Well-Designed Phosphine-Urea Ligand for Highly Diastereo- and Enantioselective 1,3-Dipolar Cycloaddition of Methacrylonitrile: A Combined Experimental and Theoretical Study

Article abstract of DOI:10.1021/jacs.8b10939

A novel chiral phosphine-urea bifunctional ligand has been developed for Cu-catalyzed asymmetric 1,3-dipolar cycloaddition of iminoesters with methacrylonitrile, a long-standing challenging substrate in asymmetric catalysis. Distortion-interaction energy analysis based on density functional theory (DFT) calculations reveals that the distortion energy plays an important role in the observed enantioselectivity, which can be attributed to the steric effect between the phosphine ligand and the dipole reactant. DFT calculations also indicate that nucleophilic addition is the enantioselectivity-determining step and hydrogen bonding between the urea moiety and methacrylonitrile assists in control of the diastereo- and enantioselectivity. By a combination of metal catalysis and organocatalysis, excellent diastereo- and enantioselectivities (up to 99:1 diastereomeric ratio, 99% enantiomeric excess) as well as good yields are achieved. A wide range of substitution patterns of both iminoester and acrylonitrile is tolerated by this catalyst system, providing access to a series of highly substituted chiral cyanopyrrolidines with up to two quaternary stereogenic centers. The synthetic utility is demonstrated by enantioselective synthesis of antitumor agent ETP69 with a pivotal nitrile pharmacophore and an all-carbon quaternary stereogenic center.

Full text of DOI:10.1021/jacs.8b10939

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Article
Well-Designed Phosphine–Urea Ligand for Highly
Diastereo- and Enantioselective 1,3-Dipolar Cycloaddition of
Methacrylonitrile: A Combined Experimental and Theoretical Study
Yang Xiong, Zhuanzhuan Du, Haohua Chen, Zhao Yang,
Qiuyuan Tan, Changhui Zhang, Lei Zhu, Yu Lan, and Min Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b10939 • Publication Date (Web): 13 Dec 2018
Downloaded from http://pubs.acs.org on December 13, 2018
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Page 1 of 13
Journal of the American Chemical Society
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Well-Designed Phosphine–Urea Ligand for Highly Diastereo- and
Enantioselective 1,3-Dipolar Cycloaddition of Methacrylonitrile: A
Combined Experimental and Theoretical Study
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Yang Xiong,†,§ Zhuanzhuan Du,†,§ Haohua Chen,‡,§ Zhao Yang,† Qiuyuan Tan,† Changhui Zhang,†
Lei Zhu,‡ Yu Lan,*‡# and Min Zhang*†
†Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences,
and ‡School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, China
#College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China
ABSTRACT: A novel chiral phosphine–urea bifunctional ligand has been developed for Cu-catalyzed asymmetric 1,3-
dipolar cycloaddition of iminoesters with methacrylonitrile, a long-standing challenging substrate in asymmetric
catalysis. Distortion–interaction energy analysis based on density functional theory (DFT) calculations reveals that the
distortion energy plays an important role in the observed enantioselectivity, which can be attributed to the steric effect
between the phosphine ligand and the dipole reactant. DFT calculations also indicate that nucleophilic addition is the
enantioselectivity-determining step and hydrogen bonding between the urea moiety and methacrylonitrile assists in
control of the diastereo- and enantioselectivity. By a combination of metal–catalysis and organocatalysis, excellent
diastereo- and enantioselectivities (up to 99:1 diastereomeric ratio, 99% enantiomeric excess) as well as good yields are
achieved. A wide range of substitution patterns of both iminoester and acrylonitrile are tolerated by this catalyst system,
providing access to a series of highly substituted chiral cyanopyrrolidines with up to two quaternary stereogenic centers.
The synthetic utility is demonstrated by enantioselective synthesis of antitumor agent ETP69 with a pivotal nitrile
pharmacophore and an all-carbon quaternary stereogenic center.
workers9a realized the first highly diastereoselective 1,3-
dipolar cycloaddition with methacrylonitrile using achiral
phosphine ligand-complexed CuI to activate the iminoester
(Scheme 1b). Theoretical calculations showed that the
presence of an electrostatic interaction between the

INTRODUCTION
Despite the great advances in asymmetric synthesis over
the last few decades, stereochemical control of substrates
that lack an effective catalyst–substrate interaction or strong
steric/electronic
biases
remains
a
challenge.1
Methacrylonitrile 1a falls into this category, presumably
because of the inferior catalyst–substrate spatial orientation
arising from the linearity of the nitrile group and the low
level of enantiofacial differentiation because of the steric
similarity between the methyl and nitrile substituents. The
poor intrinsic reactivity and challenges associated with
formation of an all-carbon quaternary stereogenic center to
form a C–C bond at the α position of methacrylonitrile
further restrict its synthetic utility (Scheme 1a).
Consequently, attempts to develop catalytic stereoselective
reactions using methacrylonitrile have resulted in limited
success.2
Scheme 1. 1,3-Dipolar Cycloaddition of Iminoesters
with Acrylonitriles
a) Challenges associated with methacrylonitrile 1a in organic synthesis
Me
CN
 low reactivity
 challenging stereocontrol
1a
b) Diastereoselective 1,3-dipolar cycloaddition with methacrylonitrile (Overman)
Me
EtO
NC
enantiomers
separation
O
Me
O
O
NC
R1
CuI/P
Me
O
N
+
CN
S
N
S
O
N
Me
N
H
O
OEt
ETP69
(S,S,S,S)-
antitumor agent
R1
Me
1a
2
3
(±)-
c) Enantioselective 1,3-dipolar cycloaddition with acrylonitriles (this work)
RO
R3
enantioselective
synthesis
R4
R2
O
NC
R1
R3
R2
CuI
ETP69
(S,S,S,S)-
O
R4
+
Catalytic diastereo- and enantioselective 1,3-dipolar
cycloadditions of iminoesters have been intensively
investigated in recent years, with many electron-deficient
alkenes used as capable dipolarophiles.4–8 However, for
cycloadditions with methacrylonitrile, which can also
N
CN
P-urea
bifunctional
ligand
N
H
OR
up to 99:1 d.r., 99% ee
1
2
36
R1
phosphine ligand and the reacting methacrylonitrile in the
transition state leads to high diastereoselectivity, otherwise
the diastereoselectivity is low. Using the racemic cycloadduct
3, Overman, Horne, and co-workers9b developed an elegant
provide
an
electron-deficient
C=C
bond,
the
diastereoselectivity rather than the enantioselectivity
remains a challenge. In 2015, Overman, Houk, and co-
synthesis of natural product analogue ETP69,
a very
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Page 2 of 13
promising clinical candidate for cancer chemotherapy. The
Reaction Optimization. We first evaluated ligand L1,
which was prepared by coupling three inexpensive
1
2
3
4
5
6
7
8
authors also showed that the preeminent cytotoxicity of this
compound depends on the nitrile pharmacophore and
largely resides in the (S,S,S,S)-enantiomer, which is obtained
by separation of the enantiomers.9b Despite this methodology
advancement and the synthetic value of chiral
cyanopyrrolidines,9 highly diastereo- and enantioselective
1,3-dipolar cycloadditions with methacrylonitrile have not
been reported.
components:
diphenylphosphino-benzoic
(R,R)-1,2-diaminocyclohexane,
acid, and
2-
3,5-
bis(trifluromethyl)-phenyl isocyanate. For the catalytic
system of L1/Cu(CH3CN)4BF4, 1,3-dipolar cycloaddition of 1a
and 2a occurred with promising enantioselectivity (76% ee),
albeit in low yield (Table 1, entry 1). Taking into account the
fact that both squaramide and thiourea are widely used as
effective hydrogen donors,15 and
Most of the previous strategies for catalytic stereoselective
1,3-dipolar cycloadditions of iminoesters use a single model
for organocatalysis or metal catalysis by acting on one of the
reaction partners (dipole or dipolarophile).3–9 From our
previous research of dipolar cycloadditions,10 we speculate
that a bifunctional catalysis,11,12 which integrates the unique
activation modes of organocatalysis with the well-established
chemistry of metal catalysis, could activate both the dipole
and dipolarophile and thus address the aforementioned
challenges associated with methacrylonitrile. With this idea
in mind, we designed a novel type of bifunctional ligands
based on privileged chiral 1,2-ethylenediamine scaffolds
(Figure 1a).13 Theoretical studies have previously been
performed to validate the feasibility. The preliminary
computational results revealed that both the phosphine
moiety and benzoyl group of the phosphinoamide unit could
coordinate with copper to activate iminoesters,14 while the
two NH groups in the (thio)urea unit could form hydrogen
bonds with the nitrile group of the acrylonitriles (Figure 1b).15
Through synergistic activation and spatial orientation of the
9
Table 1. Optimization of 1,3-Dipolar Cycloaddition of
Methacrylonitrilea
10
11
12
13
14
15
16
17
18
19
20
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23
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58
59
60
Me
NC
OMe
conditions
Me
N
OMe
+
O
NC
1a
N
H
O
2a
3a
(endo)
yield
(%)b
ee
entry ligand
metal
d.r.c
(%)d
1
2
3
4
5
6
7e
8e
9e
10e
11e
12e
13e
14e
L1
L2–L5
L6
L6
L6
Cu(MeCN)4BF4
Cu(MeCN)4BF4
Cu(MeCN)4BF4
Cu(MeCN)4PF6
Cu(MeCN)4ClO4 16
AgF
Cu(MeCN)4BF4
Cu(MeCN)4BF4
Cu(MeCN)4BF4
Cu(MeCN)4BF4
Cu(MeCN)4BF4
Cu(MeCN)4BF4
Cu(MeCN)4BF4
Cu(MeCN)4BF4
10
<5
45
18
—
—
76
—
98
98
98
88
99
-99
—
—
97
87
20
88
98:2
98:2
98:2
98:2
98:2
98:2
—
L6
L6
46
95
94
<5
<5
35
30
25
32
ent-L6
none
L7–L9
L10
L11
dipole
and
dipolarophile,
high
diastereo-
and
—
enantioselectivity could be achieved for 1,3-dipolar
cycloaddition of iminoesters with acrylonitriles particularly
methacrylonitrile. If this strategy could be successfully
implemented, a series of chiral cyanopyrrolidines with up to
two quaternary stereogenic centers could be generated
(Scheme 1c). This would be a significant advance in the field
of quaternary stereogenic center generation, because
catalytic enantioselective methods to generate quaternary
stereocenters by incorporating reaction partners in an
intermolecular manner are currently very limited.16
10:90
40:60
60:40
45:55
L12
L13
O
X1
X2
CF3
O
NH
N
NH
N
O
O
O
CF3
H
N
H
NH
N
PPh2
H
PPh2
N
CF3
H
PPh2
N
H
H
CF3
1
2
1
2
CF3
L1
L3
L2
: X =O, X =O; : X =S, X =O
1
2
1
2
L4
: X =O, X =S; : X =S, X =S
L5
L6
CF3
a) Ligand design:
synergistic recognition, activation, and spatial orientation of
dipole & dipolarophile
aConditions unless otherwise stated: 1a (0.4 mmol), 2a (0.2
mmol), ligand (5.5 mol%), metal (5 mol%), Et3N (50 mol%), 4
Å MS (200 mg), THF (4 mL), room temperature, 72 h.
bIsolated yield of the major isomer. cRatio of endo/exo
isomers, determined by HPLC analysis of the crude reaction
metal coordination
site
H-bond donor
chiral
scaffold
X
X
N
N
Ar
N
H
H
H
M
PPh2
d
dipole
dipolarophile
mixture. Determined by chiral HPLC analysis of the major
isomer. eUsing K2CO3 as the base and tBuOMe as the solvent.
 metal- and organocatalysis combination  modular synthesis of ligand
 diverse potential coordination modes
 ease of structural tuning
b) Theoretical catalytic model
O
Ph
O
O
O
Me
Me
O
O
PAr2
PAr2
N
O
N
N
P
N
N
N
O
P
O
Ph
L7
L8
L9
O
H1
Cu
L10
3,5-(tBu)2-C6H2
: Ar = 4-MeO-
O
Me
N
StBu
Me
Me
H2
N
PPh2
NMe2
PPh2
PPh2
Fe
Fe
Fe
L11
L12
L13
Figure 2. Known chiral ligands screened in 1,3-dipolar
cycloaddition of methacrylonitrile.
Figure 1. a) Ligand design; b) theoretical catalytic model.

RESULTS AND DISCUSSION
considering that incorporation of a sulfur atom into the
ligand could provide more diverse metal coordination
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modes,17 we synthesized ligands L2–L4 with one or two sulfur
atoms incorporated and ligand L5 with a squaramide group
1
to take advantage of the previous observations. However,
none of these ligands gave the desired cycloaddition product
in acceptable yield (entry 2). Upon switching the chiral
scaffold to diphenylethylenediamine, ligand L6 resulted in
significantly improved yield and degree of stereoselectivity
(entry 3). Copper salts with different counter anions gave
lower yield of 3a (entries 4 and 5), while silver salt AgF
2
3
4
5
6
7
8
9
G M11/Et2O (kcal/mol)
(H M11/Et2O (kcal/mol))
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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42
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45
46
47
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49
50
51
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54
55
56
57
58
59
60
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
H
Ph
Ph
N
N
Ph
Ph
Ph
N
P
Ph
P
P
O
Ph
Ph
O
O
P
Ph
O
O
18.4
(5.2)
9-ts-SRR
Cu
Cu
O
H
MeO
H
N
N
Cu
H
MeO
N
C
Cu
N
H
H
N
N
O
O
H
N
C
O
N
O
N
N
CN
H N
H
H N
CN
H N
O
15.2
(2.6)
9-ts-RSS
H
H
H
N
O
H
H
H
MeO
O1
OMe
9-ts-SRR
CF3
CF3
CF3
CF3
F3C
F3C
O
14.5
(0.5)
9-ts-RRR
F3C
1a
9-ts-SSS
9-ts-RSS
9-ts-RRR
H1
N1
F3C
Cu
C5
C2
C3
H
Ph
P
Ph
Ph
Ph
N
H2
10.2
(-3.8)
9-ts-SSS
C4
NC
5.2
(-10.2)
O
BCu-O1=2.32
Cu
3.5
(-10.2)
H
N
MeO
BN1-H1=2.10
BN1-H2=2.01
BC2-C5=2.05
BC3-C4=3.04
N
11-ts-SSS
C
O
N
H N
10-SSS
H
1.7
(3.3)
8
H
0.0
(0.0)
9-ts-SSS
CF3
-3.2
(-17.9)
12-SRR
7
F3C
H
Ph
H
N
11-ts-SSS
Ph
N
Ph
Ph
Ph
Ph
P
Ph
P
O
Ph
O
-4.3
(-17.7)
O
Cu
Cu
H
MeO
H
N
H
H
N
N
O
12-RSS
O
O
-6.3
N
H
H
N
H
N
(-23.0)
MeO
H
-6.2
(-22.2)
12-RRR
12-SSS
O1
CF3
CF3
7
8
F3C
O
H1
N1
F3C
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
N
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
H2
Cu
P
P
P
P
Ph
Ph
P
Ph
O
O
O
Ph
O
O
C3
C2
Cu
Cu
C4
O
O
H
H
N
Cu
Cu
N
H
H
N
Cu
H
MeO
MeO
C
N
MeO
N
N
H
N
O
H
H
BCu-O1=3.00
BN1-H1=2.07
BN1-H2=2.06
BC2-C5=2.04
BC3-C4=2.89
N
N
O
O
N
CN
C
C
O
O
O
H
N
N
N
N
H
N
C5
H N
H N
O
H
H
H N
CN
H
H
H
H
H
MeO
MeO
9-ts-RRR
CF3
CF3
CF3
CF3
CF3
F3C
F3C
12-SRR
F3C
F3C
10-SSS
12-SSS
12-RSS
12-RRR
F3C
Figure 3. Free energy profiles for catalytic asymmetric 1,3-dipolar cycloaddition of methacrylonitrile. The energy values are
given in kcal/mol and represent the relative free energies calculated by the DFT/M11 method in Et2O. The bond lengths are given
in angstroms.
produced comparable yield and d.r. with slightly lower
enantioselectivity (entry 6). Considering copper is a more
abundant metal compared to silver, Cu(CH3CN)4BF4 was
used as the metal precatalyst for further reaction
optimization, which led us to identify the optimal conditions
(Cu(CH3CN)4BF4/L6/K2CO3/tBuOMe/rt), giving 3a in 95%
yield with excellent stereoselectivities (entry 7, 98:2 d.r., 99%
ee). Performing 1,3-dipolar cycloaddition with a series of
privileged chiral ligands (Figure 2, L7–L13) under the optimal
conditions or the typical conditions found in the literatures
gave either low yields (0–35%) or poor stereoselectivities
(entries 10–14), 18 further highlighting the uniqueness of this
novel type of bifunctional ligand.
the enthalpies and free energies. The M1122 functional with
the 6–311+G(d,p) basis set (SDD basis set for Cu atoms) was
used to calculate the solvation single-point and give more
accurate energy information. The solvent effects were
considered by single-point calculations of the gas-phase
stationary points with the SMD23 solvation model in
diethylether (Et2O) solvent.
Mechanistic Study. All the density functional thery (DFT)
calculations were performed with Gaussian 09 series of
programs.19 The B3-LYP20 functional with the standard 6–
31G(d) basis set (SDD21 basis set for Cu atoms) was used for
the geometry optimizations. Harmonic vibrational frequency
calculations were performed for all of the stationary points to
confirm whether they are a local minima or transition
structures, and to derive the thermochemical corrections for
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(R,R,R)-enantiomer could form by 1,3-cycloaddition of
1
2
3
4
5
6
7
8
methacrylonitrile 1a and intermediate 8 via concerted
transition state 9-ts-RRR, which has been confirmed by an
intrinsic reaction coordinate calculation. The relative free
energy of 9-ts-RRR is 4.3 kcal/mol higher than that of 9-ts-
SSS, which suggests up to 99% ee with the major product in
the (S,S,S)-configuration, although intermolecular hydrogen
bonding also exists for 9-ts-RRR.
O1
Cu
O1
Cu
H1
N1
C2
C3
C5
C5
C2
C3
H2
C4
C4
9-ts-SSS
9-ts-RSS
G‡ = 10.2 kcal/mol
G‡ = 15.2 kcal/mol
BCu-O1 = 2.32
BCu-O1 = 2.40
BC2-C5 = 1.94
BC3-C4 = 2.74
To obtain additional insight, distortion–interaction energy
analysis was performed to explain the reactivity of the
bimolecular system (ΔEact‡=ΔEint‡+ΔEdist‡) (Figure 4).24 The
computational results show that the difference in the
interaction-energy terms (ΔEint‡) for 9-ts-SSS and 9-ts-RRR
is only 1.0 kcal/mol. However, the difference in the
distortion-energy terms (ΔEdist‡) for the two transition states
is 4.4 kcal/mol. Comparing the geometries of 9-ts-SSS and 9-
ts-RRR, the oxygen atom of the amide moiety of the ligand is
close to the Cu atom in 9-ts-SSS (BCu-O1=2.32 Å), indicating
significant coordination. However, the corresponding bond
length is 3.00 Å in 9-ts-RRR, meaning that the distortion
energy in this transition state is much higher. Thus, these
results suggest that the distortion energy plays an important
role in the observed enantioselectivity. In our theoretical
calculations, we found that another diastereomer could be
generated via transition state 9-ts-RSS. We also calculated
the distortion and interaction energies for this transition
state. The results show that the interaction energy in 9-ts-
RSS is much lower than that in 9-ts-SSS because of the
absence of hydrogen bonding between the urea moiety and
methacrylonitrile, which lead to the higher relative energy of
9-ts-RSS.
E‡ = -7.0 kcal/mol
E‡ = 10.1 kcal/mol
BN1-H1 = 2.10
BN1-H2 = 2.01
BC2-C5 = 2.05
BC3-C4 = 3.04
‡
‡
Edist = 19.5 kcal/mol
Edist = 26.0 kcal/mol
‡
‡
9
Eint = -26.5 kcal/mol
Eint = -15.9 kcal/mol
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O1
O1
H1
N1
H2
C4
C3
C4
C2
Cu
Cu
C3
C2
C5
C5
9-ts-RRR
9-ts-SRR
G‡ = 14.5 kcal/mol
G‡ = 18.4 kcal/mol
BCu-O1 = 3.00
BN1-H1 = 2.07
BN1-H2 = 2.06
BC2-C5 = 2.04
BC3-C4 = 2.89
BCu-O1=2.91
BC2-C5=1.97
BC3-C4=2.71
E‡ = -3.6 kcal/mol
E‡ = 11.1 kcal/mol
‡
‡
Edist = 23.9 kcal/mol
Edist = 26.3 kcal/mol
‡
‡
Eint = -27.5 kcal/mol
Eint = -15.2 kcal/mol
Figure 4. Distortion–interaction energy analysis of the
optimized structures of transition state 9-ts-SSS, 9-ts-RSS, 9-
ts-RRR, and 9-ts-SRR in the nucleophilic addition step.
Mechanism Verification. Based on the aforementioned
theoretical results, we hypothesized that both metal catalysis
and organocatalysis (hydrogen bonding) are crucial
components in the cycloaddition. To confirm our hypothesis,
a few N-methylated phosphine–urea ligands were designed
and calculations were performed for 1,3-dipolar cycloaddition.
As shown in Figure 5, L14 and L15 have only one of the two
nitrogen atoms containing a methyl group, while L16 has
both nitrogen atoms of the urea moiety masked by methyl
groups. The corresponding free energy profiles are shown in
Figure 6. The differences in the free energy of activation
values for the two enantiomeric transition states of L14 and
L15 are 5.2 and 6.1 kcal/mol, respectively (Figures 6a and 6b).
These free energy differences suggest that up to 99% ee could
be experimentally obtained in any cycloaddition product.
The calculated difference of the free energy of activation
values for 9-ts-RRR-L16 and 9-ts-SSS-L16 is only 0.6
kcal/mol, which suggests that poor enantioselectivity would
be experimentally observed, largely because of the absence of
hydrogen bonding in 9-ts-RRR-L16 and 9-ts-SSS-L16 (Figure
6c).
The free energy profiles for asymmetric 1,3-dipolar
cycloaddition of azomethine ylides using the synthesized
phosphine–urea bifunctional ligand L6 are shown in Figure 3.
The calculated results suggest that nucleophilic addition is
the enantioselectivity-determining step. Coordination and
deprotonation of the iminoester with the CuI catalyst gives
complex 7 and its isomer 8. The relative free energy of 8 is 1.7
kcal/mol higher than that of 7, which can be attributed to
strain repulsion between the amide group of the iminoester
and the phenyl group of the phosphine ligand. Nucleophilic
addition of the α-carbon atom of iminoester 2a to the
terminal carbon of 1a via transition state 9-ts-SSS gives
intermediate 10-SSS. The calculated activation free energy of
the first nucleophilic addition step is 10.2 kcal/mol.
Subsequent cycloaddition rapidly generates the (S,S,S)-
product-coordinated intermediate 12-SSS via transition state
11-ts-SSS with a free energy barrier of only 1.7 kcal/mol. The
geometry information of 9-ts-SSS shows that the distances
between the nitrogen atom of the cyano group and the two
hydrogen atoms of the urea moiety is 2.10 and 2.01 Å. These
two hydrogen bonds significantly stabilize the negative
charge in the formed intermediate, which leads to this
process having a low activation free energy. In another
possible case, 1,3-cycloaddition of methacrylonitrile 1a and
complex 7 via transition state 9-ts-RSS gives (R,S,S)-product-
coordinated intermediate 12-RSS with an activation free
energy of 15.2 kcal/mol. The relative free energy of 9-ts-RSS
is 5.0 kcal/mol higher than that of 9-ts-SSS because of the
absence of hydrogen bonding in 9-ts-RSS. The
computational results reveal high stereoselectivity, which
agrees with the experimental observations. Alternatively, the
1
2
L14
: R = H, R = Me
not synthesized
O
O
N
R2
CF3
CF3
1
2
L15
3a
: R = Me, R = H
NH
N
R1
: 80% yield, 92:8 d.r., 98% ee
1
2
L16
3a
: R = Me, R = Me
PPh2
: 5% yield, 40:60 d.r., 7% ee
Figure 5. Structures of the N-methylated ligands and 1,3-
dipolar cycloaddition of 1a and 2a using L15 and L16 under
the optimal conditions.
ACS Paragon Plus Environment

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Journal of the American Chemical Society
Distortion-interaction energy analysis was also performed
1
2
3
4
5
6
7
8
to explain the origin of the enantioselectivity for asymmetric
1,3-dipolar cycloaddition using the designed phosphine–urea
ligands L14, L15, and L16 (Figure 7). When the N-methyl-
monosubstituted ligands L14 and L15 with a single hydrogen
bond interaction are used, the interaction-energy terms
(ΔEint‡) in the four transition states (9-ts-RRR-L14, 9-ts-SSS-
L14, 9-ts-RRR-L15 and 9-ts-SSS-L15) are relatively low.
‡
However, the corresponding distortion energy terms (ΔEdist
)
are slightly enhanced owing to weaker activation of the
methacrylonitrile reactant compared with the L6 case.
Analogously, the calculated results suggest that the
distortion energy mainly controls the reactivity because of
the same trend of the activation free energy. Thus the large
discrepancy in the distortion energy results in high predicted
ee when L14 and L15 are used. Furthermore, when both of the
nitrogen atoms of the urea moiety are masked by methyl
groups in L16, the activation free energies of 9-ts-RRR-L16
and 9-ts-SSS-L16 in the cycloaddition step are significantly
enhanced, which can be attributed to two reasons. First, the
interaction-energy term (ΔEint‡) is significantly lower in the
absence of hydrogen bonding. Second, acrylonitrile further
distorts to react with the dipole owing to the omitted
hydrogen bond activation, which leads to increase in the
distortion energy term (ΔEdist‡) in the late-coming transition
state. Therefore, the reaction center is far from the chiral
center of the ligand owing to the lack of hydrogen bonding,
which results in the poorly regulatory effect of the ligand and
thus the low ee of the product. Based on the aforementioned
hypothesis, N-methyl-substituted phosphine–urea ligands of
L15 and L16 were synthesized and used in 1,3-dipolar
cycloaddition of 1a and 2a under the optimal conditions
(Cu(CH3CN)4BF4/L6/K2CO3/tBuOMe/rt). Ee values of 98%
and 7% are obtained for L15 and L16, respectively (Figure 5),
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
b)
c)
a)
G M11/Et2O (kcal/mol)
(H M11/Et2O (kcal/mol))
G M11/Et2O (kcal/mol)
(H M11/Et2O (kcal/mol))
G M11/Et2O (kcal/mol)
(H M11/Et2O (kcal/mol))
20.5
(5.3)
16.2
(3.2)
9-ts-RRR-L16
15.8
(0.2)
9-ts-RRR-L14
19.9
(5.5)
9-ts-SSS-L16
9-ts-RRR-L15
NC
1a
11.0
(-0.8)
9.7
(-5.6)
1a
1a
9-ts-SSS-L14
9-ts-SSS-L15
0.0
(-15.8)
0.0
0.0
0.0
(0.0)
3.4
(4.0)
8-L16
(0.0)
(0.0)
1.7
(1.9)
8-L15
-5.9
(-20.0)
7-L14
7-L15
12-SSS-L16
7-L16
-4.4
(-3.4)
-6.7
(-24.8)
12-RRR-L14
-4.2
(-20.1)
12-RRR-L16
12-RRR-L15
8-L14
-9.2
(-25.8)
-7.7
(-21.3)
12-SSS-L14
12-SSS-L15
H
H
H
Ph
H
Ph
Ph
H
Ph
H
N
Ph
Ph
N
Ph
Ph
N
Ph
Ph
N
Ph
Ph
Ph
Ph
N
Ph
Ph
N
P
P
P
Ph
P
O
Ph
P
O
Ph
O
Ph
P
Ph
O
O
O
Ph
R1
R1
N
O
Cu
Ph
Cu
R1
Cu
CN
O
Ph
R1
CN
O
R1
N
Cu
MeO
Cu
R1
N
N
N
Cu
CN
MeO
H
MeO
H
H
N
N
CN
H
O
N
O
R2
O
O
N
O
R2
R2
N
O
N
O
H
R2
N
R2
N
N
R2
N
O
H
N
N
O
H
N
H
H
MeO
H
H
H
MeO
MeO
CF3
CF3
CF3
CF3
CF3
CF3
F3C
F3C
F3C
F3C
F3C
1
F3C
1
2
1
2
1
2
1
1
2
2
: R = H , R = Me
: R = H , R = Me
: R = H , R = Me
: R = H , R2= Me
: R = H , R = Me
7-L14
7-L15
7-L16
9-ts-SSS-L14
9-ts-SSS-L15
9-ts-SSS-L16
12-SSS-L14
12-SSS-L15
12-SSS-L16
8-L14
8-L15
8-L16
9-ts-RRR-L14
9-ts-RRR-L15
9-ts-RRR-L16
12-RRR-L14
: R = H , R = Me
1
2
1
2
1
2
1
2
1
2
1
2
12-RRR-L15
12-RRR-L16
: R = Me , R = Me
: R = Me , R = H
: R = Me , R = H
: R = Me , R = H
: R = Me , R = H
: R = Me , R = H
: R = Me , R = H
1
2
1
2
1
2
1
2
1
2
1
2
: R = Me , R = Me
: R = Me , R = Me
: R = Me , R = Me
: R = Me , R = Me
: R = Me , R = Me
Figure 6. Free energy profiles for catalytic asymmetric 1,3-dipolar cycloaddition of methacrylonitrile using N-methylated ligands
ACS Paragon Plus Environment

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a) L14, b) L15, and c) L16. The values are in kcal/mol and represent the relative free energies calculated by the DFT/M11 method
in Et2O.
1
2
3
4
5
6
7
8
9
BCu-O1 = 2.44
BN1-H1 = 1.99
BC2-C5 = 2.04
BC3-C4 = 2.94
BCu-O1 = 2.91
BN1-H1 = 2.04
BC2-C5 = 2.05
BC3-C4 = 2.91
BCu-O1 = 2.34
BN1-H2 = 2.05
BC2-C5 = 2.00
BC3-C4 = 2.88
O1
Cu
O1
O1
Cu
H1
N1
C2
C3
C5 H1
N1
C3
C4
C2
C5
Cu
C2
C3
H2
C5
C4
N1
G‡ = 11.0 kcal/mol
E‡ = -2.9 kcal/mol
G‡ = 16.2 kcal/mol
E‡ = -0.1 kcal/mol
G‡ = 9.7 kcal/mol
E‡ = -1.7 kcal/mol
C4
‡
‡
‡
Edist = 21.3 kcal/mol
Edist = 23.6 kcal/mol
Edist = 21.6 kcal/mol
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
‡
‡
‡
Eint = -24.2 kcal/mol
Eint = -23.7 kcal/mol
Eint = -23.3 kcal/mol
9-ts-SSS-L14
9-ts-RRR-L14
9-ts-SSS-L15
BCu-O1 = 2.41
BC2-C5 = 1.99
BC3-C4 = 3.05
BCu-O1 = 3.29
BC2-C5 = 1.98
BC3-C4 = 2.79
BCu-O1 = 3.31
BN1-H2 = 2.05
BC2-C5 = 2.00
BC3-C4 = 2.79
O1
O1
H2
O1
G‡ = 15.8 kcal/mol
E‡ = 1.7 kcal/mol
G‡ = 19.9 kcal/mol
E‡ = 7.2 kcal/mol
G‡ = 20.5 kcal/mol
E‡ = 7.7 kcal/mol
C5
Cu
N1
C2
C3
Cu
Cu
C4
C3
C4
C4
‡
‡
‡
Edist = 26.7 kcal/mol
Edist = 27.3 kcal/mol
Edist = 30.1 kcal/mol
C3
C2
C2
C5
‡
‡
‡
Eint = -25.0 kcal/mol
Eint = -20.1 kcal/mol
Eint = -22.4 kcal/mol
C5
9-ts-RRR-L15
9-ts-SSS-L16
9-ts-RRR-L16
Figure 7. Distortion–interaction energy analysis of the optimized structures in the nucleophilic addition step using N-
methylated phosphine–urea ligands L14, L15, and L16.
which is in agreement with the computational predictions.
Notably, for L16, the yield significantly decreases to 5%,
which can be explained by the higher activation free energy
for the cycloaddition step with ligand L16. From high-
resolution mass spectrometry (HRMS) analysis, the
azomethine ylide–Cu–L6 complex (m/z=995.2246) is present
in the crude reaction mixture, suggesting that iminoester
could be preactivated by the coordination with L6–Cu
complex.18 Therefore, the combination of experimental
observations and theoretical calculations shows that both the
reactivity and stereoselectivity arise from the synergistic
activation and spatial orientation of the dipole and
dipolarophile by the amidophosphine–urea bifunctional
ligand L6–Cu complex.
Substrate Scope. Having established the optimal catalytic
system and elucidated the reaction mechanism, we next
explored the scope of iminoester
cycloaddition with methacrylonitrile (Table 2). Iminoesters
possessing both electron-deficient and electron-rich groups
on the phenyl ring gave the cycloaddition products in good
to excellent yields and with excellent stereoselectivities
(96:4–98:2 d.r., 97–99% ee) (entries 1–7). The substitution
2
in 1,3-dipolar
pattern
of
the
Table 2. Catalytic Asymmetric 1,3-Dipolar Cycloaddition of Various Iminoesters with Methacrylonitrilea
Me
NC
L6
Cu(MeCN)4BF4/
OMe
Me
R1
N
OMe
+
R1
O
NC
1a
N
H
O
2
3
(endo)
entry
3
R1
yield (%)b
d.r.c
98:2
98:2
97:3
97:3
98:2
96:4
96:4
ee (%)d
99
1
3a
3b
3c
3d
3e
3f
Ph
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
95
95
86
85
91
2
3
4
5
6
7
99
97
98
97
98
98
4-COOMeC6H4
4-CF3C6H4
86
75
3g
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8
9
3h
3i
3j
3k
3l
3m
3n
3o
2-BrC6H4
3-BrC6H4
1-naphthyl
2-naphthyl
N-Bn-2-pyrryl
2-thienyl
83
76
90
95
51
92
51
99:1
99:1
99:1
98:2
97:3
98:2
99:1
98:2
99
99
97
99
98
99
99
97
1
2
3
4
5
6
7
10
11
12
13
14
15
2-furyl
N-Bs-2-indolyl
75
8
9
aConditions: 1a (0.4 mmol), 2 (0.2 mmol), L6 (5.5 mol%), Cu(MeCN)4BF4 (5 mol%), K2CO3 (50 mol%), 4 Å MS (200 mg), tBuOMe
(4 mL), room temperature, 16–48 h. Isolated yield. Determined by HPLC analysis of the crude reaction mixture. Determined
by chiral HPLC analysis of the endo isomer. Bs=benzenesulfonyl.
b
c
d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
phenyl ring has a negligible effect on the reactivity and
Cl
Cl
Cl
NC
NC
NC
stereoselectivity, and bromo groups at ortho- meta-, and
para-positions of the phenyl ring are all tolerated in this
cycloaddition (entries 4, 8, and 9), thus providing handles on
the phenyl ring for further elaboration of the cycloaddition
products. Fused aromatic substrates, including 1- and 2-
naphthyl-substituted iminoesters also proved to be viable
azomethine ylide precursors (entries 10 and 11). Notably,
iminoesters substituted with an array of heteroaryl groups,
including pyrryl, thienyl, furyl, and indolyl groups, all worked
well (entries 12–15). However, alkyl iminoesters do not work
well under the current reaction conditions as a contrast of
aryl iminoesters.
OMe
OMe
OMe
N
H
N
H
N
H
O
O
Br
O
4a
4b
4c
: 99% yield
99:1 d.r., 94% ee
: 89% yield
>96:4 d.r., 96% ee
: 85% yield
>96:4 d.r., 96% ee
Cl
Cl
Cl
NC
NC
NC
OMe
OMe
OMe
N
N
H
N
H
O
O
4e
O
H
S
O
4d
4f
: 96% yield
>96:4 d.r., 95% ee
: 76% yield
98:2 d.r., 92% ee
: 98% yield
>96:4 d.r., 96% ee
NC
Et
Cl
NC
Ph
NC
OMe
OMe
OMe
N
N
N
H
H
NBs
O
H
O
O
4g
4h
4i
: 91% yield
99:1 d.r., 94% ee
: 95% yield
96:4 d.r., 96% ee
: 97% yield
98:2 d.r., 99% ee
Chloro-bearing stereogenic carbon centers are found in a
large number of natural products and bioactive compounds.25
Although recent years have witnessed great advances in the
development of catalytic enantioselective addition of carbon-
halogen bonds to organic molecules, enantioselective
construction of halogen-bearing quaternary stereogenic
centers remains a challenge in organic synthesis.26 As our
interest in construction of quaternary stereogenic centers,27
aConditions unless otherwise stated: 1 (0.4 mmol), 2 (0.2
mmol), L6 (5.5 mol%), Cu(MeCN)4BF4 (5 mol%), Et3N (50
mol%), 4 Å MS (200 mg), CH2Cl2 (4 mL), 0 °C or room
temperature, 16–48 h; the d.r. is the ratio of endo/exo isomers,
determined by HPLC or 1H NMR analysis of the crude reaction
mixture; the ee was determined by chiral HPLC analysis of the
endo isomer; 4i was prepared under the conditions given in
Table 2.
we
tested
whether
commercially
available
α-
chloroacrylnitrile is a suitable dipolarophile for 1,3-dipolar
cycloaddition of iminoesters (Table 3). α-Chloroacrylnitrile
reacted smoothly with iminoester 2a under slightly modified
conditions to give the corresponding product 4a in high yield
(89%) with excellent diastereo- and enantioselectivity (>96:4
d.r., 96% ee). We then briefly explored the iminoester scope.
We found that iminoesters substituted with aryl (p-Br-
phenyl and naphthyl) and heteroaryl (furyl, thienyl, and
indolyl) groups all reacted smoothly with α-chloroacrylnitrile,
giving
a series of pyrrolidines with a chloro-bearing
quaternary stereogenic center in good yields with excellent
diastereo- and enantioselectivities (4b–4g). It is noteworthy
that this study represents the first example of catalytic
enantioselective 1,3-dipolar cycloaddition of iminoesters with
α-chloroacrylnitrile. To further expand the substrate scope of
the substituted acrylonitriles, α-phenyl- and β-ethyl-
acrylonitriles were subjected to the optimal conditions. In
these two cases, good yields and stereoselectivities were
achieved (4h and 4i).
Table 3. Catalytic Asymmetric 1,3-Dipolar Cycloaddition
of Various Iminoesters with Substituted Acrylonitrilesa
R3
R4
NC
R1
R3
L6
Cu(MeCN)4BF4/
OMe
OMe
+
R1
N
R4
N
H
NC
O
O
2
1
Table 4. Catalytic Asymmetric 1,3-Dipolar Cycloaddition of Various Iminoesters with Unsubstituted Acrylonitrilea
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Page 8 of 13
NC
L6
Cu(MeCN)4BF4/
OR
OR
R1
N
1
2
+
NC
1b
R1
N
O
O
H
5
2
3
4
5
6
7
8
9
entry
5
R1/R
Ph/Me
yield (%)b
d.r.c
99:1
99:1
99:1
99:1
96:4
99:1
99:1
98:2
98:2
98:2
99:1
99:1
ee (%)d
99
1
5a
5b
5c
5d
5e
5f
95
90
85
86
82
87
77
90
87
95
82
88
2
4-F-C6H4/Me
4-Cl-C6H4/Me
4-Br-C6H4/Me
99
3
99
4
5
99
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Me-C6H4/Me
99
6
7
4-MeO-C6H4/Me
4-Me2N-C6H4/Me
4-CN-C6H4/Me
4-COOMe-C6H4/Me
4-CF3-C6H4/Me
4-NO2-C6H4/Me
2-Br-C6H4/Me
99
5g
5h
5i
98
8
9
10
11
12
98
98
5j
99
5k
5l
98
99
13
5m
3-Br-C6H4/Me
84
97:3
99
14
15
16
17
18
19
20
5n
5o
5p
5q
5r
2-F-C6H4/Me
3-F-C6H4/Me
1-naphthyl/Me
2-naphthyl/Me
2-thienyl/Me
2-furyl/Me
89
97
82
86
87
86
75
99:1
95:5
98:2
97:3
97:3
96:4
97:3
97
97
99
99
99
97
97
5s
5t
N-Bn-2-pyrryl/Me
21
5u
5v
5w
5x
3-pyridyl/Me
N-Bs-2-indolyl/Me
Ph/Et
Ph/iPr
Ph/tBu
87
80
98
91
99:1
98:2
98:2
99:1
98
95
98
98
22
23
24
25
26
5y
5z
91
99:1
98:2
98
99
Ph/Bn
90
aConditions: 1b (0.4 mmol), 2 (0.2 mmol), L6 (5.5 mol%), Cu(MeCN)4BF4 (5 mol%), Et3N (50 mol%), 4 Å MS (200 mg),
b
c
CH2Cl2 (4 mL), 0 °C, 16–48 h. Yield of the isolated endo isomer. Ratio of the endo/exo isomers, determined by HPLC
analysis of the crude reaction mixture. dDetermined by chiral HPLC analysis of the endo isomer.
We also expanded this methodology to 1,3-dipolar
cycloaddition of unsubstituted acrylonitrile (Table 4). In
theory,
and 12–15). Fused aromatic 1- and 2-naphthyl-substituted
glycine imines are also suitable azomethine ylide precursors
(entries 16 and 17). Remarkably, iminoesters substituted with
1,3-dipolar
should
cycloaddition
be less
of
unsubstituted
than
acrylonitrile
challenging
a
variety of heteroaryl groups, including thienyl,
methacrylonitrile, because it is more reactive and good
stereocontrol is easier to access in the absence of an α methyl
group. Indeed, there are a few highly enantioselective
catalytic systems that tolerate unsubstituted acrylonitrile as
the dipolarophile.8 However, a systematic investigation of the
scope of iminoesters has not been reported. A wide range of
iminoester 2 were examined using the bifunctional catalyst.
Iminoesters with electron-deficient groups or electron-rich
groups on the phenyl ring gave the cycloaddition products in
good yields (77–95%) with excellent stereoselectivities (98:2–
99:1 d.r., 98–99% ee) (entries 1–11). The substitution pattern
on the phenyl ring has no obvious effect on the reactivity and
stereoselectivity, and ortho-, meta-, and para-substituted
substrates are all tolerated in this cycloaddition (entries 2, 4,
pyrryl, pyridyl, and indolyl groups, all worked well in this
transformation (entries 18–22). When iminoesters with
different ester groups are used, excellent yields and
stereoselectivities are achieved (entries 23–26).
The substrate scope was further expanded to include α-
substituted iminoesters (Scheme 2). We did not observe any
obvious difference between iminoesters derived from L- and
D-amino acid esters in terms of the reaction rate, yield, or
stereoselectivity (6a–6c). Remarkably, the catalytic system
could tolerate the co-presence of α-substituents on the
iminoester and acrylonitrile, providing direct access to chiral
pyrrolidine 6d with two quaternary stereogenic centers,
ACS Paragon Plus Environment

Page 9 of 13
Journal of the American Chemical Society
therefore, highlighting the generality of this 1,3-dipolar
cycloaddition protocol.
enantioenriched product 3p with 2-chloropropinyl chloride
1
2
3
4
5
6
7
and then with MeNH2 results in formation of dioxopiperazine
13, which transforms to ETP69 in 38% yield by treatment
with NaHMDS/S8. Using our 1,3-dipolar cycloaddition
protocol and the following two-step reaction sequence,
almost enantiopure (>99% ee) (S,S,S,S)-ETP69 was
conveniently synthesized.
Scheme 2. Catalytic Asymmetric 1,3-Dipolar
Cycloaddition of α-Substituted Iminoesters
R3
R2
NC
R2
R3
L6
Cu(MeCN)4BF4/
OMe
OMe
+
R1
N
Et3N, 4Å MS, CH2Cl2, rt
R1
N
H
NC
O
O

CONCLUSIONS
2
1
6
We have developed
a novel simple type of chiral
8
Ph
NC
NC
NC
NC
amidophosphine–urea bifunctional ligands. By combining
metal-catalysis and organocatalysis, the first catalytic
enantioselective 1,3-dipolar cycloaddition of iminoesters with
methacrylonitrile has been realized in high yields with
excellent diastereo- and enantioslectivities (up to 99:1 d.r.,
99% ee). A wide substrate scope of both iminoesters and
acrylonitriles can be tolerated by the catalyst system of
L6/Cu, producing a series of chiral pyrrolidine derivatives
with up to two quaternary stereogenic centers. Using this
protocol, enantioselective synthesis of the nitrile
pharmacophore-bearing antitumor agent ETP69 has been
successfully achieved. DFT with the M11 functional was used
to investigate the origin of the enantio- and
diastereoselectivity of asymmetric 1,3-dipolar cycloaddition.
The DFT calculations indicate that nucleophilic addition is
the enantioselectivity-determining step and the hydrogen
bonding between the urea moiety and methacrylonitrile
assists in controlling the diastereo- and enantioselectivity.
Distortion–interaction energy analysis based on DFT
calculations reveals that the distortion energy plays an
important role in the observed enantioselectivity, which can
be attributed to the steric effect between the phosphine
ligand and the dipole reactant. Furthermore, N-methylated
phosphine–urea ligands were designed, synthesized, and
9
Me
OMe
Me
Bn
OMe
OMe
OMe
N
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
H
N
H
H
Br
O
O
O
O
6a
6b
6c
6d
: 99% yield
99:1 d.r., 99% ee
: 40% yield
: 50% yield
98:2 d.r., 94% ee
: 90% yield
94:6 d.r., 98% ee
95:5 d.r., 93% ee
The relative and absolute configurations for all of the five
different types of cycloaddition products were determined by
single-crystal X-ray crystallographic analysis (Figure 8, 3d, N-
(P-Br)Bz-4a, 5d, N-Ts-6a, and 6d),18,28 and the same
configuration were analogously assigned to the other
products.
Me
NC
NC
OMe
OMe
Cl
N
N
H
N
H
NC
Br
O
Br
O
OMe
5d
3d
O
O
Br
4a
N-(p-Br)Bz-
3d
5d
X-ray of
NC
X-ray of
Ph
NC
Me
O
OMe
Me
N
Ph
N
H
O
6d
OMe
Br
Ts
6a
N-Ts-
tested
for
asymmetric
1,3-dipolar
cycloaddition,
demonstrating that hydrogen bonding (organocatalysis) is
crucial for the high reactivity and stereoselectivity. This
combined theoretical and experimental study shows that
synergistic activation and spatial orientation of the dipole
and dipolarophile by effective integration of metal-catalysis
and organocatalysis are responsible for the high reaction
efficiency and excellent stereoselectivity for 1,3-dipolar
cycloaddition of iminoesters with acrylonitriles.
4a
X-ray of N-(p-Br)Bz-
6a
6d
X-ray of N-Ts-
X-ray of
Figure 8. X-ray structures of the representative
cycloadducts.
ASSOCIATED CONTENT
Supporting Information
Synthetic Applications. The synthetic utility of this
protocol was further investigated (Scheme 3). The reaction
between 2p and 1a was performed on the gram-scale to test
the scalability of this cycloaddition reaction. Compound 3p
was obtained in 65% yield with 95:5 d.r. and 97% ee.
According to Overman’s report on preparation of (±)-
ETP69,9b reaction of
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and compound characterization
(PDF)
Crystallographic structure of 3d (CIF)
Crystallographic structure of N-(P-Br)Bz-4a (CIF)
Crystallographic structure of 5d (CIF)
Crystallographic structure of N-Ts-6a (CIF)
Crystallographic structure of 6d (CIF)
Scheme 3. Gram-Scale 1,3-Dipolar Cycloaddition and
Enantioselective Synthesis of ETP69
L6
Me
Cu(CH3CN)4BF4/
K2CO3, tBuOMe
NC
OMe
O
O
N
O
O
+
1a
O
65% yield, 95:5 d.r.
97% ee
N
H
O
OMe
2p
3p
1 g scale
AUTHOR INFORMATION
Corresponding Author
O
Me
Me
NC
NC
Cl
Cl
H
O
O
S8, NaHMDS
O
O
N
N
S
S
Et3N, CH2Cl2
then, MeNH2
81% yield
toluene/THF
38% yield
>99% ee
O
O
N
N
Me
Me
O
O
*Email: minzhang@cqu.edu.cn
*Email: lanyu@cqu.edu.cn
Me
Me
13
ETP69
(S,S,S,S)-
d.r.= 7:1
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Journal of the American Chemical Society
Page 10 of 13
Reactions of Azomethine Ylides-A Simple Approach to Optically
Active, Highly Functionalized Proline Derivatives. Angew. Chem.
Int. Ed. 2002, 41, 4236.
Author Contributions
§These authors contributed equally to this work.
1
2
3
4
5
6
7
8
9
(5) For selected examples of metal-involved 1,3-dipolar
cycloadditions of iminoesters, see: (a) Chen, C.; Li, X.; Schreiber,
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Wang, C.-J.; Liang, G.; Xue, Z.-Y.; Gao. F. Highly Enantioselective
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Copper(I)/TF-BiphamPhos Complexes. J. Am. Chem. Soc. 2008,
130, 17250. (g) López-Pérez, A.; Adrio, J.; Carretero, J. C. The
Phenylsulfonyl Group as A Temporal Regiochemical Controller
in the Catalytic Asymmetric 1,3-Dipolar Cycloaddition of
Azomethine Ylides. Angew. Chem. Int. Ed. 2009, 48, 340. (h) Arai,
T.; Mishiro, A.; Yokoyama, N.; Suzuki, K.; Sato, H. Chiral
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Nitroalkenes. J. Am. Chem. Soc. 2010, 132, 5338. (i) Arai, T.;
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X.-P.; Wang, D.-Y.; Zheng, Z.-O. New Chiral Ferrocenyl P,S-
Ligands for Highly Diastereo-/Enantioselective Catalytic [3 + 2]
Cycloaddition of Azomethine Ylides with Cyclic and Acyclic
Enones. Org. Lett. 2010, 12, 5542. (k) Kim, H. Y.; Li, J. Y.; Kim, S.;
Oh, K. Stereodivergency in Catalytic Asymmetric Conjugate
Addition Reactions of Glycine (Ket)imines. J. Am. Chem. Soc.
2011, 133, 20750. (l) Wang, M.; Wang, Z.; Shi, Y.-H.; Shi, X.-X.;
Fossey, J. S.; Deng, W. P. An exo- and Enantioselective 1,3-
Dipolar Cycloaddition of Azomethine Ylides with Alkylidene
Malonates Catalyzed by a N,O-Ligand/Cu(OAc)2-Derived Chiral
Complex. Angew. Chem. Int. Ed. 2011, 50, 4897. (m) Hernández-
Toribio, J.; Padilla, S.; Adrio, J.; Carretero, J. C. Catalytic
Asymmetric Synthesis of α-Quaternary Proline Derivatives by 1,3-
Dipolar Cycloaddition of α-Silylimines. Angew. Chem. Int. Ed.
2012, 51, 8854. (n) Potowski, M.; Bauer, J. O.; Strohmann, C.;
Antonchick, A. P.; Waldmann, H. Highly Enantioselective
Catalytic [6+3] Cycloadditions of Azomethine Ylides. Angew.
Chem. Int. Ed. 2012, 51, 9512. (o) He, Z.-L.; Teng, H.-L.; Wang, C.-
J. Fulvenes as Effective Dipolarophiles in Copper(I)-Catalyzed
[6+3] Cycloaddition of Azomethine Ylides: Asymmetric
Construction of Piperidine Derivatives. Angew. Chem. Int. Ed.
2013, 52, 2934. (p) Narayan, R.; Bauer, J. O.; Strohmann, C.;
Antonchick, A. P.; Waldmann, H. Catalytic Enantioselective
Synthesis of Functionalized Tropanes Reveals Novel Inhibitors of
Hedgehog Signaling. Angew. Chem. Int. Ed. 2013, 52, 12892. (q)
Awata, A.; Arai, T. PyBidine/Copper catalyst. Asymmetric exo'-
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Indole. Angew. Chem. Int. Ed. 2014, 53, 10462. (r) Li, Q.-H.; Wei,
ACKNOWLEDGMENT
This work was supported by NSFC (21402015, 21672029,
21772020, 21822303) and Chongqing Provincial Human
Resources and Social Security Department (CX2017048). We
are grateful to Prof. Weiping Tang and Ms. Stephanie A.
Blaszczyk (UW-Madison) for helpful discussions and
proofreading the manuscript, and Mr. Xiangnan Gong (CQU)
for X-ray crystallographic analysis.
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(6d), and CCDC 1575128 (N-(p-Br)Bz-4a), and CCDC 1575112 (N-
Ts-6a) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre. Note: for 6d with no
heavy atom incorporated, only relative configurations were
determined.
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Table of Contents artwork：
R3
R4
R2
NC
R1
R2
R3
OMe
L
Cu/
OMe
+
R1
N
R4
N
H
NC
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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27
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49
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60
up to 99:1 d.r., 99% ee
L:
Me
NC
O
O
CF3
CF3
O
O
O
NH
N
H
N
S
N
H
S
N
PPh2
Me
O
ETP69
an antitumor agent
Me
a novel bifunctional ligand
metal catalysis and organocatalysis combination
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