbF6
(1h)
27
56
a) Two equiv. of 2,3-dihydrofuran was empoloyed. b) Isolated yield. c) Determined by 1H NMR analysis.
d) Determined by HPLC analysis using Daicel Chiralcel OD-H. e) 1.2 equiv. of 2,3-dihydrofuran was used.

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HETEROCYCLES, Vol. 68, No. 9, 2006
Table 2. Examination of various ligands of the cobalt(III) complexes
Ph
Ph
H
O
O
N
N
O
5 mol% Co(III) complex
O
Ph
Ph
CH2Cl2, -20 °C, MS4A
O
O
4a
2a
3
Time / h Yield / %a) Endo / Exob) Ee (Endo) / %c)
Co(III)complex
Entry
1
7
87
73
76
36
38
47
92 / 8
92 / 8
90 / 10
N
O
N
O
Co
O
O
O
O
(1i)
(1j)
SbF6
H3C
N
CH3
N
2
3
14
8
Co
O
O
SbF6
N
O
N
Co
O
O
O
(1h)
(1k)
SbF6
4
5
3
3
71
58
90 / 10
31
14
N
O
N
Co
O
SbF6
O
O
64 / 36
N
O
N
Co
O
SbF6
O
O
(1l)
N
O
N
Co
6
7
5
69
58
90 / 10
81 / 19
6
O
O
SbF6
O
(1m)
(1n)
O
O
N
O
N
O
O
70
19
Co
O
SbF6
a) Isolated yield. b) Determined by 1H NMR analysis. c) Determined by HPLC analysis using Daicel
Chiralcel OD-H.

HETEROCYCLES, Vol. 68, No. 9, 2006
1805
From the result it was determined that the cationic cobalt(III) hexafluoroantimonate complex
(1h) was a suitable catalyst for the endo- and enantioselective inverse electron-demand
1,3-dipolar cycloaddition reaction. In the presence of MS 3A, various nitrones with
electron-withdrawing groups were subjected to the present reaction system (Table 3). For
the reactions of the nitrones bearing 4-methoxybenzoyl (2b) and 4-phenylbenzoyl (2c) groups,
excellent endo-selectivities were observed; the enantioselectivities of the endo products were
64% ee and 63% ee, respectively, at -40 °C (Entries 2-4). The nitrone bearing the
4-(trifluoromethyl)benzoyl (2d) group afforded the endo product with 90% selectivity, though
the enantioselectivity was ca. 30% (Entry 5). The reaction of the nitrones derived from the
p-chloro (2e) and p-nitro (2f) substituted phenacyl-pyridinium-bromides 15 smoothly
proceeded to afford the corresponding cycloadducts with excellent endo-selectivities and
good-to-high enantioselectivities (Entries 6-9).16
Table 3. Endo-selective inverse electron demand 1,3-dipolar cycloaddition of nitrones
Ph
Ph
O
O
N
N
O
5 mol% Co(III) complex 1h
O
Ar
Ar
H
CH2Cl2, MS3A
O
2a-e
O
3
4a-e
Ee (Endo) / %c)
Time / h Yield / %a) Endo / Exob)
Entry ArC=O
Temp / °C
1
2a
-20
4
72
56
64
>99 / 1
>99 / 1
O
OMe
2
2b
-40
66
64
O
Ph
3
-20
-40
12
48
65
72
>99 / 1
>99 / 1
43
63
2c
4
O
CF3
5
2d
-20
10
71
31
90 / 10
O
Cl
6
-20
-40
41
43
72
67
62
72
>99 / 1
>99 / 1
2e
7
O
NO2
8
-20
-40
0.5
15
40
53
72
73
>99 / 1
>99 / 1
2f
9
O
a) Isolated yield. b) Determined by 1H NMR analysis. c) Determined by HPLC analysis using Daicel
Chiralcel IA.

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HETEROCYCLES, Vol. 68, No. 9, 2006
Single crystals of the optically pure cycloadduct (4e) were obtained from a tetrahydrofuran
and hexane solution. 17 X-Ray analysis revealed that the cycloadduct (4e) was the
endo-adduct with the (R,S,R)-absolute configuration corresponding to the (S,S)-cobalt
complex catalyst as depicted in Figure 1. On the basis of this observation, transition states
of the present 1,3-dipolar cycloaddition are proposed as plausible candidates (Figure 2). It is
fair to assume that the lone pair of the oxygen atom in the nitrone might contribute to
coordination of the cobalt atom, and that the nitrone residue could be oriented between two
coordination oxygen atoms on the planar 3-oxobutylidenaminato ligand. The TS model in
Figure 2 was constructed as a superimposed display of the MM-optimized nitrone molecule
based on the coordinate data obtained from X-Ray analysis of the cationic
ꢀ-ketoiminatocobalt(III) triflate.12 Viniyl ethers, such as 2,3-dihydrofuran, should approach
the activated nitrone from the direction that avoids the aryl groups attached to the chiral
diamine and the side chain of the 3-oxobutylideneaminato ligand, thus affording the (R)-endo
cycloadduct in good-to-high enantioselectivity and excellent endo-selectivity. This proposed
transition state can clearly explain the observed stereochemistry of the present endo- and
enantio-selective inverse electron-demand 1,3-dipolar cycloaddition of nitrones, and is also
consistent with the results4,12,13 of the corresponding Lewis acid catalyses using the optically
active ꢀ-ketoiminatocobalt complexes.
H
O
O
N
Ph
O
O
H
(R)
N
O
Cl
(R)
(S)
Cl
O
Figure 1. Absolute configuration of endo-cycloadduct corresponding to (S,S)-catalyst.
The cationic cobalt(III) complexes thus successfully catalyzed the endo- and enantioselective
inverse electron-demand 1,3-dipolar cycloaddition reaction of nitrones bearing
electron-withdrawing groups. The addition of MS 3A was effective in improving the
reaction rate and endo-selectivity, giving the corresponding cycloadducts with high
enantioselectivity.

HETEROCYCLES, Vol. 68, No. 9, 2006
1807
O
N
O
O
N
N
Co
O
O
O
N
O
O
R'
Ar
O
(S)
O
O
N
Co
(S) Ar
O
N
O
(S,S)-catalyst
O
R'
Figure 2. TS model of endo and enantio-selective inverse electron-demand 1,3-dipolar cycloaddition.
ACKNOWLEDGEMENTS
The authors would like to thank Dr. Takashiro Akitsu of Keio University for X-Ray analysis.
REFERENCES AND NOTES
1.
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Freysoldt, and F. Wierschem, Chem. Soc. Rev., 2005, 34, 507.
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Org. Chem., 1994, 59, 5687; K. V. Gothelf, R. G. Hazell, and K. A. Jørgensen, J. Org.
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S. Tsushima, T. Shimada, and H. Nishiyama, Tetrahedron, 2002, 58, 227.
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Viton, G. Bernardinelli, and P. Kündig, J. Am. Chem. Soc., 2002, 124, 4968.
S. Kezuka, N. Ohtsuki, T. Mita, Y. Kogami, T. Ashizawa, T. Ikeno, and T. Yamada,
Bull. Chem. Soc. Jpn., 2003, 76, 2197.
3.
4.
5.
6.
7.
8.
1,3-Dipolar review: K. V. Gothelf and K. A. Jørgensen, Chem. Commun., 2000, 1449;
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K. B. Simonsen, P. Bayón, R. G. Hazell, K. V. Gothelf, and K. A. Jørgensen, J. Am.
Chem. Soc., 1999, 121, 3845; K. B. Jensen, R. G. Hazell, and K. A. Jørgensen, J. Org.
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14. It should be pointed out that molecular sieves effectively improved the
enantioselectivity of the endo adduct. Among the various molecular sieves, MS 3A
and 4A were the most effective additives for the present catalytic reaction. K.
Narasaka, N. Iwasawa, M. Inoue, T. Yamada, M. Nakashima, and J. Sugimori, J. Am.
Chem. Soc., 1989, 111, 5340.

HETEROCYCLES, Vol. 68, No. 9, 2006
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15. The nitrones subjected to the present reaction were prepared as follows. Typical
preparation of N-phenyl-C-benzoylnitrone (2a): Under a nitrogen atmosphere, to a
stirred solution of nitrosobenzene (1.1 g, 10.2 mmol) in acetone (6 mL), a solution of
phenacylpyridinium bromide (3.0 g, 10.8 mmol) in water (5 mL) was added at -20 °C,
and stirring was continued for 1 h at -20 °C. An aqueous solution of NaOH (1 M, 3
mL) was dropwise added to the solution and a yellow solid precipitated. The
precipitate was collected by filtration, washed with water, and dried in vacuo. The
yellow solid was used without any further purification.
R. Huisgen, H. Hauck, H.
Seidl, and M. Burger, Chem. Ber., 1969, 102, 1117.
16. Typical procedure is as follows: Under a nitrogen atmosphere, to a stirred solution of the
cationic cobalt complex Co(III)SbF6 (1h) (14.0 mg, 0.015 mmol, 5.0 mol%) and MS3A
(25 mg) in CH2Cl2 (0.5 mL) at -20 °C were added N-phenyl-C-benzoylnitrone (2a) (67.6
mg, 0.3 mmol) in CH2Cl2 (1.0 mL) and 2,3-dihydrofuran (25.2 mg, 0.36 mmol) in
CH2Cl2 (1.0 mL). After stirring for 4 h at -20°C, the reaction was quenched by the
addition of buffer (pH 7) and then stood at rt. The product was extracted twice with
AcOEt. The organic layer was washed with brine and dried over anhydrous Na2SO4.
The solvent was then removed under reduced pressure. The residue was purified by
SiO2 column chromatography (hexane: AcOEt =10:1) to afford the product.
(3R*,3aS*,6aR*)2,3,3a,4,5,6a-Hexahydro-3-benzoyl-2-phenylfuro[3,2-d-]isoxazolidi
ne (endo-4a): Following the general procedure, the cycloadduct (4a) was obtained in
72% yield (63.7 mg) from the nitrone (2a) (67.6 mg, 0.3 mmol); Yellow solid; mp.
122-133 °C; Rf =0.30 (Hexane:AcOEt, 3:1); Daicel Chiralcel OD-H, 1.0 ml min-1,
hexane/2-propanol 97/3: minor isomer 17.01 min, major isomer 19.79 min, 64% ee; IR
(KBr): 3062 (w), 2975 (w), 1693 (s), 1596 (s), 1490 (m), 1284 (m), 1093 (s), 931 (m),
752 (s), 696 (s) cm-1. 1H NMR (CDCl3, 400 MHz) : ꢀ = 1.85-1.98 (m, 1H), 2.03-2.18
(m, 1H), 3.37-3.50 (m, 1H), 3.61-3.70 (m, 1H), 3.78 (dt, J = 8.5 Hz, J = 2.1 Hz, 1H),
4.97 (d, J = 2.0 Hz, 1H), 5.94 (d, J = 5.4 Hz, 1H), 6.86 (t, J = 7.3 Hz, 1H), 7.03 (dd, J =
8.3 Hz, J = 1.0 Hz, 2H), 7.11-7.26 (m, 2H), 7.32-7.55 (m, 3H), 7.94 (dd, J = 8.1 Hz, J =
1.5 Hz, 2H). 13C NMR (CDCl3, 100MHz): ꢀ = 31.1, 50.2, 68.2, 73.9, 108.8, 114.2,
121.6, 128. 6, 128.7, 128.7, 133. 4, 134.8, 149.4, 195.7.
17. The endo cycloadduct (4e) obtained from the reaction (Entry 7 in Table 3) was purified
by preparative HPLC using Daicel Chiralcel IA to afford the optically pure sample of
the cycloadduct (4e) for X-Ray analysis. The crystals were grown from a THF-hexane

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HETEROCYCLES, Vol. 68, No. 9, 2006
solution over the course of three days. A crystal specimen of suitable dimensions is
shown. Crystal data: C18H16NO3Cl, Mr=329.77, Monoclinic, P2yb, a=11.873(3) Å,
b=5.8199(14) Å, c=11.4619(17) Å, ꢀ=90°, ꢁ=93.266(15)°, ꢂ=90°, V=790.7(3)ꢀ3, Z=2.
The crystal structure has been deposited at the Cambridge Crystallographic Data Centre
and allocated the deposition number : CCDC 607825.