New chiral ferrocenyl P,S-ligands for highly diastereo- and enantioselective Ag(I)-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides

Article abstract of DOI:10.1016/j.tetasy.2012.02.017

A new family of chiral ferrocenyl P,S-ligands incorporating an indole ring at the α-ferrocenylmethyl position has been prepared via a Friedel-Crafts alkylation reaction of (R_c,S_Fc)-PPFA with a variety of 2-indole thioethers. These ne

Full text of DOI:10.1016/j.tetasy.2012.02.017

Tetrahedron: Asymmetry 23 (2012) 306–312
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New chiral ferrocenyl P,S-ligands for highly diastereo- and enantioselective
Ag(I)-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides
Mei-Ling Han a,b, Dao-Yong Wang b, Pei-Wei Zeng b, Zhuo Zheng b, Xiang-Ping Hu b,
⇑
a School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
b Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 February 2012
Accepted 23 February 2012
A new family of chiral ferrocenyl P,S-ligands incorporating an indole ring at the a-ferrocenylmethyl posi-
tion has been prepared via a Friedel–Crafts alkylation reaction of (Rc,SFc)-PPFA with a variety of 2-indole
thioethers. These newly developed ferrocenyl P,S-ligands proved to be efficient in the AgOAc-catalyzed
asymmetric [3+2] cycloaddition of azomethine ylides with various dipolarophiles, giving cycloadducts
with high diastereoselectivities and enantioselectivities (up to 99% ee).
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
RS
RS
NH
N
Chiral ferrocenyl derivatives based on N,N-dimethyl-1-ferroce-
nylethylamine (Ugi’s amine) have found widespread application
as chiral ligands or ligand precursors in asymmetric catalysis over
the past few decades due to their unique features.1 Of these fea-
tures, the most significant is that the functional group (normally
N
Ph2P
Ph2P
Fe
Fe
(Sc,SFc)-2
(Rc,SFc)-ImiFerroS 1
1a 1b
: R = Ph; : R = i-Pr
a dimethylamino group) at the
a-ferrocenylmethyl position on
the side chain can be readily replaced with many nucleophiles with
full retention of configuration at the stereogenic carbon center.2
One recent advance for the construction of new chiral ligands is
Figure 1. Structures of (Rc,SFc)-ImiFerroS 1 and (Sc,SFc)-2.
the introduction of a heterocyclic group at the a-ferrocenylmethyl
cyclic enones and the Ag-catalyzed [3+2] cycloadditions of azome-
thine ylides with acyclic enones. However, in the Ag-catalyzed
position.3 The presence of a heterocyclic group on the ferrocene
system could significantly improve the structure of the chiral ferro-
cene scaffold, thus creating new chiral ligands for use in asymmet-
ric reactions in which conventional ligands are not effective.
Heterocyclic groups containing an N–H fragment were used as
nucleophiles, effectively replacing the dimethylamino group of
Ugi’s amine derivatives and then incorporating a heterocyclic ring
asymmetric [3+2] cycloaddition of azomethine ylides with
a,b-
unsaturated esters, such as dimethyl maleate, these ligands dis-
played only poor to moderate enantioselectivities. We surmised
that the presence of the additional N-donor atom in the benzimid-
azole framework may have some effect on this reaction. In order to
investigate this, we therefore set out to construct an indole ana-
logue of (Rc,SFc)-ImiFerroS 1. By reacting (Rc,SFc)-PPFA 3 with indole,
we indeed obtained a new compound that incorporates an indole
through a C–N bond at the a-stereogenic center. With this strategy,
some highly effective P,P-, P,N- and P,S-ligands with a heterocyclic
motif were developed and employed successfully in a broad range
of asymmetric catalysis such as hydrogenations,3c,e allylic alkyla-
tions,3b,4 hydroborations,3a,5 and cycloadditions.3d,f,g,6 In our recent
efforts on the development of new chiral ligands for asymmetric
catalysis, we have developed a series of chiral ferrocenyl P,S-
ligands with a benzimidazole framework, (Rc,SFc)-ImiFerroS 1
(Fig. 1).
ring at the a-ferrocenylmethyl position (Scheme 1). Further struc-
tural analysis revealed, however, that the substitution had taken
place at the C3-position of the indole ring instead of the N1-posi-
tion, giving a Friedel–Crafts-type product 5. This observation
should be interesting with regards to the development of new chi-
ral ligands, since the presence of an N–H proton in the ligands may
affect their reactivity and enantioselectivity due to any potential
secondary effect between the ligand and the substrate. As a result,
we developed a series of new ferrocenyl P,S-ligands (Sc,SFc)-2
These ligands showed excellent diastereo/enantioselectivities in
the Cu-catalyzed [3+2] cycloadditions of azomethine ylides with
bearing an indole ring at the a-ferrocenylmethyl position through
a C–C bond, which displayed improved enantioselectivities in the
Ag(I)-catalyzed asymmetric [3+2] cycloadditions of azomethine
⇑
Corresponding author. Tel.: +86 411 84379276; fax: +86 411 84684746.
E-mail address: xiangping@dicp.ac.cn (X.-P. Hu).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.02.017

M.-L. Han et al. / Tetrahedron: Asymmetry 23 (2012) 306–312
307
N
Ph2P
Fe
X
(Rc,SFc)-4
NMe2
Ph2P
Fe
NH
Ph2P
Fe
(Rc,SFc)-PPFA 3
(Sc,SFc)-5
Scheme 1. Construction of the ferrocene/indole skeleton.
ylides with
a,b-unsaturated esters in comparison with those
obtained with (Rc,SFc)-ImiFerroS 1.
2. Results and discussion
2.1. Synthesis of new chiral ferrocenyl P,S-ligands 2a–g
The synthesis of the target ferrocenyl P,S-ligands is straightfor-
ward and is outlined in Scheme 2. Based on our above observa-
tions, we reacted (Rc,SFc)-PPFA with
a variety of 2-indole
thioethers in AcOH at 80 °C to give the corresponding ferrocenyl
P,S-compounds 2a–f in good yields. The structure of (Sc,SFc)-2a
was confirmed by X-ray analysis (Fig. 2).7 In order to investigate
the effect of the N–H proton, a Boc-protected ligand 2g was also
prepared.
H
N
RS
SR
Figure 2. X-Ray structure of (Sc,SFc)-2a.
NH
NMe2
Ph2P
6
Fe
Ph2P
Fe
AgOAc and 1.1 equiv of P,S-ligands 2a–f, and the results are sum-
marized in Table 1. In comparison to (Rc,SFc)-ImiferroS 1a, these
newly developed ferrocenyl P,S-ligands 2a–f showed significantly
improved enantioselectivities in this model reaction, giving the
endo-cycloadduct 9a with good diastereoselectivities and enanti-
oselectivities of up to 90% ee (entry 1 vs entries 2–7). The results
showed that substituents on the thio group significantly affected
the enantioselectivity; ligand 2a bearing a phenylthio group
proved to be the best ligand in terms of the diastereo- and enanti-
oselectivities (endo/exo = 96/4, and 90% ee for endo-adduct) (entry
2). The presence of N–H proton in the ligand proved to be highly
important. When the Boc-protected ligand 2g was employed in
this model reaction, a dramatically reduced enantioselectivity of
78% ee was observed (entry 8). With ligand 2a, we next optimized
the reaction conditions. The reaction temperature also had a
significant impact on the enantioselectivity: when the reaction
was performed at lower temperatures, it tended to give better
enantioselectivities (entries 9 and 10). When the reaction temper-
ature was carried out at ꢀ40 °C, up to 99% ee was achieved (entry
10). The reaction also proved to be highly sensitive to the catalyst
precursors. Using AgBF4, AgPF6 or AgSbF6, dramatically decreased
the conversions or enantioselectivities (entries 11–13). Solvent
screening showed that Et2O was the best solvent (entries 14–16).
Further work on the screening of various bases indicated that
Et3N was the best choice (entries 17–20).
AcOH, 80 °C
(Rc,SFc)-PPFA 3
2
(Sc,SFc)-
a
c
b
: R = Ph; : R = 4-CH3C6H4;
d
: R = 4-ClC6H4; : R = Bn;
e: R = Me; f: R = i-Pr
Boc
PhS
N
Boc2O, DMAP
CH2Cl2, rt.
Ph2P
Fe
(Sc,SFc)-2g
Scheme 2. Synthesis of new chiral ferrocenyl P,S-ligands 2a–g incorporating an
indole ring.
2.2. Catalytic asymmetric [3+2] cycloaddition reactions
With these ligands in hand, we next examined their efficiency
in the Ag-catalyzed asymmetric [3+2] cycloaddition of azomethine
ylides with various electron-deficient olefins.8 Initially, the cyclo-
addition of N-(4-chlorobenzylidene) glycine methyl ester 7a with
dimethyl maleate was selected as a model reaction. The reaction
was performed in Et2O at 0 °C in the presence of a catalytic amount
of Et3N (10 mol %) and the catalyst (3 mol %) prepared in situ from
Under the optimized reaction conditions, the scope of the pres-
ent catalytic system in the 1,3-dipolar cycloaddition was tested. As
shown in Table 2, various imino esters 7a–j derived from aromatic

308
M.-L. Han et al. / Tetrahedron: Asymmetry 23 (2012) 306–312
Table 1
Catalytic asymmetric [3+2] cycloaddition reactions of N-(4-chlorobenzylidene)glycine methyl ester 7a with dimethyl maleate 8a
COOMe
MeO2C
CO2Me
MeO2C
CO2Me
CO2Me
CO2Me
[M] / L (3 mol%)
N
+
+
p-Cl-Ph
CO2Me
base (10 mol%)
Solvent
p-Cl-Ph
CO2Me
N
H
N
H
4-ClC6H4
7a
endo-9a
Base
exo-9a
8
Entry
L
[M]
Temp (oC)
Solvent
endo/exob
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
1a
2a
2b
2c
2d
2e
2f
2g
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgBF4
0
0
0
0
0
0
0
0
ꢀ25
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
CH2Cl2
Toluene
THF
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
i-Pr2NEt
DBU
96/4
96/4
95/5
96/4
94/6
94/6
91/9
89/11
96/4
95/5
94/6
95/5
83/17
72/28
94/6
91/9
92/8
78/22
96/4
97/3
93
94
93
94
90
92
90
90
95
95
48
91
35
91
26
83
67
92
38
79
64
90
75
88
81
69
79
78
96
99
40
<5
56
91
90
8
9
10
11
12
13
14
15
16
17
18
19
20
AgPF6
AgSbF6
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Et2O
Et2O
Et2O
Et2O
82
41
98
83
DABCO
e
—
a
Reactions were performed in 1.5 mL of solvent with 0.3 mmol of substrate 7a, 10 mol % of base additives, and 3 mol % of catalyst prepared in situ from AgOAc and
1.1 equiv of ligand at the indicated temperature for 18 h.
b
Determined by 1H NMR analysis.
Isolated yields.
Enantiomeric excesses were determined by chiral HPLC (Chiralpak AS-H column, i-PrOH/hexane 50/50, 205 nm, 0.8 mL/min).
No base additives.
c
d
e
Table 2
Catalytic asymmetric [3+2] cycloaddition reactions of imino esters 7 with dimethyl maleate 8a
COOMe
MeO2C
R
CO2Me
AgOAc (3 mol%),
MeO2C
R
CO2Me
CO2Me
CO2Me
Ligand 2a (3.3 mol%)
N
R
+
+
Et3N (10 mol%)
Et2O, -40 °C
CO2Me
CO2Me
N
H
N
H
7a-k
endo-9a-k
8
exo-9a-k
b
Entry
Substrate (R)
endo/exo
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
7a (4-ClC6H4)
7b (C6H5)
7c (4-FC6H4)
95/5
96/4
96/4
95/5
91/9
96/4
95/5
97/3
96/4
96/4
97/3
95
97
95
92
94
96
92
93
95
92
28
99
91
95
91
91
95
88
94
98
98
92e
7d (4-BrC6H4)
7e (4-NO2C6H4)
7f (4-CF3C6H4)
7g (4-MeC6H4)
7h (3-NO2C6H4)
7i (3-ClC6H4)
7j (1-naphthyl)
7k (cyclohexyl)
9
10
11
a
Reactions were performed in 1.5 mL of Et2O with 0.3 mmol of substrates 7, 10 mol % of Et3N, and 3 mol % of catalyst prepared in situ from AgOAc and 1.1 equiv of ligand
2a at ꢀ40 °C for 18 h.
b
endo/exo-Ratio was determined by 1H NMR.
Isolated yields.
Enantiomeric excesses were determined by chiral HPLC.
Enantiomeric excess was determined by chiral GC.
c
d
e
aldehydes were reacted with dimethyl maleate 8 to give the corre-
sponding endo-adducts 9a–j in high yields and good to near perfect
enantioselectivities (88–99% ee) (entries 1–10). The results show
that the electronic properties of the substituent on the aromatic
ring had some effect on the enantioselectivities (entries 3–7). The
substrates bearing an electron-withdrawing substituent tended

M.-L. Han et al. / Tetrahedron: Asymmetry 23 (2012) 306–312
309
Ph
N
MeO2C
CO2Me
O
O
t-BuO2C
p-Cl-Ph
CO2Me
N
H
p-Cl-Ph
CO2Me
N
H
p-Cl-Ph
CO2Me
N
H
12
11
10
95% yield (endo / exo > 99/1)
81% yield (endo / exo = 90/10)
92% ee (endo)
92% yield (endo / exo = 91/9)
92% ee (endo)
89% ee (endo)
Cl
O
O
H3CO
p-Cl-Ph
COOCH3
p-Cl-Ph
COOCH3
N
H
N
H
14
13
94% yield (endo / exo = 94/6)
94% ee (endo)
95% yield (endo / exo = 87/13)
93% ee (endo)
Figure 3. Cycloaddition of 7a with other dipolarophiles.
to give higher enantioselectivities than those with an electron-
donating group. An azomethine ylide from 1-naphthylaldehyde
also proved to be a suitable substrate in this transformation, pro-
ducing endo-cycloadduct in 98% ee (entry 10). However, for alkyl
substituted substrate 7k, the present catalytic system showed
low reactivity (entry 11).
In order to further extend the scope of this catalytic system, the
reaction of methyl N-(4-chlorobenzylidene)glycinate 7a with other
dipolarophiles was then carried out, and the results are summa-
rized in Figure 3. With N-phenylmaleimide, high endo-selectivity
(endo/exo >99/1) and good enantioselectivity (92% ee) were
achieved. For dimethyl fumarate, the major endo-cycloadduct 11
was obtained in 92% yield and 89% ee. The reaction with tert-butyl
acrylate gave a sightly lower yield (81%) but good enantioselectiv-
ity (92% ee). The reaction of 7a with chalcones was also performed,
producing cycloadducts 13 and 14 with good endo-selectivities and
enantioselectivities.
chloroform signal at 77.0 ppm as a standard. HPLC analyses were
performed on an Agilent 1100 series instrument with a chiral col-
umn (Chiralcel AS-H) with hexane and i-PrOH as solvents. GC anal-
yses were performed on a HP4890D instrument with a chiral
column (Chiral Select-1000 column) using hydrogen as carrier
gas. Optical rotations were recorded on a Jasco P-1020 polarimeter.
The absolute configurations of the known products were deter-
mined by comparing specific rotations with the reported data.
4.2. General procedure for the synthesis of ligands 2a–f
A solution of 5.29 g (12 mmol) of (Rc,SFc)-3 together with
4 mmol of indole thioether in 10 mL of degassed acetic acid was
warmed to 80 °C and stirred at this temperature for 2 h. The reac-
tion mixture was then concentrated in vacuo and neutralized with
50 mL of saturated NaHCO3. The mixture was extracted three times
with CH2Cl2, washed with brine, and dried over Na2SO4. The sol-
vent was removed under reduced pressure and the residue was
purified by flash chromatography (ethyl acetate/petroleum
ether = 1/50) and recrystallization with hexane and CH2Cl2 to af-
ford the corresponding ligand.
3. Conclusion
In conclusion, we have developed a new family of chiral ferroce-
nyl P,S-ligands with an indole fragment through a highly efficient
and simple synthesis route. These ligands were evaluated in the
Ag(I)-catalyzed asymmetric [3+2] cycloaddition of azomethine
ylides with various electronic-deficient alkenes, in which the cor-
responding cycloadducts were obtained with high endo-selectivi-
ties and good to excellent enantioselectivities (up to 99% ee).
Further applications of these new ligands in other type of asym-
metric reactions are currently in progress.
4.2.1. 3-{(S)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyl}-2-
(phenylthio)indole (Sc,SFc)-2a
Yellow solid, 85% yield. Mp = 200–202 °C; ½a D20
¼ ꢀ100:7 (c 0.12,
ꢁ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.74 (d, J = 8.0 Hz, 3H), 3.62 (s,
1H), 4.11 (s, 5H), 4.29–4.30 (m, 1H), 4.85–4.87 (m, 2H), 6.46–6.50
(m, 2H), 6.54–6.58 (m, 2H), 6.81–6.88 (m, 2H), 6.93–6.95 (m, 1H),
7.02–7.05 (m, 3H), 7.09–7.11 (m, 2H), 7.16–7.19 (m, 2H), 7.31 (s,
3H), 7.44 (s, 2H), 7.56 (d, J = 8.0 Hz, 1H); 31P NMR (162 MHz, CDCl3):
d ꢀ23.3; 13C NMR (100 MHz, CDCl3): d 138.1 (d, J = 2.0 Hz), 137.8 (d,
J = 9.0 Hz), 137.2, 135.3 (d, J = 21.0 Hz), 131.4 (d, J = 19.0 Hz), 129.0,
128.8, 127.9 (d, J = 8.0 Hz), 127.5, 126.8, 126.7, 126.6, 125.8, 125.5,
122.6, 120.5, 120.4, 119.0, 110.8, 98.3 (d, J = 24.0 Hz), 75.3 (d,
J = 8.0 Hz), 71.8 (d, J = 4.0 Hz), 70.1 (d, J = 4.0 Hz), 69.9, 68.1, 31.1
(d, J = 7.0 Hz), 20.7; HRMS (m/z) calcd for C38H32FeNPS: 621.1343,
found: 621.1357.
4. Experimental
4.1. General
All reactions were carried out under a nitrogen atmosphere. All
solvents were purified by standard procedures, and commercially
obtained reagents were used without further purification. 1H
NMR spectra were recorded on a Bruker 400 MHz spectrometer
in deuterated chloroform. Chemical shifts are reported in ppm with
the internal TMS signal at 0.0 ppm as a standard. 13C NMR spectra
were recorded on a Bruker 100 MHz spectrometer in deuterated
chloroform. Chemical shifts are reported in ppm with the internal
4.2.2. 3-{(S)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyl}-2-
[(4-methylphenyl)- thio]indole (Sc,SFc)-2b
Yellow solid, 82% yield. Mp = 230–232 °C; ½a D20
¼ ꢀ86:8 (c 0.11,
ꢁ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.74 (d, J = 8.0 Hz, 3H), 2.26 (s,

310
M.-L. Han et al. / Tetrahedron: Asymmetry 23 (2012) 306–312
3H), 3.60 (s, 1H), 4.09 (s, 5H), 4.29 (m, 1H), 4.83–4.87 (m, 2H),
6.44–6.48 (m, 2H), 6.52–6.56 (m, 2H), 6.79–6.85 (m, 2H), 6.90–
7.06 (m, 7H), 7.29 (s, 3H), 7.39–7.43 (m, 2H), 7.53 (d, J = 8.0 Hz,
1H); 31P NMR (162 MHz, CDCl3): d ꢀ23.3; 13C NMR (100 MHz,
CDCl3): d 138.2 (d, J = 9.0 Hz), 138.0 (d, J = 10.0 Hz), 137.1, 135.5,
135.3 (d, J = 21.0 Hz), 134.1 (d, J = 2.0 Hz), 131.3 (d, J = 19.0 Hz),
129.8, 128.7, 127.8 (d, J = 8.0 Hz), 127.4, 127.0, 126.7 (d,
J = 6.0 Hz), 126.5, 125.9, 122.4, 121.2, 120.3, 118.9, 110.7, 98.3 (d,
J = 24.0 Hz), 75.5 (d, J = 9.0 Hz), 71.8 (d, J = 5.0 Hz), 70.1 (d,
J = 4.0 Hz), 69.8, 68.0, 31.0 (d, J = 8.0 Hz), 21.0, 20.6; HRMS (m/z)
calcd for C39H34FeNPS: 635.1499, found: 635.1488.
6.78–7.02 (m, 5H), 7.23–7.40 (m, 5H), 7.50 (d, J = 8.0 Hz, 1H); 31P
NMR (162 MHz, CDCl3): d ꢀ23.3; 13C NMR (100 MHz, CDCl3): d
138.1 (d, J = 10.0 Hz), 136.7, 135.2 (d, J = 21.0 Hz), 131.3 (d,
J = 19.0 Hz), 128.6, 127.8 (d, J = 8.0 Hz), 126.7 (d, J = 7.0 Hz),
126.4, 126.3, 126.0, 123.5, 121.9, 120.2, 118.6, 110.4, 98.6 (d,
J = 24.0 Hz), 75.4 (d, J = 9.0 Hz), 71.8 (d, J = 5.0 Hz), 70.2 (d,
J = 4.0 Hz), 69.8, 67.9, 40.1 (d, J = 3.0 Hz), 30.8 (d, J = 7.0 Hz), 24.2,
23.5, 20.7; HRMS calcd for
587.1482.
C35H34FeNPS: 587.1499, found:
4.3. Synthesis of N-tert-butyloxycarbonyl-3-{(S)-1-[(S)-2-
(diphenylphosphino)- ferrocenyl]ethyl}-2-(phenylthio)-
indole (Sc,SFc)-2g
4.2.3. 3-{(S)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyl}-2-
[(4-chlorophenyl)- thio]indole (Sc,SFc)-2c
Yellow solid, 77% yield. Mp = 207–209 °C; ½a D20
ꢁ
¼ ꢀ67:4 (c 0.15,
To a solution of (Sc,SFc)-2a (621.5 mg, 1 mmol) and DMAP
(2.44 mg, 0.02 mmol) in CH2Cl2 (4 mL) was added (Boc)2O
(240.2 mg, 1.1 mmol) and the solution was stirred at room temper-
ature for 2 h. The resulting mixture was evaporated under reduced
pressure and purified by flash column chromatography to afford
the N-Boc-protected ligand (Sc,SFc)-2g. Yellow solid, 80% yield.
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.72 (d, J = 4.0 Hz, 3H), 3.61 (s,
1H), 4.09 (s, 5H), 4.28 (s, 1H), 4.82 (s, 2H), 6.45–6.46 (m, 2H), 6.53–
6.54 (m, 2H), 6.79–6.93 (m, 5H), 7.02–7.13 (m, 4H), 7.29 (s, 3H),
7.41 (s, 2H), 7.54 (d, J = 8.0 Hz, 1H); 31P NMR (162 MHz, CDCl3): d
ꢀ23.4; 13C NMR (100 MHz, CDCl3): d 138.1 (d, J = 7.0 Hz), 137.7
(d, J = 10.0 Hz), 137.3, 136.7, 135.2 (d, J = 21.0 Hz), 131.4 (d,
J = 19.0 Hz), 129.0, 128.8, 128.0, 127.9, 127.8, 126.8 (d, J = 7.0 Hz),
126.6, 125.7, 122.8, 120.6, 119.8, 119.2, 110.9, 98.1 (d,
J = 24.0 Hz), 75.2 (d, J = 5.0 Hz), 71.8 (d, J = 4.0 Hz), 70.1 (d,
J = 4.0 Hz), 69.9, 68.2, 31.1 (d, J = 7.0 Hz), 20.7; HRMS calcd for
Mp = 89–92 °C; ½a 2D0
ꢁ
¼ ꢀ96:9 (c 0.12, CHCl3); 1H NMR (400 MHz,
CDCl3): d 1.35 (s, 9H), 1.63 (d, J = 8.0 Hz, 3H), 3.61 (s, 1H), 4.14 (s,
5H), 4.29 (s, 1H), 4.82 (s, 1H), 5.05–5.10 (m, 1H), 6.56–6.58 (m,
4H), 6.85 (s, 1H), 6.95–6.97 (m, 2H), 7.02–7.07 (m, 2H),7.15–7.19
(m, 3H), 7.30 (s, 3H), 7.43 (s, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.85 (d,
J = 8.0 Hz, 1H); 31P NMR (162 MHz, CDCl3): d ꢀ23.8; 13C NMR
(100 MHz, CDCl3): d 149.1, 139.8 (d, J = 2.0 Hz), 138.0, 137.6 (d,
J = 11.0 Hz), 137.2 (d, J = 9.0 Hz), 135.0 (d, J = 21.0 Hz), 134.8,
131.5 (d, J = 20.0 Hz), 128.8, 128.6, 127.9 (d, J = 7.0 Hz), 127.0,
126.8 (d, J = 6.0 Hz), 125.4, 124.7 (d, J = 6.0 Hz), 121.8, 121.7,
120.3, 115.6, 97.0 (d, J = 23.0 Hz), 83.2, 76.2 (d, J = 9.0 Hz), 72.1
(d, J = 5.0 Hz), 70.3, 69.9, 67.9, 31.7 (d, J = 6.0 Hz), 27.9, 27.8, 19.6;
HRMS (m/z) calcd for C43H40FeNO2PS: 721.1867, Found: 721.1881.
C38H31ClFeNPS: 655.0953, found: 655.0974.
4.2.4. 3-{(S)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyl}-2-
(benzylthio)indole (Sc,SFc)-2d
Yellow solid, 80% yield. Mp = 69–71 °C; ½a D20
¼ ꢀ239:6 (c 0.12,
ꢁ
CHCl3); 1H NMR (400 MHz, CDCl3): d 1.59 (d, J = 8.0 Hz, 3H), 3.63
(s, 1H), 3.85–3.94 (m, 2H), s1 (s, 5H), 4.29 (d, J = 4.0 Hz, 1H),
4.77–4.83 (m, 2H), 6.38–6.42 (m, 2H), 6.49–6.53 (m, 2H), 6.78–
7.08 (m, 7H), 7.21–7.23 (m, 3H), 7.29–7.30 (m, 3H), 7.42–7.50
(m, 3H); 31P NMR (162 MHz, CDCl3):
(100 MHz, CDCl3):
d
ꢀ22.8; 13C NMR
4.4. General procedure for the catalytic asymmetric 1,3-dipolar
cycloadditon of azomethine ylides
d
139.0, 138.7 (d, J = 9.0 Hz), 138.3 (d,
J = 9.0 Hz), 136.8, 135.4 (d, J = 21.0 Hz), 131.2 (d, J = 18.0 Hz),
129.0, 128.8, 128.5, 127.8 (d, J = 8.0 Hz), 127.1, 126.8 (d,
J = 6.0 Hz), 126.4, 126.1, 125.8, 123.4, 122.0, 120.3, 118.8, 110.5,
98.9 (d, J = 25.0 Hz), 75.3 (d, J = 9.0 Hz), 71.7 (d, J = 4.0 Hz), 70.2
(d, J = 5.0 Hz), 69.8, 68.1, 41.2 (d, J = 4.0 Hz), 31.0 (d, J = 8.0 Hz),
20.7; HRMS calcd for C39H34FeNPS: 635.1499, found: 635.1494.
Under a nitrogen atmosphere, a solution of AgOAc (0.009 mmol)
and ligand 2 (0.0099 mmol) in 1.5 mL of Et2O was stirred at room
temperature for 1 h. Imino esters (0.3 mmol), Et3N (4.2 lL,
0.03 mmol), and dimethyl maleate (0.36 mmol) were added suc-
cessively. Once the starting materials were consumed (monitored
by TLC), the mixture was passed through a short column of silica
gel and the diastereometric ratio (endo/exo) was determined by
NMR spectroscopic analysis after removal of the solvent. The resi-
due was purified by column chromatography on silica gel, and then
submitted to ee analysis by HPLC with a chiral column.
4.2.5. 3-{(S)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyl}-2-
(methylthio)indole (Sc,SFc)-2e
Yellow solid, 81% yield. Mp = 150–152 °C; ½a D20
¼ ꢀ215:0 (c
ꢁ
0.13, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.77 (d, J = 8.0 Hz, 3H),
2.29 (s, 3H), 3.59 (s, 1H), 4.11 (s, 5H), 4.27–4.28 (m,1H), 4.81–
4.84 (m, 2H), 6.37–6.41 (m, 2H), 6.49–6.52 (m, 2H), 6.77–6.80
(m, 1H), 6.86–6.90 (m, 2H), 6.97–7.01 (m, 1H), 7.10 (s, 1H), 7.26–
7.28 (m, 3H), 7.39–7.42 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H); 31P NMR
(162 MHz, CDCl3): d ꢀ23.0; 13C NMR (100 MHz, CDCl3): d 138.3
(d, J = 9.0 Hz), 138.0 (d, J = 10.0 Hz), 136.7, 135.3 (d, J = 21.0 Hz),
131.3 (d, J = 18.0 Hz), 128.7, 127.8 (d, J = 8.0 Hz), 126.6 (d,
J = 6.0 Hz), 126.3, 126.0, 125.1, 124.8, 121.9, 120.1, 118.8, 110.4,
98.5 (d, J = 24.0 Hz), 75.3 (d, J = 8.0 Hz), 71.7 (d, J = 4.0 Hz), 70.1
(d, J = 3.0 Hz), 69.8, 68.0, 30.8 (d, J = 8.0 Hz), 20.9, 19.8; HRMS calcd
for C33H30FeNPS: 559.1186, found: 559.1179.
4.4.1. Trimethyl (2S,3R,4S,5R)-5-(4-chlorophenyl)pyrrolidine-
2,3,4-tricarboxyl- ate endo-9a
White solid, 95% yield (endo/exo = 95/5), 99% ee. ½a D20
¼ þ14:2 (c
ꢁ
0.17, CHCl3). Chiral AS-H column, 40 °C, 205 nm, n-hexane/i-propa-
nol = 50/50, flow rate = 0.8 mL/min, tR = 7.7 and 10.5 min; 1H NMR
(400 MHz, CDCl3): d 7.24 (s, 4H), 4.40 (d, J = 4.0 Hz, 1H), 4.10 (d,
J = 12.0 Hz, 1H), 3.74 (s, 3H), 3.64–3.69 (m, 1H), 3.63 (s, 3H),
3.52–3.54 (m, 1H), 3.22 (s, 3H), 3.03 (br, 1H).
4.4.2. Trimethyl (2S,3R,4S,5R)-5-phenylpyrrolidine-2,3,4-
tricarboxylate endo-9b
4.2.6. 3-{(S)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyl}-2-
(i-propylthio)indole (Sc,SFc)-2f
White solid, 97% yield (endo/exo = 96/4), 91% ee. ½a D20
¼ þ62:1 (c
ꢁ
0.13, CHCl3). Chiral AS-H column, 205 nm, n-hexane/i-propa-
nol = 50/50, flow rate = 0.8 mL/min, tR = 6.5 and 11.4 min; 1H
NMR (400 MHz, CDCl3): d 7.17–7.29 (m, 5H), 4.42 (d, J = 8.0 Hz,
1H), 4.10 (d, J = 8.0 Hz, 1H), 3.74 (s, 3H), 3.64–3.66 (m, 1H), 3.62
(s, 3H), 3.51–3.53 (m, 1H), 3.16 (s, 4H).
Yellow solid, 84% yield. Mp = 120–122 °C; ½a D20
¼ ꢀ248:4 (c
ꢁ
0.12, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.21–1.26 (m, 6H),
1.77 (s, 3H), 3.13–3.18 (m, 1H), 3.55 (s, 1H), 4.12 (s, 5H), 4.26 (s,
1H), 4.77–4.83 (m, 2H), 6.38–6.41 (m, 2H), 6.50–6.54 (m, 2H),

M.-L. Han et al. / Tetrahedron: Asymmetry 23 (2012) 306–312
311
4.4.3. Trimethyl (2S,3R,4S,5R)-5-(4-fluorophenyl)pyrrolidine-
2,3,4-tricarboxyl- ate endo-9c
1H), 4.10 (d, J = 8.0 Hz, 1H), 3.74 (s, 3H), 3.64–3.69 (m, 1H), 3.62
(s, 3H), 3.50–3.54 (m, 1H), 3.37 (s, 1H), 3.23 (s, 3H).
White solid, 95% yield (endo/exo = 96/4), 95% ee. ½a D20
¼ þ68:1 (c
ꢁ
0.12, CHCl3). Chiral AS-H column, 40 °C, 205 nm, n-hexane/i-propa-
nol = 50/50, flow rate = 0.8 mL/min, tR = 7.0 and 9.9 min; 1H NMR
(400 MHz, CDCl3): d 7.22–7.26 (m, 2H), 6.89–6.93 (m, 2H), 4.38
(d, J = 4.0 Hz, 1H), 4.05 (d, J = 8.0 Hz, 1H), 3.70 (s, 3H), 3.61–3.63
(m, 1H), 3.59 (s, 3H), 3.48–3.50 (m, 1H), 3.16 (s, 3H), 2.83 (br, 1H).
4.4.10. Trimethyl (2S,3R,4S,5R)-5-(naphthalen-1-yl)pyrrolidine-
2,3,4-tricarboxylate endo-9j
White solid, 92% yield (endo/exo = 96/4), 98% ee. ½a D20
¼ þ40:7 (c
ꢁ
0.09, CHCl3). Chiral AS-H column, 205 nm, 40 °C, n-hexane/i-propa-
nol = 50/50, flow rate = 0.8 mL/min, tR = 7.9 and 14.2 min; 1H NMR
(400 MHz, CDCl3): d 7.75–7.79 (m, 4H), 7.38–7.44 (m, 3H), 4.60 (d,
J = 8.0 Hz, 1H), 4.20 (d, J = 8.0 Hz, 1H), 3.80 (s, 3H), 3.73–3.77 (m,
1H), 3.63–3.66 (m, 5H), 3.12 (s, 3H).
4.4.4. Trimethyl (2S,3R,4S,5R)-5-(4-bromophenyl)pyrrolidine-
2,3,4-tricarboxyl- ate endo-9d
White solid, 92% yield (endo/exo = 95/5), 91% ee. ½a D20
¼ þ52:6 (c
ꢁ
0.12, CHCl3). Chiral AS-H column, 40 °C, 205 nm, n-hexane/i-propa-
nol = 50/50, flow rate = 0.8 mL/min, tR = 8.0 and 11.3 min; 1H NMR
(400 MHz, CDCl3): d 7.38 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H),
4.38 (d, J = 8.0 Hz, 1H), 4.09 (d, J = 8.0 Hz, 1H), 3.73 (s, 3H), 3.64–
3.68 (m, 1H), 3.62 (s, 3H), 3.49–3.53 (m, 1H), 3.26 (s, 1H), 3.21 (s,
3H).
4.4.11. Trimethyl (2S,3R,4S,5S)-5-cyclohexylpyrrolidine-2,3,4-
tricarboxylate endo-9k
White solid, 28% yield (endo/exo = 97/3), 92% ee. ½a D20
¼ þ26:4 (c
ꢁ
0.17, CHCl3). Capillary GC, Chiral Select 1000 column, 30 m ꢂ
0.25 mm, 160 °C, 15 psi, Carrier gas: H2, tR = 35.6 and 40.7 min;
1H NMR (400 MHz, CDCl3): d 3.99 (d, J = 8.0 Hz, 1H), 3.67 (s, 3H),
3.60 (s, 3H), 3.58 (s, 3H), 3.45–3.49 (m, 1H), 3.08–3.11 (m, 1H),
2.78 (s, 1H), 2.71–2.75 (m, 1H), 1.96–2.00 (m, 1H), 1.72–1.75 (m,
1H), 1.55–1.66 (m, 3H), 1.24–1.32 (m, 1H), 0.83–1.20 (m, 5H).
4.4.5. Trimethyl (2S,3R,4S,5R)-5-(4-nitrophenyl)pyrrolidine-
2,3,4-tricarboxylate endo-9e
White solid, 94% yield (endo/exo = 91/9), 91% ee. ½a D20
¼ þ16:7 (c
ꢁ
0.12, CHCl3). Chiral AS-H column, 40 °C, 205 nm, n-hexane/i-propa-
nol = 50/50, flow rate = 0.8 mL/min, tR = 12.7 and 14.2 min; 1H
NMR (400 MHz, CDCl3): d 8.13 (d, J = 12.0 Hz, 2H), 7.52 (d,
J = 8.0 Hz, 2H), 4.52 (d, J = 8.0 Hz, 1H), 4.14 (d, J = 8.0 Hz, 1H),
3.74 (s, 3H), 3.69–3.72 (m, 1H), 3.63 (s, 3H), 3.59–3.61 (m, 1H),
3.21 (s, 3H).
4.4.12. Methyl (1S,3R,3aS,6aR)-4,6-dioxo-3,5-diphenylocta-
hydrocyclopenta[c] pyrrole-1-carboxylate endo-10
White solid, 95% yield (endo/exo >99/1), 92% ee. ½a D20
¼ þ139:5
ꢁ
(c 0.12, CHCl3). Chiral AS-H column, 40 °C, 215 nm, n-hexane/i-pro-
panol = 80/20, flow rate = 1.0 mL/min, tR = 6.5 and 14.0 min; 1H
NMR (400 MHz, CDCl3): d 7.36–7.38 (m, 4H), 7.31–7.32 (m, 3H),
7.11–7.12 (m, 2H), 4.54 (d, J = 4.0 Hz, 1H), 4.10 (d, J = 4.0 Hz, 1H),
3.84 (s, 3H), 3.67–3.68 (m, 1H), 3.51–3.53 (m, 1H), 2.29 (br, 1H).
4.4.6. Trimethyl (2S,3R,4S,5R)-5-(4-(trifluoromethyl)phenyl)-
pyrrolidine-2,3,4- tricarboxylate endo-9f
White solid, 96% yield (endo/exo = 96/4), 95% ee. ½a D20
ꢁ
¼ þ43:2 (c
4.4.13. Trimethyl (2S,3S,4S,5R)-5-phenylpyrrolidine-2,3,4-tri-
carboxylate endo-11
0.13, CHCl3). Chiral AS-H column, 40 °C, 205 nm, n-hexane/i-propa-
nol = 50/50, flow rate = 0.8 mL/min, tR = 6.0 and 7.3 min; 1H NMR
(400 MHz, CDCl3): d 7.53 (d, J = 12.0 Hz, 2H), 7.44 (d, J = 8.0 Hz,
2H), 4.48 (d, J = 4.0 Hz, 1H), 4.12 (d, J = 8.0 Hz, 1H), 3.75 (s, 3H),
3.67–3.69 (m, 1H), 3.63 (s, 3H), 3.57–3.59 (m, 1H), 3.23 (s, 1H),
3.19 (s, 3H).
White solid, 92% yield (endo/exo = 91/9), 89% ee. ½a D20
¼ þ16:9 (c
ꢁ
0.59, CHCl3). Chiral AS-H column, 40 °C, 205 nm, n-hexane/i-propa-
nol = 90/10, flow rate = 0.8 mL/min, tR = 20.5 and 22.5 min; 1H
NMR (400 MHz, CDCl3): d 7.24 (s, 4H), 4.57 (d, J = 8.0 Hz, 1H),
4.13 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 3.59–3.60 (m,
1H), 3.50–3.52 (m, 1H), 3.19 (s, 3H), 2.69 (br, 1H).
4.4.7. Trimethyl (2S,3R,4S,5R)-5-p-tolylpyrrolidine-2,3,4-tri-
carboxylate endo-9g
4.4.14. 4-t-Butyl 2-methyl (2S,4S,5R)-5-phenylpyrrolidine-2,4-
dicarboxylate endo-12
White solid, 92% yield (endo/exo = 95/5), 88% ee. ½a D20
¼ þ18:9 (c
ꢁ
0.11, CHCl3). Chiral AS-H column, 40 °C, 205 nm, n-hexane/i-propa-
nol = 50/50, flow rate = 0.8 mL/min, tR = 6.4 and 12.7 min; 1H NMR
(400 MHz, CDCl3): d 7.16 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H),
4.40 (d, J = 8.0 Hz, 1H), 4.12 (d, J = 12.0 Hz, 1H), 3.75 (s, 3H), 3.66–
3.69 (m, 1H), 3.63 (s, 3H), 3.48–3.51 (m, 1H), 3.27 (s, 1H), 3.21 (s,
3H), 2.26 (s, 3H).
White solid, 81% yield (endo/exo = 90/10), 92% ee. ½a D20
¼ þ27:1
ꢁ
(c 0.23, CHCl3). Chiral AS-H column, 40 °C, 230 nm, n-hexane/i-pro-
panol = 90/10, flow rate = 0.8 mL/min, tR = 5.8 and 7.8 min; 1H
NMR (400 MHz, CDCl3): d 7.15–7.25 (m, 4H), 4.35–4.37 (m, 1H),
3.83–3.88 (m, 1H), 3.72 (s, 3H), 3.15–3.16 (m, 1H), 2.70 (s, 1H),
2.30–2.34 (m, 1H), 2.22–2.25 (m, 1H), 0.99 (s, 9H).
4.4.8. Trimethyl (2S,3R,4S,5R)-5-(3-nitrophenyl)pyrrolidine-
2,3,4-tricarboxylate endo-9h
4.4.15. Methyl (2S,3S,4S,5R)-5-(4-chlorophenyl)-4-(4-methoxy-
benzoyl)-3-phenyl- pyrrolidine-2-carboxylate endo-13
White solid, 93% yield (endo/exo = 97/3), 94% ee. ½a D20
ꢁ
¼ þ48:4 (c
White solid, 94% yield (endo/exo = 94/6), 94% ee. ½a D20
¼ ꢀ154:0
ꢁ
0.07, CHCl3). Chiral AS-H column, 40 °C, 205 nm, n-hexane/i-propa-
nol = 50/50, flow rate = 0.8 mL/min, tR = 11.3 and 15.9 min; 1H
NMR (400 MHz, CDCl3): d 8.19 (s, 1H), 8.05–8.07 (m, 1H), 7.70–
7.71 (m, 1H), 7.43–7.47 (m, 1H), 4.54 (d, J = 8.0 Hz, 1H), 4.16 (d,
J = 8.0 Hz, 1H), 3.74 (s, 3H), 3.71–3.74 (m, 1H), 3.62–3.63 (m, 4H),
3.25 (s, 1H), 3.21 (s, 3H).
(c 0.12, CHCl3). Chiral AS-H column, 40 °C, 215 nm, n-hexane/i-pro-
panol = 80/20, flow rate = 1.0 mL/min, tR = 6.3 and 7.5 min; 1H
NMR (400 MHz, CDCl3): d 7.54–7.56 (m, 2H), 7.29–7.35 (m, 4H),
7.22–7.24 (m, 1H), 7.06 (s, 4H), 6.73–6.75 (m, 2H), 4.93 (d,
J = 8.0 Hz, 1H), 4.42–4.46 (m, 1H), 4.15–4.17 (m, 1H), 4.06–4.08
(m, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 2.79 (br, 1H).
4.4.9. Trimethyl (2S,3R,4S,5R)-5-(3-chlorophenyl)pyrrolidine-
2,3,4-tricarboxyl- ate endo-9i
4.4.16. Methyl (2S,3S,4S,5R)-4-benzoyl-3,5-bis(4-chlorophenyl)-
pyrrolidine-2- carboxylate endo-14
White solid, 95% yield (endo/exo = 96/4), 98% ee. ½a D20
ꢁ
¼ þ50:7 (c
White solid, 95% yield (endo/exo = 87/13), 93% ee. ½a D20
¼ ꢀ65:7
ꢁ
0.17, CHCl3). Chiral AS-H column, 40 °C, 205 nm, n-hexane/i-propa-
nol = 50/50, flow rate = 0.8 mL/min, tR = 7.0 and 11.6 min; 1H NMR
(400 MHz, CDCl3): d 7.29 (s, 1H), 7.18 (s, 3H), 4.39 (d, J = 4.0 Hz,
(c 0.11, CHCl3). Chiral AS-H column, 40 °C, 215 nm, n-hexane/i-pro-
panol = 80/20, flow rate = 1.0 mL/min, tR = 11.0 and 14.6 min; 1H
NMR (400 MHz, CDCl3): d 7.53–7.55 (m, 2H), 7.40–7.44 (m, 1H),

312
M.-L. Han et al. / Tetrahedron: Asymmetry 23 (2012) 306–312
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Acknowledgments
We are grateful for the generous financial support from the
National Natural Science Foundation of China (20972156), the
Planned Science and Technology Project of Dalian (2009E11
SF132) and Dalian Institute of Chemical Physics (CAS).
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