Table 1. Optimization Experiments in the Cycloaddition of 2 with Cyclopentenone Catalyzed by Fesulphos Complexes
entry
[M]
AgOAc
ligand
x
base
endo/exoa
yieldb (%)
eec (%)
1
1a
1a
1a
1a
1a
1a
1a
1a
1b
10
10
10
5
3
5
5
5
5
Et3N
Et3N
Et3N
Et3N
Et3N
DIPEA
Et3N
Et3N
Et3N
80:20
87:13
90:10
90:10
88:12
88:12
85:15
90:10
70:30
72
69
71
70
52e
66
62
58e
60
63
78
93
94
94
89
91
95
90
2d
3
AgOAc
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
4
5
6
7
8d
9
a Determined by NMR from the crude reaction mixture. b Of pure endo-3 after chromatographic purification. c ee of endo-3 determined by chiral HPLC
(Chiralcel IB). d Reaction performed at 0 °C. e The reaction did not reach complete conversion.
On the basis of the good performance of copper(I) and
silver(I) complexes of Fesulphos ligands9 (1) as catalysts in
the azomethine imine cycloaddition with several acid
derivatives4b,f (maleimides and R,ꢀ-unsaturated esters) and
bis-sulfonylethylenes,4i an extension of this catalyst system
to R,ꢀ-unsaturated ketones was particularly attractive. There-
fore, the reaction of N-benzylideneglycine methyl ester (2)
with 2-cyclopentenone catalyzed by AgI- and
CuI-Fesulphos complexes was initially investigated. Opti-
mization experiments listed in Table 1 led us to identify the
superiority of cationic copper(I) complexes10 of 1a (entries
3-8) over the corresponding silver catalyst (entries 1 and
mol % of metal/ligand catalyst to reach complete conversion
at room temperature (compare entries 4 and 5). Under such
conditions, the bicyclic pyrrolidine 3 was obtained with high
endo-selectivity (endo/exo ) 90:10), enantioselectivity (94%
ee endo-3), and chemical yield (70% in endo-3 after standard
silica gel chromatographic purification). Lowering the reac-
tion temperature (0 °C) had a detrimental effect on the
reactivity (58% isolated yield) without a significant impact
on the stereocontrol (endo/exo ) 90:10, 95% ee, entry 8).
The bulkier Fesulphos ligand 1b (R ) 1-Naph) also proved
to be suitable, yet slightly less effective, providing endo-3
in 60% yield and 90% ee (entry 9).
To evaluate the scope of this cycloaddition protocol, a
representative set of aryl imines of glycine methyl ester was
surveyed under the optimized conditions (5 mol % of chiral
catalyst, 18 mol % of Et3N, CH2Cl2 at rt, Table 2). The
corresponding endo-adduct was isolated in good yields
(61-70%) and high levels of endo-selectivity (90:10-98:
2) and enantiocontrol (91-95% ee), except for the electron-
11
2), as well as Et3N and CH2Cl2 as the optimal base and
solvent, respectively. The reaction was found to require 5
(4) For recent examples on Cu catalysts, see: (a) Oderaotoshi, Y.; Cheng,
W.; Fujitomi, S.; Kasano, Y.; Minakata, S.; Komatsu, M. Org. Lett. 2003,
5, 5043. (b) Cabrera, S.; Go´mez Arraya´s, R.; Carretero, J. C. J. Am. Chem.
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Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45, 1979.
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1795. (e) Mart´ın-Matute, B.; Pereira, S. I.; Pen˜a-Cabrera, E.; Adrio, J.; S.
Silva, A. M.; Carretero, J. C AdV. Synth. Catal. 2007, 349, 1714. (f) Cabrera,
S.; Go´mez Arraya´s, R.; Mart´ın-Matute, B.; Cossío, F. P.; Carretero, J. C.
Tetrahedron 2007, 63, 6587. (g) Shi, M.; Shi, J.-W. Tetrahedron: Asymmetry
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Lo´pez-Pe´rez, A.; Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 2008, 130,
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thine ylide 1,3-dipolar cycloadditions, see: (a) Garc´ıa Ruano, J. L.; Tito,
A.; Peromingo, M. T J. Org. Chem. 2003, 68, 10013. (b) Bashiardes, G.;
Cano, C.; Mauze, B. Synlett 2005, 587. (c) Agbodjan, A. A.; Cooley, B. E.;
Copley, R. C. B.; Corfield, J. A.; Flanagan, R. C.; Glover, B. N.; Guidetti,
R.; Haigh, D.; Howes, P. D.; Jackson, M. M.; Matsuoka, R. T.; Medhurst,
K. J.; Millar, A.; Sharp, M. J.; Slater, M. J.; Toczko, J. F.; Xie, S. J. Org.
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Manchen˜o, O.; Go´mez Arraya´s, R.; Carretero, J. C J. Am. Chem. Soc. 2004,
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(10) Other cationic CuI complexes provided similar results. For instance,
the model reaction of 2 with 2-cyclopentenone in the presence of
Cu(CH3CN)4PF6 (5 mol %), 1a (5 mol %), and Et3N (18 mol %) afforded
endo-3 in 52% isolated yield (endo/exo ) 87:13) and 93% ee.
(11) The model reaction catalyzed by Cu(CH3CN)4PF6/1a (5 mol %) in
THF led to a much lower conversion (30% isolated yield of endo-3). Very
low conversion was observed in acetonitrile.
J. M. Angew. Chem., Int. Ed. 2008, 47, 6055.
II
¨
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Org. Lett., Vol. 11, No. 2, 2009