Asymmetric [3+2] cycloaddition of azomethine ylides catalyzed by silver(I) triflate with a chiral bipyrrolidine-derived phosphine ligand

Article abstract of DOI:10.1055/s-0032-1316779

Two novel chiral bipyrrolidine-derived phosphine ligands L1 and L2 were synthesized. The AgOTf + L1 protocol catalyzes the asymmetric [3+2] cycloaddition of azomethine ylides with alkenes to give highly substituted pyrrolidines in good yields (up to 90%) with moderate to high diastereoselectivities (up to >19:1 dr) and enantioselectivities (up to 76%).

Full text of DOI:10.1055/s-0032-1316779

PAPER
▌3307
paper
Asymmetric [3+2] Cycloaddition of Azomethine Ylides Catalyzed by Silver(I)
Triflate with a Chiral Bipyrrolidine-Derived Phosphine Ligand
Asymmetric [3+2] Cycloaddition of Azomethine Ylides
Xin Gu,a Zhen-Jiang Xu,*a Vanessa Kar-Yan Lo,b Chi-Ming Che*a,b
a
Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, 345 Lingling Road,
Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: xuzhenjiang@mail.sioc.ac.cn
b
Department of Chemistry, State Key Laboratory of Synthetic Chemistry and Open Laboratory of Chemical Biology of the Institute of
Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
Fax +852(2857)1586; E-mail: cmche@hku.hk
Received: 26.06.2012; Accepted after revision: 30.08.2012
Bipyrrolidine-derived ligands L1 and L2 were prepared in
Abstract: Two novel chiral bipyrrolidine-derived phosphine li-
a single step from (R,R)-bipyrrolidine (see experimental
gands L1 and L2 were synthesized. The ‘AgOTf + L1’ protocol cat-
section for details). The ligand 6-Me2-BPBP, which gave
alyzes the asymmetric [3+2] cycloaddition of azomethine ylides
with alkenes to give highly substituted pyrrolidines in good yields
good yields and selectivities in asymmetric alkene cis-di-
(up to 90%) with moderate to high diastereoselectivities (up to hydroxylation,8a was also synthesized for comparison.
>19:1 dr) and enantioselectivities (up to 76%).
Key words: asymmetric [3+2] cycloaddition, silver catalysis, azo-
methine ylides, chiral phosphine ligand, highly substituted pyrro-
lines
O
O
N
N
N
N
PPh2
Ph2P
PPh2
Ph2P
L1
L2
Highly substituted pyrrolidine derivatives with high enan-
tiopurity are important chiral building blocks in organic
synthesis,1 and may serve as organocatalysts for asym-
metric organic transformations.2 Among different prepa-
ration strategies, transition-metal-catalyzed [3+2]
cycloaddition of an azomethine ylide with an olefinic di-
polarophile is a promising approach for the preparation of
this class of compounds.3 With the use of appropriate chi-
ral metal catalysts, particularly those with chiral phos-
phine ligands, highly substituted pyrrolidines can be
prepared in a highly enantioselective manner.4–7 Due to
the importance of this class of compounds, there has been
continued interest in the design and synthesis of new chi-
ral ligands that are used for the preparation of highly sub-
stituted pyrrolidines via metal-catalyzed asymmetric
[3+2]-cycloaddition reaction of azomethine ylides with
alkenes.
N
N
N
N
6-Me2-BPBP
Figure 1 Bipyrrolidine ligands L1, L2, and 6-Me2-BPBP
With these ligands in hand, we investigated their applica-
tion in [3+2] cycloaddition of methyl N-benzylideneglyc-
inate (1a) with dimethyl maleate (2a) as a model reaction.
As silver compounds are documented to be effective cat-
alysts for this reaction,6,7 we began with silver(I) acetate
as the metal source. The results are given in Table 1. A re-
action mixture of 1a (0.5 mmol), 2a (0.75 mmol), silver(I)
acetate (10 mol%), and ligand L1 (11 mol%) in the pres-
ence of N,N-diisopropylethylamine (10 mol%) as base in
toluene (1.5 mL) was stirred at room temperature under a
nitrogen atmosphere for eight hours, leading to the forma-
tion of tetrasubstituted pyrrolidine 3a in 67% isolated
yield favoring the formation of the endo product (ratio
endo/exo 8.2:1) with 67% ee for the endo product (entry
1). The use of L2 or 6-Me2-BPBP resulted in no enantio-
selectivity (entries 2 and 3). The superiority of L1 in this
reaction is attributed to the amide units which provide ri-
gidity to the ligand and render the phosphine groups more
electron-deficient.
Bipyrrolidine, an example of C2 symmetric chiral di-
amines, has been increasingly used as the chiral backbone
for multidentate ligands for transition-metal-catalyzed
asymmetric alkene cis-dihydroxylation,8 C–H bond oxi-
dation,9,10 and addition reactions.11 As part of our contin-
ued work on the development of transition-metal
catalysis,12 herein we report the use of new chiral bipyrro-
lidine-derived tetradentate phosphine ligands and their
application in the silver(I) triflate catalyzed asymmetric
[3+2] cycloaddition of azomethine ylides with alkenes.
The effects of different silver salts were also examined
(Table 2). Silver(I) triflate gave the best results in terms of
product yield and stereoselectivity (90% isolated yield, ra-
tio endo/exo 14.3:1, endo product with 70% ee; entry 4).
SYNTHESIS 2012, 44, 3307–3314
Advanced online publication: 14.09.2012
DOI: 10.1055/s-0032-1316779; Art ID: SS-2012-H0544-OP
© Georg Thieme Verlag Stuttgart · New York
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Table 1 Ligand Screeninga
Ph
N
COOMe
COOMe
AgOAc (10 mol%)
ligand (11 mol%)
MeOOC
Ph
COOMe
MeOOC
Ph
COOMe
1a
+
+
COOMe
COOMe
DIPEA (10 mol%)
toluene, r.t., N2, 8 h
N
H
endo
N
H
exo
MeOOC
3a
3a′
2a
Entry
Ligand
Yieldb (%)
Ratioc (endo/exo)
eed (%)
1
2
3
L1
67
31
83
8.2:1
1.5:1
2.7:1
67
<1
0
L2
6-Me2-BPBP
a Ratio 1a/2a/AgOAc/ligand/DIPEA 1:1.5:0.1:0.11:0.1, toluene (1.5 mL).
b Combined isolated yield of endo and exo products.
c Determined by 1H NMR of crude reaction mixture.
d ee value of endo product.
Table 2 Catalyst Screeninga
Ph
N
COOMe
catalyst (10 mol%)
MeOOC
Ph
COOMe
MeOOC
COOMe
L1 (11 mol%)
1a
+
+
COOMe
Ph
COOMe
DIPEA (10 mol%)
CH2Cl2, r.t., N2, 8 h
N
H
endo
N
H
exo
MeOOC
COOMe
3a
3a′
2a
Entry
Catalyst
Yieldb (%)
Ratioc (endo/exo)
eed (%)
1
2
3
4
5
6
7
8
9
AgOAc
73
0e
9.7:1
–
60
–
AgPF6
AgSbF6
0e
–
–
AgOTf
90
73
71
97
96
tracee
14.3:1
10.4:1
1:4.9
1:5.5
1:4.0
–
70
64
54f
53f
55f
–
AgNO3
CuOTf
[Cu(MeCN)4]ClO4
[Cu(MeCN)4]PF6
Cu(OTf)2
a Ratio 1a/2a/catalyst/L1/DIPEA 1:1.5:0.1:0.11:0.1, CH2Cl2 (1.5 mL).
b Combined isolated yield of endo and exo products.
c Determined by 1H NMR of crude reaction mixture.
d ee value of endo product.
e Starting material quantitatively recovered.
f ee value of exo product.
Copper catalysts also underwent smooth reaction, but in ing a catalytic amount of silver(I) triflate (5 mol%) and L1
these cases the exo product was the major product and the (5.5 mol%) underwent smooth reaction in chlorinated or
enantioselectivity was moderate (entries 6–9).
aromatic solvents (entries 1–5) to give cycloadduct 3a.
Dichloromethane was found to give the best result in
terms of product yield and stereoselectivity (78% yield,
ratio endo/exo 8.5:1, endo product with 70% ee; entry 1).
The effects of solvent and base were studied using the
‘AgOTf + L1’ protocol. As shown in Table 3, the [3+2]
cycloaddition of 1a (0.25 mmol) and 2a (0.375 mmol) us-
Synthesis 2012, 44, 3307–3314
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Asymmetric [3+2] Cycloaddition of Azomethine Ylides
3309
Table 3 Condition Optimizationa
Ph
N
COOMe
AgOTf (5 mol%)
MeOOC
Ph
COOMe
MeOOC
Ph
COOMe
L1 (5.5 mol%)
1a
+
+
COOMe
COOMe
base (10 mol%)
4 Å MS
r.t., N2, 48 h
N
H
endo
N
H
exo
MeOOC
COOMe
3a
3a′
2a
Entry
Solvent
Base
Yieldb (%)
Ratioc (endo/exo)
eed (%)
1
CH2Cl2
DCE
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
78
76
57
76
75
52
17
tracee
46
54
83
76
85
65
31
78
8.5:1
8.7:1
2.8:1
7.2:1
6.0:1
2.8:1
1.6:1
–
70
67
49
57
43
48
34
–
2
3
CHCl3
benzene
toluene
MeCN
THF
4
5
6
7
8
Et2O
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
LiHMDS
t-BuOK
K2CO3
Li2CO3
Cs2CO3
Et3N
3.2:1
1.9:1
10.7:1
12.3:1
8.4:1
7.4:1
3.1:1
5.4:1
<1
37
70
72
72
65
54
71
10
11
12
13
14
15
16
DABCO
PhNH2
a Ratio 1a/2a/AgOTf/L1/base 1:1.5:0.05:0.055:0.1, solvent (1.5 mL), 4 Å MS (150 mg).
b Combined isolated yield of endo and exo products.
c Determined by 1H NMR of crude reaction mixture.
d ee value of endo product.
e Starting material quantitatively recovered.
Other solvents such as acetonitrile, tetrahydrofuran, and depicted in Table 4. The reaction proceeded smoothly
diethyl ether gave lower yields and selectivities (entries with both electron-withdrawing groups (4-Cl, 3-Br; en-
6–8). Changing the base from N,N-diisopropylethylamine tries 3 and 8) and electron-donating groups (4-Me, 4-/2-
to lithium hexamethyldisilazanide or potassium tert-bu- /3-OMe; entries 2, 4, 6, 7), leading to tetrasubstituted pyr-
toxide gave diminished product yields and selectivities rolidines 3a–h in 75–89% yields favoring the formation of
(entries 9 and 10), while weak bases generally gave higher endo products in 61–76% ee; an alkyl-substituted azo-
product yields and better selectivities (entries 11–16). Po- methine ylide gave lower yield and selectivity (entry 9).
tassium carbonate gave both improved yield and selectiv-
ity (83% isolated yield, ratio endo/exo 10.7:1, endo
product with 70% ee; entry 11).
However, changing the dipolarophile resulted in a signif-
icant effect on both the product yield and selectivity (Ta-
ble 5). The cycloaddition of dimethyl fumarate (2b) with
As the protocol ‘AgOTf (5 mol%) + L1 (5.5 mol%)’ in the azomethine ylide 1a led to a reduction in selectivity com-
presence of potassium carbonate (10 mol%) gave the best pared to its cis-counterpart (entry 2 vs entry 1). Cyclic di-
result in terms of both product yield and selectivity within polarophiles N-substituted maleimides 2c and 2d gave
48 hours at room temperature (entry 11), these reaction pyrrolidines 3k and 3l with excellent diastereoselectivi-
conditions were adopted for subsequent studies.
ties (dr > 19.0:1) and with moderate yields and enantiose-
lectivities (entries 3 and 4). It is worthy of note that methyl
acrylate, which has a lower reactivity, underwent the
With the optimized reaction conditions, we then expanded
the substrate scope for this [3+2] cycloaddition reaction as
© Georg Thieme Verlag Stuttgart · New York
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X. Gu et al.
PAPER
Table 4 [3+2] Cycloaddition of 1 with 2a Catalyzed by Silver(I) Triflate/L1a
R
N
COOMe
MeOOC
R
COOMe
MeOOC
R
COOMe
AgOTf (5 mol%)
L1 (5.5 mol%)
1
+
+
COOMe
COOMe
K2CO3 (10 mol%)
4 Å MS
CH2Cl2, r.t., N2, 48 h
N
H
endo
N
H
exo
MeOOC
COOMe
3
3′
2a
Entry
R
Product
Yieldb (%)
Ratioc (endo/exo)
eed (%)
1
2
3
4
5
6
7
8
9
Ph
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
83
78
78
85
75
83
89
76
48
10.7:1
9.5:1
70
68
70
76
74
69
65
61
16
4-MeC6H4
4-ClC6H4
4-MeOC6H4
2-ClC6H4
2-MeOC6H4
3-MeOC6H4
3-BrC6H4
i-Pr
15.2:1
12.3:1
17.7:1
9.6:1
1g
1h
1i
3g
3h
3i
9.6:1
20.0:1
2.4:1
a Ratio 1/2a/AgOTf/L1/K2CO3 1:1.5:0.05:0.055:0.1, CH2Cl2 (1.5 mL), 4 Å MS (150 mg).
b Combined isolated yield of endo and exo products.
c Determined by 1H NMR of crude reaction mixture.
d ee value of endo product.
equiv) in anhyd CH2Cl2 (50 mL), (R,R)-2,2′-bipyrrolidine (1.0 g,
7.1 mmol) was added. The mixture was stirred at r.t. overnight. Et2O
(100 mL) was added to the mixture. The organic layer was washed
with 10% HCl (3 × 100 mL), H2O (1 × 100 mL), sat. aq NaHCO3
(3 × 100 mL), H2O (1 × 100 mL), and brine (1 × 100 mL), dried
(MgSO4), and concentrated in vacuo. Flash chromatography (silica
gel, EtOAc–hexane) gave the product (2.8 g, 3.9 mmol, 55%) as a
white solid; mp 184–186 °C.
[3+2] cycloaddition to give trisubstituted pyrrolidine 3m
in 83% isolated yield with 12.0:1 dr and 61% ee (entry 5).
It is interesting that trans-β-nitrostyrene (2f) reacted with
1a to form exo product 3n′ as the main product with 1.8:1
dr and 42% ee (entry 6).
In summary, two novel tetradentate phosphine ligands L1
and L2 based on a chiral bipyrrolidine backbone were
synthesized and their application in silver-catalyzed
asymmetric [3+2] cycloaddition reactions of azomethine
ylides with alkenes were investigated. In the presence of
5 mol% silver(I) triflate and 5.5 mol% of L1, highly sub-
stituted pyrrolidines were obtained in good yields with
moderate to high diastereoselectivities and enantioselec-
tivities. Further work on extending the application of
these ligands to other asymmetric organic reactions is in
progress.
[α]D20 +286.8 (c 1.13, CHCl3).
IR (KBr): 3435, 3050, 2963, 2874, 1735, 1632, 1584, 1477, 1434,
1413, 777, 744, 695, 503 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.40–6.98 (m, 28 H), 3.56–3.48
(m, 2 H), 2.63–2.60 (m, 2 H), 1.95–1.89 (m, 2 H), 1.46–1.24 (m, 8
H).
13C NMR (75 MHz, CDCl3): δ = 169.60, 142.77, 142.39, 136.71,
136.59, 136.55, 136.42, 135.04, 134.87, 134.81, 134.59, 133.88,
133.63, 133.22, 129.06, 128.78, 128.59, 128.46, 128.45, 128.43,
128.36, 128.32, 127.58, 127.50, 57.87, 47.83, 27.66, 22.80.
31P NMR (121 MHz, CDCl3): δ = –11.68.
MS (ESI): m/z = 717.5 [M + H]+, 739.1 [M + Na]+.
HRMS (MALDI): m/z [M + H]+ calcd for C46H43N2O2P2: 717.2794;
found: 717.2801.
All manipulations were carried out using standard Schlenk line un-
der dry nitrogen atmosphere. Solvents were dried and freshly dis-
1
tilled under an argon atmosphere. H and 13C NMR spectra were
recorded on a Varian Mercury 300 (300 MHz) or Bruker AM 400
(400 MHz) spectrometer and referenced internally to residual pro-
tio-solvent (1H) or solvent (13C) resonances and are reported relative
to TMS. HPLC analyses were performed on an Agilent 1100 Series.
(R,R)-2,2′-Bipyrrolidine13 and 6-Me-BPBP8a were synthesized ac-
cording to the literature procedures. All other reagents were com-
mercially available and were used as received.
Ligand L2
Et3N (350 μL, 3.8 equiv) was added dropwise to a soln of (R,R)-
2,2′-bipyrrolidine (167.6 mg, 1.20 mmol) and 2-(diphenylphosphi-
no)benzyl chloride (819 mg, 2.6 mmol) in THF (7.5 mL). The mix-
ture was stirred for 3 d at r.t. The white precipitate of Et3N·HCl
formed during reaction was removed by filtration and washed with
cold THF. The filtrate was washed with H2O (2 ×) and concentrated
Ligand L1
To a soln of 2-(diphenylphosphino)benzoic acid (4.83 g, 15.8
mmol, 2.2 equiv), DMAP (cat.), and EDCI (3.30 g, 17.2 mmol, 2.4
Synthesis 2012, 44, 3307–3314
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Asymmetric [3+2] Cycloaddition of Azomethine Ylides
3311
Table 5 [3+2] Cycloaddition of 1a with 2 Catalyzed by Silver(I) Triflate/L1a
Y
Y
X
X
EWG
EWG
Ph
AgOTf (5 mol%)
L1 (5.5 mol%)
EWG
X
Y
+
Ph
N
COOMe
+
Ph
COOMe
COOMe
K2CO3 (10 mol%)
4 Å MS
N
H
N
H
1a
2
CH2Cl2, r.t., N2, 48 h
3′
3
Entry
1
Dipolarophile
Product
Yieldb (%)b
drc
eed (%)
70
COOMe
MeOOC
MeOOC
COOMe
COOMe
2a
3a
82
10.1:1
COOMe
Ph
N
H
COOMe
MeOOC
MeOOC
2
3
2b
3j
80
4.6:1
57
49
COOMe
Ph
N
H
Me
N
Me
O
O
N
2c
3k
46e
>19.0:1
O
O
O
COOMe
Ph
N
H
Ph
N
Ph
N
O
O
O
4
2d
3l
72
>19.0:1
60
COOMe
Ph
N
H
MeOOC
MeOOC
O2N
5
6
2e
2f
3m
83
12.0:1
1:1.8
61
COOMe
Ph
N
H
O2N
Ph
3n′
45f
42g
Ph
COOMe
Ph
N
H
a Ratio 1a/2/AgOTf/L1/K2CO3 = 1:1.5:0.05:0.055:0.1, CH2Cl2 (1.5 mL), 4 Å MS (150 mg).
b Combined isolated yield of endo and exo products.
c Ratio of 3/3′ determined by 1H NMR of crude reaction mixture.
d ee value of endo product.
e Starting material quantitatively recovered.
f Michael addition product was obtained in 24% yield.
g ee value of exo product 3n′.
in vacuo. After purification by flash chromatography (silica gel,
EtOAc–hexane), the desired product was obtained as a white solid
(387 mg, 47%); mp 72–74 °C.
[α]D20 +120.3 (c 0.94, CHCl3).
133.54, 129.03, 128.95, 128.69, 128.45, 128.44, 128.38, 128.36,
128.29, 126.71, 65.06, 57.45 (d, J = 20.8 Hz), 54.68, 25.81, 23.59.
31P NMR (121 MHz, CDCl3): δ = –15.33.
MS (ESI): m/z = 689.6 [M + H]+.
IR (KBr): 3445, 3051, 2959, 2786, 1585, 1432, 1115, 1092, 696,
504, 459 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.54–7.50 (m, 2 H), 7.31–7.20 (m,
22 H), 7.12–7.07 (m, 2 H), 6.85–6.81 (m, 2 H), 4.08 (d, J = 13.8 Hz,
2 H), 3.54 (d, J = 13.8 Hz, 2 H), 2.72–2.70 (m, 4 H), 1.96–1.94 (m,
2 H), 1.76–1.26 (m, 8 H).
HRMS (MALDI) : m/z [M + H]+ calcd for C46H47N2P2: 689.3209;
found: 689.3203.
α-Iminoesters 1; General Procedure
A suspension of methyl glycinate hydrochloride (1.1 equiv), excess
MgSO4, and Et3N (1.1 equiv) in CH2Cl2 (1.5 mL) was stirred at r.t.
for 1 h. Aldehyde (1.0 equiv, 28.5 mmol) was added and the mixture
was stirred at r.t. overnight. MgSO4 was removed by filtration and
the filtrate was washed with H2O (1 ×). The aqueous phase was ex-
tracted with CH2Cl2 (1 ×) and the combined organic layers were
13C NMR (75 MHz, CDCl3): δ = 145.39, 145.08, 137.88, 137.17,
137.11, 136.98, 135.51, 135.31, 134.02, 133.87, 133.77, 133.61,
© Georg Thieme Verlag Stuttgart · New York
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X. Gu et al.
PAPER
washed with brine. The organic phase was dried (anhyd Na2SO4),
filtered, and concentrated in vacuo. Products obtained were suffi-
ciently pure, but were purified by either bulb-to-bulb distillation or
trituration if necessary.
Trimethyl (2R,3S,4R,5S)-5-Phenylpyrrolidine-2,3,4-tricarbox-
ylate (3a)7g
Yield: 66.8 mg (83%); HPLC (Daicel Chiralpak IC, hexane–
i-PrOH, 70:30, 0.7 mL/min, 214 nm): tR = 38.5 (minor), 42.3 min
(major); 70% ee.
Methyl N-Benzylideneglycinate (1a)15
Yield: 4.80g (95%).
1H NMR (300 MHz, CDCl3): δ = 3.78 (s, 3 H), 4.43 (d, J = 1.2 Hz,
2 H), 7.40–7.47 (m, 3 H), 7.77–7.80 (m, 2 H), 8.30 (s, 1 H).
[α]D20 –48.1 (c 0.95, CHCl3, 70% ee).
1H NMR (300 MHz, CDCl3): δ = 1.66 (br, 1 H), 3.24 (s, 3 H), 3.56–
3.76 (m, 2 H), 3.70 (s, 3 H), 3.82 (s, 3 H), 4.17 (d, J = 8.4 Hz, 1 H),
4.50 (d, J = 6.3 Hz, 1 H), 7.27–7.34 (m, 5 H).
Methyl [(4-Methylbenzylidene)amino]acetate (1b)7d
Yield: 5.12 g (94%).
MS (ESI): m/z = 322.1 [M + H]+, 344.0 [M + Na]+.
Trimethyl (2R,3S,4R,5S)-5-(4-Methylphenyl)pyrrolidine-2,3,4-
tricarboxylate (3b)7g
Yield: 65.4 mg (78%); HPLC (Daicel Chiralpak AD-H, hexane–
i-PrOH, 80:20, 0.7 mL/min, 214 nm): tR = 28.1 min, 32.6 min (mi-
nor); 68% ee.
1H NMR (300 MHz, CDCl3): δ = 2.39 (s, 3 H), 3.78 (s, 3 H), 4.40
(s, 2 H), 7.23 (d, J = 7.5 Hz, 2 H), 7.67 (d, J = 8.1 Hz, 2 H), 8.25 (s,
1 H).
Methyl [(4-Chlorobenzylidene)amino]acetate (1c)15
Yield: 5.97 g (99%).
[α]D20 –48.2 (c 1.09, CHCl3, 68% ee).
1H NMR (300 MHz, CDCl3): δ = 3.79 (s, 3 H), 4.42 (d, J = 1.2 Hz,
2 H), 7.40 (d, J = 9.0 Hz, 2 H), 7.72 (d, J = 8.1 Hz, 2 H), 8.26 (s, 1
H).
1H NMR (300 MHz, CDCl3): δ = 2.32 (s, 3 H), 3.27 (s, 3 H), 3.55
(t, J = 8.1 Hz, 1 H), 3.68–3.74 (m, 1 H), 3.69 (s, 3 H), 3.81 (s, 3 H),
4.16 (t, J = 9.3 Hz, 1 H), 4.45 (dd, J = 6.9, 11.7 Hz, 1 H), 7.13 (d,
J = 8.1 Hz, 2 H), 7.22 (d, J = 8.1 Hz, 2 H).
Methyl [(4-Methoxybenzylidene)amino]acetate (1d)15
Yield: 5.31 g (90%).
MS (ESI): m/z = 336.0 [M + H]+.
1H NMR (300 MHz, CDCl3): δ = 3.77 (s, 3 H), 3.85 (s, 3 H), 4.39
(d, J = 0.9 Hz, 2 H), 6.93 (d, J = 9.0 Hz, 2 H), 7.73 (d, J = 8.7 Hz, 2
H), 8.22 (s, 1 H).
Trimethyl (2R,3S,4R,5S)-5-(4-Chlorophenyl)pyrrolidine-2,3,4-
tricarboxylate (3c)7g
Yield: 69.3 mg (78%); HPLC (Daicel Chiralpak IC, hexane–
i-PrOH, 70:30, 0.7 mL/min, 214 nm): tR = 17.0 (minor), 20.0 min
(major); 70% ee.
Methyl [(2-Chlorobenzylidene)amino]acetate (1e)7b
Yield: 5.73 g (95%).
1H NMR (300 MHz, CDCl3): δ = 3.80 (s, 3 H), 4.48 (d, J = 1.2 Hz,
2 H), 7.26–7.39 (m, 3 H), 8.09–8.12 (m, 1 H), 8.75 (s, 1 H).
[α]D20 –44.5 (c 0.80, CHCl3, 70% ee).
1H NMR (300 MHz, CDCl3): δ = 3.28 (s, 3 H), 3.54–3.59 (m, 1 H),
3.68–3.74 (m, 1 H), 3.70 (s, 3 H), 3.81 (s, 3 H), 4.15 (t, J = 8.7 Hz,
1 H), 4.46 (dd, J = 6.9, 10.5 Hz, 1 H), 7.30 (s, 4 H).
Methyl [(2-Methoxybenzylidene)amino]acetate (1f)15
Yield: 5.43 g (92%).
1H NMR (300 MHz, CDCl3): δ = 3.78 (s, 3 H), 3.87 (s, 3 H), 4.43
(d, J = 0.9 Hz, 2 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.99 (t, J = 7.8 Hz, 1
H), 7.41 (dt, J = 1.8, 8.4 Hz, 1 H), 8.01 (dd, J = 0.9, 7.7 Hz, 1 H),
8.73 (s, 1 H).
MS (ESI): m/z = 356.0 [M + H]+.
Trimethyl (2R,3S,4R,5S)-5-(4-Methoxyphenyl)pyrrolidine-
2,3,4-tricarboxylate (3d)7g
Yield: 74.7 mg (85%); HPLC (Daicel Chiralpak AD-H, hexane–
i-PrOH, 80:20, 0.7 mL/min, 214 nm): tR = 40.0 (minor), 46.7 min
(major); 76% ee.
Methyl [(3-Methoxybenzylidene)amino]acetate (1g)16
Yield: 4.84 g (82%).
1H NMR (300 MHz, CDCl3): δ = 3.79 (s, 3 H), 3.86 (s, 3 H), 4.43
(d, J = 0.9 Hz, 2 H), 6.99–7.03 (m, 1 H), 7.27–7.39 (m, 3 H), 8.27
(s, 1 H).
[α]D20 –53.3 (c 1.07, CHCl3, 76% ee).
1H NMR (300 MHz, CDCl3): δ = 3.27 (s, 3 H), 3.53 (t, J = 5.4 Hz,
1 H), 3.69 (t, J = 6.2 Hz, 1 H), 3.69 (s, 3 H), 3.79 (s, 3 H), 3.81 (s, 3
H), 4.14 (t, J = 6.9 Hz, 1 H), 4.44 (dd, J = 5.4, 8.4 Hz, 1 H), 7.25 (d,
J = 1.8 Hz, 2 H), 7.42 (d, J = 1.8 Hz, 2 H).
Methyl [(3-Bromobenzylidene)amino]acetate (1h)17
Yield: 6.35 g (87%).
MS (ESI): m/z = 352.1 [M + H]+.
1H NMR (300 MHz, CDCl3): δ = 3.79 (s, 3 H), 4.43 (d, J = 0.9 Hz,
2 H), 7.27–7.33 (m, 1 H), 7.56–7.60 (m, 1 H), 7.67 (d, J = 7.5 Hz, 1
H), 7.98–7.99 (m, 1 H), 8.24 (s, 1 H).
Trimethyl (2R,3S,4R,5S)-5-(2-Chlorophenyl)pyrrolidine-2,3,4-
tricarboxylate (3e)7g
Yield: 66.8 mg (75%); HPLC (Daicel Chiralpak IC, hexane–
i-PrOH, 70:30, 0.7 mL/min, 214 nm): tR = 21.3 (minor), 27.4 min
(major); 74% ee.
Methyl N-Isobutylideneglycinate (1i)7g
Yield: 2.65 g (65%).
1H NMR (300 MHz, CDCl3): δ = 1.11 (d, J = 6.9 Hz, 6 H), 2.47–
2.59 (m, 1 H), 3.75 (s, 3 H), 4.17 (s, 2 H), 7.57 (d, J = 4.8 Hz, 1 H).
[α]D20 –98.2 (c 1.04, CHCl3, 74% ee).
1H NMR (300 MHz, CDCl3): δ = 1.75 (br, 1 H), 3.18 (s, 3 H), 3.66
(s, 3 H), 3.77 (t, J = 6.9 Hz, 1 H), 3.83 (s, 3 H), 3.88 (t, J = 5.4 Hz,
1 H), 4.14 (t, J = 7.2 Hz, 1 H), 4.75 (dd, J = 4.8, 8.6 Hz, 1 H), 7.19–
7.29 (m, 2 H), 7.35 (d, J = 5.7 Hz, 1 H), 7.50 (dd, J = 1.2, 5.6 Hz, 1
H).
Pyrrolidines 3 by Silver-Catalyzed [3+2] Cycloaddition Reac-
tion; General Procedure
The catalyst was prepared by stirring AgOTf (3.3 mg, 0.0125
mmol), 4 Å molecular sieves (150 mg) and L1 (10.0 mg, 0.0138
mmol) in CH2Cl2 (1 mL) for 1 h. Imine substrate 1 (0.25 mmol) was
then added followed by the dipolarophile 2 (0.375 mmol), K2CO3
(3.6 mg, 0.025 mmol), and CH2Cl2 (1 mL). Upon consumption of
the limiting reagent, CH2Cl2 was removed under reduced pressure
and the desired product was purified by flash chromatography (sil-
ica gel, EtOAc–hexane). Absolute stereochemistry of the product
was determined by comparison of [α]D20 with the literature.7g,14
MS (ESI): m/z = 356.0 [M + H]+.
Trimethyl (2R,3S,4R,5S)-5-(2-Methoxyphenyl)pyrrolidine-
2,3,4-tricarboxylate (3f)18
Yield: 73.0 mg (83%); HPLC (Daicel Chiralpak IC, hexane–
i-PrOH, 70:30, 0.7 mL/min, 214 nm): tR = 42.0 (minor), 46.4 min
(major); 69% ee.
[α]D20 –105.7 (c 1.05, CHCl3, 69% ee).
Synthesis 2012, 44, 3307–3314
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric [3+2] Cycloaddition of Azomethine Ylides
3313
1H NMR (300 MHz, CDCl3): δ = 3.18 (s, 3 H), 3.63 (s, 3 H), 3.75–
3.85 (m, 2 H), 3.82 (s, 3 H), 3.84 (s, 3 H), 4.09 (t, J = 3.3 Hz, 1 H),
4.59 (dd, J = 4.8, 9.0 Hz, 1 H), 6.85 (d, J = 6.3 Hz, 1 H), 6.93 (t,
J = 5.7 Hz, 1 H), 7.22–7.26 (m, 1 H), 7.32 (d, J = 5.4 Hz, 1 H).
Methyl (1S,2R,4S,5R)-6,8-Dioxo-4,7-diphenyl-3,7-diazabicyc-
lo[3.3.0]octane-2-carboxylate (3l)7g
Yield: 63.1 mg (72%); HPLC (Daicel Chiralpak AD-H, hexane–
i-PrOH, 80:20, 0.7 mL/min, 214 nm): tR = 33.9 (major), 62.6 min
(minor); 60% ee.
MS (ESI): m/z = 352.0 [M + H]+.
[α]D20 –36.6 (c 1.02, CHCl3, 60% ee).
Trimethyl (2R,3S,4R,5S)-5-(3-Methoxyphenyl)pyrrolidine-
2,3,4-tricarboxylate (3g)19
Yield: 78.2 mg (89%); HPLC (Daicel Chiralpak AD-H, hexane–
i-PrOH, 80:20, 0.7 mL/min, 214 nm): tR = 34.9 (major), 55.8 min
(minor); 65% ee.
1H NMR (300 MHz, CDCl3): δ = 2.53 (br, 1 H), 3.57 (t, J = 8.4 Hz,
1 H), 3.74 (t, J = 6.9 Hz, 1 H), 3.87 (s, 3 H), 4.15 (dd, J = 4.8, 6.3
Hz, 1 H), 4.62 (dd, J = 5.4, 8.7 Hz, 1 H), 7.13–7.47 (m, 10 H).
MS (ESI): m/z = 351.0 [M + H]+.
[α]D20 –37.3 (c 1.02, CHCl3, 65% ee).
Dimethyl (2R,4R,5S)-5-Phenylpyrrolidene-2,4-dicarboxylate
(3m)7g
Yield: 54.7 mg (83%); HPLC (Daicel Chiralpak AD-H, hexane–
i-PrOH, 80:20, 0.7 mL/min, 214 nm): tR = 13.9 (major), 18.2 min
(minor); 61%.
1H NMR (300 MHz, CDCl3): δ = 1.27 (br, 1 H), 3.19 (s, 3 H), 3.58
(dd, J = 6.9, 7.8 Hz, 1 H), 3.69 (s, 3 H), 3.69–3.75 (m, 1 H), 3.80 (s,
3 H), 3.81 (s, 3 H), 4.16 (t, J = 9.6 Hz, 1 H), 4.45 (dd, J = 7.2, 11.3
Hz, 1 H), 6.80 (dd, J = 2.4, 8.0 Hz, 1 H), 6.91–6.93 (m, 2 H), 7.23
(t, J = 8.4 Hz, 1 H).
[α]D20 –8.8 (c 1.02, CHCl3, 61% ee).
MS (ESI): m/z = 352.0 [M + H]+.
1H NMR (300 MHz, CDCl3): δ = 2.42 (dd, J = 6.9, 8.0 Hz, 2 H),
3.22 (s, 3 H), 3.32 (q, J = 6.9, 1 H), 3.83 (s, 3 H), 3.99 (t, J = 8.4 Hz,
1 H), 4.54 (d, J = 8.1 Hz, 1 H), 7.23–7.32 (m, 5 H).
Trimethyl (2R,3S,4R,5S)-5-(3-Bromophenyl)pyrrolidine-2,3,4-
tricarboxylate (3h)19
Yield: 76.2 mg (76%); HPLC (Daicel Chiralpak AD-H, hexane–
i-PrOH, 80:20, 0.7 mL/min, 214 nm): tR = 24.5 (major), 35.4 min
(minor); 61% ee.
MS (ESI): m/z = 264.0 [M + H]+.
Methyl (2R,3R,4S,5R)-4-Nitro-3,5-diphenylpyrrolidine-2-car-
boxylate (3n′)14
Yield: 36.9 mg (45%); HPLC (Daicel Chiralpak AD-H, hexane–
i-PrOH, 85:15, 0.7 mL/min, 214 nm): tR = 15.8 (major), 16.7 min
(minor); 42% ee.
[α]D20 –38.5 (c 1.03, CHCl3, 61% ee).
1H NMR (300 MHz, CDCl3): δ = 1.68 (br, 1 H), 3.31 (s, 3 H), 3.58
(t, J = 7.2 Hz, 1 H), 3.70 (s, 3 H), 3.69–3.75 (m, 1 H), 3.82 (s, 3 H),
4.16 (t, J = 9.0 Hz, 1 H), 4.44 (dd, J = 6.6, 11.6 Hz, 1 H), 7.20 (t,
J = 7.8 Hz, 1 H), 7.29 (t, J = 7.8 Hz, 1 H), 7.41 (d, J = 7.8 Hz, 1 H),
7.52 (s, 1 H).
[α]D20 –28.6 (c 0.63, CHCl3, 42% ee).
1H NMR (300 MHz, CDCl3): δ = 2.74 (s, 1 H), 3.30 (s, 3 H), 4.39
(t, J = 8.4 Hz, 1 H), 4.48–4.54 (m, 1 H), 4.76 (t, J = 8.4 Hz, 1 H),
5.22 (t, J = 8.1 Hz, 1 H), 7.24–7.58 (m, 10 H).
MS (ESI): m/z = 400.0 [M + H]+.
MS (ESI): m/z = 327.0 [M + H]+.
Trimethyl (2R,3S,4R,5R)-5-Isopropylpyrrolidine-2,3,4-tricar-
boxylate (3i)7g
Yield: 34.5 mg (48%); HPLC (Phenomenex PC-1, hexane–i-PrOH,
80:20, 0.7 mL/min, 214 nm): tR = 9.3 (major), 16.4 min (minor);
16% ee.
[α]D20 –4.5 (c 0.82, CHCl3, 16% ee).
1H NMR (300 MHz, CDCl3): δ = 0.98 (d, J = 6.5 Hz, 3 H), 1.09 (d,
J = 6.5 Hz, 3 H), 1.62–1.67 (m, 1 H), 2.73–2.88 (m, 1 H), 3.18–3.22
(m, 1 H), 3.55–3.61 (m, 1 H), 3.67 (s, 3 H), 3.67 (s, 3 H), 3.76 (s, 3
H), 4.09 (t, J = 9.0 Hz, 1 H).
Acknowledgment
We grateful acknowledge the financial support from The University
of Hong Kong (University Developmental Fund), Hong Kong
Research Grants Council (HKU 1/CRF/08), NSFC 21102162,
CAS-GJHZ200816 and CAS-Croucher Funding Scheme for Joint
Laboratory.
MS (ESI): m/z = 288.0 [M + H]+.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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r
itmnatr
Trimethyl (2R,3R,4R,5S)-5-Phenylpyrrolidine-2,3,4-tricarbox-
ylate (3j)7g
Yield: 64.4 mg (80%); HPLC (Daicel Chiralpak AD-H, hexane–
i-PrOH, 80:20, 0.7 mL/min, 214 nm): tR = 16.7 (minor), 21.8 min
(major); 57% ee.
[α]D20 –13.0 (c 1.08, CHCl3, 57% ee).
1H NMR (300 MHz, CDCl3): δ = 3.21 (s, 3 H), 3.55–3.61 (m, 1 H),
3.63–3.69 (m, 1 H), 3.78 (s, 3 H), 3.84 (s, 3 H), 4.21 (t, J = 8.1 Hz,
1 H), 4.66 (t, J = 9.0 Hz, 1 H), 7.25–7.33 (m, 5 H).
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