CuII-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with a chiral ferrocene-derived P,N-ligand

Article abstract of DOI:10.1016/j.tetlet.2017.05.044

A ferrocene-derived P,N-heterodonor ligand was effectively used in a Cu(OAc)₂·H₂O-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with maleate derivatives, affording cycloadducts with high yields (up to 96%), diastereoselectivities (>99 dr), and enantioselectivities (up to 99% ee).

Full text of DOI:10.1016/j.tetlet.2017.05.044

Accepted Manuscript
CuII-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with
a chiral ferrocene-derived P,N-Ligand
Bdiri Bilel, Li Dai, Zhi-Ming Zhou
PII:
S0040-4039(17)30619-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.044
TETL 48937
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 March 2017
9 May 2017
12 May 2017
Please cite this article as: Bilel, B., Dai, L., Zhou, Z-M., CuII-catalysed asymmetric 1,3-dipolar cycloaddition of
azomethine ylides with a chiral ferrocene-derived P,N-Ligand, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.05.044
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Tetrahedron Letters
journal homepage: www.elsevier.com
CuII-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with a
chiral ferrocene-derived P,N-Ligand
Bdiri Bilela , Li Daib and Zhi-Ming Zhoua,c,
a R&D Centre of Pharmaceuticals School of Chemical Engineering and the Environment, Beijing Institute of Technology, 5th Zhongguancun South
Street,Haidian District, Beijing 100081, China
bInstitut of Process Engineering, Chinese Academy of Science, 1 North 2nd Street, Zhongguancun, Haidian District, Beijing 100190 China
c State Key Laboratory of Explosion Science and Technology, Beijing Institute of Technology, 5th Zhongguancun South Street, Haidian District, Beijing100081,
China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A ferrocene-derived P,N-heterodonor ligand was effectively used in a Cu(OAc)2.H2O-catalysed
asymmetric 1,3-dipolar cycloaddition of azomethine ylides with maleate derivatives, affording
cycloadducts with high yields (up to 96%), diastreoselectivities (>99 dr), and enantioslectivities
(up to 99% ee).
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolidine
Enantioselectivity
1,3-Dipolar Cycloaddition
Ferrocene ligand
1. Introduction
The addition of 1,3-dipoles to dipolarophiles for the synthesis of five member rings is considered one of the most efficient and
powerful approaches for the preparation of different heterocycles.1 Over the past decades, among heterocycles, pyrrolidine derivatives
have received a great deal of capital attention. The reaction between azomethine ylides and α,β-unsaturated carboxylic acid derivatives
constitutes a reliable approach to the straightforward synthesis of highly substituted pyrrolidine derivatives.2 Since the pioneering work
of Grigg in which methyl acrylate was used as the first α,β-unsaturated carboxylic acid derivative in an enantioselective 1,3-dipolar
cycloaddition (1,3-DCA),3 various dipolarophiles have been extensively investigated for the 1,3-DCA, varying from standard mono- or
double-activated α,β-unsaturated carboxylic acid derivatives (such as acrylates, vinyl sulfones, maleates, fumarates, fumarodinitriles,
and maleimides) to more complicated and challenging alkenes, paving the way to the synthesis of structurally diverse pyrrolidine
derivatives.4
The reaction of azomethine ylides generated from α-iminoesters 1 and maleate ester derivatives is a useful strategy to generate
pyrrolidines bearing up to three ester groups and four stereogenic centres. The regioselectivity of this reaction has been fully studied;
endo selectivities were reported by the groups of Zhou,5a Hu,5b Zheng,5c Wang,5d Cossío,5e Gao,5f Legault,5g and Carretero5h using
Ag(I)/P,S-ligands, Cu(I)/ImiferroS/Et3N, Ag(I)/PPFAPhos/Et3N, Ag(I)/CA-AA-AmidPhos, Cu(I)/PF-L-Proline/Et3N, Cu(I)/TF-
BiphamPhos/Et3N, Ag(I)/N-acyl iminoimidazolium ylide proligands and Cu(I)/Fesulphos/Et3N complexes respectively; on the other
hand, the groups of Kobayashi,6a Raghunath,6b and Cossío5e reported high exo selectivities using AgHMDS/(R)-DTBM-SEGPHOS,
Cu(I)/N,P-ligands/DBU and Cu(I)/PF-D-Proline/Et3N complexes, respectively.
Recently, our group has synthesised new chiral N,P oxazolinylferrocene ligand L1 (siloxane-FOXAP) and used it in the asymmetric
1,3-dipolar cycloaddition of azomethine ylides with β-CF3-β,β-disubstituted nitroalkenes affording exo-trifluoromethylated pyrrolidine
derivatives in excellent diastereo and enantioselectivities (>98:2 dr and >99.9 ee, respectively).7 We have reported that
Cu(II)/K2CO3/L1 is an efficient chiral catalytic system for the asymmetric 1,3-DCA of azomethine ylides with alkylidene malonates
———
 Corresponding author. e-mail: bdiribilel@bit.edu.cn (BdiriBilel).
 Principal corresponding author. e-mail: zzm@bit.edu.cn (Z.-M. Zhou).

2
Tetrahedron Letters
and that endo tricarboxylated pyrrolidine analogues are obtained in excellent enantioselectivities (up to 99ꢀ%ee).8 We intended to
investigate
the performance of different ferrocene ligands including L1 in the asymmetric catalysed 1,3-DCA of azomethine ylides with
fumarate 2a and maleate 2b-c ester derivatives(Fig. 1).
Figure 1. Structure of N,P oxazolinylferrocene ligands
2. Results and discussion
First, we investigated the 1,3-DCA of benzaldehyde Schiff base derivatives of glycine ethyl ester (1a) with diethyl fumarate (2a) in
the presence of the chiral complex (10 mol%) prepared from Cu(OAc)2.H2O and different ferrocene ligands, using
diisopropylethylamine (DIPEA) as base in THF at room temperature. Our investigation revealed that the reaction afforded
quantitatively the desirable cycloadduct in the presence of L1, albeit with moderate stereoselectivities (entry 1, Table 1). Encouraged by
these promising results, siloxane-FOXAP L1 was selected as the ligand of choice for further metal, solvent and base screening.
Copper salts showed a significant effect on the reaction; in the presence of Cu(OAc)2.6H2O, a mixture of diastereomers
(endo/exo=9:1) was obtained in 95% yield and low enantioselectivity [40% ee (endo)] (entry 1, Table 1). The nature of the solvent used
in the 1,3-DCA reaction proved to have a remarkable influence in both catalytic activity and enantioselectivity. Thus, the yields
dropped dramatically when ether and acetonitrile were used as solvents (entries 9 and 10, Table 1) and cycloadduct 3a was not detected
when the reaction was performed in toluene (entry 11, Table 1). Instead, the reaction proceeded smoothly in dry DCM at room
temperature and both diastereomers were obtained equally (drendo/exo= 1:1) in good yield, and with excellent enantioselectivity for the
endo-cycloadduct 3a (endo-3a 92% ee, entry 8, Table 1).
Table 1. Optimisation of the reaction conditionsa
Entry
Ligand/Metal
x
Solvent
Base
(10 mol%)
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
T (°C)
Yield (%)b
drc
ee (%)d
(mol%)
endo
40
-
exo
0
1
L1/Cu(OAc)2.H2O
L2/Cu(OAc)2.H2O
L3/Cu(OAc)2.H2O
L4/Cu(OAc)2.H2O
L5/Cu(OAc)2.H2O
L1/CuBF4
10
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t
95
n.r.
23
9:1
-
2
10
10
10
10
10
10
10
10
10
10
THF
-
3
THF
1:1
2:1
-
29
39
-
15
3
4
THF
45
5
THF
n.r.
55
-
6
THF
1:1
1:1
1:1
1:1
4:1
-
35
30
50
−72
−63
-
5
7
L1/Cu(ClO4)2. 6H2O
L1/Cu(CH3CN)4ClO4
L1/Cu(CH3CN)4ClO4
L1/Cu(CH3CN)4ClO4
L1/Cu(CH3CN)4ClO4
THF
54
0
8
THF
79
10
−10
−48
-
9
Ether
CH3CN
Toluene
r.t.
r.t.
r.t.
35
10
11
45
n.r.

12
13
14
15
16
17
18
L1/Cu(CH3CN)4ClO4
L1/Cu(CH3CN)4ClO4
L1/Cu(CH3CN)4ClO4
L1/Cu(CH3CN)4ClO4
L1/Cu(CH3CN)4ClO4
L1/Cu(CH3CN)4ClO4
L1/Cu(OAc)2.H2O
10
10
10
10
5
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DIPEA
K2CO3
r.t.
r.t
r.t
r.t
r.t
-5
-5
75
80
1:1
1:1
92
86
50
29
CH3CO2Na
Cs2CO3
Cs2CO3
Cs2CO3
TEA
20
1:1
90
45
65
1:1
94
29
66
1:1
95
30
5 (4)e
71 (69)e
1:1 (1:1)e
96 (93)e
30(30)e
5
70
3:1
91
73
aReaction conditions: 1a (0.8 mmol), 2a (1.2 mmol), ligand 1 (10 mol%) and base (10 mol%) in 2.0 mL solvent at room temperature overnight.
bIsolated yield. cDetermined by chiral HPLC. dDetermined by chiral HPLC. eCatalyst loading (4 mol%)
We next investigated the effect of base additives. Cs2CO3 was found to be the best base additive, superior to all other organic and
inorganic bases tested, such as DIPEA, K2CO3, and CH3CO2Na (entries 12–15, Table 1). Lowering the amount of catalyst loading to 5
mol% did not affect significantly the yield or enantioselectivity of the reaction (entry 16, Table1). However, reducing both the catalyst
loading (5 mol%) and the temperature of the reaction (−5 °C), slightly increased the yield (71%) and enantioselectivity (96% ee) of
endo-cycloadduct 3a (entry 17, Table 1). Instead, we observed that Schiff base derived from 2-naphthaldehyde provided good to
excellent enantioselectivities for both endo- and exo-3e diasteromers (98% and 70% ee, respectively), albeit with low
diastereoselectivity (dr endo/exo= 1:1, entry 3, Table 2). Similarly, low diastereoselectivities were previously reported by the teams of
Gao9b and Kobayashi9a when fumarate ester derivatives were used as activated olefins. After column chromatography separation of the
diastereomeric mixtures of 3b and 3e, their stereochemistry was confirmed by comparing to spectroscopic (1H NMR, J values and
NOESY spectrum) and chromatographic data already well-established in the literature (see the Supporting Information).10-11
Table 2. Asymmetric 1,3-DCA of 1 with diethyl fumarate 2aa
Entry
Substrate (R)
Product
Yieldb
(%)
94
drc
ee (%)d
endo
exo
1
2
3
1b (p-BrC6H4)
1c (p-Me C6H4)
1d (2-naphthyl)
3b
3c
3e
1:1
1:1
1:1
83
81
98
19
-
86
91
70
aReaction conditions: 1a (0.8 mmol), 2a (1.2 mmol), Cu(CH3CN)4ClO4 (5 mol%), ligand L1 (5mol%) and Cs2CO3 (10 mol%) in 2.0 mL DCM at −5 C.
bIsolated yield.
cDetermined by 1H NMR spectroscopy of the crude product.
dDetermined by chiral HPLC.
Following the unsuccessful attempts to improve the diastereoselectivities, we continued our investigation by switching the nature of
the dipolarophile from diethyl fumarate (2a) to diethyl maleate (2b) (Table 3). The results in the Table 1 indicate that Cu(OAc)2.H2O
exhibits better diastereoselectivity (drendo/exo= 9:1) than Cu(CH3CN)4ClO4 (entries 1 and 4, Table 1). Based on the observation that the
nature of copper salt influences drastically the stereoselectivities, the reaction of 1d and 2b gave exclusively the exo-cycloadduct 4b
(drexo/endo >99, entries 3 and 5, Table 3) when Cu(OAc)2.H2O was used as salt instead of Cu(CH3CN)4ClO4. The reaction proved to be
highly sensitive to the base additive. Thus, the use of DIPEA and tBuOK resulted in decreased yields and enantioselectivities (54−85%
and 63−65% ee, respectively, entries 4 and 5, Table 3). Instead, in the presence of Et3N (entry 3, Table 3), 4b was obtained in excellent
yield and diastereo- and enantioselectivity (96%, drexo/endo >99 and 96% ee, respectively).
Table 3. Optimization of 1,3-DCA between 1d and diethyl maleate 2ba
Entry
Metal
Base
Yieldb
(%)
90
drc
ee (%)
(exo)d,e
75
1
2
3
4
Cu(CH3CN)4ClO4
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cs2CO3
Cs2CO3
Et3N
65:35
90:10
>99:<1
20:1
91
84
96
96
tBuOK
85
63

4
Tetrahedron Letters
5
Cu(OAc)2.H2O
DIPEA
54
>99:<1
65
aReaction conditions: 1d (0.8 mmol), 2b (1.2 mmol), copper salt (5 mol%), ligand 1 (5mol%) and base (10 mol%) in 2.0 mL DCM at −5 C.
bIsolated yield.
cDetermined by 1H NMR spectroscopy.
d Determined by chiral HPLC.
With the optimal reaction conditions in hand, we examined the scope of the substrates and the results are summarised in Table 4.
First, several Schiff bases derivatives of glycine methyl ester were screened against diethyl maleate (2b) in the presence of Cu(II)/L1
complex. High to excellent yields of exclusive exo-adducts were obtained exclusively in most cases (except for entries1 and 11: drexo/endo
=20:1, Table 4). The nature and the position of the substituents on the phenyl group of the Schiff base proved to have a remarkable
influence in both catalytic activities and stereoselectivities. Thus, electron-withdrawing substituents in para- or meta-positions on the
aromatic ring, such as halogens or amino groups, gave almost identical results to iminoester 1a, and the desired products were obtained
quantitatively in excellent enantio and diastereoselectivities (89−95% yield, 91−95% ee and >99 dr, respectively; entries 2, 4, 6, 10 and
12, Table 4). On the other hand, under the same reaction conditions the reactions did not reach completion when bromo, methoxy and
chloro meta-substituted substrates were used, and the corresponding cycloadducts 4hb, 4ib, and 4lb were obtained in lower yields
(40−65%; entries 7, 8, and 11, Table 4). 2-Naphthyl and 1-bromo-2-naphthyl substituted substrates 1d and 1f performed well, giving
exo-pyrrolidine derivatives in high yields and enantioselectivities (75−96% and 91−96% ee, respectively; entries 3, 5 and 16, Table 4).
The highest ee (99%) was obtained with N-(4-nitrobenzylidene) glycine methyl ester 1o (entry 14, Table 4). Unfortunately, Schiff bases
derived from salicylic aldehyde derivatives (1q-s) were not suitable for the 1,3-DCA reaction, probably because the free hydroxyl group
inhibits the catalytic activity of the chiral complex.
.Table 4: Cu-catalysed asymmetric 1,3-DCA: scope of azomethine ylides and maleate ester derivativesa
Entry
R1/ R2
R3
Adduct
Yieldb
(%)
63
drc
eed
(%)
91
91
96
91
91
90
82
92
95
81
83
95
92
>99
65
1
Ph/Me (1a)
Et (2b)
Et (2b)
Et (2b)
Et (2b)
Et (2b)
Et (2b)
Et (2b)
Et (2b)
Et (2b)
Et (2b)
Et (2b)
Me(2c)
Me(2c)
Me(2c)
Me(2c)
Me(2c)
Et (2b)
Et (2b)
Et (2b)
4ab
4bb
4db
4eb
4fb
4gb
4hb
4ib
20: 1
2
p-Br C6H4/Me (1b)
2-naphthyl/Me (1d)
p-F C6H4/Me (1e)
90
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
20:1
3
96
4
94
5
1-Br-2-naphthyl/Me (1f)
p-ClC6H4/Me (1g)
2,4-di-ClC6H3/Me (1h)
o-Br C6H4/Me (1i)
2,4-di-F-C6H4/Me (1j)
m-BrPh /Me (1k)
81
6
90
7
65
8
55
9
4jb
4kb
4lb
91
10
11
12
13
14
15
16
17
18
19
95
2,3-di-MeO-C6H3/Me (1l)
p-N(CH3)2C6H4/Et (1m)
Ph/Et (1n)
40
4mc
4nc
4oc
4pc
89
>99:<1
>99:<1
>99:<1
>99:<1
65
p-NO2C6H4/Et (1o)
Ph/Me (1p)
95
60
2-naphthyl/Me (1d)
o-OHC6H4/Me (1q)
3-Br-2-OH-C6H3/Me (1r)
3-NO2-2-OH- C6H3/Me (1s)
4dc
75
20: 1
91
___
___
___
n.r.
n.r.
n.r.
___
___
___
___
___
___
aAll the reactions were carried out under the optimised reaction conditions: 5 mol % of Cu(OAc)2.H2O, 5 mol % of L1, and 10 mol % of Et3Nin DCM at −5 °C
overnight.
bIsolated yields after column chromatography.
cDetermined by 1H NMR spectroscopic analysis of the crude product.
d Determined by chiral HPLC.
We rationalised the regioselectivity of this reaction, based on our previously proposed computational model.8

Figure 2. Proposed transition state leading to the major exo
product 4
The azomethine ylide, generated from the α-imino ester, coordinates to the Cu(II) catalyst in a distorted tetrahedral geometry. In this
complex, the ylide adopts an orientation in which the electrostatic and steric repulsion between the phenyl rings linked to the
phosphorus atom and the aromatic ring of the azomethine ylide are minimized as shown in Fig. 2. In the adopted geometry, the Re face
of the azomethine ylide is shielded by the phenyl and trimethylsilyl groups (shown in yellow). Therefore, we postulated that the Si face
is more accessible for the nucleophilic attack on the activated alkene 2b affording exclusively the exo- pyrrolidine derivatives 4.
3. Conclusion
In conclusion, Cu(OAc)2.H2O siloxane-FOXAP complex was found to be an efficient catalyst for the asymmetric 1,3-dipolar
cycloadditon of azomethine ylides with dimethyl maleate giving the cycloadducts in high exo-selectivities (up to >99 dr) and good to
excellent enantioselectivities (up to 99% ee). Studies regarding further applications of these ferrocenyl P,N-ligands in other type of
asymmetric reactions are currently in progress.
4. Experimental
4.1. General methods
1
All reactions were performed under an atmosphere of argon using oven-dried glassware. H NMR spectra were recorded in CDCl3
on a Bruker Avance DRX 500 spectrometer. 1H chemical shifts are reported in ppm relative to CHCl3 (7.26 ppm), 13C chemical shifts
are reported relative to the central peak of CDCl3 (77.0 ppm). Data are reported either as: s = singlet, d = doublet, dd =double doublet, t
= triplet, q = quartet, m = multiplet, br = broad, coupling constants are given in Hz. High resolution mass spectra (HRMS) experiments
were performed on an Agilent 6520 UHD Accurate-Mass Q-TOF LC/MS system. IR spectra were recorded on a Bruker Alpha-p
spectrometer. Reactions were monitored by thin layer chromatography (TLC) using silica gel plates. Flash column chromatography was
performed over silica gel (200-300 mesh).
The enantiomeric excess (ee) of the products was determined by HPLC using Daicel Chiralpak OJ-H, AD-H and ChiralcelOD-H
columns with 2-propanol/hexane as eluent
4.2. General procedure for the Cu(II)-catalysed 1,3-DCA reactions
Cu(OAc)2.H2O (7.9 mg, 0.04 mmol) and Ligand 1 (23.4 mg, 0.04 mmol) were added under argon to a 10 mL Schlenk tube,
containing activated 4 Å MS. Freshly distilled anhydrous DCM (1 mL) was added into the tube and the resulting mixture was stirred for
60 min at room temperature. The reaction mixture was cooled to 0 °C and α-imino ester 1 (0.8 mmol), olefins 2b or 2c (1.2 mmol) and
Et3N (10 μL, 0.08 mmol) were added subsequently. The reaction mixture was stirred overnight at −5 °C. The reaction was monitor by
TLC and upon completion the mixture was passed through a short column of silica gel and the diastereomeric ratio (exo/endo) was
determined by 1H NMR spectroscopic analysis of the crude product. The pure adducts were then purified by column chromatography on
silica gel (200-300 mesh).
4.3. Characterization data of product
1
13
All the products were characterized by H NMR, C NMR, HRMS
(ESI) and IR. The copies of NMR and HRMS charts were reported in Supplementary Data.
4.3.1. (2R,3R,4S,5S)-3,4-diethyl2-methyl 5-phenylpyrrolidine-2,3,4-tricarboxylate (4ab)
Yellow sticky oil: Yield 63%; ee = 91%; 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 7.4 Hz, 2H), 7.32 (t, J = 7.3 Hz, 2H), 7.26 (q, J = 7.1 Hz, 1H), 4.68
(d, J = 6.6 Hz, 1H), 4.38 (s, 1H), 4.16 (dd, J = 13.9, 6.9 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 3.60 (dd, J = 6.9, 3.8 Hz, 1H), 3.24 (t, J = 7.9
Hz, 1H), 2.77 (br, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 173.10, 171.16, 171.09, 128.50, 127.70,

6
Tetrahedron
126.98, 64.67, 61.95, 61.30, 60.96, 54.42, 52.52, 49.89, 14.05. IR (KBr) υ 2982, 1731, 1439, 1372, 1267, 1178, 911, 729, 700 cm-1. HRMS Calcd. For
C18H24NO6+ [M+H]+:350.1604; found: 350.1588. HPLC (Chiralpak AD-H column, hexane/2-propanol = 70/30, flow rate = 1 mL/min) tR = 9.48 min,
12.98 min.
4.3.2 (2R,3R,4S,5S)-3,4-diethyl2-methyl 5-(4-bromophenyl) pyrrolidine-2,3,4-tricarboxylate (4bb)
Brown sticky oil: Yield 90%; ee = 91%; 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 4.63 (d, J = 7.6 Hz, 1H), 4.32
(d, J = 5.1 Hz, 1H), 4.14 (qd, J = 7.1, 3.7 Hz, 2H), 4.08 (qd, J = 7.1, 1.4 Hz, 2H), 3.76 (s, 3H), 3.56 (dd, J = 8.5, 5.6 Hz, 1H), 3.15 (t, J = 8.2 Hz, 1H),
2.75 (br, 1H)1.23 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 173.05, 171.00, 170.81, 140.85, 131.47, 128.84, 121.43,
63.75, 61.76, 61.33, 61.02, 54.29, 52.49, 49.70, 14.05. IR (KBr) υ 2982, 1730, 1486, 1439, 1373, 1176, 1009, 910, 729 cm-1. HRMS Calcd. For
C18H23BrNO6+ [M+H]+:428.0709; found: 428.0690. HPLC (Chiralpak AD-H column, hexane/2-propanol = 70/30, flow rate = 1 mL/min) tR = 13.15
min, 14.38 min.
4.3.3 (2R,3R,4S,5S)-3,4-diethyl2-methyl 5-(naphthalen-2-yl) pyrrolidine-2,3,4-tricarboxylate (4db)
Colorless oil: Yield 96%; ee = 96%; 1H NMR (500 MHz, CDCl3) δ 7.97 – 7.41 (m, 7H), 4.58 (d, J = 12.4 Hz, 1H), 4.31 (d, J = 6.8 Hz, 1H), 4.36 – 4.05
(m, 4H), 3.81 (s, 3H), 3.64 (dd, J = 41.9, 9.6 Hz, 1H), 3.53 (s, 1H),, 2.94 (s, 1H), 1.29 (t, J = 6.3 Hz, 3H), 1.15 (t, J = 6.1 Hz, 3H). 13C NMR (126 MHz,
CDCl3) δ 172.13, 172.09, 171.22, 135.40, 133.10, 132.97, 127.98, 127.89, 127.56, 126.22, 126.05, 125.63, 65.49, 63.34, 61.56, 60.76, 53.71, 52.65,
51.13, 14.19, 13.42. IR (KBr) υ 2962, 1732, 1433, 1368, 1203, 1013, 818, 741, 551cm-1. HRMS Calcd. For C22H26NO6+ [M+H]+:400.1760 ; found:
400.1680. HPLC (Chiralpak OD-H column, hexane/2-propanol = 80/20, flow rate = 0.5 mL/min) tR = 31.11 min, 34.46 min.
4.3.4 (2R,3R,4S,5S)-3,4-diethyl2-methyl 5-(4-fluorophenyl) pyrrolidine-2,3,4-tricarboxylate (4eb)
Light yellow oil: Yield 94%; ee = 90.6%; 1H NMR (500 MHz, CDCl3) δ 7.45 – 7.39 (m, 2H), 6.97 (t, J = 8.3 Hz, 2H), 4.64 (d, J = 7.3 Hz, 1H), 4.31 (d,
J = 3.2 Hz, 1H), 4.16 – 4.11 (m, 2H), 4.07 (dd, J = 13.9, 6.8 Hz, 2H), 3.76 (s, 3H), 3.58 – 3.53 (m, 1H), 3.15 (t, J = 8.1 Hz, 1H), 2.75 (br, 1H), 1.23 (t, J
= 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 173.10, 172.11, 171.07, 163.20, 161.24, 137.40, 128.71, 128.65, 115.26,
115.09, 63.77, 63.77, 61.76, 61.76, 54.39, 52.45, 49.74, 13.99. IR (KBr) υ 2983, 1730, 1605, 1509, 1373, 1179, 1094, 1016, 836, 731 cm-1. HRMS
Calcd. For C18H23FNO6+ [M+H]+:368.1509; found: 368.1342. HPLC (Chiralpak OJ-H column, hexane/2-propanol = 70/30, flow rate = 1 mL/min) tR
= 9.08 min, 14.31 min.
4.3.5 (2R,3R,4S,5S)-3,4-diethyl 2-methyl5-(1-bromonaphthalen-2-yl) pyrrolidine-2,3,4-tricarboxylate (4fb)
Brown oil: Yield 81%; ee = 90.6%; 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 13.3, 8.4 Hz, 2H),
7.54 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 5.42 (s, 1H), 4.55 (d, J = 5.1 Hz, 1H), 4.16 (dt, J = 13.2, 6.6 Hz, 4H), 3.81 (s, 3H), 3.60 (t, J = 8.2 Hz,
1H), 3.34 (dd, J = 7.5, 4.0 Hz, 1H), 2.91 (br, 1H), 1.22 (dd, J = 10.7, 6.8 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 173.13, 171.76, 170.44, 139.85,
132.16, 128.15, 128.03, 127.44, 127.35, 126.53, 125.62, 122.99, 64.36, 61.93, 61.21, 53.97, 52.47, 48.89, 14.07. IR (KBr) υ 2982, 1731, 1438, 1373,
1259, 1179, 1027, 908, 819, 513 cm-1. HRMS Calcd. For C22H25BrNO6+[M+H]+:480.0845; found: 480.0825. HPLC (Chiralpak AD-H column,
hexane/2-propanol = 70/30, flow rate = 1 mL/min) tR = 11.73 min, 17.70 min.
4.3.6 (2R,3R,4S,5S)-3,4-diethyl2-methyl 5-(4-chlorophenyl) pyrrolidine-2,3,4-tricarboxylate (4gb)
Yellow oil: Yield 90%; ee = 90.4%; 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 4.64 (d, J = 7.2 Hz, 1H), 4.32 (d,
J = 2.7 Hz, 1H), 4.18 – 4.11 (m, 1H), 4.11 – 4.04 (m, 1H), 3.77 (s, 1H), 3.56 (dd, J = 8.2, 5.2 Hz, 1H), 3.15 (t, J = 8.1 Hz, 1H), 2.70 (br, 1H), 1.24 (t, J
= 7.1 Hz, 2H), 1.19 (t, J = 7.1 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 173.09, 171.05, 170.86, 128.53, 128.49, 63.73, 61.78, 61.34, 61.02, 54.36,
53.52, 52.50, 49.73, 14.03. IR (KBr) υ 2983, 1729, 1603, 1506, 1365, 116, 1084, 1009, 820 cm-1. HRMS Calcd. For C18H23ClNO6+
[M+H]+:384.1214; found: 384.1196. HPLC (Chiralpak AD-H column, hexane/2-propanol = 70/30, flow rate = 1 mL/min) tR = 17.63 min, 21.36 min.
4.3.7 (2R,3R,4S,5S)-3,4-diethyl2-methyl 5-(2,4-dichlorophenyl) pyrrolidine-2,3,4-tricarboxylate (4hb)
1
Orange sticky oil: Yield 65%; ee = 81.8%; H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 7.24 (d, J = 8.3 Hz, 1H), 5.01 (d, J =
3.1 Hz, 1H), 4.45 (d, J = 8.7 Hz, 1H), 4.19 – 4.07 (m, 4H), 3.78 (s, 3H), 3.46 (t, J = 8.3 Hz, 1H), 3.20 (dd, J = 7.6, 3.6 Hz, 1H), 2.76 (br, 1H), 1.22 (q, J
= 7.2 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 173.13, 171.61, 170.24, 139.05, 133.63, 133.18, 129.77, 129.07, 127.31, 61.57, 61.23, 60.91, 53.40,
52.45, 48.50, 14.01. . IR (KBr) υ 2982, 1730, 1588, 1466, 1373, 1179, 1096, 1047, 911, 825, 730 cm-1. HRMS Calcd. For C18H22Cl2NO6+
[M+H]+:418.0824; found: 418.0807. HPLC (Chiralpak AD-H column, hexane/2-propanol = 70/30, flow rate = 1 mL/min) tR = 8.36 min, 10.68 min.
4.3.8 (2R,3R,4S,5S)-3,4-diethyl2-methyl 5-(2-bromophenyl) pyrrolidine-2,3,4-tricarboxylate (4ib)
1
Colorless sticky oil: Yield = 55%; ee = 91.6%; H NMR (500 MHz, CDCl3) δ 7.77 – 7.74 (m, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H),
7.14 – 7.09 (m, 1H), 5.05 (d, J = 3.6 Hz, 1H), 4.49 (d, J = 9.0 Hz, 1H), 4.22 – 4.10 (m, 4H), 3.80 (s, 3H), 3.51 (t, J = 8.5 Hz, 1H), 3.26 (dd, J = 8.0, 3.7
Hz, 1H), 2.88 (br, 1H), 1.24 (q, J = 7.3 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 173.11, 171.79, 170.32, 141.75, 132.72, 128.97, 128.90, 127.70, 63.54,
61.75, 61.19, 53.63, 52.44, 48.46, 14.11, 14.05. IR (KBr) υ 2982, 1730, 1483, 1439, 1372, 1178, 1021, 911, 728, 647 cm-1. HRMS Calcd. For
C18H23BrNO6+ [M+H]+:428.0709; found: 428..0690. HPLC (Chiralpak AD-H column, hexane/2-propanol = 70/30, flow rate = 1 mL/min) tR = 8.56
min, 12.06 min.

4.3.9 (2R,3R,4S,5S)-3,4-diethyl2-methyl 5-(2,4-difluorophenyl) pyrrolidine-2,3,4-tricarboxylate (4jb)
Light yellow oil: Yield = 91%; ee = 94.6%; 1H NMR (500 MHz, CDCl3) δ 7.63 (dd, J = 15.2, 8.5 Hz, 1H), 6.87 (dd, J = 11.6, 4.8 Hz, 1H), 6.80 – 6.75
(m, 1H), 4.92 (d, J = 4.3 Hz, 1H), 4.39 (d, J = 5.6 Hz, 1H), 4.16 (ddd, J = 16.8, 7.1, 2.3 Hz, 3H), 3.81 (s, 3H), 3.57 (dd, J = 13.7, 6.8 Hz, 1H), 3.28 (dd,
J = 8.1, 6.5 Hz, 1H), 2.83 (br, 1H), 1.25 (dt, J = 14.4, 7.1 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 163.36 (d, JCF = 12.1 Hz), 161.35 (dd, JCF = 12.0, 8.4
Hz), 159.34 (d, JCF = 11.9 Hz), 129.80 (dd, JCF = 9.6, 5.7 Hz), 111.41 (d, JCF= 3.5 Hz), 111.24 (d, JCF = 3.5 Hz), 103.71 (t, JCF= 25.6 Hz), 61.73, 61.32,
61.17, 58.27, 53.38, 52.54, 49.28, 14.04, 13.99. IR (KBr) υ 2983, 1732, 1616, 1502, 1435, 1373, 1180, 1026, 965, 013, 848, 816, 713 cm-1. HRMS
Calcd. For C18H22F2NO6+ [M+H]+:386.1415; found: 386.1398. HPLC (Chiralpak AD-H column, hexane/2-propanol = 80/20, flow rate = 1 mL/min)
tR = 11.75 min, 18.46 min.
4.3.9 (2R,3R,4S,5S)-3,4-diethyl 2-methyl 5-(3-bromophenyl) pyrrolidine-2,3,4-tricarboxylate (4kb).
Colorless oil: Yield = 95%; ee = 81.2%; 1H NMR (500 MHz, CDCl3) δ 7.67 (s, 1H), 7.52 (dd, J = 11.7, 5.3 Hz, 1H), 7.29 (dd, J = 8.6, 6.1 Hz, 1H), 7.20
(t, J = 7.8 Hz, 1H), 4.68 (d, J = 6.8 Hz, 1H), 4.47 (d, J = 6.0 Hz, 1H), 4.20 – 4.10 (m, 4H), 3.82 (s, 3H), 3.25 (dd, J = 11.8, 4.9 Hz, 1H), 3.24 – 3.20 (m,
1H), 1.27 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 172.97, 171.04, 170.52, 144.28, 131.23, 130.76, 130.04, 126.77,
126.31, 122.59, 63.81, 61.84, 61.40, 61.14, 52.62, 51.44, 47.61, 14.08. IR (KBr) υ 2982, 1731, 1594 1570, 1434, 1176, 1023, 997, 909, 784, 694 cm-1.
HRMS Calcd. For C18H23BrNO6+ [M+H]+:428.0709; found: 428.0686. HPLC (Chiralpak AD-H column, hexane/2-propanol = 90/10, flow rate = 1
mL/min) tR =17.43 min, 27.57 min.
4.3.10 (2R,3R,4S,5S)-3,4-diethyl 2-methyl 5-(2,3-dimethoxyphenyl) pyrrolidine-2,3,4-tricarboxylate (4lb).
Light red oil: Yield = 40%; ee = 83.2%; 1H NMR (500 MHz, CDCl3) δ 7.13 – 7.09 (m, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.88 (dt, J = 8.1, 4.0 Hz, 1H), 4.93
(d, J = 6.0 Hz, 1H), 4.47 (d, J = 8.1 Hz, 1H), 4.13 (ddd, J = 14.3, 8.8, 5.3 Hz, 4H), 4.00 (s, 3H), 3.92 (s, 3H), 3.57 (t, J = 8.5 Hz, 1H), 3.36 (dd, J = 8.9,
6.0 Hz, 1H), 3.06 (s, 3H), 1.25 (t, J = 3.6 Hz, 3H), 1.23 (t, J = 5.1 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 172.71, 171.73, 170.65, 152.48, 146.63,
124.17, 119.20, 118.11, 62.36, 61.96, 61.23, 61.00, 60.69, 56.05, 55.81, 53.37, 52.55, 49.64, 14.07, 14.05. . IR (KBr) υ 2981, 1733, 1690, 1585, 1480,
1376, 1263, 1173, 1065, 1000, 910, 748cm-1. HRMS Calcd. For C20H28NO8+ [M+H]+:410.1815; found: 410.1797. HPLC (Chiralpak column,
hexane/2-propanol = 70/30, flow rate = 1 mL/min) tR = 11.03min, 15.03min.
4.3.11 (2R,3R,4S,5S)-2-ethyl 3,4-dimethyl 5-(4-(dimethylamino)phenyl) pyrrolidine-2,3,4-tricarboxylate (4mc)
Dark red oil: Yield = 89%; ee = 95.2%; 1H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 8.7 Hz, 2H), 4.58 (d, J = 8.2 Hz, 1H), 4.33
(d, J = 3.7 Hz, 1H), 4.26 (ddd, J = 9.2, 7.6, 2.6 Hz, 2H), 3.73 (s, 3H), 3.64 (s, 3H), 3.59 (dd, J = 10.5, 5.5 Hz, 1H), 3.23 (t, J = 8.7 Hz, 1H), 3.09 (s, 1H),
2.94 (s, 3H), 2.93 (s, 3H), 1.32 (d, J = 6.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 172.78, 172.54, 171.85, 171.71, 150.21, 127.79, 127.65, 112.62,
112.26, 64.47, 62.02, 61.58, 52.37, 52.04, 51.69, 50.25, 40.64, 40.56, 14.18. (KBr) υ 2951, 1732, 1614, 1523, 1435, 1347, 1165, 1036, 946, 805 cm-1.
HRMS Calcd. For C19H27N2O6+ [M+H]+:379.1869; found: 410.1849. HPLC (Chiralpak AD-H column, hexane/2-propanol = 70/30, flow rate = 1
mL/min) tR = 11.43 min, 25.81 min.
4.3.12 (2R,3R,4S,5S)-2-ethyl 3,4-dimethyl phenylpyrrolidine-2,3,4-tricarboxylate (4nc)
1
Ligh yellow oil: Yield = 65%; ee = 92.4%; H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 7.3 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.25 (d, J = 7.3 Hz, 1H),
4.66 (s, 1H), 4.34 (d, J = 1.9 Hz, 1H), 4.24 (qd, J = 7.1, 2.8 Hz, 2H), 3.70 (s, 3H), 3.63 (s, 3H), 3.62 – 3.58 (m, 1H), 3.24 (t, J = 8.3 Hz, 1H), 2.78 (br,
1H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 172.48, 171.61, 141.31, 128.52, 127.76, 126.96, 64.51, 62.01, 61.53, 54.33, 52.38, 52.09,
49.92, 14.16. (KBr) υ 2982, 1732, 1440, 1370, 1265, 1170, 910, 715 cm-1. HRMS Calcd. For C17H22NO6+ [M+H]+:336.1444; found: 336.1428. HPLC
(Chiralpak AD-H column, hexane/2-propanol = 90/10, flow rate = 1 mL/min) tR = 11.90 min, 19.93 min.
4.3.13 (2R,3R,4S,5S)-2-ethyl 3,4-dimethyl 5-(4-nitrophenyl)pyrrolidine-2,3,4-tricarboxylate (4oc)
Dark red sticky oil: Yield 95%; ee = 99.8%; 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 4.84 (d, J = 8.0 Hz, 1H),
4.35 (d, J = 4.5 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 3.67 (s, 3H), 3.63 (dd, J = 8.2, 5.0 Hz, 1H), 3.25 (dd, J = 9.7, 6.4 Hz, 1H), 2.91 (br, 1H),
1.32 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 172.43, 171.48, 170.99, 149.55, 129.00, 128.16, 123.65 (s), 61.93 (s), 61.71, 54.24, 52.57,
52.12, 49.70, 14.17. (KBr) υ 2955, 1730, 1600, 1519, 1436, 1345, 1196, 1014, 853, 699 cm-1. HRMS Calcd. For C17H21N2O8+ [M+H]+:381.1298;
found: 381.1277. HPLC (Chiralpak AD-H column, hexane/2-propanol = 70/30, flow rate = 1 mL/min) tR = 16.28 min, 20.03 min.
4.3.14 (2R,3R,4S,5S)-trimethyl 5-phenylpyrrolidine-2,3,4-tricarboxylate (4pc).
Ligh yellow oil: Yield = 60%; ee = 65.8%; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 7.3 Hz, 2H), 7.24 (t, J = 7.4 Hz, 2H), 7.18 (d, J = 7.5 Hz, 1H),
4.58 (d, J = 7.6 Hz, 1H), 4.29 (d, J = 5.9 Hz, 1H), 3.71 (br, 3H), 3.63 (s, 3H), 3.56 (s, 3H), 3.55 – 3.52 (m, 1H), 3.17 (dd, J = 10.7, 6.0 Hz, 1H), 2.62 (s,
1H).13C NMR (101 MHz, CDCl3) δ 171.97, 170.60, 170.55, 140.28, 127.53, 126.75, 125.90, 63.55, 60.80, 53.34, 51.52, 51.37, 51.07, 48.79. (KBr) υ
2982, 1730, 1436, 1265, 1180, 1025, 908, 705 cm-1.HRMS Calcd. For C16H20NO6+ [M+H]+:322.1291; found: 322.1271. HPLC (Chiralpak AD-H
column, hexane/2-propanol = 70/30, flow rate = 1 mL/min) tR = 10.23 min, 12.81 min.
4.3.15 (2R,3R,4S,5S)-trimethyl 5-(naphthalen-2-yl)pyrrolidine -2,3,4-tricarboxylate (4dc).
Colorless oil: Yield = 75%; ee = 91.2%; 1H NMR (500 MHz, CDCl3) δ 7.94 (s, 1H), 7.84 (dd, J = 9.0, 5.4 Hz, 3H), 7.60 (dd, J = 8.5, 1.5 Hz, 1H), 7.50
– 7.47 (m, 2H), 4.87 (d, J = 7.8 Hz, 1H), 4.48 (d, J = 6.1 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.71 (dd, J = 8.9, 6.1 Hz, 1H), 3.68 (s, 3H), 3.40 (t, J = 8.2
1H), 2.94 (br, 1H). 13C NMR (126 MHz, CDCl3) δ 172.96, 171.63, 171.57, 138.45, 133.28, 133.12, 128.47, 128.06, 127.64, 126.17, 126.10, 125.99,
124.79, 64.76, 61.87, 54.24, 52.64, 52.48, 52.18, 49.79. (KBr) υ 2952, 1730, 1620, 1508, 1434, 1359, 1198, 1173, 1015, 820, 747, 478 cm-1. HRMS
Calcd. For C20H22NO6+ [M+H]+:372.1447; found: 372.1442. . HPLC (Chiralpak AD-H column, hexane/2-propanol = 70/30, flow rate = 1 mL/min)
tR = 16.35 min, 18.20 min.
References and notes
1. Selected recent reviews for the asymmetric synthesis of diver heterocycles via 1,3-dipolar cycloaddition, see:
a.
Brittain WDG, Buckley BR, Fossey JS. Acs Catal. 2016; 6: 3629−3636;

8
Tetrahedron
b.
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i.
Hosamani B, Ribeiro MF, Da Silva Júnior EN, Namboothiri INN. Org Biomol Chem. 2016; 14: 6913–6931;
Hashimoto T, Maruoka K. Chem Rev. 2015; 115: 5366−5412;
Zheng Z-J, Wang D-W, Xu Z, Xu L-W, Beilstein J Org Chem. 2015, 11: 2557–2576 ;
J. Li, H. Zhao, Y. Zhang, Synlett. 2015, 26, 2745–2750;
Singh MS, Chowdhury S, Koley S, Tetrahedron. 2016; 72: 1603-1644;
H. Pellissier. Tetrahedron. 2015; 71: 8855-8869;
Ryan JH, Arkivoc. 2015: 160-183;
Tao H-Y, Wang C-J, Synlett. 2014; 25: 461–465;
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Zhang W. Chem Lett. 2013; 42: 676-681.
2. Selected recent examples for 1,3-dipolar cycloaddition of azomethine ylides with α,β-unsaturated carboxylic acid derivatives, see:
a.
b.
c.
d.
e.
Wang H-F, Deng Q-F, Zhou Z-P, Hu S-Q, Liu Z-G, Zhou L-Y. Org Lett. 2016; 18: 404−407;
Bai X-F, Zhang J, Xia C-G, Xu J-X, Xu L-W. Tetrahedron, 2016; 72: 2690-2699;
Tada A, Watanabe S, Kimura M, Tokoro Y, Fukuzawa S. Tetrahedron Lett. 2014; 55:6224–6226.
Xue Z-Y, Xiong Y, Wang C-Y, Synlett. 2014; 25: 2733–2737.
J. Mancebo-Aracil, A. Cayuelas, C. Nájera, J. M. Sansano, Tetrahedron 2015; 71: 8804-8816.
3.
4.
Allway P, Grigg R, Tetrahedron Lett. 1991; 32: 5817-5820.
Selected reviews for 1,3-dipolar cycloaddition of azomethine ylides with α,β-unsaturated carboxylic acid derivatives, see:
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Stanley LM, Sibi MP, Chem. Rev. 2008; 108: 2887-2902;
Nájera C, Sansano JM, Top Heterocycl Chem. 2008, 12, 117-145.
5.
selected examples for endo-selective 1,3-DCA of azomethine ylides with maleate ester derivatives, see:
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b.
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f.
Zeng W, Zhou Y-G, Tetrahedron Lett. 2007; 48: 4619–4622;
Han F-Z, Yu S-B, Zhang C, Hu X-P, Tetrahedron. 2016; 72: 2616-2622;
Yu S-B, Hua X-P, Deng J, Wang D-Y, Duan Z-C, Zheng Z. Tetrahedron: Asymmetry. 2009; 20: 621–625;
Wang H-F, Deng Q-F, Zhou Z-P, Hu S-Q, Liu Z-G, Zhou L-Y. Org Lett. 2016;18, 404−407;
Conde E, Bello D, de Cózar A, Sánchez M,. Vázquez MA. Cossío FP. Chem Sci. 2012; 3: 1486–1491;
Wang C-J, Liang G, Xue Z-Y, Gao F. J Am Chem. Soc. 2008; 130:17250–17251;
Guernon H, Legault CY. Organometallics. 2013; 32: 1988−1994;
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Martín-Matute B, Pereira SI, Peña-Cabrera E, Adrio J, Silva AMS, Carretero JC. Adv Synth Catal. 2007; 349:1714 – 1724.
6.
selected examples for exo-selective 1,3-DCA of azomethine ylides with maleate ester derivatives, see:
a.
b.
Yamashita Y, Imaizumi T, Guo X-X, Kobayashi S. Angew Chem Int Ed. 2011; 50: 4893 –4896;
Gao W-Z, Zhang X-M, Raghunath M. Org Lett. 2005; 19: 4241-4244.
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Tang. T-W, Zhao B-J, Dai L, Zhang M, Zhou Z-M. Chem Asian J. 2016; 16: 2470–2477.
Dai L, Xu D, Tang L-W, Zhou Z-M. Chem Cat Chem. 2015;7 :1078-1082.
selected examples for exo-selective 1,3-DCA of azomethine ylides with maleate ester derivatives, see:
a.
b.
Yamashita Y, Imaizumi T, Guo X-X, Kobayashi S. Angew Chem Int Ed. 2011; 50: 4893 –4896;
Gao W-Z, Zhang X-M, Raghunath M. Org Lett. 2005; 19: 4241-4244
10. Fukuzawa S-I, Oki H. Org. Lett. 2008; 10: 1747-1750.
11. Zeng W. Zhou Y-G. Org. Lett. 2005;7: 5055-5058.

Highlights



The regioselectivity is controlled by stepwise cis-cycloaddition pathway.
The diastereoselectivities are sensitive to the nature of Copper salt.
The stereoselectivities of 1,3-DCA reaction are sensitive to the structure of oxazoline ring

10
Tetrahedron
CuII-catalysed asymmetric 1,3-dipolar cycloaddition
of azomethine ylides with a chiral ferrocene-derived
P,N-Ligand
Leave this area blank for abstract info.
Bdiri Bilel, Dai Li and Zhi-Ming Zhou