Enantioselective Ag(I)-catalyzed [3+2] cycloaddition of azomethine ylides using a chiral ferrocene-based phosphine-phosphoramidite ligand having a stereogenic P-center

Article abstract of DOI:10.1016/j.tetasy.2009.02.058

A series of chiral ferrocene-based phosphine-phosphoramidite ligands (PPFAPhos) have been employed in the Ag(I)-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides with dimethyl maleate. The results showed that the ligand with a stereogenic P-ce

Full text of DOI:10.1016/j.tetasy.2009.02.058

Tetrahedron: Asymmetry 20 (2009) 621–625
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Enantioselective Ag(I)-catalyzed [3+2] cycloaddition of azomethine ylides
using a chiral ferrocene-based phosphine–phosphoramidite ligand
having a stereogenic P-center
Sai-Bo Yu a,b, Xiang-Ping Hu a, , Jun Deng a,b, Dao-Yong Wang a,b, Zheng-Chao Duan a,b, Zhuo Zheng a,
*
*
a Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
b Graduate School of Chinese Academy of Sciences, Beijing 100039, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral ferrocene-based phosphine–phosphoramidite ligands (PPFAPhos) have been employed
in the Ag(I)-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides with dimethyl maleate. The
results showed that the ligand with a stereogenic P-center in the phosphino moiety displayed the best
diastereo- and enantioselectivities, in which up to 99% enantiomeric excesses and 99/1 endo/exo selectiv-
ities have been achieved.
Received 22 January 2009
Accepted 18 February 2009
Available online 22 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
be successfully employed in Ag-catalyzed asymmetric [3+2]
azomethine ylide cycloadditions.3j We therefore surmised that
The asymmetric 1,3-dipolar cycloadditions of azomethine
ylides with electronic-deficient olefins represent one of the most
important methods for the stereoselective construction of biologi-
cally and synthetically important pyrrolidine derivatives.1 Follow-
ing the pioneering work by Grigg et al. on the use of chiral
unsymmetrical hybrid phosphine–phosphoramidite ligands may
also be effective for this reaction. As a result, we herein report
our investigations on the use of the complexes of PPFAPhos ligands
with AgOAc in the catalytic asymmetric 1,3-cycloadditions of
azomethine ylides with dimethyl maleate, in which up to 99% ee
and good yields for endo-adducts can be achieved.
transition metal complexes,2 which require
a stoichiometric
amount of the metal complex, in the past few years some impres-
sive advances have been made in the catalytic asymmetric [3+2]
azomethine ylide cycloadditions by employing a variety of metal
catalytic systems combining several ligand types and metal
sources3–5 or chiral organocatalysts.6 Despite this important pro-
gress, there remains a need for the development of novel catalysts
for this interesting reaction.
O
P
O
P
O
PPh2
N
N
O
PPh2
Recently, we have reported a new family of unsymmetrical
hybrid chiral ferrocene-based phosphine–phosphoramidite
ligands, PPFAPhos (as shown in Fig. 1), which showed excellent
enantioselectivities and catalytic activities in the Rh-catalyzed
asymmetric hydrogenation of a variety of functionalized olefins
Fe
Fe
(Rc,SFc,Ra)-PPFAPhos 1a
(Sc,RFc,Ra)-PPFAPhos 1b
including enamides, dimethyl itaconate,
a-dehydroamino acid
esters, and b-dehydroamino acid esters.7,8 This ligand class has
the advantages of easy accessibility, modularity, and stability
toward air and moisture, which makes this ligand class highly
practical for both academic and industrial applications. However,
research in the use of this ligand class is limited to catalytic asym-
metric hydrogenation, and its potential in other catalytic reactions
is still unexplored to date. Very recently, Nájera and Sansano et al.
have reported that monodentate phosphosphoramidite ligands can
P
P
O
P
O
O
P
O
N
N
Fe
Fe
(Sc,RFc,Sa,RP)-PPFAPhos 1c
(Sc,RFc,Ra,RP)-PPFAPhos 1d
* Corresponding authors. Tel.: +86 411 84379276; fax: +86 411 84684746.
E-mail addresses: xiangping@dicp.ac.cn (X.-P. Hu), zhengz@dicp.ac.cn (Z. Zheng).
Figure 1. Ferrocene-based phosphine–phosphoramidite ligands, PPFAPhos 1a–d
evaluated in this study.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.058

622
S.-B. Yu et al. / Tetrahedron: Asymmetry 20 (2009) 621–625
and enantioselectivity. When the reaction was performed in THF,
2. Results and discussion
the yields were dropped to 49% though good enantioselectivity
remained (entry 9). Using CH2Cl2 and toluene as the solvents, the
decreased reactivity and enantioselectivity were observed (entries
10 and 11). We finally investigated the effect of the base additives
in this cycloaddition. The results disclosed that Et3N is the best
base additives, superior to all other bases used such as i-Pr2NEt,
DBU, and DABCO (entries 13–15). The reaction without any base
additives also gave good enantioselectivity, however, the yields
were somewhat low (entry 12).
To explore the scope of the AgOAc/(Sc,RFc,Sa,RP)-PPFAPhos 1c
catalytic system, the [3+2] cycloadditions of various iminoesters
2a–l prepared from glycinate and aromatic aldehydes with
dimethyl maleate were carried out under the optimized reaction
conditions (10 mol % Et3N as the base additive, Et2O as the solvent,
ꢀ25 °C for 15 h),7 and the results are summarized in Table 2. The
results indicated that the reaction gave high yields and excellent
levels of diastereoselectivity with the endo-adducts being ob-
tained predominantly in all cases. However, the enantioselectivity
was highly dependent on the characteristics of the aromatic ring.
Thus, the substrates with a strong electron-withdrawing substitu-
ent, such as p-NO2 or p-CF3 afforded the corresponding cycload-
ducts in almost perfect enantioselectivities, whereas those with
an electron-donating group such as p-Me, only gave moderate
enantioselectivity (78% ee) (entries 7–9). For meta- or unsubstitut-
ed substrates as well as 1-naphthylmethylidene glycinate, the
reaction gave somewhat lower enantioselectivities than that
for 2a (entries 10–12). The highest ee of 99% was obtained
with N-(4-trifluoromethylbenzylidene)glycine methyl ester 2h
(entry 8).
As we have reported, chiral ferrocene-based phosphine–phos-
phoramidite ligands (PPFAPhos) can be prepared from Ugi’s amine
via a modular procedure.7 With these ligands in hand (Fig. 1), we
tested their application in the Ag-catalyzed asymmetric [3+2]
cycloaddition.
The cycloaddition of N-(4-chlorobenzylidene)glycine methyl
ester 2a with dimethyl maleate in the presence of catalytic
amounts of Et3N and AgOAc (3 mol %) was selected as a model
reaction for the screening process, and some representative re-
sults are listed in Table 1. Initially, the effect of the ligand struc-
ture on the stereoselectivity and reaction activity was
investigated in Et2O at 0 °C. The first attempt, using (Rc,SFc,Ra)-
PPFAPhos 1a bearing the matched chiral elements in the Rh-cat-
alyzed asymmetric hydrogenation, afforded the desired product
endo-3a in good yields, however, the enantioselectivities were
low (48% ee) (entry 1). Higher enantioselectivities (63% ee) were
observed when (Sc,RFc,Ra)-PPFAPhos 1b with the unmatched chiral
elements was employed in the reaction (entry 2). The introduc-
tion of a stereogenic P-center into the phosphino moiety of these
ligands resulted in dramatically changed enantioselectivity. The
use of ligand (Sc,RFc,Sa,RP)-PPFAPhos 1c has a positive effect in
enantioselectivity in which better ee values (81%) were achieved,
whereas (Sc,RFc,Ra,RP)-PPFAPhos 1d led to lower enantioselectivi-
ties (41% ee) (entries 3 and 4). Lowering the reaction temperature
to ꢀ25 °C, caused the enantioselectivity to further improve to 95%
ee (entry 5). The results also indicated that silver salts signifi-
cantly affected the reactivity and enantioselectivity (entries 5–
8). Thus, the reaction can proceed smoothly with AgO2CCF3 or
AgBF4, but giving very low enantioselectivities (entries 6 and 7).
Using AgPF6 instead of AgOAc resulted in a dramatic decrease
in reactivity (entry 8).
Our attempts to use several other dipolarophiles such as
N-phenylmaleimide, and tert-butyl acrylate proved to be unsuc-
cessful (Scheme 1). In both cases, low enantioselectivities were
achieved. However, the reaction with dimethyl fumarate also gave
good enantioselectivity (84% ee).
The nature of the solvents used in the cycloaddition reaction
proved to have a remarkable influence in both catalytic activity
Table 1
AgOAc-catalyzed asymmetric [3+2] cycloaddition of N-(4-chlorobenzylidene)glycine methyl ester 2a with dimethyl maleatea
CO2Me
1
MeO2C
p-ClC6H4
CO2Me
CO2Me
Ag-salt/
base, solvent
CO2Me
CO2Me
N
+
p-ClC6H4
N
H
2a
3a
endo
-
Entry
Ligand
Ag-salt
T (°C)
Solvent
Base
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1b
1c
1d
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgO2CCF3
AgBF4
AgPF6
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
0
0
0
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
CH2Cl2
PhMe
Et2O
Et2O
Et2O
Et2O
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
86
93
94
90
94
95
88
<5
49
25
83
79
98
93
83
48
63
81
41
95
<5
<5
n.d.d
94
85
75
93
88
<5
86
0
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
ꢀ25
e
—
i-Pr2NEt
DBU
DABCO
a
Reactions were performed in 1.5 mL of solvent with 0.23 mmol of substrate 2a, 10 mol % of base additives, and 3 mol % of catalyst prepared in situ from AgOAc and
1.1 equiv of PPFAPhos at indicated reaction temperature for 15 h. Reaction time for entries 1–4 is 3 h. endo-Adducts were achieved predominantly in all reactions.
b
Isolated yields.
c
Enantiomeric excesses were determined by chiral HPLC (Chiralpak AS-H column, i-PrOH/hexane 50/50, detector: 205 nm, 0.8 mL/min).
Not determined due to low conversion.
No base additives.
d
e

S.-B. Yu et al. / Tetrahedron: Asymmetry 20 (2009) 621–625
623
Table 2
as N-phenylmaleimide and tert-butyl acrylate, in which low
enantioselectivities were obtained.
Ag(I)-catalyzed asymmetric [3+2] of iminoester 2a–l with dimethyl maleate using
(Sc,RFc,Sa,RP)-PPFAPhos 1ca
CO2R
AgOAc (3 mol%)
MeO2C
Ar
CO2Me
CO2R
4. Experimental
4.1. General
CO2Me
CO2Me
1c
PPFAPhos
(3.3 mol%)
N
+
Et3N (10 mol%)
Et2O, -25 oC, 15 h
N
Ar
H
2
3
endo-
Yieldc (%)
All synthetic reactions and manipulations were performed in a
nitrogen or argon atmosphere using standard Schlenk techniques.
Solvents were reagent grade, dried, and distilled before use follow-
ing the standard procedures. Chiral ferrocene-based phosphine–
phosphoramidite ligands, PPFAPhos, were synthesized according
to the literature procedure.7 Iminoesters 2a–l are known com-
pounds, which were prepared according to the literature meth-
ods.3a All other chemicals were obtained commercially.
Entry
Substrate (Ar, R)
endo/exob
eed (%)
1
2
3
4
5
6
7
8
9
2a (p-ClC6H4, Me)
2b (p-ClC6H4, Et)
2c (C6H5, Me)
94/6
97/3
99/1
95/5
92/8
99/1
95/5
99/1
99/1
98/2
97/3
97/3
94
94
96
96
94
96
98
96
95
93
94
94
95
90
84
85
87
94
98
99
78
90
90
90
2d (C6H5, Et)
2e (p-FC6H4, Me)
2f (p-BrC6H4, Me)
2g (p-NO2C6H4, Me)
2h (p-CF3C6H4, Me)
2i (p-MeC6H4, Me)
2j (m-NO2C6H4, Me)
2k (m-CF3C6H4, Me)
2l (1-naphthyl, Me)
1H and 13C NMR spectra were recorded on BRUKER DEX-400
spectrometer. Chemical shift values (d) are denoted in ppm and
are referenced to residue protons in deuterated solvents for 1H
NMR (CDCl3: 7.27 ppm) and to CDCl3 (77.0 ppm) for 13C NMR.
Optical rotations were recorded using a JASCO P-1020 high sensi-
tive polarimeter. Enantiomeric excesses were determined by HPLC
analysis with a chiral column (Chiralpak AS-H, 0.46 mm ꢁ 25 cm)
for 3–6.
10
11
12
a
Reactions were performed in 1.5 mL of Et2O with 0.23 mmol of substrates 2,
10 mol % of Et3N, and 3 mol % of catalyst prepared in situ from AgOAc and 1.1 equiv
of PPFAPhos 1c at ꢀ25 °C for 15 h.
endo/exo-Ratio was determined by 1H NMR.
Isolated yields.
b
c
d
Enantiomeric excesses were determined by chiral HPLC.
4.2. General procedure for Ag(I)-catalyzed asymmetric 1,3-
dipolar cycloaddition of azomethine ylides
(Sc,RFc,Sa,RP)-PPFAPhos 1c (0.0075 mmol) and AgOAc (1.2 mg,
0.007 mmol) were placed in a dried Schlenk tube under a nitrogen
atmosphere and Et2O (1.0 mL) was added. The mixture was stirred
at room temperature for about 1 h. After it was cooled to ꢀ25 °C,
iminoester substrate (0.23 mmol) was added as a solution in
Et2O (0.5 mL) followed by dimethyl maleate (0.28 mmol) and
Et3N (0.023 mmol). After the reaction was stirred at ꢀ25 °C for
15 h, the mixture was passed through a short column of silica gel
and the diastereometric ratio (endo/exo) was determined by the
NMR spectroscopic analysis of the crude product. The pure adducts
were then purified by column chromatography on silica gel, and
were submitted to ee analysis by HPLC with a chiral column.
3. Conclusion
In conclusion, AgOAc/(Sc,RFc,Sa,RP)-PPFAPhos complex was
found to be an efficient catalyst for asymmetric 1,3-dipolar
cycloadditon of azomethine ylides with dimethyl maleate. The
results disclosed show that the endo-adducts were predominantly
produced with ee values of up to 99%, while the enantioselectivity
was highly dependent on the characteristics of the substituent in
the aromatic ring of iminoester substrates. However, the present
catalyst system is less efficient for the asymmetric 1,3-dipolar
cycloadditon of azomethine ylides with other dipolarophiles such
Ph
N
O
O
O
p-ClC6H4
CO2Me
N
Ph
N
H
O
endo
-4
full conversions, 36% ee
CO2Me
AgOAc (3 mol%)
PPFAPhos 1c (3.3 mol%)
t-BuO2C
CO2t-Bu
N
+
p-ClC6H4
CO2Me
Et3N (10 mol%)
Et2O, -25 oC, 15 h
N
H
p-ClC6H4
2a
endo -5
full conversions, 24% ee
MeO2C
MeO2C
p-ClC6H4
CO2Me
CO2Me
CO2Me
N
H
6
-
endo
full conversions, 84% ee
Scheme 1. AgOAc-catalyzed asymmetric [3+2] cycloaddition of N-(4-chlorobenzylidene)glycine methyl ester 2a with N-phenyl maleimide, t-butyl acrylate, and dimethyl
fumarate.

624
S.-B. Yu et al. / Tetrahedron: Asymmetry 20 (2009) 621–625
4.2.1. Trimethyl (2R,3S,4R,5S)-5-(4-chlorophenyl)pyrrolidine-
2,3,4-tricarboxylate 3a
4.2.7. Trimethyl (2R,3S,4R,5S)-5-(4-nitrophenyl)pyrrolidine-
2,3,4-tricarboxylate 3g
White solid; 1H NMR (CDCl3, 400 MHz): d 7.30 (s, 4H), 4.45 (d,
J = 6.8 Hz, 1H), 4.15 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 3.69–3.74 (m,
1H), 3.69 (s, 3H), 3.55–3.59 (m, 1H), 3.28 (s, 3H), 3.06 (br, 1H);
13C NMR (CDCl3, 100 MHz): d 50.9, 51.5, 52.2, 52.3, 52.5, 62.1,
64.6, 128.2, 128.5, 133.6, 135.8, 170.7, 170.9; 95% ee, HPLC (chir-
alpak AS-H column, i-PrOH/hexane 50/50, detector: 205 nm,
White solid; 1H NMR (CDCl3, 400 MHz): d 8.19–8.21 (m, 2H),
7.57–7.59 (m, 2H), 4.61 (d, J = 5.6 Hz, 1H), 4.20–4.25 (m, 1H),
3.89 (s, 3H), 3.76–3.82 (m, 1H), 3.71 (s, 3H), 3.65–3.69 (m, 1H),
3.29 (s, 3H); 13C NMR (CDCl3, 100 MHz): d 50.9, 51.6, 52.1, 52.3,
52.6, 62.0, 64.4, 123.5, 127.9, 145.1, 147.4, 170.3, 170.5, 170.8;
98% ee, HPLC (chiralpak AS-H column, i-PrOH/hexane 50/50, detec-
0.8 mL/min, tR = 7.9 and 10.4 min); ½a D22
ꢂ
¼ ꢀ33:8 (c 1.0, CHCl3).
tor: 205 nm, 0.8 mL/min, tR = 14.6 and 21.3 min); ½a D23
¼ ꢀ52:6 (c
ꢂ
1.0, CHCl3).
4.2.2. (2R,3S,4R,5S)-5-(4-Chlorophenyl)pyrrolidine-2-carbox-
ylic ethyl ester-3,4-dicarboxylic dimethyl ester 3b
4.2.8. Trimethyl (2R,3S,4R,5S)-5-(4-trifluoromethylphenyl)py-
rrolidine-2,3,4-tricarboxylate 3h
White solid; 1H NMR (CDCl3, 400 MHz): d 7.30 (s, 4H), 4.47 (d,
J = 7.2 Hz, 1H), 4.24–4.29 (q, J = 7.2 Hz, 2H), 4.13 (d, J = 7.2 Hz,
1H), 3.72 (s, 3H), 3.46–3.58 (m, 1H), 3.28 (s, 3H), 2.80 (br, 1H),
1.24–1.32 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d 14.1,
50.8, 51.5, 52.1, 52.4, 61.5, 62.3, 64.7, 128.3, 128.5, 133.5, 136.0,
170.5, 170.6, 170.8. 90% ee, HPLC (chiralpak AS-H column, i-
PrOH/hexane 50/50, detector: 205 nm, 0.8 mL/min, tR = 6.6 and
White solid; 1H NMR (CDCl3, 400 MHz): d 7.58–7.60 (m, 2H),
7.49–7.51 (m, 2H), 4.53 (d, J = 6.8 Hz, 1H), 4.16–4.18 (m, 1H),
3.82 (s, 3H), 3.73–3.79 (m, 1H), 3.70 (s, 3H), 3.61–3.68 (m, 1H),
3.25 (s, 3H), 2.81 (br, 1H); 13C NMR (CDCl3, 100 MHz): d 50.9,
51.5, 52.2, 52.5, 62.1, 64.8, 125.2, 125.3, 127.3, 141.5, 170.6,
170.6, 170.9; 99% ee, HPLC (chiralpak AS-H column, i-PrOH/hexane
50/50, detector: 205 nm, 0.8 mL/min, tR = 5.8 and 7.1 min);
13.9 min); ½a 2D2
¼ ꢀ40:9 (c 1.2, CHCl3).
ꢂ
½
a 2D3
ꢂ
¼ ꢀ39:5 (c 1.0, CHCl3).
4.2.3. Trimethyl (2R,3S,4R,5S)-5-phenylpyrrolidine-2,3,4-tri-
carboxylate 3c
4.2.9. Trimethyl (2R,3S,4R,5S)-5-p-tolylpyrrolidine-2,3,4-tri-
carboxylate 3i
White solid; 1H NMR (CDCl3, 400 MHz): d 7.12–7.55 (m, 5H),
4.49 (d, J = 6.8 Hz, 1H), 4.17 (d, J = 9.2 Hz, 1H), 3.81 (s, 3H), 3.70–
3.75 (m, 1H), 3.51–3.60 (m, 1H), 3.30 (br, 1H), 3.24 (s, 3H); 13C
NMR (CDCl3, 100 MHz): d 51.0, 51.3, 52.1, 52.4, 52.5, 62.2, 65.4,
126.7, 127.7, 128.3, 137.1, 170.8, 170.9, 171.1; 84% ee, HPLC
(chiralpak AS-H column, i-PrOH/hexane 50/50, detector:
White solid; 1H NMR (CDCl3, 400 MHz): d 7.22 (d, J = 7.5 Hz,
2H), 7.12 (d, J = 8.1 Hz, 2H), 4.46 (d, J = 6.8 Hz, 1H), 4.17 (d,
J = 8.8 Hz, 1H), 3.80 (s, 3H), 3.68–3.74 (m, 1H), 3.68 (s, 3H), 3.53–
3.57 (m, 1H), 3.27 (s, 3H), 2.38 (br, 1H), 2.32 (s, 3H); 13C NMR
(CDCl3, 100 MHz): d 21.1, 51.1, 51.4, 52.1, 52.5, 62.1, 65.2, 126.6,
129.0 (d, J = 24 Hz), 133.9, 137.4, 170.8, 170.9; 78% ee, HPLC (chir-
alpak AS-H column, i-PrOH/hexane 50/50, detector: 205 nm,
205 nm, 0.8 mL/min, tR = 7.6 and 17.6 min); ½a D23
¼ ꢀ58:0 (c 1.0,
ꢂ
CHCl3).
1.0 mL/min, tR = 6.2 and 11.7 min); ½a D23
¼ ꢀ45:7 (c 0.8, CHCl3).
ꢂ
4.2.4. (2R,3S,4R,5S)-5-Phenylpyrrolidine-2-carboxylic ethyl
ester-3,4-dicarboxylic dimethyl ester 3d
4.2.10. Trimethyl (2R,3S,4R,5S)-5-(3-nitrophenyl)pyrrolidine-
2,3,4-tricarboxylate 3j
White solid; 1H NMR (CDCl3, 400 MHz): d 7.26–7.36 (s, 5H),
4.53 (t, J = 7.2 Hz, 1H), 4.25–4.31 (q, J = 7.2 Hz, 2H), 4.18 (t,
J = 7.2 Hz, 1H), 3.71–3.74 (m, 1H), 3.71 (s, 3H), 3.55–3.59 (m, 1H),
3.24 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d
14.1, 50.9, 51.3, 52.0, 52.6, 61.5, 62.4, 65.5, 126.8, 127.7, 128.3,
137.2, 170.6, 170.8; 85% ee, HPLC (chiralpak AS-H column, i-
PrOH/hexane 50/50, detector: 205 nm, 0.8 mL/min, tR = 5.9 and
White solid; 1H NMR (CDCl3, 400 MHz): d 8.26 (m, 1H), 8.14–
8.16 (m, 1H), 7.72–7.79 (m, 1H), 7.47–7.59 (m, 1H), 5.34–5.37 (t,
J = 5.6 Hz, 1H), 4.59 (d, J = 7.2 Hz, 1H), 3.83 (s, 3H), 3.75–3.79 (m,
1H), 3.71 (s, 3H), 3.65–3.69 (m, 1H), 3.29 (s, 3H); 13C NMR (CDCl3,
100 MHz): d 50.9, 51.6, 52.0, 52.3, 52.5, 62.0, 64.3, 122.3, 122.8,
129.3, 133.0, 140.0, 148.1, 170.4, 170.5, 170.8; 90% ee, HPLC (chir-
alpak AS-H column, i-PrOH/hexane 50/50, detector: 205 nm,
16.3 min); ½a 2D3
¼ ꢀ48:3 (c 0.9, CHCl3).
ꢂ
0.8 mL/min, tR = 10.9 and 15.3 min); ½a D23
¼ ꢀ51:6 (c 1.2, CHCl3).
ꢂ
4.2.5. Trimethyl (2R,3S,4R,5S)-5-(4-fluorophenyl)pyrrolidine-
2,3,4-tricarboxylate 3e
4.2.11. Trimethyl (2R,3S,4R,5S)-5-(3-trifluoromethylphenyl)py-
rrolidine-2,3,4-tricarboxylate 3k
White solid; 1H NMR (CDCl3, 400 MHz): d 7.32–7.36 (m, 2H),
7.00–7.04 (m, 2H), 4.51 (d, J = 6.8 Hz, 1H), 4.19 (d, J = 8.4 Hz, 1H),
3.82 (s, 3H), 3.71–3.74 (m, 1H), 3.71 (s, 3H), 3.55–3.59 (m, 1H),
3.28 (s, 3H), 3.06 (br, 1H); 13C NMR (CDCl3, 100 MHz): d 50.8,
51.5, 52.2, 52.4, 52.5, 62.2, 64.7, 115.1, 115.4, 128.5, 128.6, 170.8,
170.9; 87% ee, HPLC (chiralpak AS-H column, i-PrOH/hexane 50/
50, detector: 205 nm, 0.8 mL/min, tR = 8.3 and 14.1 min);
White solid; 1H NMR (CDCl3, 400 MHz): d 7.44–7.70 (m, 4H),
4.53 (d, J = 6.8 Hz, 1H), 4.18 (d, J = 8.8 Hz, 1H), 3.82 (s, 3H), 3.72–
3.76 (m, 1H), 3.70 (s, 3H), 3.62–3.66 (m, 1H), 3.26 (s, 3H); 13C
NMR (CDCl3, 100 MHz): d 50.9, 51.4, 52.2, 52.5, 62.1, 64.8, 123.9,
124.6, 128.9, 130.2, 130.5, 138.5, 170.6, 170.8; 90% ee, HPLC (chir-
alpak AS-H column, i-PrOH/hexane 50/50, detector: 205 nm,
½
a 2D3
ꢂ
¼ ꢀ58:4 (c 1.1, CHCl3).
0.8 mL/min, tR = 5.8 and 8.5 min); ½a D23
¼ ꢀ47:7 (c 1.0, CHCl3).
ꢂ
4.2.6. Trimethyl (2R,3S,4R,5S)-5-(4-bromophenyl)pyrrolidine-
2,3,4-tricarboxylate 3f
4.2.12. Trimethyl (2R,3S,4R,5S)-5-(1-naphthyl)pyrrolidine-
2,3,4-tricarboxylate 3l
White solid; 1H NMR (CDCl3, 400 MHz): d 7.44–7.46 (m, 2H),
7.23–7.25 (m, 2H), 4.32 (d, J = 6.8 Hz, 1H), 4.14 (d, J = 8.8 Hz, 1H),
3.81 (s, 3H), 3.70–3.74 (m, 1H), 3.70 (s, 3H), 3.55–3.59 (m, 1H),
3.28 (s, 3H), 3.00 (br, 1H); 13C NMR (CDCl3, 100 MHz): d 50.9,
51.5, 52.2, 52.5, 62.1, 64.7, 121.7, 128.6, 131.5, 136.3, 170.7,
170.9; 94% ee, HPLC (chiralpak AS-H column, i-PrOH/hexane 50/
50, detector: 205 nm, 0.8 mL/min, tR = 7.9 and 11.1 min);
White solid; 1H NMR (CDCl3, 400 MHz): d 7.79–7.83 (m, 4H),
7.42–7.50 (m, 3H), 4.64 (d, J = 6.4 Hz, 1H), 4.23 (d, J = 5.2 Hz, 1H),
3.88 (s, 3H), 3.77–3.84 (m, 1H), 3.71 (s, 3H), 3.67–3.71 (m, 1H),
3.17 (s, 3H); 13C NMR (CDCl3, 100 MHz): d 51.3, 51.4, 52.2, 52.5,
62.2, 65.5, 124.8, 125.6, 126.0, 126.2, 127.6, 128.0, 128.1, 132.8,
133.2, 134.5, 170.7, 170.9, 171.1; 90% ee, HPLC (chiralpak AS-H col-
umn, i-PrOH/hexane 50/50, detector: 205 nm, 0.8 mL/min, tR = 7.8
½
a 2D3
ꢂ
¼ ꢀ47:2 (c 0.8, CHCl3).
and 14.4 min); ½a D23
¼ ꢀ38:1 (c 0.9, CHCl3).
ꢂ

S.-B. Yu et al. / Tetrahedron: Asymmetry 20 (2009) 621–625
625
2. (a) Allway, P.; Grigg, R. Tetrahedron Lett. 1991, 32, 5817; (b) Grigg, R.
Tetrahedron: Asymmetry 1995, 6, 2475.
4.2.13. Methyl (1S,3R,3aS,6aR)-3-(4-chlorophenyl)-4,6-dioxo-5-
phenyl-octahydro-pyrrolo[3,4-c]pyrrole-1-carboxylate 4
3. Ag-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides: (a)
Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400; (b)
Chen, G.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174; (c) Knöpfel, T.
F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem., Int.
Ed. 2004, 43, 5971; (d) Zeng, W.; Zhou, Y.-G. Org. Lett. 2005, 7, 5055; (e)
Alemparte, C.; Blay, G.; Jørgensen, K. A. Org. Lett. 2005, 7, 4569; (f) Stohler, R.;
Wahl, F.; Pfaltz, A. Synthesis 2005, 1431; (g) Zeng, W.; Zhou, Y.-G. Tetrahedron
Lett. 2007, 48, 4619; (h) Nájera, C.; Retamosa, M. G.; Sansano, J. M. Org. Lett.
2007, 9, 4025; (i) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am. Chem. Soc.
2007, 129, 750; (j) Nájera, C.; Retamosa, M. G.; Sansano, J. M. Angew. Chem., Int.
Ed. 2008, 47, 6055; (k) Nájera, C.; Retamosa, M. G.; Sansano, J. M.; de Cózar, A.;
Cossío, F. P. Tetrahedron: Asymmetry 2008, 19, 2913.
White solid; 1H NMR (CDCl3, 400 MHz): d 7.11–7.39 (m, 9H),
4.57 (m, 1H), 4.13 (m, 1H), 3.86 (s, 3H), 3.71–3.72 (m, 1H), 3.54–
3.55 (m, 1H), 2.42 (br, 1H); 13C NMR (CDCl3, 100 MHz): d 48.0,
49.1, 52.3, 61.8, 63.4, 125.8, 126.1, 126.5, 128.5, 128.6, 128.7,
1289.1, 129.2, 131.5, 134.0, 135.4, 170.0, 173.5, 175.0; 36% ee,
HPLC (chiralpak AS-H column, i-PrOH/hexane 30/70, detector:
230 nm, 0.8 mL/min, tR = 21.6 and 53.8 min); ½a D20
¼ þ47:4 (c 1.0,
ꢂ
CHCl3).
4. Cu-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides: (a)
Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.; Minakata, S.; Komatsu, M.
Org. Lett. 2003, 5, 5043; (b) Cabrera, S.; Arrayás, R. G.; Carretero, J. C. J. Am. Chem.
Soc. 2005, 127, 16394; (c) Gao, W.; Zhang, X.; Raghunath, M. Org. Lett. 2005, 7,
4241; (d) Llamas, T.; Arrayás, R. G.; Carretero, J. C. Org. Lett. 2006, 8, 1795; (e)
Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew.
Chem., Int. Ed. 2006, 45, 1979; (f) Shi, M.; Shi, J.-W. Tetrahedron: Asymmetry 2007,
18, 645; (g) Martín-Matute, B.; Pereira, S. I.; Peña-Cabrera, E.; Adrio, J.; Silva, A.
M. S.; Carretero, J. C. Adv. Synth. Catal. 2007, 349, 1714; (h) Cabrera, S.; Arrayás, R.
G.; Martín-Matute, B.; Cossío, F. P.; Carretero, J. C. Tetrahedron 2007, 63, 6587; (i)
Llamas, T.; Arrayás, R. G.; Carretero, J. C. Synthesis 2007, 950; (j) Fukuzawa, S.;
Oki, H. Org. Lett. 2008, 10, 1747; (k) López-Pérez, A.; Adrio, J.; Carretero, J. C. J.
Am. Chem. Soc. 2008, 130, 10084; (l) Wang, C.-J.; Liang, G.; Xue, Z.-Y.; Gao, F. J.
Am. Chem. Soc. 2008, 130, 17250; (m) López-Pérez, A.; Adrio, J.; Carretero, J. C.
Angew. Chem., Int. Ed. 2009, 48, 340; (n) Hernández-Toribio, J.; Arrayás, R. G.;
Martín-Matute, B.; Carretero, J. C. Org. Lett. 2009, 11, 393.
5. Other metal-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides: (a)
Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2002, 41, 4236; (b) Dogan, Ö.; Koyuncu, H.; Garner, P.; Bulut, A.; Youngs, W. J.;
Panzner, M. Org. Lett. 2006, 8, 4687; (c) Shi, J-W.; Zhao, M.-X.; Lei, Z.-Y.; Shi, M. J.
Org. Chem. 2008, 73, 305;; (d) Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.;
Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321.
6. (a) Vicario, J. L.; Reboredo, S.; Badía, D.; Carrillo, L. Angew. Chem., Int. Ed. 2007, 46,
5168; (b) Ibrahem, I.; Rios, R.; Vesely, J.; Córdova, A. Tetrahedron Lett. 2007, 48,
6252; (c) Xue, M.-X.; Zhang, X.-M.; Gong, L.-Z. Synlett 2008, 691.
4.2.14. (2R,4R,5S)-5-(4-Chlorophenyl)-pyrrolidine-2,4-dicarb-
oxylic acid 4-tert-butyl ester 2-methyl ester 5
White solid; 1H NMR (CDCl3, 400 MHz): d 7.30–7.33 (m, 4H),
4.46 (d, J = 8.0 Hz, 1H), 3.96 (t, J = 8.4 Hz, 1H), 3.81 (s, 3H), 3.22–
3.27 (m, 1H), 2.67 (br, 1H), 2.28–2.47 (m, 2H), 1.07 (s, 9H); 13C
NMR (CDCl3, 100 MHz): d 27.5, 33.8, 50.0, 52.2, 59.7, 64.8, 80.8,
128.2, 128.7, 133.1, 138.0, 171.5, 173.5; 24% ee, HPLC (chiralpak
AS-H column, i-PrOH/hexane 10/90, detector: 230 nm, 0.8 mL/
min, tR = 7.6 and 10.5 min); ½a D20
¼ ꢀ2:2 (c 1.0, CHCl3).
ꢂ
4.2.15. Trimethyl (2R,3R,4R,5S)-5-(4-chlorophenyl)pyrrolidine-
2,3,4-tricarboxylate 6
Colorless oil; 1H NMR (400 MHz, CDCl3): d 7.25–7.30 (m, 4H),
4.62 (d, J = 8 Hz, 1H), 4.19 (d, J = 8 Hz, 1H), 3.83 (s, 3H), 3.77 (s,
3H), 3.65–3.68 (m, 3H), 3.55–3.58 (m, 3H), 3.26 (s, 3H), 2.75 (br,
1H); 13C NMR: d 50.4, 51.7, 52.4, 52.6, 53.5, 63.1, 64.5, 128.3,
128.4, 128.6, 128.9, 133.7, 136.9, 171.4, 171.9, 172.5; 84% ee, (chir-
alpak AS-H column, i-PrOH/hexane 10/90, 215 nm, 1.0 mL/min,
tR = 17.2 and 19.1 min); ½a D22
¼ ꢀ11:4 (c 1.0, CHCl3).
ꢂ
7. (a) Jia, X.; Li, X.; Lam, W. S.; Kok, S. H. L.; Xu, L.; Lu, G.; Yeung, C.-H.; Chan, A. S. C.
Tetrahedron: Asymmetry 2004, 15, 2273; (b) Hu, X.-P.; Zheng, Z. Org. Lett. 2004, 6,
3585; (c) Hu, X.-P.; Zheng, Z. Org. Lett. 2005, 7, 419; (d) Zeng, Q.-H.; Hu, X.-P.;
Duan, Z.-C.; Liang, X.-M.; Zheng, Z. Tetrahedron: Asymmetry 2005, 16, 1233; (e)
Chen, W.; Mbafor, W.; Roberts, S. M.; Whittall, J. J. Am. Chem. Soc. 2006, 128,
3922.
Acknowledgments
This research was supported by the National Natural Science
Foundation of China (20802076, 20873145) and by the Knowledge
Innovation Program of the Chinese Academy of Sciences (DICP-
S200802).
8. For other phosphine–phosphoramidite ligands used in asymmetric catalysis, see:
(a) Franciò, G.; Faraone, F.; Leitner, W. Angew. Chem., Int. Ed. 2000, 39, 1428; (b)
Burk, S.; Franciò, G.; Leitner, W. Chem. Commun. 2005, 3460; (c) Huang, J.-D.; Hu,
X.-P.; Duan, Z.-C.; Zeng, Q.-H.; Yu, S.-B.; Deng, J.; Wang, D.-Y.; Zheng, Z. Org. Lett.
2006, 8, 4367; (d) Vallianatou, K. A.; Kostas, I. D.; Holz, J.; Börner, A. Tetrahedron
Lett. 2006, 47, 7947; (e) Zhang, W.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 5515;
(f) Yan, Y.; Zhang, X. J. Am. Chem. Soc. 2006, 128, 7198; (g) Boeda, F.; Rix, D.; Clavier,
H.; Crévisy, C.; Mauduit, M. Tetrahedron: Asymmetry 2006, 17, 2726; (h)
Wassenaar, J.; Reek, J. N. H. Dalton Trans. 2007, 3750; (i) Zhang, W.; Zhang, X. J.
Org. Chem. 2007, 72, 1020;(j)Wang, D.-Y.; Hu, X.-P.;Huang, J.-D.; Deng, J.; Yu, S.-B.;
Duan, Z.-C.; Xu, X.-F.; Zheng, Z. Angew. Chem., Int. Ed. 2007, 46, 7810; (k) Qiu, M.;
Hu, X.-P.; Wang, D.-Y.; Deng, J.; Huang, J.-D.; Yu, S.-B.; Duan, Z.-C.; Zheng, Z. Adv.
Synth. Catal. 2008, 350, 1413; (l) Wassenaar, J.; Kuil, M.; Reek, J. N. H. Adv. Synth.
Catal. 2008, 350, 1610; (m) Yu, S.-B.; Huang, J.-D.; Wang, D.-Y.; Hu, X.-P.; Deng, J.;
Duan, Z.-C.; Zheng, Z. Tetrahedron: Asymmetry 2008, 19, 1862.
References
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see: (a) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765; (b) Husinec, S.; Savic,
V. Tetrahedron: Asymmetry 2005, 16, 2047; (c) Nájera, C.; Sansano, J. M. Angew.
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