Highly exo-selective and enantioselective cycloaddition reactions of nitrones catalyzed by a chiral binaphthyldiimine-Ni(II) complex

Article abstract of DOI:10.1021/ol050397h

(Chemical Equation Presented) Significant levels of exo-selectivity (exo:endo = >99:1 to 86:14) and enantioselectivity (95-82% ee) were obtained in the 1,3-dipolar cycloadditions of a number of nitrones with 3-(2-alkenoyl)-2-thiazolidinethiones, using the

Full text of DOI:10.1021/ol050397h

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1431-1434
Highly Exo-Selective and
Enantioselective Cycloaddition
Reactions of Nitrones Catalyzed by a
Chiral Binaphthyldiimine−Ni(II) Complex
Hiroyuki Suga,* Takuya Nakajima, Kengo Itoh, and Akikazu Kakehi
Department of Chemistry and Material Engineering, Faculty of Engineering,
Shinshu UniVersity, Wakasato, Nagano 380-8553, Japan
sugahio@shinshu-u.ac.jp
Received February 23, 2005
ABSTRACT
Significant levels of exo-selectivity (exo:endo
)
>99:1 to 86:14) and enantioselectivity (95−82% ee) were obtained in the 1,3-dipolar cycloadditions
of a number of nitrones with 3-(2-alkenoyl)-2-thiazolidinethiones, using the chiral binaphthyldiimine−Ni(II) complex (5−20 mol %), which was
easily prepared form N,N -bis(3,5-dichrolo-2-hydroxybenzylidene)-1,1 -binaphthyl-2,2 -diamine and Ni(ClO4)2‚
′
′
′
6H2O in CHCl3 in the presence of
4 Å molecular sieves, as a chiral Lewis acid catalyst.
Asymmetric 1,3-dipolar cycloaddition reactions between
nitrones and alkenes are among the most efficient methods
for the construction of optically active isoxazolidines, which
are readily converted to synthetically useful chiral γ-amino
alcohols (Scheme 1).1 Recently, a number of chiral Lewis
acids have been shown to possess high enantioselectivity in
the reactions of nitrones with electron-rich and -deficient
olefins.1a-d For the reactions of electron-deficient alkenes,
3-(2-alkenoyl)-2-oxazolidinones often have been employed
as the dipolarophiles to yield, in most cases, the endo-
cycloadducts with high enantioselectivity.2,3 On the other
hand, the efficient synthesis of enantiomerically pure γ-amino
alcohols having a syn,anti diastereomeric structure via nitrone
cycloaddition reactions would require a chiral Lewis acid
that favors the exo-selective and enantioselective cycload-
ditions (Scheme 1). For example, a formal synthesis of
thienamycin and a key intermediate synthesis of carbapenems
with the enantiomerically pure syn,anti-γ-amino alcohols,
which were obtained from the cycloaddition reactions of
Scheme 1. Stereoselective Synthesis of Chiral γ-Amino
Alcohols
(1) For recent reviews, see: (a) Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry toward Heterocycles and Natural Products; Padwa,
A., Pearson, W. H., Eds.; John Wiley and Sons: Hoboken, NJ, 2003. (b)
Gothelf, K. V.; Jørgensen K. A. Chem Commun. 2000, 1449. (c) Gothelf,
K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863. (d) Frederickson, M.
Tetrahedron 1997, 53, 403. (e) 1,3-Dipolar Cycloaddition Chemistry;
General heterocyclic chemistry series; Padwa, A., Ed.; John Wiley and
Sons: New York, 1984; Vol. 2, pp 83-168.
10.1021/ol050397h CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/09/2005

nitrones attached to a chiral auxiliary with crotonate ester,
were reported.4 To date, however, only a few examples of
the exo-selective cycloadditions of nitrones with 2-alkenoic
acid derivatives in the presence of a chiral Lewis acid have
been reported.5 More recently, Sibi has reported on highly
exo-selective cycloadditions that also possess high enantio-
selectivity using the chiral relay in reactions with 2-(2-
alkenoyl)-3-pyrazolidinones as the dipolarophiles.5f This
procedure, however, remains problematic in terms of the
catalyst loading (30-50 mol %) and the generality of
nitrones. In this Letter, we report on a facile methodology
for the highly exo-selective and enantioselective cycloaddi-
tion reactions between various nitrones and 3-(2-alkenoyl)-
2-thiazolidinethiones in the presence of a chiral binaphthyl-
diimine (BINIM)-Ni(II) complex5e,6 (5-20 mol %) as the
Lewis acid catalyst.
On the basis of our previous investigations of the stereo-
selectivity of cycloaddition reactions between nitrones and
3-crotonoyl-2-oxazolidinone catalyzed by BINIM-Ni(II)
complexes,5e cycloaddition reactions between N-benzylidene-
aniline N-oxide (1a) and 3-crotonoyl-2-thiazolidinethione
(2a) in the presence of BINIM-Ni(II) complexes (10 mol
%) were initially examined (Scheme 2 and Table 1). These
Table 1. BINIM-Ni(II)-Catalyzed Enantioselective
Cycloadditions of Nitrone 1a with
3-Crotonoyl-2-thiazolinethione (2a)a
time yield
eec
entry
BINIM
solvent (h)
(%) exo:endob (%)
1
2
(R)-BINIM-DC
(R)-BINIM-2QN
(R)-BINIM-4Me-2QN CH2Cl2
(R)-BINIM-4Ph-2QN CH2Cl2
(S)-BINIM-OH
(R)-BINIM-5ClOH
(R)-BINIM-DBOH
(R)-BINIM-DCOH
(R)-BINIM-DCOH
(R)-BINIM-DCOH
(R)-BINIM-DCOH
CH2Cl2
CH2Cl2
24
80
64
72
59
83
66
86
26
40
77
93
77
90
87
62:38 -31
58:42
72:28
59:41
97:3
89
91
90
3
4
5
CH2Cl2 115
-25
-29
88
6
CH2Cl2
CH2Cl2
CH2Cl2
THF
Toluene
CHCl3
20
30
15
48
40
15
98:2
7
97:3
8
98:2
90
9
91:9
74
10
11
98:2
83
>99:1
93
a The reaction was carried out in the presence of BINIM-Ni(II) catalyst
(10 mol %), which was prepared by mixing BINIM, Ni(ClO4)2‚6H2O, and
MS 4A in the corresponding solvent, at room temperature. b Determined
by 1H NMR. c Enantiomeric excess (ee) of the exo-adduct was determined
by HPLC.
preferably obtained when thiazolidinethione 2a was used as
a dipolarophile. Although the exo-selectivities were unsat-
isfactory, quinoline-based BINIM-Ni(II) catalysts showed
high enantioselectivities toward the exo-cycloadducts (entries
2-4). Interestingly, when 2-hydroxybenzylideneamine-type
ligands were used in combination with 2a as a dipolarophile,
high exo-selectivities were observed (entries 5-8). Further-
more, the use of BINIM-DCOH or BINIM-DBOH indicated
promising levels of asymmetric induction with extremely
high exo-selectivities (entries 7 and 8). For the BINIM-
DCOH-Ni(II)-catalyzed reactions, a survey of the reaction
solvents (entries 9-11) revealed that CHCl3 provided the
most favorable results in terms of exo-selectivity (>99:1)
and enantioselectivity (93% ee) (entry 11).
Scheme 2. Asymmetric Cycloadditions between Nitrones and
3-Alkenoyl-2-thiazolidinethiones Catalyzed by Chiral
BINIM-Ni(II) Complexes
The optimized conditions with (R)-BINIM-DCOH were
subsequently applied to reactions between various nitrones
and 3-crotonoyl-2-thiazolidinethione (2a) (Scheme 2 and
Table 2). Regardless of the electron-donating or -attracting
character of the p-substituents on the N-benzene ring, high
exo-selectivities (93:7 - >99:1) and high enantioselectivities
(88-95% ee) were observed in the reactions of several
C-phenyl-N-p-substituted phenyl nitrones (1b-e, entries 2-4
and 6). It should be noted that the reactions of nitrones 1a
and 1d with 2a in the presence of 5 mol % of the (R)-BINIM-
DCOH-Ni(II) complex afforded the products in good yields
with extremely high exo-selectivities and enantioselectivities
(entries 1 and 5).7 The cycloaddition reactions of C-p-
substituted phenyl-N-phenyl nitrones 1f-h and C,N-bis(p-
chlorophenyl)nitrone 1i with 2a in the presence of (R)-
BINIM-DCOH-Ni(II) complex (10 mol %) also showed
complexes were prepared from several BINIM ligands (see
Figure 1) and Ni(ClO4)2‚6H2O in the presence of 4 Å
molecular sieves (MS 4A). Surprisingly, for almost all
BINIM ligands that were tested, the exo-cycloadduct was
(2) (a) Gothelf, K. V.; Thomsen, I.; Jørgensen, K. A. J. Am. Chem. Soc.
1996, 118, 59. (b) Kobayashi, S.; Kawamura, M. J. Am. Chem. Soc. 1998,
120, 5840. (c) Kanemasa, S.; Oderaotoshi, Y.; Tanaka, J.; Wada, E. J. Am.
Chem. Soc. 1998, 120, 12355. (d) Gothelf, K. V.; Hazell, R. G.; Jørgensen,
K. A. J. Org. Chem. 1998, 63, 5483. (e) Kobayashi, S.; Kawamura, M.
Tetrahedron Lett. 1999, 40, 3213. (f) Desimoni, G.; Faita, G.; Mortoni, A.;
Righetti, P. Tetrahedron Lett. 1999, 40, 2001. (g) Iwasa, S.; Tsushima, S.;
Shimada, T.; Nishiyama, H. Tetrahedron Lett. 2001, 42, 6715. (h) Iwasa,
S.; Tsushima, S.; Shimada, T.; Nishiyama, H. Tetrahedron 2002, 58, 227.
(3) For reactions with R,â-unsaturated aldehyds, see: (a) Viton, F.;
Bernardinelli, G.; Ku¨ndig, E. P. J. Am. Chem. Soc. 2002, 124, 4968. (b)
Mita, T.; Ohtsuki, N.; Ikeno, T.; Yamada, T. Org. Lett. 2002, 4, 2457. (c)
Shirahase, M.; Kamenasa, S.; Oderaotoshi, Y. Org. Lett. 2004, 6, 675. (d)
Carmona, D.; Lamata, M. P.; Viguri, F.; Rodriguez, R.; Oro, L. A.; Balana,
A. I.; Lahoz, F. J.; Tejero, T.; Merino, P.; Franco, S.; Montesa, I. J. Am.
Chem. Soc. 2004, 126, 2716.
(5) (a) Gothelf, K. V.; Jørgensen, K. A. J. Org. Chem. 1994, 59, 5687.
(b) Jensen, K. B.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J. Org.
Chem. 1997, 62, 2471. (c) Hori, K.; Kodama, H.; Ohta, T.; Furukawa, I. J.
Org. Chem. 1999, 64, 5017. (d) Heckel, A.; Seebach, D. Chem. Eur. J.
2002, 8, 560. (e) Suga, H.; Kakehi, A.; Ito, S.; Sugimoto, H. Bull. Chem.
Soc. Jpn. 2003, 76, 327. (f) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am.
Chem. Soc. 2004, 126, 718.
(6) (a) Suga, H.; Kakehi, A.; Mitsuda, M. Chem. Lett. 2002, 900. (b)
Suga, H.; Kakehi, A.; Mitsuda, M. Bull. Chem. Soc. Jpn. 2004, 3, 561. (c)
Suga, H.; Kitamura, T.; Kakehi, A.; Baba, T. Chem. Commun. 2004, 1414.
(4) (a) Kametani, T.; Huang, S.-P.; Nakayama, A.; Honda, T. J. Org.
Chem. 1982, 47, 2328. (b) Sofia, M. J.; Katzenellenbogen, J. A. J. Org.
Chem. 1985, 50, 2332. (c) Kametani, T.; Chu, S.-D.; Honada, T.
Heterocycles 1987, 25, 241. (d) Kametani, T.; Chu, S.-D.; Honda, T. J.
Chem. Soc., Perkin 1 1988, 1593.
1432
Org. Lett., Vol. 7, No. 7, 2005

Table 2. BINIM-DCOH-Ni(II)-Catalyzed Enantioselective
Cycloadditions of Nitrones 1a-l with
3-(2-Alkenoyl)-2-thiazolinethiones 2a-da
nitrone
2
R
time yield exo:
(h) (%) endob (%)
eec
entry
1d Ph
R1
R2
1
Ph
1a Me
1b Me
1c Me
1d Me
1d Me
1e Me
69 70
19 78
99:1
93:7
90
88
2
3
4
p-MeC6H4 Ph
p-MeOC6H4 Ph
22 36 >99:1 >90
p-ClC6H4
Ph
Ph
Ph
15 98 >99:1
64 80 >99:1
20 90
41 78 >99:1
48 92 99:1
60 85 >99:1
95
95
92
93
92
95
93
90
5d p-ClC6H4
6
7
p-BrC6H4
Ph
98:2
p-MeC6H4 1f Me
p-MeOC6H4 1g Me
8
Ph
9
Ph
p-ClC6H4
p-ClC6H4
Ph
1h Me
1i Me
1j Me
10
11
12
p-ClC6H4
Bn
60 85
78 60
98:2
93:7
86:14 85
90:10 82
97:3
93:7
Me
Ph
1k Me 117 68
13f Bn
Et
1l Me
1a Et
1d Et
96 42
52 74
15 73
98 49 >99:1
64 64
14
15
16
17
18
19
20
21
Ph
p-ClC6H4
Ph
Ph
Ph
p-ClC6H4
Ph
Ph
Ph
91
91
83
92
91
93
90
87e
87e
Ph
p-MeOC6H4 1g Et
p-ClC6H4
Ph
Ph
p-ClC6H4
Ph
Ph
1h Et
1a n-Pr 45 73
1d n-Pr 45 75 >99:1
1g n-Pr 70 95 >99:1
1a Ph
1a Ph
94:6
99:1
150 35 >99:1
69 59 >99:1
22f Ph
a The reaction was carried out in the presence of BINIM-DCOH-Ni(II)
(10 mol %), which was prepared by mixing (R)-BINIM-DCOH, Ni(ClO4)2‚
6H2O, and MS 4A in CHCl3 at room temperature. b Determined by 1H
NMR. c Enantiomeric excess (ee) of the exo-adduct was determined by
HPLC. d 5 mol % of catalyst was used. e Determined by 1H NMR after
conversion to diastereomeric amides of (R)-(+)-R-methylbenzylamine. f 20
mol % of catalyst was used.
The absolute configuration of the cycloadduct 3a obtained
from nitrone 1a and olefin 2a was determined after conver-
sion to the corresponding 4-hydroxymethylisoxazolidine by
NaBH4 reduction. Thus isoxazolidine 3a (90% ee by HPLC)
obtained from the above reaction was treated with NaBH4
in THF-water to give alcohol 4a (92% ee by HPLC)
possessing 3R,4S,5S configuration, which was determined
by comparison with the sign of specific rotation in the
Figure 1. Structures of chiral binaphthyldiimine ligands.
satisfactory results in terms of exo-selectivities (98:2 -
>99:1) and enantioselectivities (92-95% ee) (entries 7-10),
and were independent of the electronic character of the
p-substituents of the C-benzene ring.
It is noteworthy that the catalytic activities of (R)-BINIM-
DCOH-Ni(II) catalyst can be extended to N-alkyl nitrones
1j and 1k and C,N-dialkyl nitrone 1l with good exo-
selectivities and enantioselectivities (entries 11, 12, and 13).
This chiral Ni(II) catalytic system was also applicable to 1,3-
dipolar cycloaddition reactions of several nitrones with 3-(2-
pentenoyl)- (2b), 3-(2-hexenoyl)- (2c), and 3-cinnamoyl-2-
thiazolidinethione (2d) with satisfactory exo-selectivities and
enantioselectivities (entries 14-22). Although 20 mol %
catalyst was needed in the cases of the reactions of nitrone
1l with olefin 2a and nitrone 1a with olefin 2d for moderate
yield (entries 13 and 22), catalytic activity of the BINIM-
Ni(II) complex is noteworthy because these reactions under
reflux in toluene or with Sc(OTf)3 as a Lewis acid gave
almost no cycloadducts.8
literature ([R]25 +176.0 (c 1.0, CHCl3), (3R,4S,5S), 99%
D
ee),5f in 53% yield (Scheme 3). Therefore, the absolute
Scheme 3. Determination of Absolute Configuration
configuration of the cycloadduct 3a was assigned as 3R,4R,5S.
The other cycloadducts were also presumed to have the same
absolute configuration.
Although the detailed structure of the catalyst remains
unclear,9 it is apparent that 2-hydroxybenzylideneamine
moiety of the BINIM ligands in the Ni(II) complexes in
conjunction with 3-(2-alkenoyl)-2-thiazolidinethiones as di-
(7) For the reaction of 1d, decreasing the catalyst loading to 1 or 2 mol
% (rt for 112 h) resulted in lower yields (36% and 50%, respectively) and
enantioselectivity (62%ee and 83% ee, respectively), but with high exo-
selectivity (95:5 and 97:3, respectively).
(8) Reaction of 1l with 2a: reflux in toluene for 23 h, trace; Sc(OTf)3
(10 mol %) in CH2Cl2 for 160 h, 0% yield. Reaction of 1a with 2d: reflux
in toluene for 20 h, 0% yield.
Org. Lett., Vol. 7, No. 7, 2005
1433

polarophiles is extremely important for unusual exo-selectiv-
ity in the Lewis acid-catalyzed cycloaddition reactions of
nitrones. We also revealed that halogen atoms substituted at
the 3-position on benzene rings in the 2-hydroxyphenyl-based
BINIM ligands played an important role for high enantio-
selectivity. The sufficient improvement of enantioselectivity
and somewhat different ligand dependence on exo-selectivity
utilizing 3-(2-alkenoyl)-2-thiazolidinethiones as dipolaro-
philes compared with using 3-crotonyl-2-oxazolidinone are
probably due to longer and more suitable bond lengths of
Ni-S and SdC than those of Ni-O and OdC in the
BINIM-Ni(II)-catalyzed cycloaddition reactions of nitrones.
In conclusion, highly exo-selective and enantioselective
1,3-dipolar cycloaddition reactions between nitrones and
3-(2-alkenoyl)-2-thiazolidinethiones were carried out by
using (R)-BINIM-DCOH-Ni(II) as a chiral Lewis acid
catalyst. In contrast to other chiral Lewis acids that have
been reported for nitrone cycloadditions, it is noteworthy that
our methodology offers extremely high exo-selectivity along
with high enantioselectivity for a number of nitrones.
Furthermore, only the catalyst loading as small as 5-10 mol
% was active enough in most cases.
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Scientific Research (No. 15550087) from
the Ministry of Education, Science and Culture, Japan.
Supporting Information Available: Representative ex-
perimental procedures and spectroscopic data of the reaction
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) The structures of the BINIM-Ni(II) complexes were discussed in
the previous paper5e,6 on the basis of the X-ray structure analysis of DBFOX/
Ph‚Ni(ClO4)2‚3H2O complex, which was shown as an octahedral structure.10
(10) Kanemasa, S.; Oderaotoshi, Y.; Sakaguchi, S.; Yamamoto, H.;
Tanaka, J.; Wada, E.; Curran, D. P. J. Am. Chem. Soc. 1998, 120, 3074.
OL050397H
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