A class of α-amino acids-derived multifunctional amidophosphane precatalysts: application to the highly enantio- and diastereoselective silver(I)-catalyzed 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1016/j.tetasy.2017.05.014

A class of multifunctional amidophosphanes derived from chiral α-amino acids have been developed with two amide bonds, a tertiary amine and a phosphine. In combination with Ag(I) salts, these amidophosphanes have been demonstrated as highly efficient multifunctional catalysts in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides as well as the three-component reaction of the α-iminoesters in situ generated. Under optimal conditions, highly functionalized endo-8 pyrrolidines were obtained with good to excellent yields (up to 99% yield) and enantioselectivities (up to 98% ee).

Full text of DOI:10.1016/j.tetasy.2017.05.014

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A class of
a-amino acids-derived multifunctional amidophosphane
precatalysts: application to the highly enantio- and
diastereoselective silver(I)-catalyzed 1,3-dipolar cycloaddition
reaction
Yihui Hou a,b,y, Zhipeng Zhou b,y, Pingle Liu a, Jiankang Wang b, Qinglin Hou b, Pushan Wen b,
Haifei Wang b,
⇑
a College of Chemical Engineering, Xiangtan University, Xiangtan 411105, Hunan Province, PR China
b College of Life Science and Chemistry, Hunan University of Technology, Zhuzhou 412007, Hunan Province, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A class of multifunctional amidophosphanes derived from chiral
with two amide bonds, a tertiary amine and a phosphine. In combination with Ag(I) salts, these ami-
dophosphanes have been demonstrated as highly efficient multifunctional catalysts in the asymmetric
a-amino acids have been developed
Received 21 March 2017
Revised 14 May 2017
Accepted 23 May 2017
Available online xxxx
1,3-dipolar cycloaddition of azomethine ylides as well as the three-component reaction of the
a-imi-
noesters in situ generated. Under optimal conditions, highly functionalized endo-8 pyrrolidines were
obtained with good to excellent yields (up to 99% yield) and enantioselectivities (up to 98% ee).
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
cycloaddition reaction, there remains a need for new catalytic sys-
tems that can be easily prepared with different phosphanes and
Nitrogen-containing five-membered heterocycles, in particular
highly substituted pyrrolidines, are widely present in many biolog-
ically active natural products and pharmaceutically useful agents.1
Among the developed methodologies for the synthesis of highly
substituted pyrrolidines, the asymmetric 1,3-dipolar cycloaddition
reaction is one of the most powerful tools for the convergent con-
struction of optically active pyrrolidine derivatives due to the
can tolerate variation of both the dipole and the dipolarophile
components.
In previous papers, amidophosphanes have been successfully
used as effective ligands in asymmetric reactions.11 Recently, we
have made a breakthrough in the use of cinchona alkaloid-amino
acids-derived amidophosphanes serving as the desired multifunc-
tional precatalysts in combination with transition-metal ions to
cooperatively catalyze 1,3-dipolar cycloadditions of azomethine
ylides with high diastereo- and enantioselectivities.12 In view of
the excellent performance of amidophosphane, it was necessary
to develop a different skeleton type of multifunctional amidophos-
diverse and readily available 1,3-dipoles (three-atom, 4
p systems)
and dipolarophiles (two-atom, 2
p
systems).2 Since the first cat-
alytic asymmetric 1,3-dipolar cycloaddition reported by Zhang
et al. employing the AgOAc/xylyl-FAP/i-Pr2NEt system,3 several
effective chiral metal complex catalysts of silver,4 copper,5 zinc,6
nickel,7 calcium,8 gold9 and organocatalysts10 have thus far been
reported to catalyze the process with high endo/exo diastereo-
and enantioselectivities. Among the chiral metal complex catalysts,
these chiral ligands are mainly focused on the bidentate ligands of
bisphosphanes, nitrogenated phosphanes, sulfur-containing phos-
phanes, bisimines, and N,O-ligands, which easily form relatively
rigid and stable complexes with metal cations. Despite these
impressive achievements of the catalytic systems in the 1,3-dipolar
phanes and expand its application prospects. The chiral
acids are not only rich in source, but also inexpensive and easily
available. Herein we report a class of double -amino acids-
a-amino
a
derived multifunctional amidophosphanes containing two amide
bonds as the H-bond donors, a tertiary amine as a base and a phos-
phine ligand in combination with Ag(I) to cooperatively catalyze
1,3-dipolar cycloadditions of azomethine ylides as well as the
three-component reactions of the a-iminoesters generated in situ
and gram-scale synthesis of endo-adducts with high to excellent
diastereo- and enantioselectivities.
⇑
Corresponding author. Tel.: +86 731 22183793.
E-mail address: whf2107@hotmail.com (H. Wang).
These authors contributed equally to this work.
y
http://dx.doi.org/10.1016/j.tetasy.2017.05.014
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
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2
Y. Hou et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
2.2. Screening of the amidophosphanes and solvents
2. Results and discussion
The selected 1,3-dipolar cycloaddition of azomethine ylides 7a
and diethyl maleate 6 was first carried out in toluene at room tem-
perature using 4 mol % of amidophosphane 5a and 2 mol % of
Ag2CO3 with 75% yield and low enantioselectivity (ꢀ31% ee), only
the endo-isomer 8a was detected by 1H NMR analysis of reaction
mixtures (Table 1, entry 1). For obtaining higher yields and enan-
tioselectivities in the cycloaddition, the effect of amidophosphanes
2.1. Synthesis of
a
-amino acid-derived amidophosphanes 5a–g
The synthesis of natural chiral
a
-amino acid-derived ami-
dophosphane precatalysts 5a–g is straightforward and is outlined
in Scheme 1. Chiral diamines 3 were prepared via a three step reac-
tion sequence starting from N-Boc-(S)-phenylglycine 1a or N-Boc-
(S)-tert-leucine 1b according to the reported procedures.13 On the
one hand, diamine 3a was reacted with 2-(diphenylphosphino)
benzoic acid to give the amidophosphane precatalyst 5a. On the
other hand, precatalysts 5b–g were prepared starting from dia-
mide intermediates 4b–g according to the reported procedures
by our group.12
5b–f derived from double
a-amino acids on the conversions and
the enantioselectivities was also investigated in toluene (Table
1). The amidophosphane 5b derived from (S)-phenylglycine and
(S)-tert-leucine was used, and an improvement in enantioselectiv-
ity was observed (ꢀ69% ee, entry 2). Under the same conditions,
N
NHBoc
O
O
Ph2P
H
N
R1
b, e
NH
NH2
d
c
NH2
a, b
NHBoc
H
N
R2
N
N
N
HO
R1
R1
4b g
O
R1
O
R1
1
O
2
-
R2
5b-g
3
1 = Ph;
= t-Bu
1a:
1b:
R
R
1
5b: R1 = Ph; R2 = (S)-t-Bu
1
e
3a
, R = Ph
: R1 = Ph; R2 = (R)-t-Bu
: R1 = t-Bu; R2 = (R)-t-Bu
5c
5d
5e: R1 = Ph; R2 = (R)-i-Pr
5f: R1 = Ph; R2 = (R)-Ph
5g: R1 = Ph; R2 = (S)-Ph
Ph2P
H
N
N
Ph
O
5a
Scheme 1. Synthesis of
a-amino acid-derived amidophosphane precatalysts 5a–g. Reagents: a) Me2NHꢁHCl, HBTU, i-Pr2NEt, CH2Cl2; b) TFA, CH2Cl2; c) Et2O, LiAlH4; d) HBTU,
i-Pr2NEt, CH2Cl2, N-Boc-amino acid; e) HBTU, i-Pr2NEt, CH2Cl2, 2-(diphenylphosphino)benzoic acid.
Table 1
Screening Studies of the 1,3-dipolar cycloaddition of azomethine ylide 7a with diethyl maleate 6a
CO2Et
CO2Me
5
precatalyst (4 mol%)
EtO2C
Ph
CO2Et
Ag(I) (4 mol%)
+
Ph
N
CO2Me
solvent, rt
2-4 h
N
CO2Et
H
7a
Metal
endo-8a
6
Entry
Precatalyst
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5f
5f
5f
5f
5f
5f
5f
5f
5f
5f
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2O
AgOAc
AgOCOPh
AgF
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
CH2Cl2
MTBE
EtOAc
Toluene
Toluene
75
78
92
95
97
97
93
95
68
88
95
36
86
89
88
81
67
ꢀ31
ꢀ69
88
50
75
93
ꢀ92
92
9
66
50
83
32
63
90
79
93
10
11
12
13
14
15
17d
18e
93
a
b
c
Conditions: iminoester 7a (0.3 mmol), diethyl maleate 6 (0.2 mmol), Ag(I) (4 mol %), precatalyst 5 (4 mol %), toluene (1.4 ml).
Isolated yield based on 6.
Determined by HPLC.
The reaction was run at 0 °C for 3 h.
The reaction was run ꢀ5 °C for 8 h.
d
e
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Y. Hou et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
when the amidophosphane 5c derived from (S)-phenylglycine and
(R)-tert-leucine was used, the higher enantioselectivity and the
opposite absolute configuration were observed (88% ee, entry 3).
However, further tuning of the steric hindrance at the amino acid
moiety did not result in better enantioselectivity when using cata-
lyst 5d derived from (S)-tert-leucine and (R)-tert-leucine compared
to amidophosphane 5c (50% ee, entry 4). Amidophosphane 5e with
the (S)-phenylglycine and (R)-valine incorporated was also not
very effective (75% ee, entry 5). We were pleased to find that the
amidophosphane 5f, with the (S)-phenylglycine and (R)-phenylgly-
cine incorporated, afforded the desired adduct in 97% yield and
with 93% ee (entry 6). Furthermore, when the amidophosphane
5g derived from double (S)-phenylglycine was used as a diastereo-
meric ligand of 5f, excellent enantioselectivity (ꢀ92% ee) was
obtained with the opposite configuration.
To further understand the role of silver salts, Ag2O, AgOAc, AgO-
COPh, and AgF were investigated in the cycloaddition of 7a with
diethyl maleate 6 using the Ag(I)/5f/toluene system at room tem-
perature (Table 1, entries 8–11). Unfortunately, higher enantiose-
lectivities were not obtained. Therefore, Ag2CO3 proved to be an
efficient Lewis acid in this reaction. Next, solvent and temperature
effects were also studied (Table 1, entries 12–18). The reaction pro-
ceeded well in CH2Cl2, MTBE and EtOAc, and low activity was
observed in THF. The highest enantioselectivity was obtained in
toluene. Moreover, lowering the reaction temperature from room
temperature to 0 °C or ꢀ5 °C had a detrimental effect on the yield
(81% or 57% yield) with prolonged reaction time, albeit with no loss
of enantioselectivity (Table 1, entries 17–18). Thus, the optimal
conditions for the asymmetric 1,3-dipolar cycloaddition of azome-
thine ylides were Ag2CO3/5f or 5g/toluene at room temperature.
ditions.14 As shown in Table 2,
a
-iminoesters 7a–f from aromatic
aldehydes with different steric hindrance and electronic properties
reacted with diethyl maleate 6 to afford the corresponding endo-
8a–f exclusively in high yields (82–99%) and with excellent enan-
tioselectivities (92–96% ee) in the presence of precatalyst 5f
(entries 1–6). Notably, a-iminoesters 7g–i containing heteroatoms
in their aromatic rings also worked well without a significant loss
in the yields (82–99%) or enantioselectivities (92–98% ee, entries
7–9). However, when
a-iminoesters 7j–k containing an aliphatic
group were used, the endo-8j–k were obtained with decreased
enantioselectivities (64–69% ee) and moderate yields (46–51%) in
24 h (entries 10–11). The scopes and limitations of the protocol
with regards to the 2-substituted azomethine ylides 7l–q and
diethyl maleate 6 were also explored in a similar manner (entries
12–17). The reaction of iminoesters 7l–p derived from alanine with
diethyl maleate 6 using Ag2CO3/5f catalytic system led to pyrrolidi-
nes 8l–p with a quaternary center at the 2-position with sole endo-
selectivities and excellent enantioselectivities ranging from 93% to
96% ee (entries 12–16). The iminoester 7q derived from phenylala-
nine was also examined, but required prolonged reaction time and
yielded the cycloaddition product with
a
slightly lower
enantioselectivity (82% ee, entry 17). When precatalyst 5g was
used, reversal of the absolute configuration was successfully real-
ized with excellent levels of yields (84–94%) and enantioselectivi-
1. H2NCH2COOMe
MgSO4, toluene
rt, 8h
CO2Et
EtO2C
Ar
CO2Me
ArCHO
N
6
2. diethyl maleate
precatalyst 5f (4 mol%)
Ag2CO3 (2 mol%)
toluene, 2-4h
H
endo-8
8a, 82% yield, 90% ee (Ar = Ph)
8b
, 80% yield, 89% ee (Ar = 4-CH3C6H4)
8d, 76% yield, 93% ee (Ar = 4-FC6H4)
8e
2.3. Asymmetric 1,3-dipolar cycloaddition reactions
, 84% yield, 92% ee (Ar = 4-ClC6H4)
8f
,
86% yield, 92% ee (Ar = 2-naphthyl)
1,3-Cycloaddition reactions of various iminoesters 7 and diethyl
maleate 6 was investigated under the optimized experimental con-
Scheme 2. Ag(I)-catalyzed three-component reaction of the
generated.
a-iminoesters in situ
Table 2
Ag2CO3/5f catalyzed enantioselective cycloaddition of various iminoesters 7a–7p with
diethyl maleate 6a
CO2Et
R4
R4
EtO2C
R3
CO2Et
5f
5g
(4 mol%)
or
CO2Me
R3
N
CO2Me
+
Ag2CO3 (2 mol%)
toluene, rt
N
H
CO2Et
6
7
8
endo-
Entry
7 (R3/R4)
Precatalyst
Time(h)
8, yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
7a (Ph/H)
7b (4-CH3C6H4/H)
5f
5f
5f
5f
5f
5f
5f
5f
5f
5f
5f
5f
5f
5f
5f
5f
5f
5g
5g
5g
2
2
2.5
2
1
3
6
6
5
8a, 97
8b, 99
8c, 90
8d, 82
8e, 99
8f, 88
8g, 88
8h, 94
8i, 73
8j, 54
8k, 46
8l, 90
8m, 84
8n, 78
8o, 83
8p, 82
8q, 74
8b, 94
8c, 87
8d, 84
93
92
96
94
93
94
95
92
98
69
64
93
93
96
94
94
82
7c (4-CH3OC6H4/H)
7d (4-FC6H4/H)
7e (4-ClC6H4/H)
7f (2-naphthyl/H)
7g (2-furyl/H)
7h (2-thienyl/H)
7i (3-pyridyl/H)
7j (cyclohexyl/H)
7k (t-BuCH2/H)
7l (Ph/Me)
7m (4-CH3C6H4/Me)
7n (4-FC6H4/Me)
7o (4-BrC6H4/Me)
7p (2-naphthyl/Me)
7q (Ph/Bn)
7b (4-CH3C6H4/H)
7c (4-CH3OC6H4/H)
7d (4-FC6H4/H)
9
10
11
12
13
14
15
16
17
18
19
20
24
24
20
36
18
18
24
56
2
ꢀ93
ꢀ96
ꢀ95
2
1.5
a
b
c
Conditions: iminoester 7 (0.3 mmol), diethyl maleate 6 (0.2 mmol), Ag2CO3 (2 mol %), precatalyst 5f or 5g (4 mol %), toluene (1.4 ml).
Isolated yield based on 6.
Determined by HPLC.
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4
Y. Hou et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
CO2Et
CO2Me
precatalyst 5f (2 mol%)
EtO2C
Ag2CO3 (1 mol%)
CO2Et
Ph
N
CO2Me
+
toluene (20 mL)
rt, 3 h
N
Ph
CO2Et
H
7a (4.4 mmol)
6 (4 mmol)
8a
endo- , 1.312g, 94% yield, 91% ee
Scheme 3. Ag2CO3/5f-catalyzed the gram-scale synthesis of endo-8a.
Ph
O
4. Experimental
4.1. General
CO2Me
CO2Me
N
MeO2C
Ph
MeO2C
Ph
O
CO2Me
N
H
CO2Me
N
N
H
H
Ph
8t
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded on Bruker AV-400 or 500 spectrometers in CDCl3 unless
otherwise noted. CDCl3 served as internal standard (d = 7.26) for
1H NMR and (d = 77.0) for 13C NMR. High-performance liquid chro-
matography was carried out using a Agilent 1260 apparatus which
equipped with a spectrophotometric detector (monitoring at 205–
230 nm) using Daicel chiral AS-H column, OD-H column and AD-H
column. High resolution mass spectrometry was recorded with a
Micromass LCMS-IT-TOF instrument. Optical rotations were mea-
sured on a Insmark IP-digi300/2 polarimeter.
8r, yield: 96 %
, yield: 94 %
ee: 62 %
8s, yield: 84 %
ee: 92 %
ee: 40 %
Figure 1. Cycloaddition of 7a with other dipolarophiles.
ties (93–96% ee) in the reaction of iminoesters 3bꢀd and diethyl
maleate regardless of electron-rich or electron-deficient groups
on the phenyl ring of iminoesters 7 (entries 18–20).
Multicomponent reactions are a powerful chemical tool for the
preparation of complex molecules owing to their atom and step
economy.15 We then turned our attention to evaluate the three-
All reactions were carried out under an N2 atmosphere in oven
dried glassware with magnetic stirring. All solvents employed in
the reactions were distilled from appropriate drying agents prior
to use. Organic solutions were concentrated under reduced pres-
sure on a Büchi rotary evaporator. Reactions were monitored by
thin-layer chromatography (TLC) on silica gel precoated glass
plates (qingdaohaiyang GF254). Chromatograms were visualized
by fluorescence quenching with UV light at 254 nm or potassium
permanganate stains. Flash column chromatography was per-
formed using silica gel 200–300 (particle size 0.0040–
0.0750 mm) from Qingdaohaiyang. Silver Carbonate and HBTU
component 1,3-dipolar cycloaddition of
a-iminoesters generated
in situ from aromatic aldehydes and free glycine dissolved in
toluene with diethyl maleate 6 in a one-pot fashion. As shown in
Scheme 2, regardless of the substituent on the benzene ring with
different steric hindrance and electronic properties, benzaldehyde
derivatives successfully furnished five-membered heterocycles
with satisfactory yields (76–84%) and slightly decreased enantios-
electivities (89–93% ee). To further evaluate the practicality of this
cycloaddition reaction, we carried out the reaction on a gram scale.
As shown in Scheme 3, there was no change in reactivity and
almost no influence on the chemical yield (94%) and enantioselec-
tivity (91% ee) by using a lower catalyst loading of precatalyst 5f
(2 mol %) and Ag2CO3 (1 mol %) to afford 1.312 g of endo-8a at a
slightly higher concentration (0.2 M), thus indicating that this pro-
tocol should have potential for large-scale chemical productions of
the highly substituted pyrrolidine derivatives.
[O-(Benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium
hexafluo-
rophosphate] were purchased from Adamas-betaÒ Co., Ltd. Primary
amino acids were purchased from TCI Co., Ltd, and 2-
(diphenylphosphino)benzoic acid was purchased from Aldrich
Co., Ltd. The data for compounds endo-8a–s were consistent with
previously reported values.12,16
We also studied three other dipolarophiles as outlined in
Figure 1. Dimethyl maleates are popular dipolarophiles in the liter-
4.2. General procedure I: Synthesis of diamide intermediate 4
ature and were used to react with a-iminoester 7a with 96% yield
To a solution of the compound 2a or 2b (2 mmol) freshly pre-
pared from the (S)-phenylglycine or (S)-tert-leucine according to
the reported procedures in THF (5 mL),13 LiAlH4 (4 equiv) was
added in portions at 0 °C. The reaction was stirred at 0 °C for
30 min and then at RT for 30 min, after which the mixture was
heated at reflux for 2 h. The reaction was then cooled, quenched
with water, and the suspension obtained was filtered over Celite
(washings with CH2Cl2). The combined organic extracts were dried
over MgSO4, filtered and concentrated under reduced pressure to
afford the crude amine 3a or 3b as a colourless oil without purifi-
cation for the next reaction. Dipeptides 4b–4f were prepared
according to the reported procedures, starting from 3 to yield the
desired product.
and 92% ee. For methyl acrylate, relatively low reactivity was
observed with 84% yield and 40% ee. N-Phenylmaleimide also only
gave the endo-adduct 8t in 94% yield and with 62% ee.
3. Conclusion
In conclusion, we have developed
a-amino acids-derived ami-
dophosphanes, which were then used as multifunctional precata-
lysts in combination with silver carbonate to cooperatively
catalyze the 1,3-dipolar cycloaddition of azomethine ylides, fur-
nishing substituted pyrrolidines in high yields and with excellent
enantioselectivities under mild conditions, especially for hetero-
cyclic and 2-substituted azomethine ylides. The procedure is easy
to perform and allows for the rapid, diversity-oriented, and enan-
tioselective synthesis of pyrrolidine derivatives. In addition, the
catalytic system, Ag2CO3/5f has also been successfully applied in
4.2.1. tert-Butyl((S)-1-(((S)-2-(dimethylamino)-1-phenylethyl)-
amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate 4b
30
White solid, yield: 671 mg (89%); Mp = 117–120 °C; [
a
]
=
D
+18.9 (c 1.06, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.31–7.20
(m, 5H), 6.74 (br, 1H), 5.19 (d, J = 9.6 Hz, 1H), 4.76 (t, J = 5.2 Hz,
1H), 3.90 (d, J = 9.2 Hz, 1H), 2.54 (dd, J = 12.0, 11.2 Hz, 1H), 2.38
(dd, J = 12.8, 4.8 Hz, 1H), 2.22 (s, 6H), 1.43 (s, 9H), 1.01 (s, 9H);
13C NMR (100 MHz, CDCl3): d 170.9, 156.0, 141.0, 128.5, 127.2,
the three-component reaction of
a-iminoesters generated in situ
and the gram-scale synthesis of endo-adduct 8a without a serious
loss of enantioselectivity. Further investigations of multifunctional
amidophosphane in this field of catalysis are currently ongoing and
will be reported in due course.
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Y. Hou et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
126.0, 79.5, 64.6, 62.4, 52.0, 45.2, 34.3, 28.3, 26.5; HRMS (ESI):
4.3.1. (S)-N-(2-(Dimethylamino)-1-phenylethyl)-2-
(diphenylphosphino)benzamide 5a
calcd for C21H35N3O3 [M+H]+ 378.2751, found 378.2753.
White solid, yield: 325 mg (72%); Mp = 56–61 °C; [
a
]
30 = +7.2 (c
D
4.2.2. tert-Butyl((R)-1-(((S)-2-(dimethylamino)-1-phenylethyl)-
0.21, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.70–7.68 (m, 1H),
7.41–7.19 (m, 17H), 6.98–6.95 (m, 1H), 6.82 (br, 1H), 4.94 (dd,
J = 10.0, 5.2 Hz, 1H), 2.45 (dd, J = 12.4, 10.0 Hz, 1H), 2.37 (dd,
J = 12.4, 5.6 Hz, 1H), 2.12 (s, 6H); 13C NMR (100 MHz, CDCl3): d
168.9, 142.2, 141.9, 141.0, 137.6, 137.5, 137.2, 137.0, 135.6,
135.4, 134.4, 133.9, 133.7, 130.1, 128.8, 128.7, 128.6, 128.6,
128.5, 128.4, 128.3, 128.2, 127.0, 126.4, 64.4, 52.6, 45.3; 31P NMR
(162 MHz, CDCl3): d ꢀ10.9; HRMS (ESI): calcd for C29H29N2O1P1
[M+H]+ 453.2090, found 453.2092.
amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate 4c
30
White solid, yield: 686 mg (91%); Mp = 158–159 °C; [
a]
=
D
+35.2 (c 0.91, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.33–7.21
(m, 5H), 6.66 (br, 1H), 5.24 (d, J = 9.2 Hz, 1H), 4.79 (dd, J = 10.0,
4.8 Hz, 1H), 3.88 (d, J = 9.2 Hz, 1H), 2.59 (dd, J = 12.4, 10.4 Hz,
1H), 2.40 (dd, J = 12.4, 5.2 Hz, 1H), 2.22 (s, 6H), 1.43 (s, 9H), 0.96
(s, 9H); 13C NMR (100 MHz, CDCl3): d 171.2, 155.8, 141.1, 128.5,
127.3, 126.4, 79.5, 64.4, 62.3, 52.4, 45.2, 34.7, 28.3, 26.6; HRMS
(ESI): calcd for C21H35N3O3 [M+H]+ 378.2751, found 378.2754.
4.3.2. N-((S)-1-(((S)-2-(Dimethylamino)-1-phenylethyl)amino)-
3,3-dimethyl-1-oxobutan-2-yl)-2-(diphenylphosphino)
benzamide 5b
4.2.3. tert-Butyl((R)-1-(((S)-1-(dimethylamino)-3,3-dimethylbutan-
2-yl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate 4d
White solid, yield: 628 mg (88%); Mp: 92–94 °C; [
a
]
30 = +26.7 (c
White solid, yield: 446 mg (79%); Mp = 63–70 °C; [a]
30 = +11.2
D
D
1.20, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 5.78 (br, 1H), 5.23 (d,
J = 8.8 Hz, 1H), 3.91–3.82 (m, 1H), 2.51 (br, 1H), 2.37–2.29 (m,
1H), 2.27–2.25 (m, 1H), 2.14 (s, 6H), 1.42 (s, 9H), 1.02 (s, 9H),
0.90 (s, 9H); 13C NMR (100 MHz, CDCl3): d 171.3, 155.9, 79.6,
63.1, 59.0, 54.6, 45.3, 34.4, 34.1, 28.3, 26.7; HRMS (ESI): calcd for
(c 0.60, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.53–7.50 (m, 1H),
7.36–7.18 (m, 17H), 6.99–6.96 (m, 1H), 6.89 (br, 1H), 6.57 (d,
J = 9.2 Hz, 1H), 4.79 (dd, J = 10.4, 5.2 Hz, 1H), 4.47 (d, J = 9.6 Hz,
1H), 2.57 (dd, J = 12.4, 10.4 Hz, 1H), 2.41 (dd, J = 12.4, 5.2 Hz, 1H),
2.23 (s, 6H), 0.97 (s, 9H); 13C NMR (100 MHz, CDCl3): d 170.2,
169.0, 141.7, 141.4, 140.8, 137.6, 137.5, 137.4, 136.3, 136.1,
134.6, 133.8, 133.7, 133.6, 133.5, 130.2, 128.8, 128.5, 128.5,
128.4, 127.4, 127.4, 127.2, 126.2, 64.5, 61.2, 52.1, 45.2, 34.7, 26.5;
C
19H39N3O3 [M+H]+ 358.3064, found 358.3060.
4.2.4. tert-Butyl((R)-1-(((S)-2-(dimethylamino)-1-phenylethyl)-
amino)-3-methyl-1-oxobutan-2-yl)carbamate 4e
31P NMR (162 MHz, CDCl3): d –10.6; HRMS (ESI): calcd for C35H40
-
30
White solid, yield: 624 mg (86%); Mp = 124–125 °C. [
a]
=
N3O2P1 [M+H]+ 566.2931, found 566.2935.
D
+42.3 (c 1.33, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.40–7.18
(m, 5H), 6.82 (br, 1H), 5.12 (d, J = 7.6 Hz, 1H), 4.84–4.81 (m, 1H),
4.01–3.97 (m, 1H), 2.59 (dd, J = 12.4, 10.8 Hz, 1H), 2.40 (dd,
J = 12.8, 5.2 Hz, 1H), 2.23 (s, 6H), 2.13 (br, 1H), 1.44 (s, 9H), 0.93
(d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 171.7, 155.9, 141.2, 128.5, 127.3, 126.3, 79.6, 64.5, 59.8,
52.0, 45.2, 31.3, 28.3, 19.3, 17.6; HRMS (ESI): calcd for
4.3.3. N-((R)-1-(((S)-2-(Dimethylamino)-1-phenylethyl)amino)-
3,3-dimethyl-1-oxobutan-2-yl)-2-(diphenylphosphino)
benzamide 5c
White solid, yield: 423 mg (75%); Mp = 52–54 °C; [a]
30 = +31.7
D
(c 0.83, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.62–7.59 (m, 1H),
7.39–7.21 (m, 17H), 7.00–6.97 (m, 2H), 6.73 (d, J = 8.8 Hz, 1H),
4.81 (dd, J = 10.0, 4.8 Hz, 1H), 4.42 (d, J = 8.8 Hz, 1H), 2.63 (dd,
J = 12.4, 10.8 Hz, 1H), 2.38 (dd, J = 12.4, 5.2 Hz, 1H), 2.21 (s, 6H),
0.91 (s, 9H); 13C NMR (100 MHz, CDCl3): d 170.5, 168.8, 141.5,
141.3, 141.1, 137.5, 137.4, 137.3, 136.3, 136.1, 134.5, 133.8,
133.6, 130.3, 128.8, 128.6, 128.6, 128.5, 128.5, 127.6, 127.5,
127.3, 126.5, 64.3, 61.3, 52.4, 45.1, 34.8, 26.7; 31P NMR
(162 MHz, CDCl3): d ꢀ10.5; HRMS (ESI): calcd for C35H40N3O2P1
[M+H]+ 566.2931, found 566.2935.
C
20H33N3O3 [M+H]+ 364.2595, found 364.2597.
4.2.5. tert-Butyl ((R)-2-(((S)-2-(dimethylamino)-1-phenylethyl)-
amino)-2-oxo-1-phenylethyl)carbamate 4f
White solid, yield: 674 mg (85%); Mp = 74–79 °C; [
a
]
30 = ꢀ39.1
D
(c 0.82, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.43–7.22 (m,
10H), 6.95 (br, 1H), 5.95 (br, 1H), 5.22 (d, J = 3.6 Hz, 1H), 4.65 (dt,
J = 9.6, 4.8 Hz, 1H), 2.48 (dd, J = 12.4, 10.4 Hz, 1H), 2.32 (dd,
J = 12.4, 5.2 Hz, 1H), 1.98 (s, 6H), 1.41 (s, 9H); 13C NMR
(100 MHz, CDCl3): d 170.2, 155.1, 140.9, 138.8, 128.8, 128.4,
128.0, 127.2, 127.0, 126.0, 79.7, 64.0, 58.4, 52.1, 44.7, 29.6, 28.2;
4.3.4. N-((R)-1-(((S)-1-(Dimethylamino)-3,3-dimethylbutan-2-
yl)amino)-3,3-dimethyl-1-oxobutan-2-yl)-2-
(diphenylphosphino)benzamide 5d
HRMS (ESI): calcd for
398.2440.
C
23H31N3O3 [M+H]+ 398.2438, found
White solid, yield: 371 mg (68%); Mp = 78–85 °C; [a]
30 = +10.7
D
(c 0.60, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.60–7.57 (m, 1H),
7.41–7.37 (m, 1H), 7.35–7.29 (m, 7H), 7.26–7.23 (m, 4H), 7.03–
7.00 (m, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.44 (br, 1H), 4.39 (d,
J = 8.4 Hz, 1H), 3.94 (dd, J = 11.2, 4.0 Hz, 1H), 2.49 (dd, J = 12.0,
11.2 Hz, 1H), 2.32 (dd, J = 12.4, 4.0 Hz, 1H), 2.19 (s, 6H), 0.95 (s,
9H), 0.93 (s, 9H); 13C NMR (100 MHz, CDCl3): dd 170.8, 169.1,
142.1, 141.9, 137.3, 137.2, 137.1, 137.0, 135.6, 135.4, 134.6,
133.7, 133.7, 133.5, 130.3, 129.0, 128.7, 128.6, 128.6, 128.5,
127.7, 127.6, 62.1, 59.0, 54.6, 45.3, 34.5, 34.2, 26.8, 26.8; 31P
NMR (162 MHz, CDCl3): d –11.6; HRMS (ESI): calcd for C33H44N3O2-
P1 [M+H]+ 546.3244, found 546.3249.
4.2.6. tert-Butyl ((S)-2-(((S)-2-(dimethylamino)-1-phenylethyl)-
amino)-2-oxo-1-phenylethyl)carbamate 4g
White solid, yield: 624 mg (79%); Mp = 34–36 °C; [a]
30 = +93.4
D
(c 1.00, CH2Cl2); 1H NMR (500 MHz, CDCl3): d 7.41–7.22 (m,
10H), 6.89 (br, 1H), 5.93–5.92 (m, 1H), 5.21–5.20 (m, 1H), 4.62
(dt, J = 10.0, 4.5 Hz, 1H), 2.47 (dd, J = 12.0, 5.5 Hz, 1H), 2.32 (dd,
J = 12.5, 5.5 Hz, 1H), 1.97 (s, 6H), 1.40 (s, 9H); 13C NMR
(125 MHz, CDCl3): d 170.3, 155.1, 140.9, 138.8, 128.9, 128.5,
128.1, 127.3, 127.1, 126.1, 79.7, 64.0, 58.5, 52.2, 44.7, 28.3, 28.2;
HRMS (ESI): calcd for
398.2441.
C
23H31N3O3 [M+H]+ 398.2438, found
4.3.5. N-((R)-1-(((S)-1-(Dimethylamino)-3,3-dimethylbutan-2-
yl)amino)-3,3-dimethyl-1-oxobutan-2-yl)-2-
(diphenylphosphino)benzamide 5e
4.3. General procedure II: Synthesis of amidophosphanes 5a–5f
Amidophosphanes 5a–g were prepared according to the
reported procedures by our group, starting from 3a (1 mmol) or
diamide intermediates 4b–g (1 mmol).12
White solid, yield: 419 mg (76%); Mp = 55–62 °C; [a]
30 = +31.1
D
(c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.63–7.60 (m, 1H),
7.41–7.20 (m, 18H), 7.02–6.99 (m, 1H), 6.56 (d, J = 7.2 Hz, 1H),
Please cite this article in press as: Hou, Y.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.014

6
Y. Hou et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4.88 (dt, J = 8.4, 5.2 Hz, 1H), 4.50 (dd, J = 8.4, 5.2 Hz, 1H), 2.65 (dd,
J = 12.4, 11.2 Hz, 1H), 2.39 (dd, J = 12.4, 5.2 Hz, 1H), 2.20 (s, 6H),
2.00–190 (m, 1H), 0.85 (d, J = 6.8 Hz, 3H), 0.75 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d 170.9, 169.1, 141.7, 141.4, 141.1,
137.1, 137.0, 136.9, 135.9, 135.7, 134.5, 133.9, 133.8, 133.7,
133.6, 130.3, 128.9, 128.8, 128.7, 128.6, 128.6, 128.5, 127.7,
127.7, 127.3, 126.4, 64.5, 58.9, 52.2, 45.2, 31.0, 19.2, 17.6; 31P
NMR (162 MHz, CDCl3): d –11.2; HRMS (ESI): calcd for C34H38N3O2-
P1 [M+H]+ 552.2774, found 552.2778.
give the corresponding cycloaddition product endo-8, which was
then directly analyzed by chiral HPLC.
General procedure C of Ag2CO3/5f catalyzed gram-scale synthesis of
endo-8a: Under an N2 atmosphere, a solution of precatalyst of 5f
(46.8 mg, 0.08 mmol) and Ag2CO3 (0.004 mmol) in toluene
(1.4 ml) in a flame dried glass tube with aluminum foil was stirred
for 1 h at room temperature, followed by the addition of diethyl
maleate
6 (688 mg, 4 mmol) and iminoester 7 (778.8 mg,
4.4 mmol). Once the starting material was consumed (monitored
by TLC), the mixture was purified by column chromatography to
give the corresponding cycloaddition product endo-8a (1.312 g,
94% yield, 91% ee).
4.3.6. N-((R)-2-(((S)-2-(Dimethylamino)-1-phen ylethyl)amino)-
2-oxo-1-phenylethyl)-2-(diphenylphosphino)benzamide 5f
White solid, yield: 468 mg (80%); Mp = 108–115 °C;
[a
]
D
30 = ꢀ58.6 (c 1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.63–
4.4.1. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 5-phenylpyrrolidine-
7.60 (m, 1H), 7.37–7.17 (m, 21H), 7.08–7.05 (m, 3H), 6.99–6.96
(m, 1H), 5.60 (d, J = 6.8 Hz, 1H), 4.87 (dt, J = 8.4, 5.2 Hz, 1H), 2.55
(dd, J = 12.4, 11.2 Hz, 1H), 2.38 (dd, J = 12.4, 5.2 Hz, 1H), 2.21 (s,
6H); 13C NMR (100 MHz, CDCl3): d 169.5, 168.3, 141.0, 140.8,
140.8, 137.8, 137.2, 137.1, 136.9, 136.8, 136.2, 136.0, 134.4,
133.9, 133.8, 133.7, 133.6, 130.4, 128.8, 128.7, 128.7, 128.6,
128.5, 128.5, 128.4, 128.4, 128.1, 128.0, 127.9, 127.6, 127.2,
126.0, 64.5, 57.8, 52.2, 45.2; 31P NMR (162 MHz, CDCl3): d ꢀ10.8;
HRMS (ESI): calcd for C37H36N3O2P1 [M+H]+ 586.2618, found
586.2621.
2,3,4-tricarboxylate 8a
Yield: 68 mg (97%); [
a]
30 = ꢀ54.2 (c 1.02, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) d 7.36–7.25 (m, 5H), 4.47 (d, J = 6.8 Hz, 1H),
4.16–4.11 (m, 3H), 3.81 (s, 3H), 3.76–3.62 (m, 3H), 3.59 (t,
J = 7.6 Hz, 1H), 3.43 (br s, 1H), 1.24 (t, J = 7.2 Hz, 3H), 0.80 (t,
J = 7.2 Hz, 3H); The ee value was 93%, tR (minor) = 6.64 min, tR
(major) = 12.16 min (Chiralcel AS–H, k = 205 nm, i-PrOH/hexanes
50:50, flow rate = 0.8 mL/min).
4.4.2. (2S,3R,4S,5R)-3,4-Diethyl 2-methyl 5-phenylpyrrolidine-
2,3,4-tricarboxylate 8a
4.3.7. N-((S)-2-(((S)-2-(Dimethylamino)-1-phenylethyl)amino)-
Yield: 65 mg (93%); [a]
30 = +58.7 (c 1.30, CH2Cl2); The ee value
D
2-oxo-1-phenylethyl)-2-(diphenylphosphino)benzamide 5g
was ꢀ92%, tR (major) = 6.58 min, tR (minor) = 12.24 min (Chiralcel
AS-H, k = 205 nm, i-PrOH/hexanes 50:50, flow rate = 0.8 mL/min).
30
White solid, yield: 398 mg (68%); Mp = 198–199 °C; [
a]
=
D
+91.4 (c 1.20, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.61–7.60
(m, 1H), 7.35–7.12 (m, 24H), 6.94–6.93 (m, 1H), 5.55 (d,
J = 6.0 Hz, 1H), 4.73 (ddd, J = 14.0, 9.6, 5.2 Hz, 1H), 2.52 (dd,
J = 12.0, 10.4 Hz, 1H), 2.40 (dd, J = 12.4, 5.2 Hz, 1H), 2.00 (s, 6H);
13C NMR (100 MHz, CDCl3): d 169.7, 168.2, 140.8, 140.8, 140.5,
137.8, 137.1, 137.0, 136.9, 136.7, 136.3, 136.1, 134.2, 133.8,
133.8, 133.6, 133.6, 130.3, 128.7, 128.6, 128.6, 128.5, 128.4,
128.4, 128.0, 127.9, 127.3, 127.3, 126.4, 63.9, 57.7, 52.2, 44.8; 31P
NMR (162 MHz, CDCl3): d ꢀ10.4; HRMS (ESI): calcd for C37H36N3-
O2P1 [M+H]+ 586.2618, found 586.2620.
4.4.3. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 5-(p-tolyl)pyrrolidine-
2,3,4-tricarboxylate 8b
Yield: 72 mg (99%); [
a]
30 = ꢀ46.6 (c 1.20, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) d 7.21 (d, J = 7.6 Hz, 2H), 7.10 (d, J = 7.6 Hz, 2H),
4.43 (d, J = 6.4 Hz, 1H), 4.14–4.09 (m, 3H), 3.79 (s, 3H), 3.75–3.64
(m, 3H), 3.57–3.53 (m, 2H), 2.30 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H),
0.83 (t, J = 7.2 Hz, 3H); The ee value was 92%, tR (minor)
= 6.27 min, tR (major) = 12.34 min (Chiralcel AS-H, k = 230 nm, i-
PrOH/hexanes 50:50, flow rate = 0.8 mL/min).
4.4. Ag2CO3/5f catalyzed the synthesis of endo-8
4.4.4. (2S,3R,4S,5R)-3,4-Diethyl 2-methyl 5-(p-tolyl)pyrrolidine-
2,3,4-tricarboxylate 8b
General procedure A of Ag2CO3/5f or 5g catalyzed cycloaddition of
various iminoesters 7: Under an N2 atmosphere, a solution of pre-
catalyst 5f or 5g (4.68 mg, 0.008 mmol) and Ag2CO3 (1.10 mg,
0.004 mmol) in toluene (1.4 ml) in a flame dried glass tube with
aluminum foil was stirred for 1 h at room temperature, followed
by the addition of the dipolarophile (0.2 mmol) and the iminoester
7 (0.3 mmol). Once the starting material was consumed (moni-
tored by TLC), the mixture was purified by column chromatogra-
phy to give the corresponding cycloaddition product endo-8,
which was then directly analyzed by chiral HPLC.
Yield: 68 mg (94%); [a]
30 = +43.4 (c 1.00, CH2Cl2); The ee value
D
was ꢀ93%, tR (major) = 6.26 min, tR (minor) = 12.50 min (Chiralcel
AS-H, k = 230 nm, i-PrOH/hexanes 50:50, flow rate = 0.8 mL/min).
4.4.5. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 5-(4-methoxyphenyl)
pyrrolidine-2,3,4-tricarboxylate 8c
Yield: 68 mg (90%); [
a
]
30 = ꢀ48.0 (c 1.30, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) d 7.28 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H),
4.43 (d, J = 6.8 Hz, 1H), 4.15–4.10 (m, 3H), 3.80 (s, 3H),3.78 (s,
3H), 3.71–3.67 (m, 3H), 3.55 (t, J = 6.8 Hz, 1H), 3.22 (br s, 1H),
1.24 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H); The ee value was
96%, tR (minor) = 7.70 min, tR (major) = 14.41 min (Chiralcel AS-H,
k = 230 nm, i-PrOH/hexanes 50:50, flow rate = 0.8 mL/min).
General procedure B of Ag2CO3/5f catalyzed three-component reac-
tion of the a-iminoesters in situ generated: To the aromatic aldehyde
(2.0 equiv) was added a solution of methyl glycinate (3 equiv)
(washing glycine methyl ester hydrochloride methylene chloride
solution with a mixture of 1 M sodium hydroxide aqueous solution
and brine (1:1) followed by drying over sodium sulfate, filtration
and concentration) in toluene (50 mg/mL) then dried over MgSO4
(4 equiv). This suspension was tumbled for 8 h. Under an N2 atmo-
sphere, the above solution was transferred by syringe to a solution
of precatalyst 5f (4.68 mg, 0.008 mmol) and Ag2CO3 (1.10 mg,
0.004 mmol) in toluene (0.5 ml) and stirred for 1 h at room tem-
perature, followed by the addition of diethyl maleate 6 (34.4 mg,
0.2 mmol). Once the starting material was consumed (monitored
by TLC), the mixture was purified by column chromatography to
4.4.6. (2S,3R,4S,5R)-3,4-Diethyl 2-methyl 5-(4-methoxyphenyl)
pyrrolidine-2,3,4-tricarboxylate 8c
Yield: 66 mg (87%); [a]
30 = +44.2 (c 0.93, CH2Cl2); The ee value
D
was ꢀ96%, tR (minor) = 7.80 min, tR (major) = ) = 14.27 min (Chiral-
cel AS-H, k = 230 nm, i-PrOH/hexanes 50:50, flow rate = 0.8 mL/
min).
4.4.7. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 5-(4-fluorophenyl)-
pyrrolidine-2,3,4-tricarboxylate 8d
Yield: 60 mg (82%); [
(400 MHz, CDCl3) d 7.33–7.32 (m, 2H), 7.01–6.99 (m, 2H), 4.44
a
]
30 = ꢀ52.8 (c 1.14, CH2Cl2); 1H NMR
D
Please cite this article in press as: Hou, Y.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.014

Y. Hou et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
(d, J = 6.8 Hz, 1H), 4.12–4.09 (m, 3H), 3.78 (s, 3H), 3.74–3.62 (m,
4.4.14. (2R,3S,4R,5R)-3,4-Diethyl 2-methyl 5-
3H), 3.57–3.53 (m, 1H), 3.18 (br s, 1H), 1.22 (t, J = 7.2 Hz, 3H),
0.83 (t, J = 7.2 Hz, 3H); The ee value was 94%, tR (minor)
= 7.05 min, tR (major) = 11.05 min (Chiralcel AS-H, k = 230 nm, i-
PrOH/hexanes 50:50, flow rate = 0.8 mL/min).
cyclohexylpyrrolidine-2,3,4-tricarboxylate 8j
Yield: 38 mg (54%); [
a]
D
30 = ꢀ4.3 (c 0.95, CH2Cl2); 1H NMR
(400 MHz, CDCl3) d 4.25–4.17 (m, 1H), 4.13–4.06 (m, 3H), 4.02
(d, J = 10.0 Hz, 1H), 3.74 (s, 3H), 3.52 (dd, J = 10.0, 7.6 Hz, 1H),
3.18 (dd, J = 7.2, 4.8 Hz, 1H), 2.79 (dd, J = 10.0, 4.8 Hz, 1H), 2.73
(br, 1H), 2.06 (d, J = 12.8 Hz, 1H), 1.87 (d, J = 12.4 Hz, 1H), 1.73–
1.63(m, 3H), 1.41–1.32 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H), 1.22 (t,
J = 7.2 Hz, 3H), 1.27–1.11 (m, 3H), 1.09–0.94 (m, 2H); The ee value
was 69%, tR (major) = 8.76 min, tR (minor) = 10.61 min (Chiralcel
AD-H, k = 210 nm, i-PrOH/hexanes 15:85, flow rate = 0.8 mL/min).
4.4.8. (2S,3R,4S,5R)-3,4-Diethyl 2-methyl 5-(4-fluorophenyl)-
pyrrolidine-2,3,4-tricarboxylate 8d
Yield: 61 mg (84%); [a]
30 = +48.6 (c 1.10, CH2Cl2); The ee value
D
was ꢀ95%, tR (minor) = 6.93 min, tR (major) = 10.94 min (Chiralcel
AS-H, k = 230 nm, i-PrOH/hexanes 50:50, flow rate = 0.8 mL/min).
4.4.9. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 5-(4-chlorophenyl)-
4.4.15. (2R,3S,4R,5R)-3,4-Diethyl 2-methyl 5-
pyrrolidine-2,3,4-tricarboxylate 8e
neopentylpyrrolidine-2,3,4-tricarboxylate 8k
Yield: 76 mg (99%); [
a
]
D
30 = ꢀ46.2 (c 0.92, CH2Cl2); 1H NMR
Yield: 32 mg (46%); [a]
30 = +2.6 (c 1.00, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) d 7.33–7.28 (m, 4H), 4.44 (d, J = 6.8 Hz, 1H),
4.16–4.10 (m, 3H), 3.80 (s, 3H), 3.76–3.68 (m, 3H), 3.60–3.56 (m,
1H), 3.27 (br s, 1H), 1.24 (t, J = 7.2 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H);
The ee value was 93%, tR (minor) = 7.41 min, tR (major)
= 12.17 min (Chiralcel AS-H, k = 230 nm, i-PrOH/hexanes 50:50,
flow rate = 0.8 mL/min).
(400 MHz, CDCl3) d 4.14 (q, J = 6.0 Hz, 2H), 4.08 (q, J = 6.0 Hz, 2H),
3.98 (d, J = 7.2 Hz, 1H), 3.73 (s, 3H), 3.53–3.50 (m, 1H), 3.19–3.16
(m, 1H), 3.12–3.10 (m, 1H), 2.61 (br, 1H), 1.52 (dd, J = 11.2,
3.2 Hz, 1H), 1.39 (dd, J = 11.2, 6.0 Hz, 1H), 1.25 (t, J = 6.0 Hz, 3H),
1.22 (t, J = 6.0 Hz, 3H), 0.94 (s, 9H); 13C NMR (100 MHz, CDCl3) d
171.4, 171.2, 170.1, 61.8, 60.9, 60.4, 59.5, 52.1, 52.1, 44.2, 30.3,
29.9, 14.2, 14.0; HRMS (ESI): calcd for
C
17H29N1O6 [M+H]+
4.4.10. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 5-(naphthalen-2-yl)
pyrrolidine-2,3,4-tricarboxylate 8f
344.2068, found 344.2063; The ee value was 64%, tR (major)
= 7.96 min, tR (minor) = 8.62 min (Chiralcel AD-H, k = 210 nm, i-
PrOH/hexanes 15:85, flow rate = 0.7 mL/min).
Yield: 70 mg (88%); [
a
]
D
30 = ꢀ32.4 (c 1.10, CH2Cl2); 1H NMR
(400 MHz, CDCl3) d 7.83–7.78 (m, 4H), 7.47–7.44 (m, 3H), 4.61
(dd, J = 6.4, 2.4 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 3.79–
3.75 (m, 1H), 3.71–3.53 (m, 3H), 3.42 (br s, 1H), 1.24 (t,
J = 7.2 Hz, 3H), 0.67 (t, J = 7.2 Hz, 3H); The ee value was 94%, tR
(minor) = 7.69 min, tR (major) = 21.51 min (Chiralcel AS-H,
k = 230 nm, i-PrOH/hexanes 50:50, flow rate = 0.8 mL/min).
4.4.16. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 2-methyl-5-
phenylpyrrolidine-2,3,4-tricarboxylate 8l
Yield: 65 mg (90%); [
a
]
30 = ꢀ41.2 (c 1.25, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) d 7.37–7.24 (m, 5H), 4.63 (d, J = 6.4 Hz, 1H),
4.20 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 3.78–3.65 (m, 2H), 3.47 (t,
J = 7.2 Hz, 1H), 3.28 (d, J = 6.8 Hz, 1H), 1.68 (s, 3H), 1.29 (t,
J = 7.2 Hz, 3H), 0.80 (t, J = 7.2 Hz, 3H); The ee value was 93%, tR
(major) = 7.49 min, tR (minor) = 12.88 min (Chiralcel AD-H,
k = 210 nm, i-PrOH/hexanes 15:85, flow rate = 0.8 mL/min).
4.4.11. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 5-(furan-2-yl)
pyrrolidine-2,3,4-tricarboxylate 8g
Yield: 60 mg (88%); [
a]
30 = ꢀ36.8 (c 1.43, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) d 7.33–7.32 (m, 1H), 6.33–6.31 (m, 2H), 4.47
(d, J = 6.8 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 4.22 (d, J = 8.8 Hz, 1H),
3.94–3.85 (m, 2H), 3.78 (s, 3H), 3.62 (dd, J = 8.0, 8.8 Hz, 1H), 3.50
(t, J = 7.6 Hz, 1H), 3.24 (br s, 1H), 1.23 (t, J = 7.2 Hz, 3H), 1.03 (t,
J = 7.2 Hz, 3H); The ee value was 95%, tR (minor) = 7.16 min, tR
(major) = 16.40 min (Chiralcel AS-H, k = 230 nm, i-PrOH/hexanes
50:50, flow rate = 0.8 mL/min).
4.4.17. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 2-methyl-5-(p-tolyl)
pyrrolidine-2,3,4-tricarboxylate 8m
Yield: 67 mg (84%); [
a]
30 = ꢀ26.9 (c 0.75, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) d 7.22 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 7.6 Hz, 2H),
4.56 (d, J = 6.4 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.77 (s, 3H), 3.77–
3.66 (m, 3H), 3.43 (t, J = 6.8 Hz, 1H), 3.25 (d, J = 6.8 Hz, 1H), 2.29
(s, 3H), 1.65 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 0.81 (t, J = 7.2 Hz, 3H);
The ee value was 93%, tR (major) = 7.46 min, tR (minor)
= 10.48 min (Chiralcel AD-H, k = 210 nm, i-PrOH/hexanes 15:85,
flow rate = 0.8 mL/min).
4.4.12. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 5-(thiophen-2-yl)
pyrrolidine-2,3,4-tricarboxylate 8h
Yield: 67 mg (94%); [
a]
30 = ꢀ40.2 (c 1.20, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) d 7.19 (d, J = 4.8 Hz, 1H), 7.02–7.01 (m, 1H),
6.94–6.92 (m, 1H), 4.59 (d, J = 6.8 Hz, 1H), 4.13–4.10 (m, 3H),
3.86–3.82 (m, 2H), 3.77 (s, 3H), 3.67 (dd, J = 9.2, 8.0 Hz, 1H), 3.67
(dd, J = 8.0, 6.8 Hz, 1H), 3.34 (br s, 1H), 1.23 (t, J = 7.2 Hz, 3H),
0.96 (t, J = 7.2 Hz, 3H); The ee value was 92%, tR (minor)
= 7.65 min, tR (major) = 17.53 min (Chiralcel AS-H, k = 230 nm, i-
PrOH/hexanes 50:50, flow rate = 0.8 mL/min).
4.4.18. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 5-(4-fluorophenyl)-2-
methylpyrrolidine-2,3,4-tricarboxylate 8n
Yield: 59 mg (78%); [
a]
D
30 = ꢀ34.6 (c 1.34, CH2Cl2); 1H NMR
(400 MHz, CDCl3) d 7.35–7.32 (m, 2H), 7.00–6.96 (m, 2H), 4.59
(d, J = 6.4 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.77 (s, 3H), 3.69–3.66
(m, 2H), 3.58 (br s, 1H), 3.44 (t, J = 7.2 Hz, 1H), 3.25 (d, J = 7.2 Hz,
1H), 1.64 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H);
The ee value was 96%, tR (major) = 8.56 min, tR (minor)
= 13.13 min (Chiralcel AD-H, k = 210 nm, i-PrOH/hexanes 15:85,
flow rate = 0.8 mL/min).
4.4.13. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 5-(pyridine-3-yl)
pyrrolidine-2,3,4-tricarboxylate 8i
Yield: 51 mg (73%); Mp. 102–105 °C; [
a]
D
30 = ꢀ48.5. (c 0.84, CH2-
Cl2); 1H NMR (400 MHz, CDCl3) d 8.60–8.52 (m, 2H), 7.79 (d,
J = 7.2 Hz, 1H), 7.29–7.26 (m, 1H), 4.51 (d, J = 6.4 Hz, 1H), 4.17–
4.12 (m, 3H), 3.81 (s, 3H), 3.78–3.63 (m, 4H), 3.37 (br, 1H), 1.25
(t, J = 7.2 Hz, 3H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 170.7, 170.2, 170.0, 149.0, 148.9, 134.3, 133.1, 123.2, 62.8, 62.2,
61.2, 60.6, 52.4, 52.3, 50.9, 14.0, 13.6; The ee value was 98%, tR
(minor) = 9.06 min, tR (major) = 10.59 min (Chiralcel AS-H,
k = 230 nm, i-PrOH/hexanes 50:50, flow rate = 0.8 mL/min).
4.4.19. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 5-(4-bromophenyl)-
2-methylpyrrolidine-2,3,4-tricarboxylate 8o
Yield: 73 mg (83%) [
a
]
30 = ꢀ25.6 (c 1.40, CH2Cl2). 1H NMR
D
(400 MHz, CDCl3) d 7.37 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H),
4.51 (d, J = 6.6 Hz, 1H), 4.12 (q, J = 7.1 Hz, 1H), 3.71 (s, 3H), 3.79–
3.46 (m, 3H), 3.39 (t, J = 6.9 Hz, 1H), 3.19 (d, J = 7.1 Hz, 1H), 1.59
(s, 3H), 1.22 (t, J = 7.1 Hz, 3H), 0.79 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): 174.3, 170.5, 170.3, 136.7, 131.3, 128.8, 121.5,
Please cite this article in press as: Hou, Y.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.014

8
Y. Hou et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
77.3, 77.0, 76.7, 68.6, 63.0, 61.1, 60.3, 57.8, 52.9, 52.6, 28.1, 14.1,
13.7; The ee value was 94%, tR (major) = 9.28 min, tR (minor)
= 10.83 min (Chiralcel OD-H, k = 210 nm, i-PrOH/hexanes 15:85,
flow rate = 0.8 mL/min).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.05.
014.
4.4.20. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 2-methyl-5-(naphth-
alen-2-yl)pyrrolidine-2,3,4-tri carboxylate 8p
References
Yield: 67 mg (82%); [
a
]
D
30 = ꢀ19.8 (c 1.06, CH2Cl2); 1H NMR
1. (a) Denhart, D. J.; Griffith, D. A.; Heath-cock, C. H. J. Org. Chem. 1998, 63, 9616–
9617; (b) Overman, L. E.; Tellew, J. E. J. Org. Chem. 1996, 61, 8338–8340; (c)
(400 MHz, CDCl3) d 7.85–7.77 (m, 4H), 7.53–7.44 (m, 3H), 4.77
(d, J = 6.4 Hz, 1H), 4.23–4.18 (m, 2H), 3.81 (s, 1H), 3.70–3.55 (m,
4H), 3.33 (d, J = 7.2 Hz, 1H), 1.72 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H),
0.66 (t, J = 7.2 Hz, 3H); The ee value was 94%, tR (major)
= 17.94 min, tR (minor) = 20.87 min (Chiralcel OD-H, k = 210 nm,
i-PrOH/hexanes 15:85, flow rate = 0.8 mL/min).
Alvarez-Ibarra, C.; Cslkþ, A. G.; Lüpez, I.; Quiroga, M. L. J. Org. Chem. 1997, 62,
479–484; (d) Obst, U.; Betschmann, P.; Lerner, C.; Seiler, P.; Diederich, F. Helv.
Chim. Acta 2000, 83, 855–909; (e) Sebahar, P. R.; Williams, R. M. J. Am. Chem.
Soc. 2000, 122, 5666–5667.
2. Recent reviews of catalytic asymmetric 1,3-dipolar cycloadditions: (a)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–
5569; (b) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887–2902; (c)
MacMillan, D. W. C. Nature 2008, 455, 304–308; (d) Adrio, J.; Carretero, J. C.
Chem. Commun. 2011, 6784–6794; (e) Moyano, A.; Rios, R. Chem. Rev. 2011, 111,
4703–4832; (f) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2011, 50, 8492–8509; (g) Maroto, E. E.; Izquierdo, M.; Reboredo, S.; Marco-
Martínez, J.; Filippone, S.; Martín, N. Acc. Chem. Res. 2014, 47, 2660–2670; (h)
Adrio, J.; Carretero, J. C. Chem. Commun. 2014, 12434–12446; (i) Han, M.-Y.; Jia,
J.-Y.; Wang, W. Tetrahedron Lett. 2014, 55, 784–794; (j) Hashimoto, T.;
Maruoka, K. Chem. Rev. 2015, 115, 5366–5412.
4.4.21. (2R,3S,4R,5S)-3,4-Diethyl 2-methyl 2-benzyl-5-phenyl-
pyrrolidine-2,3,4-tricarboxylate 8q
Yield: 65 mg (74%); [
a
]
30 = ꢀ34.1 (c 1.12, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) d 7.46–7.44 (m, 2H), 7.31–7.26 (m, 8H), 4.26
(q, J = 7.2 Hz, 2H), 4.11 (d, J = 5.6 Hz, 1H), 3.76–3.67 (m, 2H), 3.74
(s, 3H), 3.60 (br s, 1H), 3.30–3.17 (m, 4H), 1.38 (t, J = 7.2 Hz, 3H),
0.79 (t, J = 7.2 Hz, 3H); The ee value was 82%, tR (major)
= 6.63 min, tR (minor) = 10.00 min (Chiralcel OD-H, k = 210 nm, i-
PrOH/hexanes 15:85, flow rate = 0.8 mL/min).
3. Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400–13401.
4. Recent references on chiral silver catalysts: (a) Xue, Z.-Y.; Liu, T.-L.; Lu, Z.;
Huang, H.; Tao, H.-Y.; Wang, C.-J. Chem. Commun. 2010, 1727–1729; (b) Oura,
I.; Shimizu, K.; Ogata, K.; Fukuzawa, S. Org. Lett. 2010, 12, 1752–1755; (c)
Yamashita, Y.; Imaizumi, T.; Guo, X.-X.; Kobayashi, S. Chem. - Asian J. 2011, 6,
2550–2559; (d) Yamashita, Y.; Imaizumi, T.; Kobayashi, S. Angew. Chem., Int. Ed.
2011, 50, 4893–4896; (e) Jing, X.; He, C.; Dong, D.; Yang, L.; Duan, C. Angew.
Chem., Int. Ed. 2012, 51, 10127–10131; (f) Guernon, H.; Legault, C. Y.
Organometallics 2013, 32, 1988–1994; (g) Kudryavtsev, K. V.; Ivantcova, P.
M.; Churakov, A. V.; Wiedmann, S.; Luy, B.; Muhle-Goll, C.; Zefirov, N. S.; Brase,
S. Angew. Chem., Int. Ed. 2013, 52, 12736–12740; (h) Gerosa, G. G.; Spanevello,
R. A.; Suárez, A. G.; Sarotti, A. M. J. Org. Chem. 2015, 80, 7626–7634.
5. Recent references on chiral copper catalysts: (a) Robles-Machín, R.; González-
Esguevillas, M.; Adrio, J.; Carretero, J. C. J. Org. Chem. 2010, 75, 233–236; (b)
Arai, T.; Mishiro, A.; Yokoyama, N.; Suzuki, K.; Sato, H. J. Am. Chem. Soc. 2010,
132, 5338–5339; (c) Zhang, C.; Yu, S.-B.; Hu, X.-P.; Wang, D.-Y.; Zheng, Z. Org.
Lett. 2010, 12, 5542–5545; (d) Wang, M.; Wang, Z.; Shi, Y.-H.; Shi, X.-X.; Fossey,
J. S.; Deng, W.-P. Angew. Chem., Int. Ed. 2011, 50, 4897–4900; (e) Kim, H. Y.; Li,
J.-Y.; Kim, S.; Oh, K. J. Am. Chem. Soc. 2011, 133, 20750–20753; (f) González-
Esguevillas, M.; Adrio, J.; Carretero, J. C. Chem. Commun. 2012, 2149–2151; (g)
Conde, E.; Bello, D.; de Cózar, A.; Sánchez, M.; Vázquez, M. A.; Cossío, F. P. Chem.
Sci. 2012, 3, 1486–1491; (h) Castelló, L. M.; Nájera, C.; Sansano, J. M.; Larrañaga,
O.; de Cózar, A.; Cossío, F. P. Org. Lett. 2013, 15, 2902–2905; (i) Arai, T.; Ogawa,
H.; Awata, A. M.; Sato, M.; Watabe, M.; Yamanaka Angew. Chem., Int. Ed. 2015,
54, 1595–1599; (j) Li, J.-Y.; Kim, H. Y.; Oh, K. Org. Lett. 2015, 17, 1288–1291; (k)
Wang, Z.; Yu, X.; Tian, B.-X.; Payne, D. T.; Yang, W.-L.; Liu, Y.-Z.; Fossey, J. S.;
Deng, W.-P. Chem. -Eur. J. 2015, 21, 10457–10465; (l) He, F.-S.; Zhu, H.; Wang,
Z.; Gao, M.; Yu, X.-X.; Deng, W.-P. Org. Lett. 2015, 17, 4988–4991; (m) Li, C.-Y.;
Yang, W.-L.; Luo, X.-Y.; Deng, W.-P. Chem. -Eur. J. 2015, 21, 19048–19057; (n)
Tang, F.-F.; Yang, W.-L.; Yu, X.-X.; Deng, W.-P. Catal. Sci. Technol. 2015, 5, 3568–
3575; (o) Yang, W.-L.; Tang, F.-F.; He, F.-S.; Li, C.-Y.; Yu, X.-X.; Deng, W.-P. Org.
Lett. 2015, 17, 4822–4825; (p) Han, F.-Z.; Yu, S.-B.; Zhang, C.; Hu, X.-P.
Tetrahedron 2016, 72, 2616–2622; (q) Pascual-Escudero, A.; de Cózar, A.;
Cossío, F. P.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2016, 55, 15334–
15338. and references therein.
4.4.22. (2R,3S,4R,5S)-Trimethyl 5-phenylpyrrolidine-2,3,4-
tricarboxylate 8r
Yield: 62 mg (96%); [
a]
30 = ꢀ60.8 (c 0.84, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) d 7.35–7.26 (m, 5H), 4.49 (d, J = 6.8 Hz, 1H),
4.17 (d, J = 8.8 Hz, 1H), 3.82 (s, 3H), 3.75–3.70 (m, 1H), 3.70 (s,
3H), 3.58 (t, J = 7.2 Hz, 1H), 3.23 (s, 3H); The ee value was 92%, tR
(minor) = 7.08 min, tR (major) = 14.56 min (Chiralcel AS-H,
k = 205 nm, i-PrOH/hexanes 50:50, flow rate = 0.8 mL/min).
4.4.23. (2R,4R,5S)-Dimethyl 5-phenylpyrrolidine-2,4-dicarbox-
ylate 8s
Yield: 44 mg (84%); [
a
]
D
30 = ꢀ27.4 (c 1.04, CH2Cl2); 1H NMR
(400 MHz, CDCl3) d 7.31–7.21 (m, 5H), 4.53 (d, J = 8.0 Hz, 1H),
3.98 (t, J = 8.0 Hz, 1H), 3.81 (s, 3H), 3.30 (dd, J = 14.4, 6.8 Hz, 1H),
3.20 (s, 3H), 2.94 (br s, 1H), 2.40 (t, J = 8.0 Hz, 2H); The ee value
was 40%, tR (minor) = 12.69 min, tR (major) = 19.14 min (Chiralcel
AS-H, k = 205 nm, i-PrOH/hexanes 10:90, flow rate = 1.0 mL/min).
4.4.24. (1R,3S,3aR,6aS)-Methyl 4,6-dioxo-3,5-diphenyloctahydr-
opyrrolo[3,4-c]pyrrole-1-carboxylate 8t
Yield: 66 mg (94%); [
a]
30 = ꢀ78.5 (c 1.34, CH2Cl2); 1H NMR
D
(400 MHz, CDCl3) d 7.47–7.31 (m, 8H), 7.16–7.14 (m, 2H), 4.63
(dd, J = 8.8, 5.2 Hz, 1H), 4.16 (dd, J = 6.4, 5.2 Hz, 1H), 3.88 (s, 3H),
3.76–3.73 (m, 1H), 3.58 (t, J = 8.2 Hz, 1H), 2.54–2.52 (m, 1H); 13C
NMR (100 MHz, CDCl3) d 175.1, 173.6, 170.0, 136.6, 131.6, 129.0,
128.5, 127.1, 126.1, 64.2, 61.9, 52.3, 49.4, 48.3; HRMS (ESI): calcd
for C20H18N2O4 [M+H]+ 351.1339, found 351.1342;The ee value
was 62%, tR (minor) = 17.33 min, tR (major) = 32.91 min (Chiralcel
AS-H, k = 205 nm, i-PrOH/hexanes 50:50, flow rate = 0.8 mL/min).
6. Recent references on chiral zinc catalyst: (a) Gothelf, A. S.; Gothelf, K. V.; Hazell,
R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 4236–4238; (b) Dogan, O.;
Koyuncu, H.; Garner, P.; Bulut, A.; Youngs, W. J.; Panzner, M. Org. Lett. 2006, 8,
4687–4690.
7. Recent references on chiral nickel catalyst: (a) Shi, J.-W.; Zhao, M.-X.; Lei, Z.-Y.;
Shi, M. J. Org. Chem. 2008, 73, 305–308; (b) Arai, T.; Yokoyama, N.; Mishiro, A.;
Sato, H. Angew. Chem., Int. Ed. 2010, 49, 7895–7898.
8. Select references on chiral calcium catalysts: (a) Saito, S.; Tsubogo, T.;
Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 5364–5365; (b) Tsubogo, T.; Saito,
S.; Seki, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321–
13332.
Acknowledgments
´
9. Select references on chiral gold catalysts: (g) Martín-Rodríguez, M.; Najera, C.;
Sansano, J. M.; Coz´ar, A.; Cossío, F. P. Chem. -Eur. J. 2011, 17, 14224–14233.
10. For some recent examples on organo-catalyzed asymmetric 1,3-dipolar
cycloaddition of azomethine ylide: (a) Guo, C.; Song, J.; Gong, L.-Z. Org. Lett.
2013, 15, 2676–2679; (b) Wang, C.-S.; Zhu, R.-Y.; Zheng, J.; Shi, F.; Tu, S.-J. J. Org.
Chem. 2015, 80, 512–520; (c) Dai, W.; Jiang, X.-L.; Wu, Q.; Shi, F.; Tu, S.-J. J. Org.
Chem. 2015, 80, 5737–5744; (d) Sun, X.-X.; Zhang, H.-H.; Li, G.-H.; He, Y.-Y.; Shi,
F. Chem. Eur. J. 2016, 22, 17526–17532; (e) Wang, Y.-M.; Zhang, H.-H.; Li, C.;
Fan, T.; Shi, F. Chem. Commun. 2016, 1804–1807.
11. For selected examples on amidophosphine ligands, see: (a) Clayden, J.;
Johnson, P.; Pink, J. H.; Helliwell, M. J. Org. Chem. 2000, 65, 7033–7040; (b)
Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122, 12055–12056;
(c) Dai, W.-M.; Yeung, K. K. Y.; Liu, J.-T.; Zhang, Y.; Williams, I. D. Org. Lett. 2002,
We are grateful to the National Natural Science Foundation of
China (Nos. 21202042, 51174085, 51374103), the Hunan Provin-
cial Natural Science Foundation of China (Nos. 2017JJ2067,
13JJ4090, 2015JJ3063), the National Natural Science Foundation
of Hunan University of Technology (No. 2014HZX01), Zhuzhou
Municipal Science and Ttechnology Program and Graduate Student
Innovation Foundation of Hunan Province (CX2016B642) for sup-
port of this research.
Please cite this article in press as: Hou, Y.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.014

Y. Hou et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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4, 1615–1618; (d) Kuriyama, M.; Nagai, K.; Yamada, K.; Miwa, Y.; Taga, T.;
Tomioka, K. J. Am. Chem. Soc. 2002, 124, 8932–8939; (e) Kuriyama, M.; Soeta, T.;
Hao, X.; Chen, Q.; Tomioka, K. J. Am. Chem. Soc. 2004, 126, 8128–8129; (f)
Rageot, D.; Woodmansee, D. H.; Pugin, B.; Pfaltz, A. Angew. Chem., Int. Ed. 2011,
50, 9598–9601.
the Supporting Information), and those of other adducts were deduced on the
basis of these results.
15. For recent leading reviews on multicomponent reactions (MCRs), see: (a)
Touré, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439–4486; (b) Dömling, A.;
Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083–3135; (c) de Graaff, C.; Ruijter,
E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41, 3969–4009; (d) Brauch, S.; van Berkel,
S. S.; Westermann, B. Chem. Soc. Rev. 2013, 42, 4948–4962; (e) Cioc, R. C.;
Ruijter, E.; Orru, R. V. A. Green Chem. 2014, 16, 2958–2975. For a related book,
see; (f) Zhu, J.; Bienaymé, H. Multicomponent reactions; Wiley-VCH: Weinheim,
2005.
12. Wang, H.-F.; Deng, Q. Org. Lett. 2016, 18, 404–407.
13. (a) Nolwenn, J. A. M.; Lidia, O.; Benjamin, L. J. Am. Chem. Soc. 2007, 129, 8976–
8977; (b) Guo, C.; McAlpine, I.; Zhang, J.; Knighton, D. D.; Kephart, S.; Johnson,
M. C.; Li, H.; Bouzida, D.; Yang, A.; Dong, L.; Marakovits, J.; Tikhe, J.; Richardson,
P.; Guo, L. C.; Kania, R.; Edwards, M. P.; Kraynov, E.; Christensen, J.; Piraino, J.;
Lee, J.; Dagostino, E.; Del-Carmen, C.; Deng, Y.-L.; Smeal, T.; Murray, B. W. J.
Med. Chem. 2012, 55, 4728–4739.
16. Cabrera, S.; Arrayás, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394–
16395.
14. The absolute configurations of the known products 8aꢀe were assigned by
HPLC and specific rotation comparisons with the reported data (see Ref. 12 and
Please cite this article in press as: Hou, Y.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.014