A Chiral Secondary Amine-Amidophosphane Precatalyst for Silver-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition Reactions

Article abstract of DOI:10.1055/s-0037-1609492

A class of multifunctional amidophosphanes derived from chiral 1,2-diphenylethylenediamines and natural α-amino acids has been developed. Among these, in combination with silver(I) salts, a chiral secondary amine-amidophosphane precatalyst has been demonstrated as being a highly efficient multifunctional precatalyst in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides, including a series of heterocyclic, aliphatic, and 2-substituted azomethine ylides, and aromatic α,β-unsaturated aldehyde derived imino esters with different electron-deficient alkenes, as well as the three-component reaction of α-imino esters generated in situ by using N, N ′-diisopropylcarbodiimide as dehydrating agent. Under optimal conditions, highly functionalized endo -adducts were obtained in high to excellent yields (up to 99% yield) and enantioselectivities (up to >99.9% ee).

Full text of DOI:10.1055/s-0037-1609492

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–L
paper
A
en
X. Zheng et al.
Paper
Synthesis
A Chiral Secondary Amine–Amidophosphane Precatalyst for
Silver-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition Reactions
Xiaojun Zheng◊
Qifu Deng◊
CO2Et
R4
Base and H donor
EtO2C
Ph
Ph
NH
NH
R4
Qinglin Hou
Kaiqiang Zhang
Pushan Wen
Shunqin Hu
CO2Et
CO2Et
precatalyst (4 mol%)
CO2Me
H donors
R5
N
CO2Me
N
H
+
R5
Ag2CO3 (2 mol%)
toluene, r.t.
H
AmidPhos
ligand
N
O
O
endo
Ph
precatalyst
PPh2
31 examples
up to 99 yield, >99.9% ee
R4, R5 = aryl, alkyl
Haifei Wang*
College of Life Science and Chemistry, Hunan
University of Technology, Zhuzhou 412007,
P. R. of China
wanghaifei@hut.edu.cn
◊ These authors contributed equally to this work.
Received: 14.12.2017
Accepted after revision: 05.03.2018
Published online: 16.04.2018
chiral metal complexes as catalysts, there remains a great
need for a new cooperative catalytic system using multi-
functional organic scaffolds in combination with transition-
metal ions to achieve this important transformation.
DOI: 10.1055/s-0037-1609492; Art ID: ss-2017-h0807-op
Abstract A class of multifunctional amidophosphanes derived from
chiral 1,2-diphenylethylenediamines and natural α-amino acids has
been developed. Among these, in combination with silver(I) salts, a chi-
ral secondary amine–amidophosphane precatalyst has been demon-
strated as being a highly efficient multifunctional precatalyst in the
asymmetric 1,3-dipolar cycloaddition of azomethine ylides, including a
series of heterocyclic, aliphatic, and 2-substituted azomethine ylides,
and aromatic α,β-unsaturated aldehyde derived imino esters with dif-
ferent electron-deficient alkenes, as well as the three-component reac-
tion of α-imino esters generated in situ by using N,N′-diisopropylcarbo-
diimide as dehydrating agent. Under optimal conditions, highly
functionalized endo-adducts were obtained in high to excellent yields
(up to 99% yield) and enantioselectivities (up to >99.9% ee).
Cooperative catalysis using multifunctional organic
scaffolds in combination with transition-metal ions is
emerging as a powerful tool in asymmetric synthesis and
has allowed the development of unprecedented transfor-
mations in terms of reactivity and stereocontrol.11 In our
previous papers, we have made a breakthrough in the use
of multifunctional amidophosphanes derived from differ-
ent scaffolds of cinchona alkaloid–α-amino acids or double
α-amino acids in combination with transition-metal ions to
cooperatively catalyze 1,3-dipolar cycloadditions of azome-
thine ylides with high diastereo- and enantioselectivities.4f,g
In view of the excellent performance of amidophosphanes,
it was advisable to develop a different skeleton type of mul-
tifunctional amidophosphane and expand its application
prospects. Herein, we report a chiral secondary amine–
amidophosphane precatalyst derived from (1S,2S)-1,2-di-
phenylethylenediamine and (S)-phenylglycine, containing a
terminal secondary amine serving the dual role of base and
H-bond donor, two amide moieties as H-bond donors, and a
phosphine ligand, in combination with silver(I) to coopera-
tively catalyze 1,3-dipolar cycloadditions of azomethine
ylides, including heterocyclic, aliphatic, and 2-substituted
azomethine ylides, and aromatic α,β-unsaturated aldehyde
derived imines, as well as the three-component reaction of
α-imino esters generated in situ, with high to excellent di-
astereo- and enantioselectivity.
Key words secondary amine, amidophosphanes, silver carbonate,
1,3-dipolar cycloaddition, pyrrolidines
The catalytic asymmetric 1,3-dipolar cycloaddition re-
action can be considered as one of the most powerful and
reliable tools for the enantioselective synthesis of five-
membered heterocyclic compounds.1 The asymmetric 1,3-
dipolar cycloaddition of azomethine ylides with electron-
deficient olefins is of particular interest because it allows
the preparation of enantiomerically enriched pyrrolidine
structures,2 which are widely present in many biologically
active natural products and pharmaceutically useful
agents.3 To date, several effective chiral metal complex cata-
lysts of silver,4 copper,5 zinc,6 nickel,7 calcium,8 gold,9 and
organocatalysts10 have been reported as successfully cata-
lyzing the process for constructing highly substituted pyr-
rolidines with high endo/exo diastereo- and enantioselec-
tivity. However, despite intensive efforts in recent years by
several research groups who have developed a number of
very efficient protocols for performing this reaction with
Initially, multifunctional amidophosphane precatalysts
1a–i were easily synthesized from chiral (1R,2R)- or (1S,2S)-
1,2-diphenylethylenediamine and natural α-amino acids, as
illustrated in Scheme 1. Amidophosphane 1a was prepared
via three steps starting from (1R,2R)-N,N-dimethyl-1,2-di-
phenyl-1,2-ethanediamine and N-Boc-(S)-valine according
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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X. Zheng et al.
Paper
Synthesis
R1
N
R1
Ph
Ph
R2
O
Ph2P
NH
Ph
Ph
N
R2
COOH
PPh2
1a: R1 = Me; R2 = Me; R3 = i-Pr
R1
R1
N
NH
NH2
TFA
CH2Cl2
R2
O
O
Ph
Ph
R2
O
R3
O
Ph
Ph
N
HBTU
NHBoc
or
1b: R1 = Me; R2 = Me; R3 = i-Pr
1c: R1 = Me; R2 = Me; R3 = Me
1d: R1 = Me; R2 = Me; R3 = t-Bu
1e: R1 = Me; R2 = Me; R3 = Ph
1f: R1 = Et; R2 = Et; R3 = Ph
1g: R1 = H; R2 = i-Bu; R3 = Ph
1h: R1 = Me; R2 = i-Bu; R3 = Ph
1i: R1 = H; R2 = Ts; R3 = Ph
HO
NHBoc
NH2
i-Pr2NEt
CH2Cl2
R1
N
HBTU,
i-Pr2NEt
CH2Cl2
NH
R1
N
NH
R3
R3
R3
Ph
Ph
R2
O
Ph2P
Ph
Ph
R2
1a'–i'
1a''–i''
NH
NH
NH2
R3
O
Scheme 1 Synthesis of amidophosphanes 1a–i
to our reported procedures.4f Other amidophosphanes 1b–i
were prepared according to the procedure used to synthe-
size precatalyst 1a, starting from the corresponding substi-
tuted (1S,2S)-1,2-diphenylethylenediamines and different
natural α-amino acids, to yield the desired products.
decreased to 78% ee, albeit with the same reaction rate (en-
try 8). Precatalyst 1i with a 4-tolylsulfonamido group af-
forded a dual detrimental effect on the enantioselectivity
and the reaction rate, by comparison with precatalyst 1g
To investigate the 1,3-dipolar cycloaddition reaction,
azomethine ylide 3a (from glycine) and diethyl maleate (2a)
were selected as the model substrates to evaluate the reac-
tion parameters (Table 1). In our initial investigation, we
found the catalytic system Ag2CO3/amidophosphane 1a, de-
rived from (1R,2R)-1,2-diphenylethylenediamine and (S)-
valine, can efficiently catalyze the cycloaddition of imino
ester 3a with diethyl maleate (2a) in toluene at room tem-
perature in high yield (88%) and enantioselectivity (62%
ee); only endo-4a was detected by 1H NMR analysis of reac-
tion mixtures (entry 1). To further understand the effect of
central chirality on the enantioselectivity and absolute con-
figuration of the product, amidophosphane 1b derived from
(1S,2S)-1,2-diphenylethylenediamine and (S)-valine was
used, and an improvement in enantioselectivity was ob-
served, with the same absolute configuration (86% ee, entry
2).
Encouraged by these results, the effect of ligands 1c–e
derived from the same (1S,2S)-1,2-diphenylethylenedi-
amine and different α-amino acids on the conversion and
the enantioselectivity was investigated in toluene (entries
3–5). Ligands 1c,d derived from (S)-alanine and (S)-tert-leu-
cine, respectively, were not very effective, by comparison
with ligand 1b, with slightly lower enantioselectivities (en-
tries 3 and 4). Delightfully, high enantioselectivity (90% ee)
was achieved with the (S)-phenylglycine-derived ligand 1e
(entry 5). Next, the influence of substituents on the termi-
nal amino group was also studied (entries 6 and 7). When
the terminal dimethylamino group was replaced by a di-
ethylamino group, the enantioselectivity was slightly de-
creased (85% ee, entry 6). We were pleased to find that pre-
catalyst 1g, with a terminal isobutylamino group, afforded
the desired adduct in 94% yield and 98% enantioselectivity
(entry 7). However, when precatalyst 1h (derived from pre-
catalyst 1g by replacing the terminal amino hydrogen by a
methyl group) was used, the enantioselectivity was sharply
Table 1 Optimization of the Conditions for the Reaction of Azomethine
Ylide 3a with Diethyl Maleate (2a)a
CO2Et
CO2Et
precat. 1 (4 mol%)
EtO2C
Ph
+
Ph
N
CO2Me
CO2Me
MLn (4 mol%)
solvent, r.t.
CO2Et
N
H
2a
3a
endo-4a
Entry Precatalyst MLn
Solvent
Time (h) Yield (%)b ee (%)c
1
1
2
1a
1b
1c
1d
1e
1f
Ag2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
EtOAc
3
3
88
92
62
86
74
70
90
85
98
78
78
96
83
69
–
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2O
3
3
89
4
3
85
5
3
87
6
3
90
7
1g
1h
1i
3
94
8
3
95
9
21
2
86
10
11
12
13
14
15
16
17
18
19
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
93
AgF
4
89
AgOAc
AgOTf
4.5
75
10
10
3
trace
trace
88
Cu(OTf)2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
–
89
78
92
93
86
CH2Cl2
Et2O
3
82
93
88
4
t-BuOMe
THF
3
5
78
a Reaction conditions: imino ester 3a (0.24 mmol), diethyl maleate (2a, 0.2
mmol), MLn (4 mol%), precatalyst 1 (4 mol%), toluene (1.4 mL).
b Isolated yield based on 2a.
c Determined by HPLC.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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X. Zheng et al.
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Synthesis
(78% ee, 21 h; entry 9). These results strongly suggest that
the terminal secondary isobutylamino group on precatalyst
1g has the dual role of base and H donor.
Table 2 Ag2CO3/1g Catalyzed Cycloaddition of Various Aromatic Alde-
hyde Derived Imino Esters 3a–r with Diethyl Maleate (2a)a
R4
CO2Et
R4
CO2Et
Furthermore, screening metal salts, such as Ag2O, AgF,
AgOAc, AgOTf, and Cu(OTf)2, showed that Ag2CO3 gave opti-
mal results in terms of yield and enantioselectivity of ad-
duct 4a (Table 1, entries 10–14). Screening solvents re-
vealed toluene to be optimal of those tried in terms of both
yield and enantioselectivity (entries 15–19). Thus, the opti-
mal conditions for the asymmetric 1,3-dipolar cycloaddi-
tion of the azomethine ylide were established as Ag2-
CO3/1g/toluene at room temperature.
With the optimal reaction conditions in hand, we exam-
ined the scope of the substrates. As shown in Table 2, α-imi-
no esters 3a–i from aromatic aldehydes with different steric
hindrance and electronic properties reacted with diethyl
maleate (2a) to afford the corresponding endo-4a–i adducts
exclusively in high yields (85–99%) and excellent enantiose-
lectivities (94 to >99.9% ee) in the presence of precatalyst
1g (entries 1–9).12 Notably, when Ar was a heteroaromatic
group (entries 10–12), the endo-4j–l adducts were success-
fully obtained with high yields (73–95%) and excellent en-
antioselectivities (96 to >99.9% ee). The scope and limita-
tions of the protocol with regard to the 2-substituted
azomethine ylides 3m–r and diethyl maleate (2a) were also
explored in a similar manner (entries 13–18). The reaction
of imino esters 3m–q derived from alanine with 2a using
the Ag2CO3/1g catalytic system led to pyrrolidines 4m–q
with a quaternary center at the 2-position, with sole endo
selectivity and excellent enantioselectivity (98% ee, entries
13–17). Furthermore, imino ester 3r derived from phenylal-
anine has also been examined, albeit requiring prolonged
reaction time, which yielded the cycloaddition product 4r
without loss of enantioselectivity (98% ee, entry 18).
EtO2C
Ar
precat. 1g (4 mol%)
+
Ar
N
CO2Me
CO2Me
Ag2CO3 (2 mol%)
toluene, r.t.
CO2Et
N
H
3
2a
endo-4
Entry
3 (Ar/R4)
3a (C6H5/H)
Time (h)
4, Yield (%)b
ee (%)c
1
2
3
4.5
7
4a, 94
4b, 98
4c, 88
4d, 95
4e, 99
4f, 95
4g, 85
4h, 94
4i, 98
4j, 76
4k, 95
4l, 73
4m, 91
4n, 88
4o, 91
4p, 95
4q, 90
4r, 80
98
>99.9
>99.9
98
3b (4-MeC6H4/H)
3c (4-MeOC6H4/H)
3d (4-FC6H4/H)
3e (4-ClC6H4/H)
3f (4-BrC6H4/H)
3g (4-NCC6H4/H)
3h (1-naphthyl/H)
3i (2-naphthyl/H)
3j (2-furyl/H)
3
4
2
5
2
99
6
2
98
7
1
94
8
2
>99.9
>99.9
>99.9
96
9
3
10
11
12
13
14
15
16
17
18
6
3k (2-thienyl/H)
3l (3-pyridyl/H)
3m (C6H5/Me)
6
5
97
40
40
40
40
40
56
98
3n (4-FC6H4/Me)
3o (4-ClC6H4/Me)
3p (4-BrC6H4/Me)
3q (2-naphthyl/Me)
3r (C6H5/Bn)
98
98
98
98
98
a Reaction conditions: imino ester 3 (0.24 mmol), diethyl maleate (2a, 0.2
mmol), Ag2CO3 (2 mol%), precatalyst 1g (4 mol%), toluene (1.4 mL).
b Isolated yield based on 2a.
c Determined by HPLC.
Next, we tried to expand our methodology to reactions
of imino esters prepared from aliphatic aldehydes and aro-
matic α,β-unsaturated aldehydes (Table 3). Usually, 1,3-di-
polar cycloaddition reactions using aliphatic imines, espe-
cially primary alkyl imines, are recognized to be very diffi-
cult, as such imines are easily converted into enamines in
the presence of base, leading to undesired side reactions
such as self-condensation. In fact, successful examples of
asymmetric 1,3-dipolar cycloadditions of aliphatic alde-
hyde derived imino esters with high enantioselectivities are
quite limited.4b As shown in Table 3, we first tested the 1,3-
dipolar cycloaddition reaction of imino esters 3s–w bearing
a branched or cyclic alkyl substituent with diethyl maleate
(2a) to afford the desired cycloadducts 4s–w in 46–70%
yield and 76–87% enantioselectivity under the standard re-
action conditions (entries 1–5). Delightfully, when primary
alkyl imino ester 3x derived from hydrocinnamaldehyde
was used, the endo-4x adduct was successfully obtained
with high enantioselectivity (90% ee), albeit in moderate
yield (65%, entry 6). Significantly, regardless of the substitu-
ent on the aromatic ring with different steric hindrance and
electronic properties, a wide range of imino esters 3y–ze
derived from aromatic α,β-unsaturated aldehydes were also
tolerated, leading to the formation of the desired adducts
4y–ze in high yields (73–94%) and excellent enantioselec-
tivities (92–98% ee, entries 7–13).13 Notably, to the best of
our knowledge, the azomethine ylides generated from gly-
cine and the α,β-unsaturated aldehydes have not previously
been systematically evaluated as substrates for 1,3-dipolar
addition with diethyl maleate (2a) catalyzed by a chiral
metal complex.
We next transferred our attention to evaluate the three-
component 1,3-dipolar cycloaddition of α-imino esters gen-
erated in situ from aromatic aldehydes and free glycine es-
ter dissolved in toluene with diethyl maleate (2a) in a one-
pot fashion.14 As shown in Table 4, when no additive was
added, only a trace of product 4a was observed (entry 1).
Then, we investigated the effect of water-absorbing addi-
tives. DIC was found to be the best water-absorbing addi-
tive, superior to all other inorganic and organic additives
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Table 3 Ag2CO3/1g Catalyzed Cycloaddition of Aliphatic and Unsatu-
rated Aldehyde Derived Imino Esters 3s–ze with Diethyl Maleate (2a)a
Table 4 Ag2CO3/1g Catalyzed Three-Component Reaction of α-Imino
Esters Generated in situa
CO2Et
CO2Et
CO2Et
EtO2C
EtO2C
R5
precat. 1g (4 mol%)
A. H2NCH2COOMe
additive, toluene
R5
N
CO2Me
+
CO2Me
CO2Me
Ag2CO3 (2 mol%)
toluene, r.t.
CO2Et
ArCHO
N
N
H
Ar
H
B. diethyl maleate (2a)
3
precat. 1g (4 mol%)
2a
endo-4
endo-4
Ag2CO3 (2 mol%)
toluene, r.t.
Entry
3 (R5)
Time (h)
4, Yield (%)b ee (%)c
Entry
Ar
C6H5
Additive
Time (h)b
4, Yield (%)c
ee (%)d
1
2
3s (i-Pr)
3t (i-Bu)
24
31
48
10
24
24
10
4s, 70
76
84
87
82
78
90
98
92
97
96
93
96
94
1e
2f
3g
4
–
12 + 12
10 + 6
12 + 6
4 + 3
4a, trace
4a, 70
–
4t, 57
3
3u (t-Bu)
4u, 50
4v, 68
4w, 46
4x, 65
4y, 89
4z, 82
4za, 94
4zb, 92
4zc, 81
4zd, 86
4ze, 73
C6H5
MgSO4
4 Å MS
DCC
DIC
88
–
4
3v (neopentyl)
3w (cyclohexyl)
3x (C6H5CH2CH2)
3y (C6H5CH=CH)
C6H5
4a, trace
4a, 83
5
C6H5
95
95
–
6
5
C6H5
3 + 3
4a, 94
6h
7
C6H5
DIC
3 + 10
3 + 5
4a, trace
4b, 94
4c, 89
7
8
3z (2-MeOC6H4CH=CH)
3za (2-FC6H4CH=CH)
3zb (4-FC6H4CH=CH)
3zc (4-ClC6H4CH=CH
3zd (4-BrC6H4CH=CH)
3ze (2-furylCH=CH)
28
10
9
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
DIC
92
95
92
96
95
9
8
DIC
3 + 6
10
11
12
13
9
DIC
3 + 3
4d, 96
4e, 99
4f, 95
10
10
16
10
11
DIC
3 + 3
DIC
3 + 4
a Reaction conditions: aldehyde (0.30 mmol), methyl glycinate (0.30
mmol), additive (0.30 mmol), diethyl maleate (2a, 0.2 mmol), Ag2CO3 (2
mol%), precatalyst 1g (4 mol%), toluene (1.4 mL); DCC = N,N′-dicyclohexyl-
carbodiimide; DIC = N,N′-diisopropylcarbodiimide.
b Reaction time for the two steps.
a Reaction conditions: imino ester 3 (0.24 mmol), diethyl maleate (2a, 0.2
mmol), Ag2CO3 (2 mol%), precatalyst 1g (4 mol%), toluene (1.4 mL).
b Isolated yield based on 2a.
c Determined by HPLC.
c Isolated yield based on 2a.
d Determined by HPLC.
e No additive was added.
f MgSO4 (4 equiv) was added.
tested, such as MgSO4, 4 Å molecular sieves, and DCC (en-
tries 2–5). However, under the same conditions, when
methyl glycinate hydrochloride and Et3N (0.30 mmol) were
used, almost no product was observed (entry 6). Delightful-
ly, under the action of DIC serving as water-absorbing addi-
tive, regardless of the substituent on the benzene ring with
different steric hindrance and electronic properties, ad-
ducts 4b–f derived from free glycine ester were successfully
obtained in a one-pot process in satisfactory yields (89–
99%) and, in two cases with slightly decreased enantiose-
lectivity relative to 4a (92–96% ee, entries 7–11).
We also probed another three dipolarophiles, as out-
lined in Figure 1. Only the endo-adducts were isolated in all
cases. Dimethyl maleate, as a popular dipolarophile in the
literature, was used in the reaction with α-imino ester 3a to
provide 4zf in 94% yield and with 96% ee. For the reactions
g 4 Å MS (100 mg) were added.
h Methyl glycinate hydrochloride (0.30 mmol) and Et3N (0.30 mmol) were
used.
of dimethyl fumarate and methyl acrylate with 3a, adducts
4zg and 4zh with relatively lower enantioselectivities of
28% and 56% ee, respectively, were observed.
In conclusion, we have developed a series of multifunc-
tional amidophosphane precatalysts derived from chiral
1,2-diphenylethylenediamines and α-amino acids. Among
these, the (1S,2S)-1,2-diphenylethylenediamine and (S)-
phenylglycine-derived secondary amine–amidophosphane
1g served as a highly efficient multifunctional precatalyst
in combination with silver carbonate to cooperatively cata-
lyze the 1,3-dipolar cycloaddition of azomethine ylides 3
and diethyl maleate (2a), furnishing highly functionalized
endo-4 adducts in moderate to excellent yields (46–99%)
and enantioselectivities (76 to >99.9%) under mild condi-
tions, especially for heterocyclic, aliphatic, and 2-substitut-
ed azomethine ylides, and aromatic α,β-unsaturated alde-
hyde derived imino esters. In addition, the catalytic system
Ag2CO3/1g/toluene has also been successfully applied in
three-component reactions of α-imino esters generated in
situ under the conditions using DIC as dehydrating agent
CO2Me
CO2Me
MeO2C
MeO2C
Ph
MeO2C
Ph
CO2Me
CO2Me
CO2Me
N
N
N
Ph
H
H
H
4zg, yield: 91%
4zh, yield: 82%
4zf, yield: 94%
ee: 28%
ee: 56%
ee: 96%
Figure 1 Cycloadducts of 3a with other dipolarophiles
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Synthesis
and with other electron-deficient alkenes. Additional inves-
tigations into the substrate scope and mechanistic aspects
are in progress.
N-((S)-1-(((1S,2S)-2-(Dimethylamino)-1,2-diphenylethyl)amino)-
3-methyl-1-oxobutan-2-yl)-2-(diphenylphosphino)benzamide
(1b)
Catalyst 1b was prepared according to the procedure used to synthe-
size catalyst 1a, starting from 1b′ (439 mg, 1.0 mmol), which yielded
1b as a white solid (502 mg, 80%).
Melting points are uncorrected. 1H and 13C NMR spectra were record-
ed in CDCl3 on Bruker AV-400 spectrometers, unless otherwise noted.
CDCl3 served as internal standard (1H NMR, δ = 7.26; 13C NMR, δ =
77.0). High-performance liquid chromatography was carried out us-
ing an Agilent 1260 apparatus which was equipped with a spectro-
photometric detector (monitoring at 205–230 nm) and using a Daicel
chiral AS-H column, OD-H column, or AD-H column. High-resolution
mass spectrometry was recorded with a Micromass LCMS-IT-TOF in-
strument. Optical rotations were measured on an Insmark IP-di-
gi300/2 polarimeter. All reactions were carried out under N2 atmo-
sphere in oven-dried glassware with magnetic stirring. All solvents
employed in the reactions were distilled from appropriate drying
agents prior to use. All reagents, unless stated otherwise, were of
commercial origin and were used without further purification.
Mp 105–107 °C; [α]D30 –76.8 (c 1.20, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 3.6 Hz, 1 H), 7.55–7.52 (m, 1
H), 7.36–7.20 (m, 15 H), 7.12–7.01 (m, 7 H), 6.99–6.96 (m, 1 H), 6.52
(d, J = 8.8 Hz, 1 H), 5.09 (dd, J = 11.2, 4.0 Hz, 1 H), 4.50 (dd, J = 8.4, 6.4
Hz, 1 H), 3.65 (d, J = 11.2 Hz, 1 H), 2.14 (s, 6 H), 2.12–2.07 (m, 1 H),
0.96 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ (C–P coupling not removed) = 170.4,
168.8, 141.3, 141.0, 140.6, 137.5, 137.5, 137.4, 137.4, 136.5, 136.3,
134.5, 133.9, 133.7, 132.3, 130.3, 129.7, 128.7, 128.6, 128.5, 128.5,
128.4, 127.9, 127.7, 127.6, 127.5, 127.3, 126.8, 73.5, 59.0, 54.6, 40.7,
31.2, 19.1, 18.2.
31P NMR (162 MHz, CDCl3): δ = –10.2.
HRMS (ESI): m/z [M + H]+ calcd for C40H43N3O2P: 628.3093; found:
628.3096.
N-((S)-1-(((1R,2R)-2-(Dimethylamino)-1,2-diphenylethyl)amino)-
3-methyl-1-oxobutan-2-yl)-2-(diphenylphosphino)benzamide
(1a); Typical Procedure
N-((S)-1-(((1S,2S)-2-(Dimethylamino)-1,2-diphenylethyl)amino)-
1-oxopropan-2-yl)-2-(diphenylphosphino)benzamide (1c)
Compound 1a′ was prepared according to the reported procedure.4f
1a′ (439 mg, 1 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (1 mL)
was dropwise added at 0 °C. Then, the reaction mixture was stirred
for 18 h at r.t. All volatile compounds were removed in vacuo and the
residue was dissolved in water and treated with saturated Na2CO3
solution. The resulting mixture was extracted with CH2Cl2 (3 ×) and
the combined organic layers were dried over Na2SO4. After filtration
and then evaporation of the solvent, the crude free amine was ob-
tained without purification for the next step. To a solution of the free
amine in CH2Cl2 (8 mL) was added O-(benzotriazol-1-yl)-N,N,N′,N′-te-
tramethyluronium hexafluorophosphate (HBTU; 417 mg, 1.1 mmol),
followed by the addition of N,N-diisopropylethylamine (367 μL, 2.2
mmol) and 2-(diphenylphosphino)benzoic acid (306 mg, 1 mmol).
The reaction mixture was then stirred for 6 h at r.t. The mixture was
combined with CH2Cl2 and water, and the organic layer was separat-
ed, washed with saturated NaHCO3 solution (2 ×), and dried over
Na2SO4. The solvent was removed in vacuo to afford the crude product
as a colorless oil, which was purified by flash chromatography (20%
EtOAc in hexanes) yielding precatalyst 1a as a white solid (514 mg,
82%).
Catalyst 1c was prepared according to the procedure used to synthe-
size catalyst 1a, starting from 1c′ (411 mg, 1.0 mmol), which yielded
1c as a white solid (413 mg, 69%).
Mp 109–111 °C; [α]D30 –65.6 (c 1.40, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.67–7.53 (m, 2 H), 7.31–7.21 (m, 15
H), 7.09–6.94 (m, 8 H), 6.93 (br s, 1 H), 5.09 (d, J = 10.4 Hz, 1 H), 4.59–
4.54 (m, 1 H), 3.69 (d, J = 10.4 Hz, 1 H), 2.14 (s, 6 H), 1.25 (d, J = 6.8 Hz,
3 H).
13C NMR (100 MHz, CDCl3): δ (C–P coupling not removed) = 171.7,
168.4, 140.6, 140.6, 140.3, 137.3, 137.2, 137.1, 137.1, 136.7, 136.5,
134.0, 134.0, 133.8, 133.8, 132.5, 130.3, 129.7, 128.8, 128.7, 128.6,
128.5, 128.5, 127.9, 127.8, 127.7, 127.7, 127.6, 127.4, 126.9, 73.4, 54.6,
49.2, 40.6, 18.2.
31P NMR (162 MHz, CDCl3): δ = –9.3.
HRMS (ESI): m/z [M + H]+ calcd for C38H39N3O2P: 600.2780; found:
600.2783.
N-((S)-1-(((1S,2S)-2-(Dimethylamino)-1,2-diphenylethyl)amino)-
3,3-dimethyl-1-oxobutan-2-yl)-2-(diphenylphosphino)ben-
zamide (1d)
Mp 93–95 °C; [α]D30 +20.8 (c 1.20, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.63–7.61 (m, 2 H), 7.38–7.18 (m, 15
H), 7.12–6.98 (m, 8 H), 6.71 (d, J = 8.0 Hz, 1 H), 5.08 (dd, J = 11.2, 3.6
Hz, 1 H), 4.53 (dd, J = 8.4, 5.6 Hz, 1 H), 3.68 (d, J = 11.2 Hz, 1 H), 2.12 (s,
6 H), 2.12–2.04 (m, 1 H), 0.84 (d, J = 7.2 Hz, 3 H), 0.82 (d, J = 7.2 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ (C–P coupling not removed) = 171.1,
168.7, 141.2, 141.0, 140.5, 137.6, 137.5, 137.4, 136.6, 136.4, 134.5,
133.9, 133.8, 133.7, 132.1, 130.3, 129.7, 128.7, 128.6, 128.5, 128.5,
128.4, 127.9, 127.7, 127.7, 127.5, 127.5, 126.9, 73.2, 58.5, 54.8, 40.5,
31.8, 19.1, 18.0.
Catalyst 1d was prepared according to the procedure used to synthe-
size catalyst 1a, starting from 1d′ (453 mg, 1.0 mmol), which yielded
1d as a white solid (417 mg, 65%).
Mp 103–104 °C; [α]D30 –64.3 (c 1.12, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.57–7.44 (m, 2 H), 7.33–7.18 (m, 15
H), 7.11–6.95 (m, 8 H), 6.53 (d, J = 9.2 Hz, 1 H), 5.05 (dd, J = 11.2, 3.2
Hz, 1 H), 4.55 (d, J = 9.6 Hz, 1 H), 3.60 (d, J = 11.2 Hz, 1 H), 2.15 (s, 6 H),
1.01 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ (C–P coupling not removed) = 170.0,
168.9, 141.8, 141.5, 140.5, 137.7, 137.6, 137.5, 136.4, 136.2, 134.6,
133.8, 133.7, 133.6, 133.5, 132.0, 130.2, 129.8, 128.7, 128.6, 128.5,
128.4, 128.4, 128.3, 127.9, 127.7, 127.6, 127.3, 127.2, 126.7, 73.6, 61.1,
54.6, 40.7, 34.9, 26.5.
31P NMR (162 MHz, CDCl3): δ = –10.2.
HRMS (ESI): m/z [M + H]+ calcd for C40H43N3O2P: 628.3093; found:
628.3095.
31P NMR (162 MHz, CDCl3): δ = –10.5.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

F
X. Zheng et al.
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C41H45N3O2P: 642.3249; found:
2-(Diphenylphosphino)-N-((S)-2-(((1S,2S)-2-(isobutyl(meth-
642.3253.
yl)amino)-1,2-diphenylethyl)amino)-2-oxo-1-phenylethyl)ben-
zamide (1h)
N-((S)-2-(((1S,2S)-2-(Dimethylamino)-1,2-diphenylethyl)amino)-
2-oxo-1-phenylethyl)-2-(diphenylphosphino)benzamide (1e)
Catalyst 1h was prepared according to the procedure used to synthe-
size catalyst 1a, starting from 1h′ (515 mg, 1.0 mmol), which yielded
1h as a white solid (435 mg, 62%).
Mp 124–126 °C; [α]D30 +5.52 (c 0.87, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.63–7.55 (m, 3 H), 7.44–7.42 (m, 2 H),
7.34–7.17 (m, 18 H), 7.15–7.06 (m, 5 H), 6.96–6.90 (m, 3 H), 5.54 (d,
J = 6.4 Hz, 1 H), 4.84 (dd, J = 11.2, 6.0 Hz, 1 H), 3.61 (d, J = 10.8 Hz, 1 H),
1.99–1.94 (m, 1 H), 1.74–1.57 (m, 2 H), 1.51 (s, 3 H), 0.82 (d, J = 6.8 Hz,
3 H), 0.80 (d, J = 6.4 Hz, 3 H).
Catalyst 1e was prepared according to the procedure used to synthe-
size catalyst 1a, starting from 1e′ (473 mg, 1.0 mmol), which yielded
1e as a white solid (489 mg, 74%).
Mp 122–124 °C; [α]D30 –1.9 (c 0.80, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.61–7.08 (m, 28 H), 6.94–6.93 (m, 3
H), 5.50 (d, J = 5.6 Hz, 1 H), 4.85 (d, J = 10.4 Hz, 1 H), 3.55 (d, J = 10.8
Hz, 1 H), 1.78 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ (C–P coupling not removed) = 169.9,
167.9, 140.7, 140.6, 140.4, 138.4, 137.7, 137.6, 137.3, 137.2, 136.9,
136.7, 134.3, 133.9, 133.8, 133.7, 133.6, 132.7, 130.2, 129.6, 128.9,
128.4, 128.4, 128.3, 128.3, 128.2, 128.0, 127.8, 127.7, 127.7, 127.6,
127.2, 127.0, 72.4, 63.2, 57.4, 55.3, 34.7, 25.4, 20.8, 20.7.
31P NMR (162 MHz, CDCl3): δ = –9.7.
HRMS (ESI): m/z [M + H]+ calcd for C46H47N3O2P: 704.3406; found:
13C NMR (100 MHz, CDCl3): δ (C–P coupling not removed) = 169.8,
168.1, 140.4, 138.4, 137.5, 137.4, 137.2, 136.9, 136.7, 134.3, 133.9,
133.9, 133.7, 133.7, 132.2, 130.3, 129.6, 128.9, 128.5, 128.4, 128.4,
128.0, 128.0, 127.7, 127.7, 127.3, 127.1, 127.0, 73.3, 57.6, 54.9, 40.1.
31P NMR (162 MHz, CDCl3): δ = –9.7.
HRMS (ESI): m/z [M + H]+ calcd for C43H41N3O2P: 662.2936; found:
662.2934.
704.3410.
N-((S)-2-(((1S,2S)-2-(Diethylamino)-1,2-diphenylethyl)amino)-2-
oxo-1-phenylethyl)-2-(diphenylphosphino)benzamide (1f)
2-(Diphenylphosphino)-N-((S)-2-(((1S,2S)-2-(4-methylphenylsul-
fonamido)-1,2-diphenylethyl)amino)-2-oxo-1-phenylethyl)ben-
zamide (1i)
Catalyst 1f was prepared according to the procedure used to synthe-
size catalyst 1a, starting from 1f′ (501 mg, 1.0 mmol), which yielded
1f as a white solid (449 mg, 65%).
Mp 142–143 °C; [α]D30 +16.5 (c 1.12, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ (C–P coupling not removed) = 7.58–7.41
(m, 5 H), 7.33–7.07 (m, 23 H), 6.97–6.90 (m, 3 H), 5.54 (d, J = 6.0 Hz,
1 H), 4.89 (d, J = 10.0 Hz, 1 H), 3.77 (d, J = 10.8 Hz, 1 H), 2.37 (q, J = 7.2
Hz, 2 H), 1.95 (q, J = 7.2 Hz, 2 H), 0.68 (t, J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 169.3, 168.0, 140.8, 140.7, 140.4,
138.2, 137.8, 137.6, 137.4, 137.3, 136.9, 136.7, 134.3, 133.9, 133.9,
133.7, 133.7, 130.2, 129.5, 129.1, 128.5, 128.4, 128.3, 128.3, 128.2,
128.0, 127.8, 127.6, 127.5, 127.2, 127.0, 68.8, 57.5, 54.9, 42.7, 13.3.
Catalyst 1i was prepared according to the procedure used to synthe-
size catalyst 1a, starting from 1i′ (599 mg, 1.0 mmol), which yielded
1i as a white solid (457 mg, 58%).
Mp 139–140 °C; [α]D30 +49.3 (c 0.93, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.65–7.62 (m, 1 H), 7.50–7.48 (m, 1 H),
7.35–6.85 (m, 31 H), 6.66 (d, J = 7.2 Hz, 2 H), 6.01 (br s, 1 H), 5.58 (d,
J = 6.8 Hz, 1 H), 5.20 (dd, J = 8.4, 8.0 Hz, 1 H), 4.56 (d, J = 8.0 Hz, 1 H),
2.23 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ (C–P coupling not removed) = 170.4,
168.6, 142.6, 140.7, 140.5, 137.4, 137.4, 137.1, 136.8, 136.6, 136.5,
136.4, 135.7, 135.5, 134.3, 133.8, 133.7, 133.6, 133.5, 130.5, 129.0,
128.9, 128.8, 128.7, 128.6, 128.5, 128.5, 128.4, 128.2, 127.9, 127.9,
127.8, 127.5, 127.4, 126.9, 62.4, 58.8, 58.2, 21.3.
31P NMR (162 MHz, CDCl3): δ = –9.8.
HRMS (ESI): m/z [M + H]+ calcd for C45H45N3O2P: 690.3249; found:
690.3255.
31P NMR (162 MHz, CDCl3): δ = –11.0.
HRMS (ESI): m/z [M + H]+ calcd for C48H43N3O4PS: 788.2712; found:
788.2718.
2-(Diphenylphosphino)-N-((S)-2-(((1S,2S)-2-(isobutylamino)-1,2-
diphenylethyl)amino)-2-oxo-1-phenylethyl)benzamide (1g)
Catalyst 1g was prepared according to the procedure used to synthe-
size catalyst 1a, starting from 1g′ (501 mg, 1.0 mmol), which yielded
1g as a white solid (482 mg, 70%).
Mp 112–116 °C; [α]D30 +53.7 (c 1.26, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.61–7.59 (m, 1 H), 7.34–6.86 (m, 30
H), 5.56 (d, J = 6.4 Hz, 1 H), 4.93–4.90 (m, 1 H), 3.86 (d, J = 4.0 Hz, 1 H),
2.07–1.98 (m, 2 H), 1.48 (br s, 1 H), 0.88–0.83 (m, 1 H), 0.71 (d, J = 6.0
Hz, 3 H), 0.69 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ (C–P coupling not removed) = 169.1,
168.2, 140.7, 140.5, 140.0, 139.9, 137.9, 137.4, 137.3, 137.1, 137.0,
136.7, 136.4, 134.3, 133.9, 133.9, 133.7, 133.7, 130.3, 129.0, 128.6,
128.6, 128.5, 128.5, 128.4, 128.3, 128.1, 127.9, 127.9, 127.4, 127.2,
127.2, 126.5, 66.9, 59.1, 57.8, 55.1, 28.3, 20.5, 20.3.
Ag2CO3/1g Catalyzed Cycloaddition of Various Imino Esters 3; Gen-
eral Procedure
Precatalyst 1g (5.51 mg, 0.008 mmol) and Ag2CO3 (1.09 mg, 0.004
mmol) were dissolved in toluene (1.4 mL). The reaction mixture was
stirred for 1 h at r.t., followed by the addition of diethyl maleate (2a;
34.4 mg, 0.2 mmol) and imine substrate 3 (0.24 mmol). Once starting
material had been consumed (monitored by TLC), the mixture was
purified by column chromatography to give the corresponding cyc-
loaddition product 4, which was then directly analyzed by chiral
HPLC.
Ag2CO3/1g Catalyzed Three-Component Reaction of α-Imino Esters
Generated in Situ (Table 4); General Procedure
31P NMR (162 MHz, CDCl3): δ = –10.2.
HRMS (ESI): m/z [M + H]+ calcd for C45H45N3O2P: 690.3249; found:
To the aromatic aldehyde (1.5 equiv) was added a solution of methyl
glycinate (1.5 equiv) (by washing methyl glycinate hydrochloride di-
chloromethane solution with a mixture of aqueous 1 N NaOH and
brine (1:1), followed by drying over Na2SO4, filtration, and concentra-
690.3253.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

G
X. Zheng et al.
Paper
Synthesis
tion) in toluene (50 mg/mL) followed by dried N,N′-diisopropylcarbo-
diimide (37.8 mg, 0.3 mmol). This suspension was tumbled for 3 h.
Under N2 atmosphere, a solution of precatalyst 1g (5.51 mg, 0.008
mmol) and Ag2CO3 (1.09 mg, 0.004 mmol) in toluene (0.5 mL), which
was stirred for 1 h at r.t., was added to the above solution by syringe,
followed by the addition of diethyl maleate (2a; 34.4 mg, 0.2 mmol).
Once starting material had been consumed (monitored by TLC), the
mixture was purified by column chromatography to give the corre-
sponding cycloaddition product endo-4, which was then directly ana-
lyzed by chiral HPLC.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.32 (m, 2 H), 7.01–6.99 (m, 2 H),
4.44 (d, J = 6.8 Hz, 1 H), 4.12–4.09 (m, 3 H), 3.78 (s, 3 H), 3.74–3.62 (m,
3 H), 3.57–3.53 (m, 1 H), 3.18 (br s, 1 H), 1.22 (t, J = 7.2 Hz, 3 H), 0.83
(t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.9, 170.3, 163.4, 160.9, 133.1,
133.0, 128.6, 128.5, 115.2, 115.0, 64.6, 62.1, 61.1, 60.4, 52.7, 52.2,
51.1, 14.0, 13.6.
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(4-Chlorophenyl)pyrroli-
dine-2,3,4-tricarboxylate (4e)4f
White solid; yield: 76 mg (99%); 99% ee [tR = 6.89 (major), 11.44 (mi-
nor) min (Chiralcel AS-H, λ = 230 nm, i-PrOH/hexanes, 50:50, flow
rate = 0.8 mL/min)].
Mp 117–118 °C; [α]D30 +49.7 (c 1.14, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.33–7.28 (m, 4 H), 4.44 (d, J = 6.8 Hz, 1
H), 4.16–4.10 (m, 3 H), 3.80 (s, 3 H), 3.76–3.68 (m, 3 H), 3.60–3.56 (m,
1 H), 3.27 (br s, 1 H), 1.24 (t, J = 7.2 Hz, 3 H), 0.87 (t, J = 7.2 Hz, 3 H).
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-Phenylpyrrolidine-2,3,4-tri-
carboxylate (4a)4f
White solid; yield: 66 mg (94%); 98% ee [tR = 5.72 (major), 10.90 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow
rate = 0.8 mL/min)].
Mp 120–121 °C; [α]D30 +58.1 (c 1.20, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.36–7.25 (m, 5 H), 4.47 (d, J = 6.8 Hz, 1
H), 4.16–4.11 (m, 3 H), 3.81 (s, 3 H), 3.76–3.62 (m, 3 H), 3.59 (t, J = 7.6
Hz, 1 H), 3.43 (br s, 1 H), 1.24 (t, J = 7.2 Hz, 3 H), 0.80 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.8, 170.1, 135.8, 133.4, 128.3,
128.3, 64.6, 62.0, 61.1, 60.4, 52.5, 52.2, 51.1, 14.0, 13.6.
13C NMR (100 MHz, CDCl3): δ = 171.0, 170.4, 170.25, 137.0, 128.2,
127.6, 126.7, 65.3, 62.1, 61.0, 60.3, 52.7, 52.2, 51.2, 14.0, 13.5.
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(4-Bromophenyl)pyrroli-
dine-2,3,4-tricarboxylate (4f)4f
White solid; yield: 81 mg (95%); 98% ee [tR = 7.42 (major), 12.33 (mi-
nor) min (Chiralcel AS-H, λ = 230 nm, i-PrOH/hexanes, 50:50, flow
rate = 0.8 mL/min)].
Mp 108–110 °C; [α]D30 +53.8 (c 1.14, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.46–7.43 (m, 2 H), 7.27–7.24 (m, 2 H),
4.42 (d, J = 7.2 Hz, 1 H), 4.16–4.10 (m, 3 H), 3.80 (s, 3 H), 3.80–3.55 (m,
4 H), 3.27–3.26 (m, 1 H), 1.24 (t, J = 7.2 Hz, 3 H), 0.87 (t, J = 7.2 Hz, 3
H).
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(p-Tolyl)pyrrolidine-2,3,4-
tricarboxylate (4b)4f
White solid; yield: 71 mg (98%); >99.9% ee [tR = 6.36 (major) min (Chi-
ralcel AS-H, λ = 230 nm, i-PrOH/hexanes, 50:50, flow rate = 0.8
mL/min)].
Mp 115–117 °C; [α]D30 +52.3 (c 1.24, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 7.6 Hz, 2 H), 7.10 (d, J = 7.6
Hz, 2 H), 4.43 (d, J = 6.4 Hz, 1 H), 4.14–4.09 (m, 3 H), 3.79 (s, 3 H),
3.75–3.64 (m, 3 H), 3.57–3.53 (m, 2 H), 2.30 (s, 3 H), 1.23 (t, J = 7.2 Hz,
3 H), 0.83 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.8, 170.2, 136.3, 131.3, 128.6,
121.5, 64.7, 62.1, 61.1, 60.5, 52.5, 52.3, 51.1, 14.0, 13.6.
13C NMR (100 MHz, CDCl3): δ = 171.0, 170.4, 170.2, 137.2, 133.9,
128.9, 126.6, 65.1, 62.1, 61.0, 60.3, 52.8, 52.2, 51.3, 21.0, 14.0, 13.6.
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(4-Cyanophenyl)pyrrolidine-
2,3,4-tricarboxylate (4g)4f
White solid; yield: 64 mg (85%); 94% ee [tR = 12.69 (major), 16.60 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow
rate = 0.8 mL/min)].
Mp 140–142 °C; [α]D30 +35.8 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 8.0 Hz, 2 H), 7.51 (d, J = 8.0
Hz, 2 H), 4.50 (d, J = 7.2 Hz, 1 H), 4.15–4.11 (m, 3 H), 3.79 (s, 3 H),
3.77–3.67 (m, 3 H), 3.63–3.60 (m, 1 H), 3.22 (br s, 1 H), 1.23 (t, J = 7.2
Hz, 3 H), 0.84 (t, J = 7.2 Hz, 3 H).
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(4-Methoxyphenyl)pyrroli-
dine-2,3,4-tricarboxylate (4c)4f
White solid; yield: 67 mg (88%); >99.9% ee [tR = 8.38 (major) min (Chi-
ralcel AS-H, λ = 230 nm, i-PrOH/hexanes, 50:50, flow rate = 0.8
mL/min)].
Mp 84–86 °C; [α]D30 +50.2 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.28 (d, J = 8.4 Hz, 2 H), 6.85 (d, J = 8.4
Hz, 2 H), 4.43 (d, J = 6.8 Hz, 1 H), 4.15–4.10 (m, 3 H), 3.80 (s, 3 H), 3.78
(s, 3 H), 3.71–3.67 (m, 3 H), 3.55 (t, J = 6.8 Hz, 1 H), 3.22 (br s, 1 H),
1.24 (t, J = 7.2 Hz, 3 H), 0.86 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.7, 170.0, 169.9, 143.0, 132.0,
127.8, 118.5, 111.5, 64.6, 62.0, 61.3, 60.6, 52.4, 52.3, 51.1, 14.0, 13.6.
13C NMR (100 MHz, CDCl3): δ = 171.0, 170.5, 170.3, 159.0, 129.2,
128.0, 113.6, 64.9, 62.1, 61.0, 60.3, 55.2, 52.8, 52.2, 51.1, 14.0, 13.6.
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(1-Naphthyl)pyrrolidine-
2,3,4-tricarboxylate (4h)4f
White solid; yield: 75 mg (94%); >99.9% ee [tR = 11.49 (major) min
(Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow rate = 0.8
mL/min)].
Mp 77–79 °C; [α]D30 +212.4 (c 1.04, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 8.0
Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.59 (d, J = 7.2 Hz, 1 H), 7.53–7.40 (m,
3 H), 5.14 (d, J = 6.8 Hz, 1 H), 4.20–4.06 (m, 3 H), 3.93–3.82 (m, 2 H),
3.84 (s, 3 H), 3.45–3.31 (m, 3 H), 1.17 (t, J = 7.2 Hz, 3 H), 0.37 (t, J = 7.2
Hz, 3 H).
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(4-Fluorophenyl)pyrroli-
dine-2,3,4-tricarboxylate (4d)4f
White solid; yield: 70 mg (95%); 98% ee [tR = 7.39 (major), 11.89 (mi-
nor) min (Chiralcel AS-H, λ = 230 nm, i-PrOH/hexanes, 50:50, flow
rate = 0.8 mL/min)].
Mp 101–103 °C; [α]D30 +48.6 (c 1.20, CH2Cl2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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Synthesis
13C NMR (100 MHz, CDCl3): δ = 171.1, 170.2, 170.0, 133.4, 132.3,
131.0, 128.8, 128.2, 126.1, 125.4, 125.1, 123.2, 122.7, 61.5, 61.2, 60.9,
59.9, 52.2, 52.1, 51.3, 13.9, 13.1.
13C NMR (100 MHz, CDCl3): δ = 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.
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 2-Methyl-5-phenylpyrrolidine-
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(2-Naphthyl)pyrrolidine-
2,3,4-tricarboxylate (4m)4f
2,3,4-tricarboxylate (4i)4f
Colorless oil; yield: 66 mg (91%); 98% ee [tR = 7.81 (minor), 11.70 (ma-
jor) min (Chiralcel AD-H, λ = 210 nm, i-PrOH/hexanes, 15:85, flow
rate = 0.8 mL/min)].
[α]D30 +40.8 (c 1.20, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.37–7.24 (m, 5 H), 4.63 (d, J = 6.4 Hz, 1
H), 4.20 (q, J = 7.2 Hz, 2 H), 3.79 (s, 3 H), 3.78–3.65 (m, 2 H), 3.47 (t, J =
7.2 Hz, 1 H), 3.28 (d, J = 6.8 Hz, 1 H), 1.68 (s, 3 H), 1.29 (t, J = 7.2 Hz, 3
H), 0.80 (t, J = 7.2 Hz, 3 H).
White solid; yield: 78 mg (98%); >99.9% ee [tR = 11.41 (major) min
(Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow rate = 0.8
mL/min)].
Mp 122–124 °C; [α]D30 +32.5 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.83–7.78 (m, 4 H), 7.47–7.44 (m, 3 H),
4.61 (dd, J = 6.4, 2.4 Hz, 1 H), 4.19 (dd, J = 8.8, 2.0 Hz, 1H), 4.13 (qd, J =
7.2, 1.6 Hz, 2 H), 3.83 (s, 3 H), 3.79–3.75 (m, 1 H), 3.71–3.53 (m, 3 H),
3.42 (br s, 1 H), 1.24 (t, J = 7.2 Hz, 3 H), 0.67 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.0, 170.4, 170.2, 134.5, 133.1,
132.7, 128.0, 127.8, 127.5, 126.1, 125.9, 125.4, 124.9, 65.4, 62.0, 61.1,
60.3, 52.7, 52.3, 51.5, 14.0, 13.5.
13C NMR (100 MHz, CDCl3): δ = 174.3, 170.5, 170.5, 137.3, 128.2,
127.7, 126.9, 68.6, 63.7, 61.0, 60.2, 58.0, 53.2, 52.5, 28.3, 14.1, 13.6.
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(4-Fluorophenyl)-2-meth-
ylpyrrolidine-2,3,4-tricarboxylate (4n)4f
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(2-Furyl)pyrrolidine-2,3,4-
White solid; yield: 67 mg (88%); 98% ee [tR = 8.24 (minor), 12.53 (ma-
jor) min (Chiralcel AD-H, λ = 210 nm, i-PrOH/hexanes, 15:85, flow
rate = 0.8 mL/min)].
Mp 87–88 °C; [α]D30 +41.2 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.35–7.32 (m, 2 H), 7.00–6.96 (m, 2 H),
4.59 (d, J = 6.4 Hz, 1 H), 4.17 (q, J = 7.2 Hz, 2 H), 3.77 (s, 3 H), 3.69–3.66
(m, 2 H), 3.58 (br s, 1 H), 3.44 (t, J = 7.2 Hz, 1 H), 3.25 (d, J = 7.2 Hz, 1
H), 1.64 (s, 3 H), 1.27 (t, J = 7.2 Hz, 3 H), 0.82 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.3, 170.6, 170.4, 163.4, 161.0,
133.4, 128.8, 128.7, 115.2, 114.9, 68.6, 63.0, 61.0, 60.2, 57.6, 53.0,
52.5, 28.1, 14.0, 13.7.
tricarboxylate (4j)4f
White solid; yield: 52 mg (76%); >99.9% ee [tR = 7.21 (major) min (Chi-
ralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow rate = 0.8
mL/min)].
Mp 104–106 °C; [α]D30 +24.6 (c 1.20, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.33–7.32 (m, 1 H), 6.33–6.31 (m, 2 H),
4.47 (d, J = 6.8 Hz, 1 H), 4.13 (q, J = 7.2 Hz, 2 H), 4.07 (d, J = 8.8 Hz, 1 H),
3.94–3.85 (m, 2 H), 3.78 (s, 3 H), 3.62 (dd, J = 8.0, 8.8 Hz, 1 H), 3.50 (t,
J = 7.6 Hz, 1 H), 3.24 (br s, 1 H), 1.23 (t, J = 7.2 Hz, 3 H), 1.03 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.7, 170.2, 170.0, 151.0, 141.8,
110.4, 107.2, 62.0, 61.1, 60.7, 59.5, 52.3, 51.5, 50.8, 14.0, 13.8.
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(4-Chlorophenyl)-2-meth-
ylpyrrolidine-2,3,4-tricarboxylate (4o)4f
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(2-Thienyl)pyrrolidine-2,3,4-
Colorless oil; yield: 72 mg (91%); 98% ee [tR = 9.73 (minor), 10.43 (ma-
jor) min (Chiralcel OD-H, λ = 210 nm, i-PrOH/hexanes, 15:85, flow
rate = 0.8 mL/min)].
[α]D30 +39.2 (c 1.24, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.32 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.8
Hz, 2 H), 4.59 (d, J = 6.8 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 3.80 (s, 3 H),
3.78–3.69 (m, 2 H), 3.61 (br s, 1 H), 3.46 (t, J = 6.8 Hz, 1 H), 3.27 (d, J =
7.2 Hz, 1 H), 1.66 (s, 3 H), 1.30 (t, J = 7.2 Hz, 3 H), 0.86 (t, J = 7.2 Hz, 3
H).
tricarboxylate (4k)4f
White solid; yield: 67 mg (95%); 96% ee [tR = 7.22 (major), 17.67 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow
rate = 0.8 mL/min)].
Mp 88–90 °C; [α]D30 +36.7 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.19 (d, J = 4.8 Hz, 1 H), 7.02–7.01 (m, 1
H), 6.94–6.92 (m, 1 H), 4.59 (d, J = 6.8 Hz, 1 H), 4.13–4.10 (m, 3 H),
3.86–3.82 (m, 2 H), 3.77 (s, 3 H), 3.67 (dd, J = 9.2, 8.0 Hz, 1 H), 3.53
(dd, J = 8.0, 6.8 Hz, 1 H), 3.34 (br s, 1 H), 1.23 (t, J = 7.2 Hz, 3 H), 0.96 (t,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.3, 170.5, 170.3, 136.2, 133.4,
128.5, 128.4, 68.6, 63.0, 61.1, 60.3, 57.8, 53.0, 52.6, 28.2, 14.1, 13.7.
13C NMR (100 MHz, CDCl3): δ = 170.6, 170.2, 169.9, 139.9, 126.7,
124.9, 124.5, 61.9, 61.3, 61.1, 60.6, 52.8, 52.2, 51.3, 14.0, 13.6.
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(4-Bromophenyl)-2-meth-
ylpyrrolidine-2,3,4-tricarboxylate (4p)4h
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(3-Pyridyl)pyrrolidine-2,3,4-
Colorless oil; yield: 84 mg (95%); 98% ee [tR = 9.78 (minor), 10.77 (ma-
jor) min (Chiralcel OD-H, λ = 210 nm, i-PrOH/hexanes, 15:85, flow
rate = 0.8 mL/min)].
[α]D30 +31.6 (c 1.20, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.37 (d, J = 8.3 Hz, 2 H), 7.19 (d, J = 8.1
Hz, 2 H), 4.51 (d, J = 6.6 Hz, 1 H), 4.12 (q, J = 7.1 Hz, 2 H), 3.71 (s, 3 H),
3.70–3.46 (m, 3 H), 3.39 (t, J = 6.9 Hz, 1 H), 3.19 (d, J = 7.1 Hz, 1 H),
1.59 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H), 0.79 (t, J = 7.1 Hz, 3 H).
tricarboxylate (4l)4g
White solid; yield: 51 mg (73%); 97% ee [tR = 9.11 (major), 10.62 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow
rate = 0.8 mL/min)].
Mp 102–105 °C; [α]D30 +54.2 (c 1.40, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 8.60–8.52 (m, 2 H), 7.79 (d, J = 7.2 Hz, 1
H), 7.29–7.26 (m, 1 H), 4.51 (d, J = 6.4 Hz, 1 H), 4.17–4.12 (m, 3 H),
3.81 (s, 3 H), 3.78–3.63 (m, 4 H), 3.37 (br s, 1 H), 1.25 (t, J = 7.2 Hz, 3
H), 0.84 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.3, 170.5, 170.3, 136.7, 131.3,
128.8, 121.5, 68.6, 63.0, 61.1, 60.3, 57.8, 52.9, 52.6, 28.1, 14.1, 13.7.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 2-Methyl-5-(2-naphthyl)pyrro-
HRMS (ESI): m/z [M + H]+ calcd for C16H28NO6: 330.1917; found:
330.1921.
lidine-2,3,4-tricarboxylate (4q)4f
Colorless oil; yield: 74 mg (90%); 98% ee [tR = 17.88 (minor), 19.69
(major) min (Chiralcel OD-H, λ = 210 nm, i-PrOH/hexanes, 15:85,
flow rate = 0.8 mL/min)].
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-tert-Butylpyrrolidine-2,3,4-
tricarboxylate (4u)
[α]D30 +22.5 (c 0.90, CH2Cl2).
Colorless oil; yield: 33 mg (50%); 87% ee [tR = 6.12 (major), 6.81 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 15:85, flow
rate = 0.8 mL/min)].
[α]D30 +18.5 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 4.11–4.00 (m, 5 H), 3.74 (s, 3 H), 3.45
(dd, J = 10.4, 7.2 Hz, 1 H), 3.08 (dd, J = 6.8, 4.8 Hz, 1 H), 2.96 (br s, 1 H),
2.79 (d, J = 4.0 Hz, 1 H), 1.23 (t, J = 7.2 Hz, 3 H), 1.20 (t, J = 7.2 Hz, 3 H),
0.98 (s, 9 H).
1H NMR (400 MHz, CDCl3): δ = 7.85–7.77 (m, 4 H), 7.53–7.44 (m, 3 H),
4.77 (d, J = 6.4 Hz, 1 H), 4.23–4.13 (m, 3 H), 3.81 (s, 3 H), 3.70–3.55 (m,
4 H), 3.33 (d, J = 7.2 Hz, 1 H), 1.72 (s, 3 H), 1.30 (t, J = 7.2 Hz, 3 H), 0.66
(t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.3, 170.5, 134.8, 133.1, 132.8,
128.0, 127.9, 127.5, 126.1, 125.9, 125.5, 125.0, 68.5, 63.7, 61.0, 60.2,
58.3, 53.1, 52.6, 28.5, 14.1, 13.5.
13C NMR (100 MHz, CDCl3): δ = 172.0, 171.4, 169.6, 72.7, 60.8, 60.5,
(2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 2-Benzyl-5-phenylpyrrolidine-
52.2, 52.1, 47.8, 32.6, 27.4, 14.0, 13.8.
HRMS (ESI): m/z [M + H]+ calcd for C16H28NO6: 330.1917; found:
2,3,4-tricarboxylate (4r)4f
White solid; yield: 70 mg (80%); 98% ee [tR = 6.08 (minor), 9.91 (ma-
jor) min (Chiralcel AD-H, λ = 210 nm, i-PrOH/hexanes, 15:85, flow
rate = 0.8 mL/min)].
Mp 77–78 °C; [α]D30 +34.4 (c 1.20, CH2Cl2).
330.1919.
(2S,3R,4S,5S)-3,4-Diethyl 2-Methyl 5-Neopentylpyrrolidine-2,3,4-
tricarboxylate (4v)
1H NMR (400 MHz, CDCl3): δ = 7.46–7.44 (m, 2 H), 7.31–7.26 (m, 8 H),
4.26 (q, J = 7.2 Hz, 2 H), 4.11 (d, J = 5.6 Hz, 1 H), 3.76–3.67 (m, 2 H),
3.74 (s, 3 H), 3.60 (br s, 1 H), 3.30–3.17 (m, 4 H), 1.38 (t, J = 7.2 Hz, 3
H), 0.79 (t, J = 7.2 Hz, 3 H).
White solid; yield: 47 mg (68%); 82% ee [tR = 6.70 (major), 7.16 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 15:85, flow
rate = 0.8 mL/min)].
Mp 56–57 °C; [α]D30 +7.1 (c 1.32, CH2Cl2).
13C NMR (100 MHz, CDCl3): δ = 174.1, 170.8, 170.2, 137.6, 136.1,
131.1, 128.2, 128.0, 127.5, 126.9, 126.7, 72.5, 63.8, 61.0, 60.0, 54.3,
52.4, 52.3, 44.9, 14.1, 13.6.
1H NMR (400 MHz, CDCl3): δ = 4.16–4.06 (m, 4 H), 4.01 (d, J = 9.6 Hz, 1
H), 3.73 (s, 3 H), 3.52 (dd, J = 10.0, 8.0 Hz, 1 H), 3.20 (dd, J = 7.2, 4.0 Hz,
1 H), 3.12 (dd, J = 7.6, 6.0 Hz, 1 H), 2.95 (br s, 1 H), 1.52 (dd, J = 14.4,
4.0 Hz, 1 H), 1.40 (dd, J = 14.4, 7.6 Hz, 1 H), 1.25 (t, J = 7.2 Hz, 3 H), 1.22
(t, J = 7.2 Hz, 3 H), 0.94 (s, 9 H).
(2S,3R,4S,5S)-3,4-Diethyl 2-Methyl 5-Isopropylpyrrolidine-2,3,4-
tricarboxylate (4s)
13C NMR (100 MHz, CDCl3): δ = 171.4, 171.1, 170.0, 61.6, 61.0, 60.5,
Colorless oil; yield: 44 mg (70%); 76% ee [tR = 7.85 (major), 9.05 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 10:90, flow
rate = 0.8 mL/min)].
[α]D30 +8.6 (c 1.20, CH2Cl2).
59.4, 52.2, 52.0, 51.4, 44.0, 30.3, 29.8, 14.2, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C17H30NO6: 344.2073; found:
344.2077.
1H NMR (400 MHz, CDCl3): δ = 4.12–3.97 (m, 5 H), 3.69 (s, 3 H), 3.51
(dd, J = 10.0, 7.6 Hz, 1 H), 3.15 (dd, J = 7.2, 5.6 Hz, 1 H), 2.68–2.64 (m, 2
H), 1.63–1.60 (m, 1 H), 1.20 (t, J = 7.2 Hz, 3 H), 1.17 (t, J = 7.2 Hz, 3 H),
1.03 (d, J = 6.8 Hz, 3 H), 0.93 (d, J = 6.8 Hz, 3 H).
(2S,3R,4S,5S)-3,4-Diethyl 2-Methyl 5-Cyclohexylpyrrolidine-2,3,4-
tricarboxylate (4w)4f
White solid; yield: 33 mg (46%); 78% ee [tR = 6.32 (minor), 7.60 (ma-
jor) min (Chiralcel AD-H, λ = 205 nm, i-PrOH/hexanes, 15:85, flow
rate = 1 mL/min)].
13C NMR (100 MHz, CDCl3): δ = 171.4, 171.1, 169.8, 70.1, 61.2, 60.9,
Mp 81–83 °C; [α]D30 +11.6 (c 1.10, CH2Cl2).
60.4, 52.1, 49.4, 29.6, 21.4, 20.6, 14.0, 13.9.
HRMS (ESI): m/z [M + H]+ calcd for C15H26NO6: 316.1760; found:
316.1764.
1H NMR (400 MHz, CDCl3): δ = 4.25–4.17 (m, 1 H), 4.13–4.06 (m, 3 H),
4.02 (d, J = 10.0 Hz, 1 H), 3.74 (s, 3 H), 3.52 (dd, J = 10.0, 7.6 Hz, 1 H),
3.18 (dd, J = 7.2, 4.8 Hz, 1 H), 2.79 (dd, J = 10.0, 4.8 Hz, 1 H), 2.73 (br s,
1 H), 2.06 (d, J = 12.8 Hz, 1 H), 1.87 (d, J = 12.4 Hz, 1 H), 1.73–1.63 (m,
3 H), 1.41–1.32 (m, 1 H), 1.25 (t, J = 7.2 Hz, 3 H), 1.22 (t, J = 7.2 Hz, 3
H), 1.21–1.11 (m, 3 H), 1.09–0.94 (m, 2 H).
(2S,3R,4S,5S)-3,4-Diethyl 2-Methyl 5-Isobutylpyrrolidine-2,3,4-tri-
carboxylate (4t)
White solid; yield: 38 mg (57%); 84% ee [tR = 6.08 (major), 6.76 (mi-
nor) min (Chiralcel AD-H, λ = 205 nm, i-PrOH/hexanes, 15:85, flow
rate = 1 mL/min)].
13C NMR (100 MHz, CDCl3): δ = 171.5, 171.2, 169.9, 68.8, 61.2, 60.9,
60.4, 52.1, 52.0, 49.1, 39.0, 31.5, 30.9, 26.2, 25.7, 14.2, 14.0.
Mp 84–85 °C; [α]D30 +7.2 (c 1.00, CH2Cl2).
(2S,3R,4S,5S)-3,4-Diethyl 2-Methyl 5-Phenethylpyrrolidine-2,3,4-
tricarboxylate (4x)
1H NMR (400 MHz, CDCl3): δ = 4.15–4.06 (m, 4 H), 3.98 (d, J = 9.6 Hz, 1
H), 3.74 (s, 3 H), 3.54 (dd, J = 9.2, 8.0 Hz, 1 H), 3.25–3.22 (m, 1 H), 3.16
(dd, J = 7.6, 6.0 Hz, 1 H), 2.79 (brs, 1 H), 1.79–1.74 (m, 1 H), 1.46–1.43
(m, 2 H), 1.25 (t, J = 6.8 Hz, 3 H), 1.21 (t, J = 6.8 Hz, 3 H), 0.93 (d, J = 4.4
Hz, 3 H), 0.89 (d, J = 4.4 Hz, 3 H).
Colorless oil; yield: 49 mg (65%); 90% ee [tR = 8.54 (major), 9.63 (mi-
nor) min (Chiralcel OD-H, λ = 205 nm, i-PrOH/hexanes, 25:75, flow
rate = 0.8 mL/min)].
[α]D30 +10.5 (c 1.10, CH2Cl2).
13C NMR (100 MHz, CDCl3): δ = 171.3, 171.1, 170.1, 67.7, 61.0, 60.5,
60.4, 52.2, 51.6, 50.7, 39.5, 25.8, 23.0, 22.4, 14.2, 14.0.
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X. Zheng et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.30–7.28 (m, 2 H), 7.20–7.17 (m, 3 H),
4.18–4.08 (m, 4 H), 3.98 (d, J = 9.6 Hz, 1 H), 3.78 (s, 3 H), 3.55 (dd, J =
9.2, 8.0 Hz, 1 H), 3.24–3.14 (m, 2 H), 2.86–2.76 (m, 3 H), 1.94–1.86 (m,
2 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.24 (t, J = 7.2 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H25FNO6: 394.1666; found:
394.1664.
(2S,3R,4S,5S)-3,4-Diethyl 2-Methyl 5-((E)-4-Fluorostyryl)pyrroli-
dine-2,3,4-tricarboxylate (4zb)
13C NMR (100 MHz, CDCl3): δ = 171.1, 171.0, 170.0, 141.1, 128.3,
128.2, 125.9, 61.5, 60.9, 60.5, 52.1, 51.5, 50.4, 33.3, 32.1, 14.1, 13.9.
HRMS (ESI): m/z [M + H]+ calcd for C20H28NO6: 378.1917; found:
378.1919.
Colorless oil; yield: 72 mg (92%); 96% ee [tR = 7.40 (major), 9.65 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow
rate = 0.8 mL/min)].
[α]D30 +5.5 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.30 (dd, J = 8.4, 5.2 Hz, 2 H), 6.97 (t, J =
8.8 Hz, 2 H), 6.56 (d, J = 16.0 Hz, 1 H), 6.20 (dd, J = 16.0, 8.0 Hz, 1 H),
4.16–4.02 (m, 6 H), 3.76 (s, 3 H), 3.56 (t, J = 8.0 Hz, 1 H), 3.43 (t, J = 8.0
Hz, 1 H), 2.80 (br s, 1 H), 1.25 (t, J = 7.2 Hz, 3 H), 1.11 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.8, 170.6, 170.2, 163.6, 161.2,
132.5, 132.5, 132.2, 128.0, 128.0, 125.6, 115.5, 115.3, 63.2, 62.6, 61.1,
60.7, 52.3, 52.0, 50.3, 14.2, 14.0.
(2S,3R,4S,5S)-3,4-Diethyl 2-Methyl 5-((E)-Styryl)pyrrolidine-2,3,4-
tricarboxylate (4y)
Colorless oil; yield: 67 mg (89%); 98% ee [tR = 8.20 (major), 13.31 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow
rate = 0.8 mL/min)].
[α]D30 +7.8 (c 1.02, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.34–7.20 (m, 5 H), 6.61 (d, J = 15.6 Hz,
1 H), 6.27 (dd, J = 15.6, 8.0 Hz, 1 H), 4.17–4.02 (m, 6 H), 3.76 (s, 3 H),
3.57 (t, J = 8.0 Hz, 1 H), 3.44 (t, J = 8.0 Hz, 1 H), 2.98 (br s, 1 H), 1.26 (t,
J = 7.2 Hz, 3 H), 1.12 (t, J = 7.2 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H25FNO6: 394.1666; found:
394.1665.
13C NMR (100 MHz, CDCl3): δ = 170.8, 170.5, 170.2, 136.3, 133.5,
128.5, 127.8, 126.5, 125.7, 63.3, 62.5, 61.0, 60.7, 52.3, 52.0, 50.4, 14.1,
14.0.
HRMS (ESI): m/z [M + H]+ calcd for C20H26NO6: 376.1760; found:
376.1765.
(2S,3R,4S,5S)-3,4-Diethyl 2-Methyl 5-((E)-4-Chlorostyryl)pyrroli-
dine-2,3,4-tricarboxylate (4zc)
Colorless oil; yield: 66 mg (81%); 93% ee [tR = 12.12 (major), 14.72
(minor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 25:75, flow
rate = 0.8 mL/min)].
[α]D30 +7.9 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 9.2 Hz, 2 H), 7.25 (d, J = 9.2
Hz, 2 H), 6.56 (d, J = 15.6 Hz, 1 H), 6.28 (dd, J = 15.6, 8.0 Hz, 1 H), 4.16–
4.02 (m, 6 H), 3.77 (s, 3 H), 3.56 (t, J = 8.0 Hz, 1 H), 3.44 (t, J = 8.0 Hz, 1
H), 2.69 (br s, 1 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.12 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.8, 170.6, 170.1, 134.9, 133.4,
132.1, 128.7, 127.7, 126.7, 63.1, 62.6, 61.1, 60.8, 52.3, 52.1, 50.3, 14.2,
14.1.
(2S,3R,4S,5S)-3,4-Diethyl 2-Methyl 5-((E)-2-Methoxystyryl)pyrroli-
dine-2,3,4-tricarboxylate (4z)
Colorless oil; yield: 66 mg (82%); 92% ee [tR = 9.05 (major), 21.00 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow
rate = 0.8 mL/min)].
[α]D30 +4.3 (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.37 (d, J = 7.6 Hz, 1 H), 7.24–7.19 (m, 1
H), 6.97–6.87 (m, 2 H), 6.84 (d, J = 8.0 Hz, 1 H), 6.25 (dd, J = 16.0, 8.0
Hz, 1 H), 4.17–4.03 (m, 6 H), 3.81 (s, 3 H), 3.77 (s, 3 H), 3.59 (dd,
J =16.0, 8.0 Hz, 1 H), 3.44 (dd, J = 8.0, 8.0 Hz, 1 H), 2.88 (br s, 1 H), 1.26
(t, J = 7.2 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H25ClNO6: 410.1370; found:
410.1372.
(2S,3R,4S,5S)-3,4-Diethyl 2-Methyl 5-((E)-4-Bromostyryl)pyrroli-
13C NMR (100 MHz, CDCl3): δ = 170.9, 170.6, 170.4, 156.7, 128.8,
128.4, 126.9, 126.0, 125.4, 120.5, 110.7, 63.9, 62.6, 61.0, 60.7, 55.3,
52.3, 52.3, 50.5, 14.1, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C21H28NO7: 406.1866; found:
406.1867.
dine-2,3,4-tricarboxylate (4zd)
Colorless oil; yield: 78 mg (86%); 96% ee [tR = 10.65 (minor), 18.71
(major) min (Chiralcel AD-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow
rate = 1.5 mL/min)].
[α]D30 +9.1 (c 1.20, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 8.4 Hz, 2 H), 7.19 (d, J = 8.4
Hz, 2 H), 6.52 (d, J = 15.6 Hz, 1 H), 6.29 (dd, J = 15.6, 8.0 Hz, 1 H), 4.16–
4.01 (m, 6 H), 3.75 (s, 3 H), 3.55 (t, J = 8.0 Hz, 1 H), 3.43 (t, J = 8.0 Hz, 1
H), 2.59 (br s, 1 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.10 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.8, 170.6, 170.1, 135.3, 132.1,
131.6, 128.0, 126.8, 121.6, 63.1, 62.6, 61.1, 60.7, 52.3, 52.0, 50.3, 14.2,
14.0.
(2S,3R,4S,5S)-3,4-Diethyl 2-Methyl 5-((E)-2-Fluorostyryl)pyrroli-
dine-2,3,4-tricarboxylate (4za)
Colorless oil; yield: 74 mg (94%); 97% ee [tR = 7.37 (major), 13.33 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow
rate = 0.8 mL/min)].
[α]D30 +6.2 (c 1.10, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.42–7.38 (m, 1 H), 7.21–7.16 (m, 1 H),
7.07–6.97 (m, 2 H), 6.75 (d, J = 16.0 Hz, 1 H), 6.36 (dd, J = 16.0, 8.0 Hz,
1 H), 4.16–4.01 (m, 6 H), 3.75 (s, 3 H), 3.56 (t, J = 8.0 Hz, 1 H), 3.45 (t,
J = 8.0 Hz, 1 H), 2.53 (br s, 1 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.13 (t, J = 7.2
Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H25BrNO6: 454.0865; found:
454.0868.
(2S,3R,4S,5S)-3,4-Diethyl 2-Methyl 5-((E)-2-(2-Furyl)vinyl)pyrroli-
dine-2,3,4-tricarboxylate (4ze)
13C NMR (100 MHz, CDCl3): δ = 170.8, 170.6, 170.2, 161.4, 158.9,
129.1, 129.0, 128.6, 128.6, 127.5, 127.5, 125.8, 125.8, 124.1, 124.1,
124.0, 115.7, 115.5, 63.5, 62.6, 61.0, 60.8, 52.3, 52.1, 50.3, 14.0, 14.0.
Colorless oil; yield: 53 mg (73%); 94% ee [tR = 8.54 (major), 12.65 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow
rate = 0.8 mL/min)].
[α]D30 +5.2 (c 1.04, CH2Cl2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

K
X. Zheng et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.31 (d, J = 1.2 Hz, 1 H), 6.43 (d, J = 15.6
Hz, 1 H), 6.34 (dd, J = 3.2, 1.8 Hz, 1 H), 6.23 (d, J = 3.2 Hz, 1 H), 6.19
(dd, J = 15.6, 7.6 Hz, 1 H), 4.15–4.02 (m, 6 H), 3.77 (s, 3 H), 3.56 (t, J =
7.6 Hz, 1 H), 3.41 (t, J = 7.6 Hz, 1 H), 2.62 (br s, 1 H), 1.25 (t, J = 7.2 Hz,
3 H), 1.15 (t, J = 7.2 Hz, 3 H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609492.
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13C NMR (100 MHz, CDCl3): δ = 170.8, 170.4, 170.3, 151.9, 142.2,
124.0, 121.7, 111.2, 108.5, 63.1, 62.4, 61.1, 60.8, 52.3, 52.0, 50.5, 14.1,
14.0.
HRMS (ESI): m/z [M + H]+ calcd for C18H24NO7: 366.1553; found:
366.1555.
References
(1) For reviews, see: (a) Goti, A.; Cardon, F.; Cicchi, S.; Cordero, F.
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2819.
(2S,3R,4S,5R)-Trimethyl 5-Phenylpyrrolidine-2,3,4-tricarboxylate
(4zf)4f
White solid; yield: 60 mg (94%); 96% ee [tR = 7.42 (major), 16.18 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 50:50, flow
rate = 0.8 mL/min)].
Mp 94–95 °C; [α]D30 +68.4 (c 1.20, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.35–7.26 (m, 5 H), 4.49 (d, J = 6.8 Hz, 1
H), 4.17 (d, J = 8.8 Hz, 1 H), 3.82 (s, 3 H), 3.75–3.70 (m, 1 H), 3.70 (s, 3
H), 3.58 (t, J = 7.2 Hz, 1 H), 3.23 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.1, 170.9, 170.8, 137.0, 128.3,
127.7, 126.6, 65.4, 62.1, 52.5, 52.4, 52.1, 51.3, 50.9.
(2S,3S,4S,5R)-Trimethyl 5-Phenylpyrrolidine-2,3,4-tricarboxylate
(4zg)4f
Colorless oil; yield: 58 mg (91%); 28% ee [tR = 14.98 (major), 29.14
(minor) min (Chiralcel OD-H, λ = 220 nm, i-PrOH/hexanes, 20:80,
flow rate = 1.0 mL/min)].
[α]D30 +6.2 (c 1.20, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.34–7.26 (m, 5 H), 4.66 (d, J = 8.0 Hz, 1
H), 4.21 (d, J = 6.8 Hz, 1 H), 3.84 (s, 3 H), 3.77 (s, 3 H), 3.67–3.64 (m, 1
H), 3.58 (dd, J = 8.0, 4.4 Hz, 1 H), 3.20 (s, 3 H), 2.85 (br s, 1 H).
(3) (a) Alvarez-Ibarra, C.; Csákÿ, A. G.; López de Silanes, I.; Quiroga,
M. L. J. Org. Chem. 1997, 62, 479. (b) Denhart, D. J.; Griffith, D. A.;
Heathcock, C. H. J. Org. Chem. 1998, 63, 9616. (c) Obst, U.;
Betschmann, P.; Lerner, C.; Seiler, P.; Diederich, F. Helv. Chim.
Acta 2000, 83, 855. (d) Sebahar, P. R.; Williams, R. M. J. Am.
Chem. Soc. 2000, 122, 5666.
13C NMR (100 MHz, CDCl3): δ = 172.5, 172.0, 171.6, 138.0, 128.6,
128.2, 127.8, 127.0, 126.7, 65.3, 63.2, 53.7, 52.5, 52.5, 51.5, 50.6.
(4) Selected references on chiral silver catalysts: (a) Longmire, J. M.;
Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400.
(b) Yamashita, Y.; Imaizumi, T.; Kobayashi, S. Angew. Chem. Int.
Ed. 2011, 50, 4893. (c) Jing, X.; He, C.; Dong, D.; Yang, L.; Duan, C.
Angew. Chem. Int. Ed. 2012, 51, 10127. (d) Kudryavtsev, K. V.;
Ivantcova, P. M.; Churakov, A. V.; Wiedmann, S.; Luy, B.; Muhle-
Goll, C.; Zefirov, N. S.; Bräse, S. Angew. Chem. Int. Ed. 2013, 52,
12736. (e) Gerosa, G. G.; Spanevello, R. A.; Suárez, A. G.; Sarotti,
A. M. J. Org. Chem. 2015, 80, 7626. (f) Wang, H.; Deng, Q.; Zhou,
Z.; Hu, S.; Liu, Z.; Zhou, L.-Y. Org. Lett. 2016, 18, 404. (g) Zhou, Z.;
Zheng, X.; Liu, J.; Li, J.; Wen, P.; Wang, H. Synlett 2017, 28, 999.
(h) Hou, Y.; Zhou, Z.; Liu, P.; Wang, J.; Hou, Q.; Wen, P.; Wang, H.
Tetrahedron: Asymmetry 2017, 28, 930.
(2S,4S,5R)-Dimethyl 5-Phenylpyrrolidine-2,4-dicarboxylate (4zh)4f
White solid; yield: 43 mg (82%); 56% ee [tR = 12.43 (major), 19.37 (mi-
nor) min (Chiralcel AS-H, λ = 205 nm, i-PrOH/hexanes, 10:90, flow
rate = 1.0 mL/min)].
Mp 72–73 °C; [α]D30 +17.6 (c 1.20, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.31–7.21 (m, 5 H), 4.53 (d, J = 8.0 Hz, 1
H), 3.98 (t, J = 8.0 Hz, 1 H), 3.81 (s, 3 H), 3.30 (dd, J = 14.4, 6.8 Hz, 1 H),
3.20 (s, 3 H), 2.94 (br s, 1 H), 2.40 (t, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 173.6, 172.8, 138.9, 128.0, 127.4,
126.5, 65.6, 59.7, 52.0, 51.0, 49.5, 33.1.
(5) Selected recent references on chiral copper catalysts: (a) Arai,
T.; Ogawa, H.; Awata, A.; Sato, M.; Watabe, M.; Yamanaka, M.
Angew. Chem. Int. Ed. 2015, 54, 1595. (b) Li, J.-Y.; Kim, H. Y.; Oh,
K. Org. Lett. 2015, 17, 1288. (c) Yang, W.-L.; Tang, F.-F.; He, F.-S.;
Li, C.-Y.; Yu, X.-X.; Deng, W.-P. Org. Lett. 2015, 17, 4822. (d) Han,
F.-Z.; Yu, S.-B.; Zhang, C.; Hu, X.-P. Tetrahedron 2016, 72, 2616.
(e) Pascual-Escudero, A.; de Cózar, A.; Cossío, F. P.; Adrio, J.;
Carretero, J. C. Angew. Chem. Int. Ed. 2016, 55, 15334; and refer-
ences cited therein.
Funding Information
We are grateful to the Natural Science Foundation of China (Nos.
21202042, 51374103, 51674114), the Hunan Provincial Natural Sci-
ence Foundation of China (Nos. 2017JJ2067, 13JJ4090, 2015JJ3063),
and the Zhuzhou Municipal Science and Technology Program and
Graduate Student Innovation Fund of Hunan Province (CX2016B642)
for support of this research.
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(6) Selected references on chiral zinc catalysts: (a) Gothelf, A. S.;
Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem. Int. Ed.
2002, 41, 4236. (b) Dogan, O.; Koyuncu, H.; Garner, P.; Bulut, A.;
Youngs, W. J.; Panzner, M. Org. Lett. 2006, 8, 4687.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

L
X. Zheng et al.
Paper
Synthesis
(7) Selected references on chiral nickel catalysts: (a) Shi, J.-W.;
Zhao, M.-X.; Lei, Z.-Y.; Shi, M. J. Org. Chem. 2008, 73, 305.
(b) Arai, T.; Yokoyama, N.; Mishiro, A.; Sato, H. Angew. Chem. Int.
Ed. 2010, 49, 7895.
(8) Selected references on chiral calcium catalysts: (a) Saito, S.;
Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 5364.
(b) Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.; Kobayashi, S.
J. Am. Chem. Soc. 2008, 130, 13321.
(9) Selected reference on chiral gold catalysts: Martín-Rodríguez,
M.; Najera, C.; Sansano, J. M.; Coźar, A.; Cossío, F. P. Chem. Eur. J.
2011, 17, 14224.
(10) For selected examples of organocatalysts, see: (a) Guo, C.; Song,
J.; Gong, L.-Z. Org. Lett. 2013, 15, 2676. (b) Sun, X.-X.; Zhang, H.-
H.; Li, G.-H.; He, Y.-Y.; Shi, F. Chem. Eur. J. 2016, 22, 17526.
(c) Wang, Y.-M.; Zhang, H.-H.; Li, C.; Fan, T.; Shi, F. Chem.
Commun. 2016, 52, 1804.
Acc. Chem. Res. 2008, 41, 222. (c) Shao, Z.-H.; Zhang, H.-B. Chem.
Soc. Rev. 2009, 38, 2745. (d) Du, Z. T.; Shao, Z.-H. Chem. Soc. Rev.
2013, 42, 1337. (e) Allen, A. E.; MacMillan, D. W. C. Chem. Sci.
2012, 3, 633. (f) Chen, D.-F.; Han, Z.-Y.; Zhou, X.-L.; Gong, L.-Z.
Acc. Chem. Res. 2014, 47, 2365. (g) Jindal, G.; Kisan, H. K.; Sunoj,
R. B. ACS Catal. 2015, 5, 480.
(12) The absolute configuration of endo-4a was assigned by HPLC
and optical rotation comparisons with reported data (see ref. 4f
and the Supporting Information), and that of other adducts was
deduced on the basis of these results.
(13) Selected reference on the 1,3-dipolar cycloaddition of α,β-
unsaturated aldehyde derived imino esters: Chen, X.-H.; Zhang,
W.-Q.; Gong, L.-Z. J. Am. Chem. Soc. 2008, 130, 5652.
(14) For selected examples of multicomponent reactions, see:
(a) Mancebo-Aracil, J.; Nájera, C.; Sansano, J. M. Chem. Commun.
2013, 49, 11218. (b) Mancebo-Aracil, J.; Nájera, C.; Castelló, L.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L