Enantioselective Synthesis of Multisubstituted Spirocyclopentane Oxindoles Enabled by Pd/Chiral Rh(III) Complex Synergistic Catalysis

Article abstract of DOI:10.1021/acs.orglett.0c03588

An asymmetric [3 + 2]-cycloaddition reaction of α,β-unsaturated 2-acyl imidazoles with spirovinylcyclopropanyl-2-oxindoles catalyzed synergistically by an achiral palladium(0) catalyst and a chiral-at-metal rhodium(III) complex has been developed. A series of biologically important 3-spirocyclopentane-2-oxindoles with four contiguous stereocenters were synthesized in high yields (up to 99%) with excellent stereoselectivities (up to 99% ee, 20:1 dr).

Full text of DOI:10.1021/acs.orglett.0c03588

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Letter
Enantioselective Synthesis of Multisubstituted Spirocyclopentane
Oxindoles Enabled by Pd/Chiral Rh(III) Complex Synergistic Catalysis
Qian Wan, Liang Chen, Shiwu Li, Qiang Kang, Yaofeng Yuan,* and Yu Du*
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ABSTRACT: An asymmetric [3 + 2]-cycloaddition reaction of α,β-unsaturated 2-acyl imidazoles with spirovinylcyclopropanyl-2-
oxindoles catalyzed synergistically by an achiral palladium(0) catalyst and a chiral-at-metal rhodium(III) complex has been
developed. A series of biologically important 3-spirocyclopentane-2-oxindoles with four contiguous stereocenters were synthesized in
high yields (up to 99%) with excellent stereoselectivities (up to 99% ee, 20:1 dr).
pirocyclic oxindoles play an important role as a fascinating
framework in many natural products and biologically
control of diastereoselectivity during the bond formation is
also a daunting challenge.5 Therefore, the development of
novel efficient asymmetric synthetic methods for the direct
construction of the spirocyclic oxindole skeleton is in high
demond, as new catalysts and synthetic strategies are desirable.
In the past few years, several elegant protocols that allow
facile access to spirocyclopentane oxindoles via either
transition metal catalyzed or organocatalytic [3 + 2]-cyclo-
addition reactions have been developed.6 On the basis of the
extraordinary performance of vinylcyclopropanes (VCPs) in
construction of multicyclic and spirocyclic derivatives,7,8 the
ring-opening [3 + 2]-annulation of 2-oxindole derived
spirovinylcyclopropanes (SVCPs) for the formation of racemic
spirocyclic oxindoles has been realized with the aid of
Pd(OAc)2.9 However, efficient methods for the catalytic
asymmetric construction of 3-spirocyclopentane-2-oxindole
scaffold by using chiral Lewis acid catalyst have rarely been
disclosed. Inspired by these encouraging advances, and our
previous work in developing chiral-at-metal rhodium(III)
complexes10 for highly enantioselective organic synthesis,11
especially the asymmetric [3 + 2]-cycloaddition between 1,3-
dipoles and chiral Lewis acid activated dipolarophiles,11e,g the
S
active molecules.1 Particularly, natural alkaloids bearing 3-
spirocyclopentane-2-oxindole scaffold exhibit a broad range of
biological and pharmacological activities (e.g., notoamides,
paraherquamides, citrinalins, and cyclopiamines, Figure 1).2
Figure 1. Representative examples of natural alkaloids containing the
3-spirocyclopentane-2-oxindole scaffold.
Attracted by the complex structure and potential application of
chiral spirocyclopentane oxindole, significant attention has
been paid to their catalytic asymmetric synthesis in the past
few decades.3 However, the construction of quaternary carbon
stereocenters remains a challenging task in organic synthesis.4
In addition, the construction of spiro systems often requires
overcoming ring strain for functionalization and is accom-
panied by the generation of multiple stereocenters; thus, the
Received: October 27, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03588
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
exploitation of a new asymmetric dual-catalytic system with the
combination of an achiral Pd catalyst and a chiral Rh(III)
complex is quite attractive to achieve the direct catalytic
enantioselective synthesis of 3-spirocyclopentane-2-oxindole
derivatives and allow for the facile construction of a wide range
of spirocyclic scaffolds starting from VCPs.
Table 1. Optimization of Reaction Conditions
It would be logical to expect that bimetallic catalytic system
can promote unprecedented new protocols that are not
accessible conveniently via a single catalytic system. So far,
much progress has been made in tandem bimetallic catalysis.12
However, fewer examples of enantioselective synergistic
bimetallic catalysis have been reported.13 Recently, our group
has developed a bimetallic gold(I)/chiral Rh(III) complex
relay catalysis for asymmetric cascade reaction of keto esters
with alkynyl alcohols and amides.12g Thus, we envisioned that
spirocyclopentane skeletons could be constructed through
enantioselective synergistic bimetallic catalyzed [3 + 2]-
cycloaddition reaction between modified SVCPs as dipoles in
the presence of Pd and dipolarophiles mediated by chiral
Rh(III) complex (Scheme 1). Herein we report the successful
implementation of this idea to provide 3-spirocyclopentane-2-
oxindole derivatives in high yields with excellent enantiopur-
ities.
Scheme 1. Asymmetric Construction of Spirocyclopentane
Oxindole Scaffolds via Bimetallic Catalytic [3 + 2]-
Cycloaddition
a
Unless otherwise noted, reactions were carried out by using 1a (0.10
mmol), 2a (0.12 mmol), Λ-Rh (0.002 mmol, 2.0 mol %), and Pd-
catalyst (0.005 mmol, 5.0 mol %) in solvent (0.5 mL) at 50 °C under
b
argon atmosphere. Isolated yields of diastereomeric mixtures.
c
Diastereomeric ratio, determined via 1H NMR analysis of
d
diastereomeric mixtures. Enantiomeric excess of the major isomer,
determined by chiral HPLC analysis. n.a. = not available.
To evaluate the viability of this designed approach to the
chiral 3-spirocyclopentane-2-oxindoles, a model reaction of
Bn-protected SVCP-oxindole 1a9a and α,β-unsaturated 2-acyl
imidazole 2a has been investigated in the presence of 5.0 mol
% of Pd2(dba)3·CHCl3 and 2.0 mol % of Λ-Rh114 in THF at
50 °C. The desired cycloaddition reaction proceeded
smoothly, delivering spirocyclic oxindole 3aa in 93% yield
with 96% ee and 10:1 dr (Table 1, entry 1). Chiral rhodium
complexes have been evaluated (entries 1−3); the catalyst Λ-
Rh1 is the superior one that affords the highest dr and ee
values. Some Pd(II) catalysts have also been tested (entries 4−
6), the reaction could be finished in the presence of Pd(OAc)2
to give adduct 3aa in only 87% ee (entry 4), and no reaction
occurred in the case of PdBr2 and Pd(PPh3)2Cl2 used (entries
5, 6). A screen of solvents (entries 7−11) showed that CH3CN
could lead to the formation of 3aa in the highest yield (99%)
and ee (98%) within 12 h, although the diastereoselectivity was
relatively lower (entry 7, 6:1 dr). Remarkably, the catalyst
loading of Pd2(dba)3·CHCl3 can be reduced to 2.0 mol %
without any significant influence on reactivity and stereo-
selectivity, only a slightly diminished yield (entry 12).
Considering that the use of THF would lead to good
diastereocontrol (entry 13), while CH3CN gave better
enantioselectivity, a mixed solvent of THF/CH3CN (1:1)
has been tried, and product 3aa was obtained in 93% yield,
99% ee, and 9:1 dr (entry 14). Control experiments confirmed
that both Pd2(dba)3·CHCl3 and Λ-Rh1 are essential in this
reaction. No target molecule could be obtained without the Pd
catalyst or chiral Rh(III) complex (entries 15−16).
Using the optimal reaction conditions (Table 1, entry 14),
the generality of the substrate α,β-unsaturated 2-acyl
imidazoles 2 was examined by using SVCP-oxindole 1a as
the coupling partner. As summarized in Table 2, different
substituents (e.g., methyl, isopropyl and phenyl, entries 1−3)
on imidazole were tolerated in the title reaction, and the
highest yield and stereoselectivity were obtained by using N-
isopropyl substrate 2a (entry 1). β-Aryl substituents bearing
electron-donating or -withdrawing groups were evaluated
(entries 4−9), delivering the corresponding products in
excellent yields (up to 99%) with high stereoselectivities
(99% ee, up to 9.4:1 dr). β-Naphthyl and heteroaryl (e.g., furyl
and thienyl) substrates were also suitable (entries 10−12),
leading to the formation of the target molecules in excellent
yields (up to 99%) and enantioselectivities (up to 99% ee), and
moderate to high diastereoselectivities (up to 12.4:1 dr). In the
case of β-2-(5-Br)-furyl substrate 2m (entry 13), a low yield
(3am, 27%) was obtained. A rationalized explanation is that
bromide could interact with the Pd(0)-catalyst to inhibit its
catalytic activity toward ring opening of SVCP-oxindole.
Further replacing β-aryl groups with ester or methyl
substituents was also well tolerated (entries 14−15), providing
B
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methyl (R3 = Me) and β-2-naphthyl (R4 = 2-naphthyl)
substituted substrate 2p has been checked in the title reaction
with SVCP-oxindole 1a using the optimal conditions (entry
16), and the corresponding product 3ap was obtained in high
yield (91%) with excellent stereoselectivity (99% ee, 12:1 dr).
A cyclic substrate 2q and an α-methyl substituted substrate 2r
have also been checked;15 however, no target molecule was
obtained, and substrates were totally recovered. This may be
because the substituent hinders the activation of double bond
by chiral Lewis acid or the steric hindrance prevents the bond
formation.
Table 2. Substrate Scope of α,β-Unsaturated 2-Acyl
imidazoles
a
time
(h)
yield
b
c
d
entry
R3
R4
3
(%)
dr
ee (%)
1
iPr
Me
Ph
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Me
Me
Ph
Ph
Ph
12
12
12
24
12
17
12
24
17
17
15
17
34
36
12
12
3aa
3ab
3ac
3ad
3ae
3af
93
94
78
95
96
88
91
99
98
99
91
99
27
96
99
91
9:1
8.5:1
6.5:1
5.4:1
6:1
99/54
99/73
99/70
99/31
99/66
99/55
99/70
99/37
99/86
99
Further investigation of the substrate scope of SVCP-
oxindoles 1 was carried out under optimal conditions with 2a
(Table 3). SVCP-oxindoles 1 with various electron-rich and
-deficient arenes were examined (entries 1−8). In almost all
cases, high yields (up to 99%) and excellent stereoselectivities
(up to 99% ee, 20:1 dr) could be achieved, except for
substrates 5-OMe-1c and 5-NO2-1d, the dr values of their
corresponding products (3ca and 3da) dramatically decreased.
SVCP-oxindoles 1 with some other protecting groups on
nitrogen (e.g., methyl, allyl, and 4-tBu-benzyl) also worked very
well under the optimal conditions (entries 9−11).
2
3
4
2-Me-C6H4
3-Me-C6H4
4−F-C6H4
4−Cl-C6H4
4-OMe-C6H4
4-NO2-C6H4
2-naphthyl
2-furyl
5
6
9.4:1
7.6:1
6.4:1
6:1
7
3ag
3ah
3ai
8
9
10
11
12
13
14
15
16
3aj
12.4:1
2.5:1
3.5:1
3:1
3ak
3al
97/84
96/70
96/82
96/83
99/89
99
2-thienyl
2-(5-Br)-furyl
CO2Et
3am
3an
3ao
3ap
During the characterization of these cycloaddition products,
it has been found that some properties (e.g., solubilities and
2:1
1
Me
2-naphthyl
10:1
12:1
polarities) and H NMR spectra of products 3an and 3ao,
derived from β-alkyl substituted α,β-unsaturated 2-acyl
imidazoles (Table 2, entries 14−15), were quite different
from the others. On the basis of careful analysis of the NOE
interactions, the relative configuration of the major diaster-
eomers of 3an and 3ao was assigned as model a (Figure 2),
and the major isomers of the other products were assigned as
model b but model a for their minor isomers (for details, see
the Supporting Information). This conclusion could be
partially proved by the absolute configuration of the optically
active 3ja determined by X-ray crystallographic studies (Figure
2).16 In theory, starting from (E)-alkenes, 2 would generate
final products 3 with four pairs of diastereomers. Exper-
a
Unless otherwise noted, reactions were carried out by using 1a (0.10
mmol), 2 (0.12 mmol), Λ-Rh1 (0.002 mmol, 2.0 mol %), and
Pd2(dba)3·CHCl3 (0.002 mmol, 2.0 mol %) in mixed CH3CN/THF
b
(1:1, 0.5 mL) at 50 °C under argon atmosphere. Isolated yields of
c
diastereomeric mixtures. Determined via 1H NMR analysis of
d
diastereomeric mixtures. The ee of the major/minor isomer,
determined by chiral HPLC analysis.
the corresponding products 3an and 3ao in excellent yields
and enantioselectivities. However, reactions involving β-
heteroaryl or β-ethyl formate substituted substrates (2k−2n)
gave relatively low diastereoselectivities (entries 11−14). A N-
a
Table 3. Substrate Scope of SVCP-Oxindoles
b
c
d
entry
R1
R2
time (h)
3
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Allyl
5-Me
5-OMe
5-NO2
5-F
5-Cl
4-Cl
6-Cl
7-Cl
H
17
16
36
17
20
16
20
20
16
16
15
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
93
88
99
92
91
89
97
98
98
99
95
10:1
2:1
1.4:1
8:1
99/52
99/75
95/47
99/23
99/43
99
99
99
99
99
6:1
13.5:1
14.5:1
20:1
14:1
12:1
15:1
9
10
11
3ja
3ka
3la
H
H
4-tBu-benzyl
99
a
Unless otherwise noted, reactions were carried out by using 1 (0.10 mmol), 2a (0.12 mmol), Λ-Rh1 (0.002 mmol, 2.0 mol %), and Pd2(dba)3·
b
CHCl3 (0.002 mmol, 2.0 mol %) in mixed CH3CN/THF (1:1, 0.5 mL) at 50 °C under argon atmosphere. Isolated yields of diastereomeric
c
d
mixtures. Determined via 1H NMR analysis of diastereomeric mixtures. The ee of the major/minor isomer, determined by chiral HPLC analysis.
C
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Figure 3. Proposed intermediate and plausible stereochemical
outcome.
Figure 2. Structures of [3 + 2]-cycloaddition products.
imentally, more isomers could be observed in NMR spectra of
a few compounds but too little to be characterized.
To illustrate the synthetic potential of current protocol, the
cycloaddition of SVCP-oxindole 1a (2.5 mmol) and α,β-
unsaturated 2-acyl imidazole 2a (3.0 mmol) was conducted on
a gram-scale by employing 0.5 mol % of Λ-Rh1 and 2 mol %
Pd2(dba)3·CHCl3. Gratifyingly, product 3aa was obtained in
96% yield (1.24 g) with 99% ee and 9:1 dr (Scheme 2a). Then
zwitterionic π-allylpalladium intermediate I is formed via a
palladium-catalyzed ring opening of SVCP-oxindole 1a.
Meanwhile substrate 2a coordinates with the rhodium complex
Λ-Rh1 to generate a bidentate N,O-coordinated intermediate
II. The Si-face of the double bond of intermediate II is
shielded by one of the tert-butyl groups, then π-allylpalladium
intermediate I can attack from its Re-face. Presumably, during
the bond formation, π−π stacking effect and antiattack of a
nucleophile to π-allylpalladium leads to the same orientation of
the vinyl group and the acyl imidazole, and the steric repulsion
between two phenyl moieties (A and B) renders transition
state TS2 unfavorable and thus facilitates the generation of
major isomer 3aa via transition state TS1.
Scheme 2. Gram-Scale Experiments and Synthetic
Transformations of Product 3ja
During our research, the diastereoselectivity of the title
reaction is affected by many factors such as solvent,
temperature, chiral rhodium catalyst, palladium catalyst,
substituent, and so on. By now it is still very difficult to
address the reason underlying the abnormalities in dr values
(e.g., 3ak−3an in Table 2, 3ca and 3da in Table 3). The
configuration inversion that took place on spirocyclic of major
diastereomers of 3an and 3ao (Figure 2) might be the result of
replacing the β-aryl substituents with smaller ones such as ethyl
formate group and methyl (Table 2, entries 14−15). With the
disappearance of the steric repulsion, the phenyl moiety A
(Figure 3) of oxindole tends to depart far away from rhodium
complex and get close to β-alkyl groups of α,β-unsaturated 2-
acyl imidazoles. The protecting group on oxindole nitrogen
(R1 in Table 3) could rotate around the carbon−nitrogen
single bond and move far away from reaction center; thus, it
does not affect diastereoselectivity much.
In conclusion, a highly efficient bimetallic synergistic
catalysis for enantioselective [3 + 2]-cycloaddition reaction
of SVCP-oxindoles with α,β-unsaturated 2-acyl imidazoles has
been developed, with the combination of an achiral
palladium(0) catalyst and a chiral rhodium(III) complex. A
variety of biologically important 3-spirocyclopentane-2-oxin-
doles containing four contiguous stereocenters could be
obtained in high yields with excellent enantiopurities. This
work demonstrates the unique charm of the bimetallic catalytic
system, presenting a bright prospect for development of chiral
Lewis acid catalysis.
the catalyst loading of Pd2(dba)3·CHCl3 was further reduced
to 0.5 mol %, which was equal to Λ-Rh1 in this gram-scale
reaction, and product 3aa was formed with 99% ee, in a
diminished yield (1.02 g, 79%), and decreased dr (7:1).
Moreover, the product 3ja could be transformed into optically
active ester 4 and aldehyde 5 by removal of imidazole moiety
in good yields without any loss in enantiomeric excess
(Scheme 2b).17
On the basis of these experimental results, and literature
precedents on chiral-at-metal octahedral rhodium catalysis14
and palladium-catalyzed ring-opening annulation of VCPs,7−9
a plausible mechanism is proposed in Figure 3. A Pd-stabilized
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03588.
D
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1
copies of H, 13C, and some two-dimensional NMR
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(PDF)
Accession Codes
CCDC 1998725 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Yu Du − State Key Laboratory of Structural Chemistry, Fujian
Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou 350002, P. R. China;
orcid.org/0000-0003-2287-5265; Email: duyu@
fjirsm.ac.cn
Yaofeng Yuan − College of Chemistry, Fuzhou University,
Fuzhou 350108, P. R. China; Email: yaofeng_yuan@
fzu.edu.cn
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Qian Wan − College of Chemistry, Fuzhou University, Fuzhou
350108, P. R. China
Liang Chen − State Key Laboratory of Structural Chemistry,
Fujian Institute of Research on the Structure of Matter,
Chinese Academy of Sciences, Fuzhou 350002, P. R. China
Shiwu Li − State Key Laboratory of Structural Chemistry,
Fujian Institute of Research on the Structure of Matter,
Chinese Academy of Sciences, Fuzhou 350002, P. R. China
Qiang Kang − State Key Laboratory of Structural Chemistry,
Fujian Institute of Research on the Structure of Matter,
Chinese Academy of Sciences, Fuzhou 350002, P. R. China;
orcid.org/0000-0002-9939-0875
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03588
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Grant Nos. 21871261, 21772023) and
the Research Fund for the State Key Laboratory of Structural
Chemistry of Fujian Institute of Research on the Structure of
Matter, Chinese Academy of Sciences (Grant No. 20180020).
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