Copper(i)/Ganphos catalysis: enantioselective synthesis of diverse spirooxindoles using iminoesters and alkyl substituted methyleneindolinones

Article abstract of DOI:10.1039/d0ob00546k

A copper-catalyzed asymmetric 1,3-dipolar cycloaddition of glycine iminoesters with alkyl substituted 3-methylene-2-oxindoles is described. By usingde novodesign of P-stereogenic phosphines as ligands, spiro[pyrrolidin-3,3'-oxindole]s are generated in good to excellent yields with high asymmetric induction. A further reduced catalyst loading of 0.1 mol% is sufficient to achieve a satisfactory enantioselectivity of 90% ee. The DFT calculations suggest the second Michael addition of the 1,3-dipole to be the rate- andenantio-determining step. A key feature of this 1,3-dipolar cycloaddition is the wide substrate applicability, even with alkyl aldehyde-derived azomethine ylide; thus it has streamlined a highly enantioselective access to a new class of antiproliferative agents, MDM2-p53.

Full text of DOI:10.1039/d0ob00546k

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10.1039/D0OB00546K.
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Number 47
21 December 2017
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DOI: 10.1039/D0OB00546K
ARTICLE
Copper(I)/Ganphos Catalysis: Enantioselective Synthesis of
Diversified Spirooxindoles Using Alkyl Substituted Imino Ester and
Methyleneindolinones
Received 00th January 20xx,
Accepted 00th January 20xx
Hao Cui‡,a, Ke Li‡,a, Yue Wanga, Manman Songa, Congcong Wanga, Donghui Wei,*,a Er-Qing Li,*,a
DOI: 10.1039/x0xx00000x
Zheng Duan,*,a and François Matheya
A copper-catalyzed asymmetric 1,3-dipolar cycloaddition of glycine iminoesters with alkyl substituted 3-methylene-2-
oxindoles is described. By using De Novo design of P-stereogenic phosphines as ligands, the spiro[pyrrolidin-3,3’-oxindole]s
are generated in good to excellent yields with high asymmetric induction. A further reduced catalyst loading of 0.1 mol% is
sufficient to achieve a satisfactory enantioselectivity of 90% ee. The DFT calculations suggest the second Michael addition
of the 1,3-dipole to be the rate- and enantio-determining step. A key feature of this 1,3-dipolar cycloaddition is the wide
substrate applicability, even with alkyl aldehyde-derived azomethine ylide, thus it has streamlined
enantioselective access to a new class of antiproliferative agents, MDM2-p53.
a highly
The catalytic asymmetric 1,3-dipolar cycloaddition of
iminoesters and activated alkenes represents
Introduction
a
straightforward, powerful, and highly atom-economic
approach for the enantioselective synthesis of spirooxindole
systems.4 The first catalytic asymmetric 1,3-dipolar
cycloaddition route to spiro[pyrrolidin-3,3’-oxindole] was
shown by Gong and co-workers in 2009, who realized a
Brønsted acid catalyzed asymmetric three-component 1,3-
dipolar cycloaddition to enantioselective access to this
spirocycle class.5 In 2010, Waldmann reported a Lewis acidic
Cu(I)-catalyzed (3+2) cycloaddition of aryl substituted 3-
methylene-2-oxindole and iminoesters.6 Shortly thereafter,
Wang realized also the asymmetric synthesis of
Spiro-oxindole scaffold is found in numerous bioactive natural
products, which is a proven and rich source of disease-
modulating drugs.1 In particular, the 2-oxospiro[indoline-3,3′-
pyrrolidine] inhibits the cell cycle and represents a novel type
of potent inhibitor of the MDM2-p53 interaction that is crucial
for the regulation of the tumor-suppressing activity of the p53
protein (Figure 1).2 Thus great effort has been encouraged in
optimizing the efficiency and scope of these bioactive products
in the past two decades.3 In spite of this progress, the
synthesis of spiro[pyrrolidin-3,3’-oxindole] remains
a
significant challenge in organic chemistry.
spiro[pyrrolidin-3,3’-oxindole],
albeit
with
moderate
CO2H
O
enantioselectivity.7 Besides, Arai found that their
bis(imidazolidine)pyridine (PyBidine) ligand was similarly able
to promote the (3+2) cycloaddition of iminoesters.8 However,
the example of a catalytic asymmetric reaction using alkyl
substituted 3-methylene-2-oxindole and iminoesters, which
usually own lower reactivity relative to aryl substituent, has
been rarely reported due to the lack of suitable chiral ligands
to improve the reactivity as well as controlling the
enantioselectivity.
N
Cl
Cl
O
Cl
N
O
NH
NH
F
O
NH
Et
F
NH
N
O
O
N
N
H
O
Cl
Cl
N
H
H
Cl
1
2
3
Figure 1. Representatives of the MDM2-p53 inhibitors
displaying spiro(pyrrolidine)oxindole core structures.
As parts of our continued interest in organophosphine
chemistry,9 we are devoted to De Novo design of chiral
phosphine ligands to empower asymmetric metal catalysis to a
greater extent. We set our goal to evolve novel P-stereogenic
phosphines that would be complementary to the known chiral
phosphine ligands, thus offering us more dimensions for the
discovery of metal/phosphine complex-mediated asymmetric
catalytic reactions.10 Based on this, we developed a series of
a. College of Chemistry, Green Catalysis Center, International Phosphorus
Laboratory, International Joint Research Laboratory for Functional
Organophosphorus Materials of Henan Province, Zhengzhou University,
Zhengzhou 450001, P. R. China. E-mail: donghuiwei@zzu.edu.cn;
lierqing@zzu.edu.cn; duanzheng@zzu.edu.cn
‡ These authors contributed equally to this work.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
novel P-stereogenic ligands, bearing
a
flexible 1-
phosphanorbornediene moiety, so-called Ganphos, which
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Organic & Biomolecular Chemistry
Page 2 of 6
ARTICLE
Journal Name
showed good performance in asymmetric 1,3-dipolar diastereoselectivity (Table 1, entry 17). When weViuewseAdrtictlehOenDlinee
cycloaddition.11 We reported herein copper-catalyzed Novo of designed P-stereogenic KephosDaOsIl:i1g0a.1n0d3,9t/Dh0eOrBe0a0c5t4io6nK
a
asymmetric 1,3-dipolar cycloaddition using alkyl substituted 3- also proceeded smoothly, producing the desired adduct 3a in
methylene-2-oxindole and glycine iminoesters. Replacing the excellent yield and slightly low enantioselectivity (Table 1,
S-stereocenter
bis(trifluoromethyl)benzoyl
of
Ganphos
moiety,
with
another
3,5- entry 18), which proved the efficiency of this new chiral ligand.
novel The structures and stereochemistries of 3 were characterized
bifunctional P-stereogenic ligand (Kephos) was developed, by a combination of NMR, HPLC, HRMS spectra, and single
which proved to be especily efficient to promote the synthesis crystal X-ray analysis (3ad) (see Supporting Information).15
of MDM2-p53 precursor (Scheme 1). Our catalytic system
realized considerable improvements in this reaction, such as :
(1) Broad substrate scope (both aryl and alkyl substituted 3-
Table 1. Optimization of reaction conditions.a
methylene-2-oxindole and glycine iminoesters); (2) lower
CO2Me
catalyst loading (as low as 0.1 mol%); (3) the enantioselective
NH
Ph
metal
ligand
synthesis of MDM2-p53 precursor.
tBu
Ph
N
CO2Me
+
O
O
THF,Et3N, rt
EtOH (4.0 eq)
N
H
1a
Ph
P*
N
H
3aa
Ph
tBu
*
P
2a
HN
Ph
O
S
Ph
O
HN
Entry Metal salt
Ligand Yield
[%]b
dr
ee
[%]d
91
[%]c
F3C
Kephos (Rp, S)
CF3
1
Cu(CH3CN)4BF4 L1
80
81:19
Ganphos (Rp, S, Rs)
2
3
4
5
6
7
8
9
Cu(CH3CN)4BF4 L2
Cu(CH3CN)4BF4 L3
Cu(CH3CN)4BF4 L4
Cu(CH3CN)4BF4 L5
Cu(CH3CN)4BF4 L6
Cu(CH3CN)4BF4 L7
Cu(CH3CN)4BF4 L8
Cu(CH3CN)4BF4 L9
Cu(CH3CN)4BF4 L10
77
62
44
41
28
27
trace
36
62
54
84
45
30
89
87
80
96
71:29
63:37
85:15
68:32
86:14
60:40
-
85:15
95:5
78:22
67:33
95:5
86
85
76
66
34
70
-
30
84
30
26
84
89
84
88
95
87
CO2Me
NH
R1
R1
Cu(I)
P*
R3
O
R2
R3
N
CO2Me
R2
+
O
N
N
H
H
R1 = alkyl; R3 = aryl;
R1 = aryl; R3 = aryl or alkyl;
was used
Kephos
Ganphos
was used
Scheme 1. Our catalytic system for the synthesis of chiral
spiro[pyrrolidin-3,3’-oxindole]s.
10
11
12
13
14
15
16
17e
AgSbF6
AgOAc
Cu(OTf)2
CuI
Cu(OAc)2
CuSO4
L1
L1
L1
L1
L1
L1
Results and discussion, Experimental
84:16
54:46
66:34
92:8
Initially, 3-(cyclohexylmethylene)-indolin-2-one 1a and glycine
iminoester 2a as the model substrates, were treated with a
variety of solvents and bases in the presence of catalytic
amounts of Cu(CH3CN)4BF4/Ganphos ( Supplementary Table
S1). From this initial series of experiments, the use of both
Cu(CH3CN)4BF4 L1
Cu(CH3CN)4BF4 L11
18e
92:8
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol),
Cu(CH3CN)4BF4 (3 mol%), L (6 mol%), Et3N (20 mol%) and EtOH
Cu(CH3CN)4BF4 (3 mol%) and
Ganphos (6 mol%) in
b
(4.0 eq) in THF (1.0 mL), rt, N2, 4-6 h. Yields of isolated
product. Determined by 1H NMR analysis of the crude
mixture. Determined by chiral HPLC analysis. The reaction
was performed at -20 oC.
tetrahydrofuran (THF) and EtOH as additive emerged as most
advantageous with respect to yield, enantioselectivity and
diastereoselectivity (Table 1, entry 1). Remarkably, the
c
d
e
additive
(EtOH)
diastereoselectivity of
could
significantly
improve
the
t
O
L1
L2
L3
L4
L5
L6
Ganphos
Ar = 4- BuC6H4
(
)
the reaction. Subsequently, we
Ph
Ar2P
Fe
Ar = 2-naphthyl
P
N
Ar
investigated the effects of chiral ligands, and found that the
known ligand L8 was a poor ligand, Mingphos L10 could also
receive an acceptable result. Finally, Cu(I)/Ganphos catalyst
smoothly catalyzed the reaction to give the best yield,
diastereo- and enantioselectivity (Table 1, entries 1-10).12
Screening of metals showed that Ag(I) wasn’t good catalysts,13
resulting in low diastereo- and enantioselectivity compare with
Cu metal salts (Table 1, entries 11, 12 vs 12-16 ). Gratifyingly,
rarely used cheaper and more stable Cu(II) salts (even CuSO4)
could catalyze the reaction with high enantioselectivity, albeit
with low diastereoselectivity (Table 1, entries 15-16).14 An
experiment at -20 ° C led to an apparent rise in
Ph
Ar = 4-cyclohexylC6H4
P(tBu)2
PPh2
HN
n
Fe
O
Ar = 4- BuC6H4
S
t
Ar = 3,5- BuC6H3
L7
L8
Ar = 2,6-MeOC6H3
Ar = o-methylphenyl
Ph
tBu
P
PPh2
PPh2
Ph
O
HN
O
S
N
H
PPh2
F3C
CF3
L9
L10
L11
Kephos
2 | J. Name., 2012, 00, 1-3
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Under the optimized conditions, the substrate scope for
catalytic asymmetric (3+2) cycloaddition was investigated. As
outlined in Scheme 2, various alkyl substituted 3-methylene-2-
oxindoles 1 provided the desired products 3 with usually high
yields, diastereoselectivities, and enantioselectivities (Scheme
2, 3aa-3ka). The steric hindrance of alkyl substituent of 3-
ARTICLE
View Article Online
DOI: 10.1039/D0OB00546K
In the Cu(I)/Ganphos catalysis system, aryl substituted 3-
methylene-2-oxindoles
1
resulted
in
sightly
low
enantioselectivity (Supplementary Table S2). To further
explore the scope of the reaction, we designed a novel P-
stereogenic phosphine ligand (Kephos). As outlined in Scheme
3, the reaction between benzylidene indolinones and
iminoesters with varying substituents provided the desired
cycloadducts in moderate to good yields and with high
diastereoselectivities and enantioselectivities (Scheme 3, 3la-
3mi). Remarkably, even aliphatic iminoesters participated in
this (3+2) cycloaddition to afford spiro[pyrrolidin-3,3’-
oxindole]s 3mk-3mm, the reaction occurred with acceptable
yields and good to excellent enantioselectivities as well as
diastereoselectivities (Scheme 3, 3mk-3mm). Furthermore, our
catalyst system proved to be especially efficient to promote
the synthesis of MDM2-p53 precursor, a new class of
antiproliferative agents against cancer cell lines, in moderate
yield with excellent ee value (Scheme 3, 3ql). In Waldmann’s
report, an imine derived from an aliphatic aldehyde was not
methylene-2-oxindoles has
a
certain influence on
enantioselectivities (Scheme 2, entries 3aa-3ia), and methyl
substituted 3-methylene-2-oxindole 1f resulted in moderate
ee value (Scheme 2, entry 3fa). Remarkably, when alkyl
substituted 3-methylene-2-oxindoles 1 derived from aliphatic
ketones were applied, the reaction proceeded smoothly,
producing the desired adducts 3ga-3ia (with two all-carbon
quaternary centres and two tertiary stereocentres) in good
yields and enantioselectivities as well as diastereoselectivities
(Scheme 2, 3ga-3ia). Next, the applicability of the substituted
iminoesters for an array of diversified spiro[pyrrolidin-3,3’-
oxindole]s was examined. Both electron-donating and –
withdrawing substituents on the aromatic ring gave the
desired products 3ab-3ah with good to excellent
enantioselectivities (Scheme 2, 3ab-3ah). However, ortho-
substituent in the aryl ring resulted in lower reactivities and
enantioselectivities (Table 2, 3ae vs 3ag). Thienyl-substituted
methyleneindolinone 1i also afforded the desired 3ai with high
reactive even at high catalyst loading.6
CO2Me
Cu(CH3CN)4BF4
Ar
(3 mol %)
Ar
NH
Kephos
(6 mol %)
Et3N (20 mol %)
THF, -20 o
EtOH (4.0 eq)
+
R
N
CO2Me
O
R
O
N
H
C
N
enantioselectivity (Scheme 2, 3ai).
H
1
2
3
CO2Me
R2
Cu(CH3CN)4BF4
R2
NH
(3 mol %)
Ganphos
(6 mol %)
Ar
O
R1
+
O
Ar
N
CO2Me
3la; Ar = 4-BrC6H4, R = Ph: 63% yield; >20:1dr; 90% ee
3lc
CO2Me
NH
R1
Et3N (20 mol %)
EtOH (4.0 eq)
THF, -20 oC, 4-6h
N
: Ar = 4-BrC6H4, R = 3-BrC6H4: 61% yield; >20:1 dr; 86% ee
; Ar = 4-BrC6H4, R = 4-BrC6H4: 90% yield; >20:1 dr; 88% ee
; Ar = Ph, R = 4-ClC6H4: 79% yield; >20:1 dr; 89% ee
; Ar = 4-CNC6H4, R = 4-BrC6H4: 68% yield; >20:1 dr; 83% ee
: Ar = 4-NO2C6H4, R = 4-BrC6H4: 92% yield; >20:1 dr; 87% ee
; Ar = 4-CF3C6H4, R = 4-BrC6H4: 85% yield; >20:1 dr; 81% ee
N
H
H
3lj
3mk
3nj
3oj
3pj
1
3
2
Ar
R
O
CO2Me
NH
CO2Me
CO2Me
NH
CO2Me
NH
CO2Me
NH
Ph
N
H
NH
Ph
Ph
Ph
Ph
O
O
O
O
O
CO2Me
CO2Me
N
N
N
N
CO2Me
NH
N
H
H
H
H
H
3aa
; 80% yield;
3ba
3ca
NH
; 98% yield;
; 91% yield;
85:15 dr; 97% ee
3da
; 91% yield;
92:8 dr; 85% ee
3ea
; 89% yield;
82:18 dr; 85% ee
NH
92:8 dr; 95% ee
>20:1 dr; 93% ee
CO2Me
S
CO2Me
CO2Me
CO2Me
CO2Me
O
O
Br
O
NH
NH
NH
N
H
NH
NH
N
N
H
Cl
H
Ph
O
Ph
O
Ph
O
Ph
O
Ph
O
3mk
;
50% yield;
3mi
;
99% yield;
3kj
N
H
; 98% yield;
>20:1 dr; 86% ee
N
H
N
H
N
H
N
H
>20:1 dr; 90% ee
>20:1 dr; 84% ee
3fa
; 72% yield;
3ga
3ha
; 58% yield;
; 93% yield;
>20:1 dr; 93% ee
3ia
; 69% yield;
3ja
; 64% yield;
85:15 dr; 83% ee
>20:1 dr; 70% ee
>20:1 dr; 90% ee
>20:1 dr; 89% ee
CO2Me
NH
Cl
CO2Me
NH
CO2Me
NH
CO2Me
NH
CO2Me
NH
CO2Me
NH
CO2Me
NH
F
CO2Me
NH
Ph
O
O
O
N
O
O
O
N
H
O
O
N
H
N
H
N
H
N
H
Cl
F
H
Cl
Br
N
H
N
H
Cl
3ab
3ac
; 66% yield;
>20:1 dr; 90% ee
; 77% yield;
>20:1 dr; 92% ee
3ka
; 88% yield;
95:5 dr; 84% ee
3ad
; 91% yield;
>20:1 dr; 89% ee
3ae
; 85% yield;
80:20 dr; 96% ee
3mm
;
47% yield;
75:25 dr; 70% ee
3ml
;
46% yield;
>20:1 dr; 84% ee:
3ql
;
46% yield;
>20:1 dr; 94% ee
CO2Me
NH
CO2Me
NH
CO2Me
CO2Me
NH
a Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), Cu(CH3CN)4BF4 (3
mol%), Kephos (6 mol%), Et3N (20 mol%) and EtOH (4.0 eq) in THF
(1.0 mL), rt, N2, 4-6 h. Yields of isolated product. Determined by
1H NMR analysis of the crude mixture. Determined by chiral HPLC
NH
S
O
O
O
O
N
N
N
N
H
H
OMe
H
b
c
OPh
H
3ag
; 53% yield;
75:25 dr; 72% ee
3ah
; 72% yield;
90:10 dr; 92% ee
3af
3ai
; 68% yield;
>20:1 dr; 91% ee
; 82% yield;
83:17 dr; 92% ee
d
analysis.
a
Scheme 3. Asymmetric (3+2) cycloaddition catalyzed by
Reaction conditions:
1
(0.1 mmol),
2
(0.2 mmol),
[Cu(I)/Kephos] complex.a,b,c,d
Cu(CH3CN)4BF4 (3 mol%), Ganphos (6 mol%), Et3N (20 mol%)
and EtOH (4.0 eq) in THF (1.0 mL), rt, N2, 4-6 h. Yields of
isolated product. Determined by 1H NMR analysis of the
crude mixture. d Determined by chiral HPLC analysis.
Scheme 2. Asymmetric (3+2) cycloaddition catalyzed by
[Cu(I)/Ganphos] Complex.a,b,c,d
b
c
To prove the efficiency of our catalytic system, the influence of
catalytic loading was tested.16 To our delighted, the reaction
proceeded smoothly in a remarkably low 0.1 mol% catalyst loading
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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CO Me
View Ar2ticle Online
to form the desired adduct in good yield and ee. When catalyst
loading reduced to 0.05 mol%, the reaction still occurred, albeit
with slightly low yield and ee (Table 2).
Cu(CH3CN)4BF4
(3 mol%)
DOI: 10.1039/D0OB00546K
NH
GanPhos
(6 mol%)
Et3N (20 mol %)
THF, -20 o
+
O
Ph
N
CO2Me
Ph
O
N
PG
C
N
Table 2. Exploration of the influence of catalyst loading.
EtOH (4.0 eq)
PG
2a
1
3
CO2Me
CO2Me
NH
CO2Me
Cu(CH3CN)4BF4
NH
CO2Me
NH
CO2Me
GanPhos
NH
Ph
+
O
Ph
Ph
N
CO2Me
NH
Ph
Ph
O
Et3N (20 mol %)
THF, -20 o
EtOH (4.0 eq)
N
H
O
Ph
O
C
O
N
H
O
N
N
N
N
2a
1c
O
3ca
Ph
Ac
Ph
Cu(CH3CN)4BF4 (mol%) GanPhos (mol%) yield (%)[b] dr[c]
ee (%)[d]
3sa
; 59% yield;
>20:1 dr; 76% ee
3ra
3ua
; 60% yield;
>20:1 dr; 94% ee
;
45% yield;
3ta
;
54% yield;
>20:1 dr; 75% ee
>20:1 dr; 70% ee
1[a]
2[e]
3[f]
0.5
0.1
1
73
70
50
85:15
80:20
73:27
95
90
CO2Me
NH
0.2
0.1
Cu(CH3CN)4BF4
(3 mol %)
0.05
80
L*
(6 mol%)
Et3N (20 mol %)
THF, -20 o
EtOH (4.0 eq)
1c
2a
(1.0 mmol),
Reaction conditions: [a] Reaction conditions:
(0.5 mmol),
+
O
Ph
N
CO2Me
Ph
O
N
H
solvent (1.0 mL), N2, 4 h. [b] Yields of isolated product. [c] Determined by
1H NMR analysis of the crude mixture. [d] Determined by chiral HPLC analysis.
C
N
H
3aa
3a
1a
1c
2a
1c
(2.0 mmol), solvent (2.0 mL), N2, 8 h. [f] (2.0 mmol),
[e]
(1.0 mmol),
2a
(4.0 mmol), solvent (2.0 mL), N2, 24 h.
Ph
P
tBu
Ph
P
Ph
tBu
tBu
P
Ph
Ph
Ph
A gram-scale synthesis of 3ba was executed with a catalyst
loading of only 0.5 mol%. The desired pyrrolidine was obtained in
98 % yield with >20:1 dr and 86% ee (Scheme 4).
N
O
S
HN
O
N
O
S
S
Ph
80% yield; 92:8 dr
95% ee
55% yield; 92:8 dr
57% ee
63% yield; 92:8 dr
93% ee
CO2Me
Cu(CH3CN)4BF4
(0.5 mol%)
NH
Ph
Scheme 5. Control experiments.
GanPhos
( 1 mol%)
+
O
Ph
N
CO2Me
Et3N (20 mol %)
THF (10 ml), -20 o
EtOH (4.0 eq)
Based on these expriment results, the reaction pathway was
proposed (Scheme 6). The P-stereogenic ligands and in situ formed
azomethine ylide coordinated to the Cu (I) center, leading to the
tetracoordinated species, which facilitated the deprotonation by
Et3N to generate a well organized enantioenriched N-metalated
azomethine ylide B. Enantioselective conjugate addition of the
enolate to 3-(cyclohexylmethylene)-indolin-2-one 1a gave the
zwitterionic intermediate M1R. The following intramolecular
cyclization yielded the intermediate M2R. Finally, protonation
provided the product 3aa and regenerates the catalyst.
N
H
O
C
N
H
2a
10 mmol
1b
5 mmol
3ba
1.90 g 98% yield;
>20:1 dr; 86% ee
Scheme 4. Gram-scale preparation of 3ba.
Several control experiments were conducted to gain insight
into the mechanism.17 When N-methylated, N-acetyl and N-benzoyl
3-methylene-2-oxindoles were used, evidently lower ee value were
obtained (Scheme 5, 3ra-3ta). While N-benzyl 3-methylene-2-
oxindole could result in high enantioselectivity (Scheme 5, 3ua). It
was noted that the N-protection of 3-methylene-2-oxindoles could
improve the diastereoselectivity. Next, different N-protected (Me,
Bn) P-stereogenic ligands were applied to explore the influence on
enantioselectivity. A dramatically lower ee value was obtained with
N-Me protection, while the chiral selectivity was retained with N-Bn
protected P-stereogenic ligands. On the basis of the above result, it
is not hard to conclude that either free N−H bond or appropriately
steric hindrance contributes significantly to the enhancement of the
enantioselectivity and reactivity (Scheme 5).
P
Cu
NEt3
O
Ph
NEt3H
P
2a
N
O
O
MeO
Cu
A
Ph
N
O
O
P*
1a
MeO
Cu
B
3aa
NEt3
NEt3H
H
Ph
N
O
*
P
O
P*
Cu
N
O
O
Cu
O
N
O
O
Ph
O
NH
PreR
M2R
P
O
Cu
Ph
O
N
O
O
NH
M1R
Scheme 6. Proposed Reaction Mechanism.
4 | J. Name., 2012, 00, 1-3
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Page 5 of 6
Organic & Biomolecular Chemistry
Journal Name
ARTICLE
DFT calculations were performed to understand the
View Article Online
DOI: 10.1039/D0OB00546K
19
mechanism and origin of stereoselectivity.18,
and more
O
C-H
(2.4 Å)
O
(2.4 Å)
computational details can be found in Supporting Information. As
shown in Figure 2, two C-C bond formation steps via transition state
TS1S/R (11.4/17.4 kcal/mol) and transition state TS2R/S (20.2/22.6
kcal/mol) were computed and compared to explain the
stereoselectivity. Transition state TS2R/S had the highest energy in
Gibbs energy profile of the entire reaction, so the second step
should be the stereoselectivity-determining step. Noteworthy, the
energy of TS2R was 2.4 kcal/mol lower than that of TS2S, indicating
the pathway associated with R,R,R,S-isomer should be more
energetically favorable in kinetics. This conclusion was in agreement
with the experimental results.
C-H
C-H
O
C-H
(2.5 Å)
S
O
C-H
(1.9 Å)
O
C-H
(2.8 Å)
(2.8 Å)
lp
(3.2 Å)

TS2S
TS2R
Figure 3. The non-covalent interactions analyses of the key
transition states.
(kcal/mol)
G
HN
HN
HN
O
O
O
CH(CH3
O
)
Conclusions
2
CH(CH3
O
)
2
CH(CH3
)
2
Ph
Ph
Ph
N
N
N
O
In summary, we have developed
phosphines/Cu(I) complex catalyzed enantioselective 1,3-
dipolar cycloaddition of imino esters and
methyleneindolinones. This protocol features several notable
characteristics: 1) wide substrate scope involving
a
P-stereogenic
O
O
Cu
O
Ph
Cu
Cu
Ph
Ph
P
O
P
O
P
O
S
tBu
S
tBu
S
tBu
N
Ph
N
Ph
N
Ph
H
H
H
tBu
tBu
a
tBu
TS1R
TS2R
TS2S
TS2S
22.6
methyleneindolinones and imino esters derived from aliphatic
aldehydes and ketones as well as aryl aldehydes; 2) De Novo
design of P-stereogenic phosphine ligands; 3) the asymmetric
synthesis is achieved at the lowest level of catalyst loading (0.1
mol %) among the already established 1,3-dipolar
cycloaddition reactions; 4) the first enantioselective synthesis
of MDM2-p53 precursor (3ql); 5) the proposed transition state
model by a monomeric active Cu(I) species is supported by DFT
calculations. This work not only promotes the design of novel
chiral phosphine ligands, but also provides an efficient method
for constructing the spiro[pyrrolidin-3,3’-oxindole]s. The
employment of the P-stereogenic phosphine ligands to other
reactions are currently in progress.
TS1S
17.4
20.3
M2S
14.5
M2R
CH(CH3
)
2
NEt3 H+

20.2
TS2R
M1S
10.32
11.4
TS1R
10.5
PreS
Cat+NEt3
R2
HN
O
5.3
1.8
M1R
0.3
PR/S
0.0
PreR
R1
HN
HN
O
HN
Ph
O
O
CH(CH3
O
)
2
CH(CH3
)
CH(CH3)
2
2
Ph
N
Ph
Ph
N
N
N
O
O
O
O
O
O
Cu
O
Cu
Cu
Cu
Ph
Ph
Ph
Ph
O
S
P
O
P
O
P
O
P
S
tBu
S
tBu
S tBu
tBu
N
Ph
N
Ph
N
N
Ph
Ph
H
H
H
H
tBu
tBu
tBu
M2R
tBu
R1
PreR
M1R
Figure 2. Energy profiles on the competing reaction pathways (All
the energies were computed at the M06-L20/6-31G(d, p)/SMDTHF
level of theory).
Conflicts of interest
There are no conflicts to declare.
The origin and determining factor of enantioselectivity was
revealed by performing non-covalent interaction (NCI) analysis.21 As
shown in Figure 3, there were two C–H⋯O (1.9 and 2.4 Å) and one
C–H⋯S (2.8 Å) interactions in TS2S, while there were three C–H⋯O
(2.4, 2.5 and 2.8 Å) and one lp⋯π interactions in TS2R, indicating
the lp⋯π interaction between the C=C bond of catalyst and oxygen
atom of substrate contributes significantly for the stereoselectivity
in the reaction.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 21702189, 21672193 and 21272218), Key scientific
and technological project of Henan Province (202102310004),
China Ministry of industry and information technology
(Z135060009002), China Postdoctoral Science Foundation (No.
2017M610458 and 2018T110737), Postdoctoral Research
Grant in Henan Province (No. 001701006) and Zhengzhou
University of China for financial support of this research.
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This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
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6 | J. Name., 2012, 00, 1-3
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