exo- and Enantioselective Cycloaddition of Azomethine Ylides Generated from N-Alkylidene Glycine Esters Using Chiral Phosphine - Copper Complexes

Article abstract of DOI:10.1021/ol036076s

(Equation presented) High diastereo- and enantioselectivities were obtained for the asymmetric 1,3-dipolar cycloaddition of azomethine ylides generated from N-alkylideneglycine esters with dipolarophiles using chiral phosphine-copper complexes as catalysts. Whereas the cycloaddition of azomethine ylides catalyzed by metal salts generally afforded endo-adducts as the predominant product, the present method is the first example of an exo-selective cycloaddition.

Full text of DOI:10.1021/ol036076s

ORGANIC
LETTERS
2003
Vol. 5, No. 26
5043-5046
exo- and Enantioselective Cycloaddition
of Azomethine Ylides Generated from
N-Alkylidene Glycine Esters Using
Chiral Phosphine−Copper Complexes
Yoji Oderaotoshi, Wenji Cheng, Shintaro Fujitomi, Yukihiro Kasano,
Satoshi Minakata, and Mitsuo Komatsu*
Department of Applied Chemistry, Graduate School of Engineering, Osaka UniVersity,
Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
komatsu@chem.eng.osaka-u.ac.jp
Received October 24, 2003
ABSTRACT
High diastereo- and enantioselectivities were obtained for the asymmetric 1,3-dipolar cycloaddition of azomethine ylides generated from
N-alkylideneglycine esters with dipolarophiles using chiral phosphine−copper complexes as catalysts. Whereas the cycloaddition of azomethine
ylides catalyzed by metal salts generally afforded endo-adducts as the predominant product, the present method is the first example of an
exo-selective cycloaddition.
The cycloaddition of azomethine ylides, a representative 1,3-
dipole, with alkenes is a useful tool for the construction of
the pyrrolidine ring contained in many biologically active
compounds,1a and the development of methods for the
diastereo- and enantioselective cycloaddition of 1,3-dipoles
is important in modern synthetic organic chemistry.1b,c Thus
far, azomethine ylides have been generated by the ring
opening of aziridines,2 the 1,2-proton shift of N-arylidene-
benzylamines,3 abstraction of the R-proton from iminium
salts4 or metal complexes of N-alkylidene-R-amino acid
esters,5 and related reactions. We are also in the process of
studying the cycloaddition of azomethine ylides generated
by 1,2-silatropy of N-arylidene-R-silylbenzylamines6 and 1,4-
metallatropy of R-metalloamides.6g,7 Among these, the dia-
stereoselective cycloaddition of azomethine ylides generated
from N-alkylideneamino acid esters in the presence of metal
salts and bases has been a subject of active investigation.
(5) For examples, see: (a) Tsuge, O.; Kanemasa, S.; Yoshioka, M. J.
Org. Chem. 1988, 53, 1384-1391. (b) Grigg, R.; Montgomery, J.;
Somasunderam, A. Tetrahedron 1992, 48, 10431-10442.
(6) (a) Komatsu, M.; Okada, H.; Yokoi, S.; Minakata, S. Tetrahedron
Lett. 2003, 44, 1603-1606. (b) Okada, H.; Akaki, T.; Oderaotoshi, Y.;
Minakata, S.; Komatsu, M. Tetrahedron 2003, 59, 197-205. (c) Komatsu,
M.; Okada, H.; Akaki, T.; Oderaotoshi, Y.; Minakata, S. Org. Lett. 2002,
4, 3505-3508. (d) Ohno, M.; Komatsu, M.; Miyata, H.; Ohshiro, Y.
Tetrahedron Lett. 1991, 32, 5813-5816. (e) Komatsu, M.; Ohno, M.; Tsuno,
S.; Ohshiro, Y. Chem. Lett. 1990, 575-576. (f) Iyoda, M.; Sultana, F.;
Kato, A.; Yoshida, M.; Kuwatani, Y.; Komatsu, M.; Nagase, S. Chem. Lett.
1997, 63-64. (g) Iyoda, M.; Sultana, F.; Komatsu, M. Chem. Lett. 1995,
1133-1134.
(1) (a) Gribble, G. W. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.: Pergamon: Oxford,
U.K., 1996; Vol. 2, pp 207-257. (b) Gothelf, K. V.; Jørgensen, K. A. Chem.
ReV. 1998, 98 , 863-909. (c) Lown, J. W. In 1,3-Dipolar Cycloaddition
Chemistry; Padwa A., Ed.; John Wiley & Sons: New York, 1984; Vol. 1,
pp 653-732.
(2) Huisgen, R.; Scheer, W.; Huber, H. Tetrahedron Lett. 1966, 7, 397-
464.
(7) (a) Komatsu, M.; Kasano, Y.; Yamaoka, S.; Minakata, S. Synthesis
2003, 1398-1402. (b) Washizuka, K.-I.; Nagai, K.; Minakata, S.; Ryu, I.;
Komatsu, M. Tetrahedron Lett. 2000, 41, 691-695. (c) Washizuka, K.-I.;
Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron 1999, 55, 12969-12976.
(d) Washizuka, K.-I.; Nagai, K.; Minakata, S.; Ryu, I.; Komatsu, M.
Tetrahedron Lett. 1999, 40, 8849-8853.
(3) For examples, see: (a) Grigg, R.; Kemp, J. J. Chem. Soc., Chem.
Commun. 1978, 109-111. (b) Grigg, R.; Donegan, G.; Gunaratne, H. Q.
N. Tetrahedron 1989, 45, 1723-1746.
(4) Huisgen, R.; Grashey, R. Tetrahedron Lett. 1963, 4, 1441-1445.
10.1021/ol036076s CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/03/2003

Moreover, several examples of the asymmetric cycloaddition
of azomethine ylides catalyzed by chiral metal complexes
have been reported.8 However, most 1,3-dipolar cycloaddi-
tions of azomethine ylides catalyzed by chiral metal com-
plexes have shown only endo-selectivity. Because it is
important that any of the desired diastereomers of cyclo-
adducts can be synthesized selectively, a study of methods
of exo-selective cycloaddition controlled by metal complexes
is also needed. Herein, we report on the asymmetric cyclo-
addition of azomethine ylides with dipolarophiles catalyzed
by copper(II)-chiral phosphine complexes. Surprisingly, this
new method afforded the corresponding exo-cycloadducts
exclusively in high enantioselectivity.
Table 1. Asymmetric 1,3-Dipolar Cycloaddition of
Azomethine Ylides with N-Phenylmaleimide (2a)a
cycloadducts
exo/ ee
endob (exo, %)
Our initial study showed that the Cu(II)-triphenylphos-
phine complex successfully catalyzes the exo-selective cy-
cloaddition of N-benzylideneglycine methyl ester (1a) with
N-phenylmaleimide (2a) in the presence of triethylamine at
room temperature (endo/exo ) 36/64, Scheme 1). To extend
time yield
ligand (h) (%)
entry
R
1
2
3
4
5
6
7
8
9
Ph (1a )
Ph (1a )
Ph (1a )
Ph (1a )
4-MeOC6H4 (1b)
4-MeOC6H4 (1b)
4-NO2C6H4 (1c)
4-NO2C6H4 (1c)
4-ClC6H4 (1d )
7
8
9
10
7
10
7
10
7
10
24 71 (3a ) >95/<5
24 40 (3a ) >95/<5
64c
47c
60c
72c
87d
48 25 (3a )
93/7
48 78 (3a )
85/15
48 83 (3b) >95/<5
48 0 (3b) -/-
24 77 (3c) >95/<5
24 32 (3c) >95/<5
48 83 (3d ) >95/<5
48 94 (3d ) >95/<5
Scheme 1. Asymmetric 1,3-Dipolar Cycloaddition of
Azomethine Ylides Catalyzed by Chiral Phosphine Ligands
62d
19d
65d
75d
10
4-ClC6H4 (1d )
a Reaction conditions: imine 1 (1.0 equiv), 2a (1.1 equiv), Cu(OTf)2
(2.0 mol %), ligand (2.2 mol %), NEt3 (4 mol %), CH2Cl2 (2.5 mL) at -40
°C. b Determined by 1H NMR analysis. c Determined by HPLC analysis
using DAICEL CHIRALPAK AS. d Determined by 1H NMR analysis of
the cycloadduct (exo) in the presence of Eu(hfc)3.
were examined (Table 1, entries 1-4). When the BINAP-
Cu(II) complex was used, cycloadducts were obtained with
the highest exo-selectivity (exo/endo ) 99/1). In the case of
SEGPHOS (10), the reaction afforded the highest ee of the
exo-adduct (72% ee).
the result to higher exo- and enantioselectivities, several
chiral phosphine ligands (Figure 1, ligands 4-7) were
examined.
To extend the scope of this reaction, some other imines
1b-d were employed in reactions catalyzed by BINAP-
or SEGPHOS-Cu(OTf)2 complexes (entries 5-10). Com-
plete exo-selectivity was observed in the reactions of imines
1b-d. When imines 1b and 1c were used, reactions using
BINAP as the ligand showed reactivity and enantioselectivity
higher than those for SEGPHOS. However, in the case of
imine 1d, having a chloro group on the phenyl ring, the
reaction in the presence of SEGPHOS-Cu(OTf)2 catalyst
In the reactions using 20 mol % of Cu(OTf)2 and 10 mol
% of chiral phosphine ligands at room temperature, the use
of BINAP (7) showed the best exo- and enantioselectivity
(exo/endo ) 87/13; ee of exo-adduct ) 34%). To improve
the exo- and enantioselectivities, reactions using BINAP and
BINAP derivatives 8-10 under low-temperature conditions
(8) (a) Allway, P.; Grigg, R. Tetrahedron Lett. 1991, 32, 5817-5820.
(b) Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475-2486. (c) Gothelf,
A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2002, 41, 4236-4238. (d) Longmire, J. M.; Wang, B.; Zhang, X. J.
Am. Chem. Soc. 2002, 124, 13400-13401. (e) Chen, C.; Li, X.; Schreiber,
S. L. J. Am. Chem. Soc. 2003, 125, 10174-10175.
(9) A part of references of chiral phosphine ligands are as follows.
CHIRAPHOS: Fryzuk, M. D.; Bosnish, B. J. Am. Chem. Soc. 1977, 99,
6262-6267. BDPP: MacNeil, P. A.; Roberts, N. K.; Bosnich, B. J. Am.
Chem. Soc. 1981, 103, 2273-2280. DIOP: Dang, T. P.; Kagan, H. B. J.
Chem. Soc., Chem. Commun. 1971, 481. BINAP: Miyashita, A.; Takeya,
H.; Souchi, T.; Noyori R. Tetrahedron 1984, 40, 1245-1253. Tol-BINAP:
Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki, K.; Kumo-
bayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.; Takaya, H. J.
Org. Chem. 1994, 59, 9, 3064. H8-BINAP: Uemura, T.; Zhang, X.;
Matsumura, K.; Sayo, N.; Kumobayashi, H.; Ohta, T.; Nozaki, K.; Takaya,
H.; J. Org. Chem. 1996, 61, 5510. SEGPHOS: Saito, T.; Sayo, N.;
Xiaoyaong, Z.; Yokozawa, T. Patent EP 0850945, 1998.
Figure 1. Chiral phosphine ligands9 used in the asymmetric
cycloaddition with imines 1 and dipolarophiles.
5044
Org. Lett., Vol. 5, No. 26, 2003

Table 2. Asymmetric 1,3-Dipolar Cycloaddition of an Azomethine Ylide with Dipolarophilesa
a Reaction conditions: imine 1a (1.0 equiv), dipolarophile (1.1 equiv), Cu(OTf)2 (2.0 mol %), ligand (2.2 mol %), NEt3 (4 mol %), CH2Cl2 (2.5 mL) at
-40 °C. b Determined by 1H NMR analysis. c Determined by HPLC analysis using DAICEL CHIRALPAK AS. d Determined by HPLC analysis using
DAICEL CHIRALCEL OD. e Determined by 1H NMR analysis of the cycloadduct (exo) in the presence of Eu(hfc)3. f In comparison with the result of entry
6, the enantioselectivities were reversed in the reaction giving cycloadducts 13 and 14 in entry 7.
proceeded in higher yield and enantioselectivity than with
the BINAP catalyst.
and Figure 2, respectively. Imines 1 coordinate to the chiral
phosphine-Cu(II) complexes, and azomethine ylide-Cu(II)
complexes are then generated by abstraction of R-protons
Reactions using several other dipolarophiles were also
investigated in a similar manner (Table 2). In the reaction
with N-methylmaleimide (2b), exo-selectivity decreased in
comparison with the reaction with N-phenylmaleimide
(entries 1 and 2). Use of SEGPHOS (10) led to enantio-
selectivity higher than that with BINAP (7). In the cases
where acyclic dipolarophiles such as dimethyl fumarate (2c)
and fumaronitrile (2d) were used, both diastereomers were
obtained in high enantioselectivity, except for the reaction
with dipolarophile 2c catalyzed by the SEGPHOS-Cu(II)
complex (entries 5, 7, and 8). Interestingly, the reversal of
enantioselectivity of the exo-adduct between the reactions
catalyzed by BINAP- and SEGPHOS-Cu(II) complex was
observed for the reactions with fumaronitrile (2d). These
results strongly suggest that use of a suitable chiral ligand
can lead to a high diastereo- and enantioselectivity in
reactions with a variety of substrates.
Scheme 2. Plausible Mechanism of the 1,3-Dipolar
Cycloaddition of Azomethine Ylides Catalyzed by Chiral
Phosphine-Cu(II) Complexes
A plausible mechanism for the cycloaddition reaction and
explanation for diastereoselectivity are shown in Scheme 2
Org. Lett., Vol. 5, No. 26, 2003
5045

maleimides and the phenyl group on the phosphorus atom
of the chiral phosphine ligands in the transition state
corresponding to the endo approach. Reactions with N-
phenylmaleimide gave higher exo-selectivity than those with
N-methylmaleimide (Table 2, entries 1-4), since the phenyl
group is bulkier than a methyl group.
In summary, we report here on the high exo- and
enantioselective 1,3-dipolar cycloaddition of azomethine
ylides catalyzed by chiral phosphine ligand-Cu(II) com-
plexes. As a result, exo- and endo-selectivity can be
controlled by the nature of the chiral metal complexes used
in the reaction. An appropriate combination of chiral
phosphine complexes and substrates led to the production
of cycloadducts with high diastereo- and enantioselectivities.
A detailed mechanistic study on enantioselectivity is cur-
rently, underway.
Figure 2. Proposed transition states leading to exo- and endo-
cycloadducts.
of imine 1-Cu(II) complexes by NEt3. The azomethine
ylide-Cu(II) complexes react with dipolarophiles, followed
by elimination of the cycloadducts from the chiral Cu(II)
complexes.
Transition state models of exo- and endo-selective reac-
tions are shown in Figure 2. Stable isomers of azomethine
ylide-Cu(II)-BINAP complexes were calculated by the
ZINDO method.10 It is thought that an exo approach of
N-substituted maleimides to the Cu(II) complexes occurs
predominantly because of steric repulsion between the
substituents on the nitrogen atom of the N-substituted
Acknowledgment. This work was supported, in part, by
a Grant-in-Aid for Scientific Research from Japan Society
for the Promotion of Science and a Grant-in-Aid from Handai
Frontier Research Center. We also wish to acknowledge Dr.
T. Saito, Takasago International Co., for providing some of
the chiral phosphine ligands and the Instrumental Analysis
Center, Faculty of Engineering, Osaka University.
Supporting Information Available: Experimental pro-
cedures and characterization of the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
(10) The method is in Cache ver. 4.0 program (Fujitsu Corporation).
OL036076S
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Org. Lett., Vol. 5, No. 26, 2003