Highly enantioselective asymmetric 1,3-dipolar cycloaddition of azomethine ylide catalyzed by a copper(l)/clickferrophos complex

Article abstract of DOI:10.1021/ol8003996

A copper(l)/ClickFerrophos complex catalyzed the asymmetric 1.3-dipolar cycloaddition reaction of methyl N-benzyhdeneglycmate (the source of azomethlne ylides) with vinyl sulfone to give the exo-2,4,5-trisubstituted pyrrolidine in good yield with high enantioselectivity (99% ee). The complex also effectively catalyzed reactions of other dipolarophiles such as acrylates. maleate, and maleimides to give the exo-2,4.5-, and 2,3,4,5-substituted pyrrolidine derivatives with high diastereo- and enantioselectivities. American Chemical society.

Full text of DOI:10.1021/ol8003996

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1747-1750
Highly Enantioselective Asymmetric
1,3-Dipolar Cycloaddition of Azomethine
Ylide Catalyzed by a Copper(I)/
ClickFerrophos Complex
Shin-ichi Fukuzawa* and Hiroshi Oki
Department of Applied Chemistry, Institute of Science and Engineering,
Chuo UniVersity, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
fukuzawa@chem.chuo-u.ac.jp
Received February 20, 2008
ABSTRACT
A copper(I)/ClickFerrophos complex catalyzed the asymmetric 1,3-dipolar cycloaddition reaction of methyl N-benzylideneglycinate (the source
of azomethine ylides) with vinyl sulfone to give the exo-2,4,5-trisubstituted pyrrolidine in good yield with high enantioselectivity (99% ee). The
complex also effectively catalyzed reactions of other dipolarophiles such as acrylates, maleate, and maleimides to give the exo-2,4,5-, and
2,3,4,5-substituted pyrrolidine derivatives with high diastereo- and enantioselectivities.
Catalytic asymmetric 1,3-dipolar cycloaddition of azomethine
ylides with alkenes is currently of interest, as the reaction is
one of the most useful convergent strategies for stereose-
lective synthesis of optically active five-membered hetero-
cycles such as pyrrolidine and proline derivatives, whose ring
systems are key building blocks for many pharmaceuticals
and biologically active natural products. Several effective
chiral metal complex catalysts have thus far been reported.1
The development of more effective catalysts for the reaction
is of great importance, and proposed chiral metal complex
diastereoselectivity dependent on the metal complex catalyst
employed; Cu/P,P-ligand and Ag/P,N-ligand complexes,
respectively, give the exo and endo isomers exclusively.1
In previous work, we developed a new chiral ferrocenyl
ligand, ClickFerrophos, using click chemistry methodology,
and reported that its rhodium and ruthenium complexes
efficiently catalyzed asymmetric hydrogenation of alkenes
and ketones with excellent enantioselectivity (up to 99.7%
ee).6 ClickFerrophos is a 1,5-diphosphine whose structure
is similar to that of Taniaphos but which gives higher
3
catalysts include silver,2 copper, zinc,4 and nickel.5 The
(2) (a) Zeng, W.; Zhou, Y.-G. Tetrahedron Lett. 2007, 48, 4619–4622.
(b) Nájera, C.; Retamosa, M. D. G.; Sansano, J. M. Org. Lett. 2007, 9,
4025–4028. (c) Nyerges, M.; Bendell, D.; Arany, A.; Hibbs, D. E.; Coles,
S. J.; Hursthouse, M. B.; Groundwater, P. W.; Meth-Cohn, O. Tetrahedron
2005, 61, 3745–3753. (d) Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis 2005,
1431–1436. (e) Zeng, W.; Zhou, Y.-G. Org. Lett. 2005, 7, 5055–5058. (f)
Alemparte, C.; Blay, G.; Jorgensen, K. A. Org. Lett. 2005, 7, 4569–4572.
(g) Knöpfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira,
E. M. Angew. Chem., Int. Ed. 2004, 43, 5971–7973. (h) Chen, C.; Li, X.;
Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174–10175. (i) Longmire,
J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400–13401.
reaction of methyl N-benzylideneglycinate (the source of
azomethine ylides) with acrylate, maleate, or maleimide gives
tri- and tetra-substituted exo and/or endo pyrrolidines, with
(1) For reviews: (a) Pandey, G.; Banerjee, P.; Gadre, S. Chem. ReV.
2006, 106, 4484–4517. (b) Husuinec, S.; Savic, V. Tetrahedron: Asymmetry
2005, 16, 2047–2061. (c) Nájera, C.; Sansano, J. M. Angew. Chem., Int.
Ed. Engl. 2005, 44, 6272–6276. (d) Kanemasa, S. Synlett 2002, 1371–1387.
10.1021/ol8003996 CCC: $40.75
Published on Web 03/29/2008
2008 American Chemical Society

enantioselectivities in some cases (Figure 1).7 We are
interested in the 1,3-dipolar addition reaction of azomethine
ylide with vinyl sulfone, which gives 4-sulfonylpyrrolidines.
A Cu/Taniaphos complex was found to catalyze the reaction
with high enantioselectivity and was highly effective com-
pared to other phosphine ligands.8 This reaction is expected
to be useful for obtaining 2,5-disubstituted pyrrolidines, since
the sulfone group can be removed by reduction. In this work,
we used ClickFerrophos for Cu (or Ag)-catalyzed asymmetric
1,3-dipolar cycloaddition and found that the complex is
sometimes more effective than Taniaphos for this reaction.
Reactions using other dipolarophiles such as acrylates,
maleate, and maleimide were also studied.
chose the inexpensive CuOAc as the metal salt for subse-
quent investigations. CuOAc has an additional advantage
over other copper salts in that the reaction did not require
the addition of amine, which was required for the other
copper salt catalyst systems. Combinations of other Click-
Ferrophos variations (1b and 1c) with CuOAc were exam-
ined, but these were not as effective as 1a (entries 2–3). The
complex with AgOAc somewhat effective but gave a lower
yield and ee % than CuOAc (entry 8). It was previously
reported that Ag salts are suitable for combining with P,N-
ligands,1 therefore, a combination of AgOAc with 2 was
examined, but this gave a poor result (entry 9).
Table 1. Reaction of 3a with Vinyl Sulfone Catalyzed by Metal
Salt/ClickFerrophosa
entry
metal salt
ligand (L)
yield (%)b
ee (%)c
1d
2d
3d
4
CuOAc
CuOAc
CuOAc
CuOTf
CuClO4
CuClO4
Cu(OTf)2
AgOAc
AgOAc
1a
1b
1c
1a
87
68
78
87
80
87
48
75
23
96
76
82
97
98
83
83
82
24
Figure 1. Taniaphos and ClickFerrophos.
5
1a
6e
7
Taniaphos
We first investigated the reaction of methyl N-ben-
zylideneglycinate (3a) with vinyl phenyl sulfone (4) using a
combination of ClickFerrophos 1a-c, 2, and various metal
complexes; the metal salts used were CuOAc, Cu(MeCN)4-
ClO4, CuOTf·C6H6, Cu(OTf)2, and AgOAc. A typical reac-
tion was carried out in toluene at 0 °C for 24 h using a
ClickFerrophos metal complex (5 mol %), and the ee % of
the product was determined by HPLC (Chiralcel AS-H). As
shown in Table 1, the combination of CuOAc or CuOTf·C6H6
with 1a was the most effective for the reaction, giving only
the exo 4-sulfonyl pyrrolidine 5a in good yield (87%) with
high enantioselectivity (96–97% ee) (entries 1 and 4), while
the other metal salts gave the product with good enantiose-
lectivity but unsatisfactory yields. Cu(MeCN)4ClO4 was
another possible choice for the metal salt as it gave the
product with high enantioselectivity (entry 5)—higher than
that of Taniaphos (entry 6)—but for reasons of safety
(Cu(MeCN)4ClO4 is potentially explosive) and economy, we
1a
1a
2
8
9
a Reactions run using 3a (0.2 mmol), 4 (0.2 mmol), metal salt (0.01
mmol), L (0.011 mmol), Et3N (0.018 mmol), and toluene (2 mL). b Isolated
yield. c Determined by HPLC. d Without Et3N. e Data from ref 3.
Next, we optimized the reaction by employing CuOAc/
1a as a catalyst under various reaction conditions. Diethyl
ether was found to be the most suitable solvent for the
reaction, with a high yield (94%) and enantioselectivity of
up to 99.9% at -40 °C. These results are summarized in
Table 2.
With the reaction conditions thus optimized, the reaction
with vinyl sulfone was expanded to substituted azomethine
ylide precursors (dipoles), including 4-substituted phenyl
derivatives, 2-naphthyl, and cyclohexyl derivatives, in diethyl
ether at -40 °C (Table 3). Similarly to the reaction with 3a,
the exo products were obtained in good yield and with high
enantioselectivity (up to 99% ee) as single diastereomers.
In the reaction with R-substituted dipole 3f, the 2,2-
disubstituted pyrrolidine containing an ester group cis to the
phenyl group was produced almost as the sole product in
good yield with high enantioselectivity. The CuOAc/1a
catalyst gave high enantioselectivities, similar to those
(3) (a) Cabrera, S.; Gómez Arrayás, R.; Martín-Matute, B.; Cossío, F. P.;
Carretero, J. C. Tetrahedron 2007, 63, 6587–6602. (b) Shi, M.; Shi, J.-W.
Tetrahedron: Asymmetry 2007, 18, 645–650. (c) Yan, X.-X.; Peng, Q.;
Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D Angew. Chem.,
Int. Ed. 2006, 45, 1979–1983. (d) Cabrera, S. A., R. G.; Carretero, J. C.
J. Am. Chem. Soc. 2005, 127, 16394–16395. (e) Oderaotoshi, Y.; Cheng,
W.; Fujitomi, S.; Kasano, Y.; Minakata, S.; Komatsu, M. Org. Lett. 2005,
5, 5043–5046. (f) Gao, W.; Zhang, X.; Raghunath, M. Org. Lett. 2005, 7,
4241–4244.
(4) (a) Dogan, O.; Koyuncu, H.; Garner, P.; Bulut, A.; Youngs, W. J.;
Panzner, M. Org. Lett. 2006, 8, 4687–4690. (b) Gothelf, A. S.; Gothelf,
K. V.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41,
4236–4238.
(7) We recently reported the correct structure of Taniaphos: Fukuzawa,
S.-i.; Yamamoto, M.; Hosaka, M.; Kikuchi, S. Eur. J. Org. Chem. 2007,
5540–5545.
(5) Shi, J.-W.; Zhao, M.-X.; Lei, Z.-Y.; Shi, M. J. Org. Chem. 2008,
73, 305–308.
(8) (a) Llamas, T.; Arrayas, R. G.; Carretero, J. C. Org. Lett. 2006, 8,
1795–1798. (b) Llamas, T.; Ramón Gómez, A.; Carretero, J. C. Synthesis
2007, 950–956.
(6) Fukuzawa, S.-i.; Oki, H.; Hosaka, M.; Sugasawa, J.; Kikuchi, S.
Org. Lett. 2007, 9, 5557–5560.
1748
Org. Lett., Vol. 10, No. 9, 2008

Table 2. Reaction of 3a with Vinyl Sulfonea Catalyzed by
CuOAc/ClickFerrophos 1a
entry
solvent
temp (°C)
yield (%)b
ee (%)c
1
2
3
4
5
6
toluene
CH2Cl2
THF
Et2O
Et2O
0
0
0
87
50
95
90
90
94
96
94
94
90
98
0
-20
-40
Et2O
>99.9
a Reactions run using 3a (0.2 mmol), 4 (0.2 mmol), CuOAc (0.01 mmol),
1a (0.011 mmol), and solvent (2 mL). b Isolated yield. c Determined by
HPLC.
Figure 2. Dipolarophiles and pyrrolidine products.
obtained using Cu(I)/Taniaphos, even gave higher yields and
% ee in reactions with certain dipolarophiles, such as 3d, in
which Cu(I)/Taniaphos is less effective.8
Table 4. Reaction of 3a with Various Dipolarophilesa
yield (%)b,
exo/endoc
entry
dipolarophile
product
ee (%) (exo)d
Table 3. Reactions with Various Dipolesa
1
2
3
4
5
8a
8b
9
10
11
12a
12b
13
14
15
89, 70/30
87, 95/5
66, 98/2
71, 2/98
95, 75/25
96
91
80
91
91
a Reactions run using 3a (0.2 mmol), dipolarophile (0.2 mmol), CuOAc
(0.01 mmol), 1a (0.011 mmol), diethyl ether (2 mL). b Total isolated yield.
c
Determined by H NMR. d Determined by HPLC.
yield (%)b
ee (%)c
1
entry
dipole
R1
R2
1
2
3
4
5
3b
3c
3d
3e
3f
4-FC6H4
4-MeOC6H4
2-C8H9
Cy
H
H
H
H
80
91
87
81
83
95
96
94
99
93
acrylate, maleate, fumarate, and maleimide (Figure 2). The
results are outlined in Table 4. In the reaction with methyl
acrylate 8a, the exo cycloadduct 12a was obtained preferentially
in high enantioselectivities (96% ee), although accompanied by
significant amounts of the endo isomer (exo/endo ) 70:30)
(entry 1). In the reaction with tert-butyl acrylate 8b, exo
diastereoselectivity was improved (exo/endo ) 95:5) with high
ee% (entry 2). In the reactions with dimethyl maleate 9 the exo
isomers 13 was obtained predominantly (exo/endo ) 98:2) with
high enantioselectivity (80% ee, entry 3). Zhang et al. reported
that high diastereoselectivity and enantioselectivity can be
achieved in the reaction of azomethine ylide with 8b and 9 using
a Cu(I)/chiral ferrocenyloxazoline phosphine complex in which
the phosphinyl substituent is a bulky 3,5-xylyl group.3 The
phosphinyl substituent of ClickFerrophos used here was a
simple phenyl group, which implies that the structure of
ClickFerrophos itself is effective for asymmetric induction. On
the other hand, with fumarate (10), the endo cycloadduct 14
was obtained exclusively with 91% ee (entry 4). The reaction
with N-phenylmaleimide (11) gave the exo adduct 15 with
moderate diastereoselectivity (exo/endo ) 75:25) and 91% ee
(entry 5).
Ph
Me
a Reactions run using dipole (0.2 mmol), 4 (0.2 mmol), CuOAc (0.01
mmol), 1a (0.011 mmol), and diethyl ether (2 mL). b Isolated yield.
c Determined by HPLC.
The sulfonyl group of N-methyl derivative 6 was removed
by reduction with samarium(II) iodide/THF-HMPA rather than
the Carretero desulfonylation method using Na(Hg)/NaHPO4,
as the former method does not require the use of harmful
mercury,8 and cis-2,5-disubstituted pyrrolidine 7 was obtained
in good yield without loss of optical purity (Scheme 1).9
Scheme 1. Desulfonylation of 6
(9) Künzer, H.; Stahnke, M.; Sauer, G.; Wiechert, R. Tetrahedron Lett.
1991, 32, 1949–1952. . The cleavage of C-N bond was accompanied to
yield (E)-methyl 2-(methylamino)-5-phenylpent-4-enoate (10% yield).
Finally, we used the CuOAc/1a catalyst in reactions of 3a
with a variety of dipolarophiles, including methyl and tert-butyl
Org. Lett., Vol. 10, No. 9, 2008
1749

In conclusion, Cu(I)/ClickFerrophos complex was found
to be an efficient catalyst for asymmetric 1,3-dipolar cy-
cloaddition of azomethine ylide with dipolarophiles. In
reactions with vinyl sulfone, acrylates, maleate, and male-
imide, the exo isomers were produced predominantly, with
high enantioselectivity (up to 99.9% ee).
from the Japan Society for the Promotion of Science (JSPS)
and a Chuo University Grant for Special Research.
Supporting Information Available: Full experimental
1
procedures, characterization data, HPLC analyses, and H
and 13C NMR spectra (PDF) for pyrrolidine derivatives
5a-5f, 6,7, 12a,b, 13-15. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This study was financially supported
by a Grant-in-Aid, No 16550044, for Scientific Research
OL8003996
1750
Org. Lett., Vol. 10, No. 9, 2008