Catalytic Asymmetric Tandem Cycloisomerization/[5+2] Cycloaddition Reaction of N-Aryl Nitrone Alkynes with Methyleneindolinones

Article abstract of DOI:10.1021/acs.orglett.9b04572

An asymmetric tandem cycloisomerization and intermolecular [5+2] cycloaddition reaction of 2-ethynylphenyl-substituted nitrones with methyleneindolinones was realized. The process includes the palladium(II)-promoted in situ formation of azomethine ylide and the following chiral N,N′-dioxide-Co(II) complex-catalyzed regio-, diastereo-, and enantioselective [5+2] cycloaddition reaction. The desired spiro-tropanyl oxindoles were obtained in good yields with excellent dr and ee values. On the basis of the determination of the catalyst structure, a possible transition state model was proposed.

Full text of DOI:10.1021/acs.orglett.9b04572

pubs.acs.org/OrgLett
Letter
Catalytic Asymmetric Tandem Cycloisomerization/[5+2]
Cycloaddition Reaction of N‑Aryl Nitrone Alkynes with
Methyleneindolinones
Bowen Hu, Xiying Zhang, Yuhao Mo, Jinzhao Li, LiLi Lin, Xiaohua Liu, and Xiaoming Feng*
Cite This: https://dx.doi.org/10.1021/acs.orglett.9b04572
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: An asymmetric tandem cycloisomerization and intermolecular [5+2] cycloaddition reaction of 2-ethynylphenyl-
substituted nitrones with methyleneindolinones was realized. The process includes the palladium(II)-promoted in situ formation of
azomethine ylide and the following chiral N,N′-dioxide-Co(II) complex-catalyzed regio-, diastereo-, and enantioselective [5+2]
cycloaddition reaction. The desired spiro-tropanyl oxindoles were obtained in good yields with excellent dr and ee values. On the
basis of the determination of the catalyst structure, a possible transition state model was proposed.
itrone is a kind of widely used 1,3-dipole in cyclo-
additions, giving various five-membered isoxazolidines,
azomethine ylide intermediate, there is still no catalytic
asymmetric example of the cycloisomerization/[5+2] cyclo-
addition tandem reaction to obtain enantiomerically enriched
tropanyl compounds.
N
which have been well studied.1,2 It was also found that 2-
ethynylphenyl-substituted nitrones could form other useful
isoquinoline-containing cyclic azomethine ylides in the
presence of transition metal salts, through N−O bond cleavage
and the addition of imine to α-carbonyl carbenoid (Scheme
1a).3 These cyclic azomethine ylides can be applied to the
dipolar cycloadditions, leading to the easy construction of
seven-membered nitrogen bridge rings.4 Regioselectivity arises
from resonance structures A and B of the cyclic azomethine
ylides thereof, in the cycloadditions of olefins or alkynes,5 such
as the reaction initiated by the iridium(III) complex catalyst.6
Although the deprotonation of 4-hydroxy-N-substituted
isoquinolinium salts also enables the generation of such ylides,
the nitrone-based method has the advantage of environmental
friendliness and atom economy. Shin and co-workers
pioneered a AuCl3-catalyzed intramolecular tandem cyclo-
isomerization/dipolar cycloaddition reaction of nitrone
alkynes, providing the tricyclic products with fair yields and
diastereoselectivities.7 Then, they introduced a chiral auxiliary
group into the N substituent of nitrones to achieve the
asymmetric version of this reaction (Scheme 1b).8 Later,
iridium(III) and palladium(II) catalyst systems were developed
to catalyze this type of tandem reaction.6,9 Nevertheless, to the
best of our knowledge, due to the high reactivity of the
We envisage that if a chiral Lewis acid could confirm the
reactivity and selectivity of the [5+2] cycloaddition step after
the transition metal-promoted formation of key intermediate
azomethine ylide, the catalytic asymmetric cycloisomerization/
[5+2] cycloaddition reaction would be realized. This dual
metallic relay catalysis strategy, combining two metal catalysts
in one pot,10,11 is a pathway worth trying (Scheme 1c). To test
our hypothesis, methyleneindolinones were selected as the
dipolarophiles because the resulting spiro-tropanyl oxindoles
are important groups of monoterpene alkaloids and often
associated with significant pharmacological activity (Scheme
1d).12−14 Herein, we reported a new catalytic asymmetric
cycloisomerization/[5+2] cycloaddition of 2-ethynylphenyl-
substituted nitrones with methyleneindolinones by dual
metallic relay catalysis (Scheme 1c). Chiral spiro-tropanyl
Received: December 19, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04572
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 1. [5+2] Cycloaddition of Cyclic Azomethine Ylide
Table 1. Screening of Conditions
b
c
d
entry
ligand
metal salt
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
L-PiMe2
−
−
−
−
R-BINAP
CPA
L-PiMe2
L-PrMe2
L5
−
AuCl3
−
−
−
−
−
−
e
−
−
−
−
−
e
[(IrCp*Cl2)]2
Pd(OAc)2
Pd(PPh)3Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
<10
trace
−
52
78
75
57
38
−
−
0
95
96
<5
0
89:11
97:3
93:7
96:4
91:9
9
10
11
L6
a
Unless otherwise noted, all of the reactions were performed with 1a
(0.1 mmol), 2a (0.2 mmol), Co(BF4)2·6H2O (10 mol %), ligand (10
mol %), and transition metal salt (10 mol %) in DCM (1.0 mL) at
b
c
−10 °C for 8 h. Isolated yield. Determined by SFC analysis.
d
Determined by SFC analysis on chiral stationary phases for the
major diastereoisomer. A complex mixture was found.
e
PiMe2 was applied as the ligand, 3aa was obtained in 78% yield
with 97:3 dr and 95% ee (entry 8). The ligand L-PrMe2 derived
from L-proline afforded a result similar to L-PiMe2 (entry 9).
When chiral ligands L5 (tBu-BOX) and L6 (Ph-PyBoX) were
applied, poor enantioselectivities were determined (entries 10
and 11, respectively). After careful reaction condition screen-
ing (for details, see the Supporting Information), the
optimized reaction condition was established as Pd(OAc)2
and Co(BF4)2·6H2O/L-PiMe2 as dual catalysts in DCM at −10
°C. It was worth mentioning that, under standard reaction
conditions, only a trace amount of [3+2] byproduct 4aa was
found, and the regioisomer arising from the different resonance
structure azomethine ylide A was not detected (Scheme 1c).
With the optimized reaction conditions in hand, the
substrate scope was then tested. For methyleneindolinones,
when different substituents on oxindole substrates 1 were
tested, good results could be obtained, regardless of the
electron-donating groups or electron-withdrawing groups at
position 5 or 6 of the indole ring. Generally, electron-donating
groups led to better diastereoselectivities and electron-
withdrawing groups led to higher reactivities (for 3ba−3ia),
because the electron-withdrawing groups caused the back-
ground reaction of methyleneindolinones with the ylide
intermediate to increase. Substrate 1j bearing a 5,7-dimethyl
group was also suitable, furnishing the desired product 3ja in
71% yield, >19:1 dr, and 90% ee. The ester group had little
effect on reactivity but a definite effect on stereoselectivity. For
oxindole structures with four continuous chiral carbon centers
were readily available in one pot. The regio-, diastereo-, and
enantioselectivity associated in the process were well
addressed.
In the initial study, (2-ethynylphenyl)-N-phenylmethani-
mine oxide 2a and methyleneindolinone 1a were selected as
the model substrates to identify the reaction conditions.
Co(BF4)2·6H2O/L-PiMe2 was first tested as the catalyst, and a
competing [3+2] cycloaddition reaction occurred to yield
product 4aa (89% yield, 99% ee, and 9:1 dr), and no desired
[5+2] cycloaddition product 3aa was observed (Table 1, entry
1). Then, transition metal salts, such as Au(III), Ir(III), and
Pd(II), were used to promote the formation of azomethine
ylide in situ. It was found that the desired relay reaction worked
with the addition of Pd(OAc)2, affording the desired product
3aa in <10% yield (entries 2−5). When R-BINAP was used as
the ligand for coordination with Pd(OAc)2, no reaction
occurred (entry 6). CPA was used as a co-catalyst with
Pd(OAc)2, providing the desired product 3aa in 52% yield but
no ee value (entry 7). These experiments indicated that it was
difficult to implement the asymmetric synthesis with a single
catalyst. The combination of Pd(OAc)2 and N,N′-dioxide/
Co(BF4)2·6H2O complex catalyst15,16 could improve the
reactivity significantly with stereoselectivity varied. When L-
B
https://dx.doi.org/10.1021/acs.orglett.9b04572
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
instance, when the ester group was changed from a tert-butyl
group (1a) to a less steric methyl group (1k), the yield
remained high but the dr was decreased from >19:1 to 78:22
and the ee decreased from 95% to 87% ee, implying that a
bulky R2 group is essential for the stereocontrol.
Subsequently, the scope of (2-ethynylphenyl)-N-arylmetha-
nimine oxides 2b−2j was investigated (Scheme 2, 3ab−3aj).
Electron-donating and electron-withdrawing groups (R3) on
the phenyl ring had little impact on the reaction except for the
methoxyl-containing substrate 2d. The consumption of the
starting material 2d was significantly slower, caused by the
strong electron-donating group. On the other hand, different
aryl substituents on nitrones (NAr) were examined, and the
desired products were also obtained in high yields and
excellent diastereo- and enantioselectivities (3ag−3aj). The
absolute configuration of product 3aj was determined to be
3R,5′R,6′S,8′S by X-ray crystallography analysis.17
To evaluate the synthetic potential of this bimetallic catalytic
system, a gram-scale synthesis of spiro-tropanyl oxindole 3aa
was conducted. Under the optimal reaction conditions, 3
mmol of 1a and 6 mmol of 2a reacted smoothly, giving 0.98 g
(59% yield) of the desired product in >95:5 dr and 93% ee.
After recrystallization (PE/EA at −20 °C), 0.71 g of optically
pure product (>95:5 dr, >99% ee) was obtained. When the
reaction was performed at 0 °C, 1.25 g (73% yield, 93:7 dr, and
93% ee) of 3aa was given (Scheme 3a). Moreover, the
a
Scheme 2. Substrate Scope
Scheme 3. (a) Gram-Scale Version of the Reaction and (b)
Synthesis of 5a
existence of cyclic azomethine ylide could be demonstrated by
the formation of isoquinoline salt 5a. Treatment of starting
material 1a with Pd(OAc)2 in DCM for 1 h and then direct
addition of CH3I give 5a in 71% yield after recrystallization
(Scheme 3b). The efficient transformation of cyclic azome-
thine ylide could be confirmed by the operando IR experiment,
which shows that the level of the cycloaddition product
increases along with the consumption of the two starting
materials (see the Supporting Information for details).
To explore the origin of chiral induction, the single crystal of
the chiral L-PiMe2−Co(II) complex catalyst was prepared.17
After X-ray crystal analysis, it was found that the chiral ligand
L-PiMe2 coordinates to Co(II) with two amine oxide oxygens
and two amide oxygens to form an octahedral complex, and
two other coordination sites were occupied by two solvent
molecules (Scheme 4). On the basis of the experiments and
analysis described above, possible transition state models were
proposed (Scheme 4, TS1 and TS2). The bidentate
methyleneindolinone 1a coordinates to the Co(II) center at
the position of two solvent molecules. The cycloaddition
occurs preferentially from its β-re-face, because the β-si-face of
1a was shielded by the underneath 2,6-dimethylphenyl group
of the ligand. The in situ-generated azomethine ylide applies as
the resonance structure B and attacks from the methyl-
eneindolinone 1a with the facial selectivity shown in TS1,
which will give the product with a 3R,5′R,6′S,8′S absolute
configuration.17 In comparison, the arrangement shown in TS2
was disfavored because of the steric hindrance between the N-
aryl group of B and the β-ester substituent of 1a, and the
a
Unless otherwise noted, all of the reactions were performed with 1
(0.1 mmol), 2 (0.2 mmol), Co(BF4)2·6H2O/L-PiMe2 (1:1, 10 mol
%), and Pd(OAc)2 (10 mol %) in DCM (1.0 mL) at −10 °C. The
1
yield was the isolated yield. The dr was determined by H NMR
analysis. The ee was determined by HPLC analysis on chiral
stationary phases for the major diastereoisomer. 3ba and 3ja were
obtained at 0 °C. 3ca and 3ga were obtained at 10 °C. 3ab−3aj were
obtained with L-PrMe2.
C
https://dx.doi.org/10.1021/acs.orglett.9b04572
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Other Authors
Scheme 4. Proposed Transition State Model Based on the
X-ray Crystal Structure of the Catalyst
Bowen Hu − Sichuan University, Chengdu, China
Xiying Zhang − Sichuan University, Chengdu, China
Yuhao Mo − Sichuan University, Chengdu, China
Jinzhao Li − Sichuan University, Chengdu, China
LiLi Lin − Sichuan University, Chengdu, China
Xiaohua Liu − Sichuan University, Chengdu, China;
orcid.org/0000-0001-9555-0555
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04572
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors appreciate the National Natural Science
Foundation of China (21772127 and 21890723) for financial
support. The authors thank Dr. Daibing Luo from the
Analytical@Testing Center of Sichuan University for his help
with crystal structural analysis.
isoquinoline backbone of ylide B and the top 2,6-
dimethylphenyl group of the ligand. As a result, the spiro-
tropanyl oxindole product could be afforded in high diastereo-
and enantioselectivity.
REFERENCES
■
(1) For selected reviews, see: (a) Gothelf, K. V.; Jørgensen, K. A.
Catalytic enantioselective 1,3-dipolar cycloaddition reactions of
nitrones. Chem. Commun. 2000, 1449−1458. (b) Stanley, L. M.;
Sibi, M. P. Enantioselective Copper-Catalyzed 1,3-Dipolar Cyclo-
additions. Chem. Rev. 2008, 108, 2887−2902. (c) Kissane, M.;
Maguire, A. R. Asymmetric 1,3-dipolar cycloadditions of acrylamides.
Chem. Soc. Rev. 2010, 39, 845−883. (d) Hashimoto, T.; Maruoka, K.
Recent Advances of Catalytic Asymmetric 1,3-Dipolar Cycloadditions.
Chem. Rev. 2015, 115, 5366−5412. (e) Murahashi, S. I.; Imada, Y.
Synthesis and Transformations of Nitrones for Organic Synthesis.
Chem. Rev. 2019, 119, 4684−4716.
In summary, we have developed a palladium(II) and chiral
N,N′-dioxide/Co(II) relay catalytic system to achieve an
asymmetric tandem cycloisomerization and intermolecular
[5+2] cycloaddition reaction. A series of spiro-tropanyl
oxindole products were synthesized in high yields and good
to excellent diastereo- and enantioselectivities under mild
reaction conditions. The synthetic potential of this catalyst
system was certified by the gram-scale reaction. The reaction
pathway was confirmed by the control and operando IR
experiments, and a possible transition state model was
proposed on the basis of the X-ray crystal structures of the
catalyst and product. Further studies of dual metal complex
relay catalysis for other reactions are underway.
(2) For selected examples, see: (a) Yang, X.; Cheng, F.; Kou, Y. D.;
Pang, S.; Shen, Y. C.; Huang, Y. Y.; Shibata, N. Catalytic Asymmetric
1,3-Dipolar Cycloaddition of β-Fluoroalkylated α,β-Unsaturated 2-
Pyridylsulfones with Nitrones for Chiral Fluoroalkylated Isoxazoli-
dines and γ-Amino Alcohols. Angew. Chem., Int. Ed. 2017, 56, 1510−
1514. (b) Sibi, M. P.; Ma, Z.; Jasperse, C. P. Exo Selective
Enantioselective Nitrone Cycloadditions. J. Am. Chem. Soc. 2004, 126,
718−719. (c) Chen, D. H.; Wang, Z.; Li, J.; Yang, Z.; Lin, L. L.; Liu,
X. H.; Feng, X. M. Catalytic Asymmetric 1,3-Dipolar Cycloaddition of
Nitrones to Alkylidene Malonates: Highly Enantioselective Synthesis
of Multisubstituted Isoxazolidines. Chem. - Eur. J. 2011, 17, 5226−
5229. (d) Xie, L.; Yu, X.; Li, Q. J.; Zhang, Z. H.; Qin, Z. H.; Fu, B.
Ni(II)-Catalyzed Enantioselective 1, 3-Dipolar Cycloaddition of
Nitrones with α, β-Unsaturated Acyl Carboxylates. Eur. J. Org.
Chem. 2017, 2017, 657−661. (e) Zhang, D.; Yin, C. K.; Zhou, Y. H.;
Xu, Y. L.; Lin, L. L.; Liu, X. H.; Feng, X. M. Chiral N,N’-dioxide/
Co(II)-promoted asymmetric 1,3-dipolar cycloaddition of nitrones
with methyleneindolinones. Chem. Commun. 2017, 53, 7925−7928.
(f) Hu, J. L.; Wang, L. J.; Xu, H.; Xie, Z. W.; Tang, Y. Highly
Diastereoselective and Enantioselective Formal [4 + 3] Cycloaddition
of Donor−Acceptor Cyclobutanes with Nitrones. Org. Lett. 2015, 17,
2680−2683. (g) Palomo, C.; Oiarbide, M.; Arceo, E.; García, J. M.;
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04572.
Experimental procedures, full spectroscopic data for all
1
new compounds, and copies of H, 13C, and 19F NMR
and HPLC spectra (PDF)
Accession Codes
CCDC 1946247 and 1971929 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
́
́
Lopez, R.; Gonzalez, A.; Linden, A. Lewis Acid Catalyzed Asymmetric
Cycloadditions of Nitrones: α′-Hydroxy Enones as Efficient Reaction
Partners. Angew. Chem., Int. Ed. 2005, 44, 6187−6190. (h) Jen, W. S.;
Wiener, J. J. M.; MacMillan, D. W. C. New Strategies for Organic
Catalysis: The First Enantioselective Organocatalytic 1,3-DipolarCy-
cloaddition. J. Am. Chem. Soc. 2000, 122, 9874−9875. (i) Karlsson, S.;
Hogberg, H. -E. Catalytic enantioselective 1,3-dipolar cycloaddition of
nitrones to cyclopent-1-enecarbaldehyde. Tetrahedron: Asymmetry
2002, 13, 923−926. (j) Shen, Z.-L.; Goh, K. K. K.; Wong, C. H. A.;
Loo, W.-Y.; Yang, Y.-S.; Lu, J.; Loh, T.-P. Synthesis and application of
AUTHOR INFORMATION
Corresponding Author
■
Xiaoming Feng − Sichuan University, Chengdu, China;
orcid.org/0000-0003-4507-0478; Email: xmfeng@
scu.edu.cn
D
https://dx.doi.org/10.1021/acs.orglett.9b04572
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a recyclable ionic liquid-supported imidazolidinone catalyst in
enantioselective 1,3-dipolar cycloaddition. Chem. Commun. 2012,
48, 5856−5858. (k) Cai, X. R.; Wang, C.; Sun, J. Organocatalytic
Enantioselective Dipolar [3 + 2] Cycloadditions of Acetylenic
Aldehydes with Nitrones for the Formation of Chiral 4-Isoxazolines.
Adv. Synth. Catal. 2012, 354, 359−363. (l) Xu, P.-W.; Liu, J.-K.; Shen,
L.; Cao, Z.-Y.; Zhao, X.-L.; Yan, J.; Zhou, J. Diastereo- and
enantioselective [3 + 3] cycloaddition of spirocyclopropyl oxindoles
using both aldonitrones and ketonitrones. Nat. Commun. 2017, 8,
1619.
(3) For selected reviews, see: (a) Zheng, Z.; Wang, Z.; Wang, Y.;
Zhang, L. Au-Catalysed oxidative cyclisation. Chem. Soc. Rev. 2016,
45, 4448−4458. (b) Qian, D.; Zhang, J. Gold-catalyzed cyclo-
propanation reactions using a carbenoid precursor toolbox. Chem. Soc.
Rev. 2015, 44, 677−698. (c) Dorel, R.; Echavarren, A. M. Gold(I)-
Catalyzed Activation of Alkynes for the Construction of Molecular
Complexity. Chem. Rev. 2015, 115, 9028−9072.
(4) For selected examples, see: (a) Garling, D. L.; Cromwell, N. H.
Polycyclic aziridines. 1-Alkyl-6-oxo-1,1a,6,6a-tetrahydro-la-
phenylindeno[1,2-b]azirines. J. Org. Chem. 1973, 38, 654−658.
(b) Constable, K. P.; Blough, B. E.; Carroll, F. I. Benzyne addition
to N-alkyl-4-hydroxy-1-methylisoquinolinium salts; a new and
convenient synthesis of (+)-5-methyl-l0,11-dihydro-5H-dibenzo-
[a,d]cyclohepten-5,lO-imine (MKSOl). Chem. Commun. 1996, 717−
718. (c) Dicesare, J. C.; Burgess, J. P.; Mascarella, S. W.; Carroll, F. I.;
Rothman, R. B. Synthesis and structural determination of 5H-
benzocycloheten-5,8-imines. J. Heterocycl. Chem. 1994, 31, 187−192.
(d) Fielding, M. R.; Grigg, R.; Sridharan, V.; Thornton-Pett, M.;
Urch, C. J. Sequential oxopyridinium betaine cycloaddition−
palladium catalysed cyclisation−anion capture processes. Tetrahedron
2001, 57, 7737−7748. (e) Pollini, G. P.; Benetti, S.; De Risi, C.;
Zanirato, V. Synthetic Approaches to Enantiomerically Pure 8-
Azabicyclo[3.2.1]octane Derivatives. Chem. Rev. 2006, 106, 2434−
2454. (f) Zhang, Y. Q.; Liebeskind, L. S. Organometallic
Enantiomeric Scaffolding: Organometallic Chirons. Total Synthesis
of (−)-Bao Gong Teng A by a Molybdenum-Mediated [5 + 2]
Cycloaddition. J. Am. Chem. Soc. 2006, 128, 465−472.
(5) For similar examples of the resonance structure of the cyclic
ylide, see: (a) Peese, K. M.; Gin, D. Y. Efficient Synthetic Access to
the Hetisine C20-Diterpenoid Alkaloids. A Concise Synthesis of
Nominine via Oxidoisoquinolinium-1,3-Dipolar and Dienamine-
Diels-Alder Cycloadditions. J. Am. Chem. Soc. 2006, 128, 8734−
8735. (b) Zhao, C. G.; Glazier, D. A.; Yang, D. S.; Yin, D.; Guzei, I.
A.; Aristov, M. M.; Liu, P.; Tang, W. P. Intermolecular Regio- and
Stereoselective Hetero-[5 + 2] Cycloaddition of Oxidopyrylium
Ylides and Cyclic Imines. Angew. Chem., Int. Ed. 2019, 58, 887−891.
(c) Ren, H. L.; Wu, C. R.; Ding, X. X.; Chen, X. G.; Shi, F. Aryne
cycloaddition with 3-oxidopyridinium species. Org. Biomol. Chem.
2012, 10, 8975. (d) Edmunds, J. J.; Cheng, X.-M.; Tobias, B.
Synthesis of benzocycloheptenones by 1,3-dipolar additions of 2-(1,3-
benzodioxol-5-ylmethyl)-4-hydroxy-3-methoxy-carbonylisoquinolin-
2-ium chloride with dipolarophiles. J. Chem. Soc., Perkin Trans. 1
1996, 2005−2008.
(10) For a selected review involving bimetallic catalysis, see:
(a) Matsunaga, S.; Shibasaki, M. Recent advances in cooperative
bimetallic asymmetric catalysis: dinuclear Schiff base complexes.
Chem. Commun. 2014, 50, 1044−1057. For selected examples, see:
(b) Corkey, B. K.; Toste, F. D. Catalytic Enantioselective Conia-Ene
Reaction. J. Am. Chem. Soc. 2005, 127, 17168−17169. (c) Wang, Y.
Z.; Liu, L. Z.; Zhang, L. M. Combining Zn ion catalysis with
homogeneous gold catalysis: an efficient annulation approach to N-
protected indoles. Chem. Sci. 2013, 4, 739−746. (d) Suga, H.; Inoue,
K.; Inoue, S.; Kakehi, A. Highly Enantioselective 1,3-Dipolar
Cycloaddition Reactions of 2-Benzopyrylium-4-olate Catalyzed by
Chiral Lewis Acids. J. Am. Chem. Soc. 2002, 124, 14836−14837.
(e) Guan, X.-Y.; Yang, L.-P.; Hu, W. H. Cooperative Catalysis in
Multicomponent Reactions: Highly Enantioselective Synthesis of γ-
Hydroxyketones with a Quaternary Carbon Stereocenter. Angew.
Chem., Int. Ed. 2010, 49, 2190−2192. (f) Huo, X. H.; He, R.; Zhang,
X.; Zhang, W. B. An Ir/Zn Dual Catalysis for Enantio- and
Diastereodivergent α-Allylation of α-Hydroxyketones. J. Am. Chem.
Soc. 2016, 138, 11093−11096. (g) Zhang, L.; Qureshi, Z.; Sonaglia,
L.; Lautens, M. Sequential Rhodium/Palladium Catalysis: Enantiose-
lective Formation of Dihydroquinolinones in the Presence of Achiral
and Chiral Ligands. Angew. Chem., Int. Ed. 2014, 53, 13850−13853.
(11) For selected reviews involving relay catalysis, see: (a) Rueping,
M.; Koenigs, R. M.; Atodiresei, I. Unifying Metal and Brønsted Acid
Catalysis-Concepts, Mechanisms, and Classifications. Chem. - Eur. J.
2010, 16, 9350−9365. (b) Du, Z.; Shao, Z. Combining transition
metal catalysis and organocatalysis − an update. Chem. Soc. Rev. 2013,
42, 1337−1378. (c) Wu, X.; Li, M. L.; Gong, L. Z. Asymmetric Relay
Catalysis Reaction Consisting of Metal Complex and Chiral
Phosphoric. Huaxue Xuebao 2013, 71, 1091−1100.
(12) (a) Wearing, X. Z.; Cook, J. M. Enantiospecific, Stereospecific
Total Synthesis of the Oxindole Alkaloid Alstonisine. Org. Lett. 2002,
4, 4237−4240. (b) Yang, J.; Wearing, X. Z.; Le Quesne, P. W.;
Deschamps, J. R.; Cook, J. M. Enantiospecific Synthesis of
(+)-Alstonisine via a Stereospecific Osmylation Process. J. Nat.
Prod. 2008, 71, 1431−1440. (c) Cao, Z.-Y.; Zhou, F.; Zhou, J.
Development of Synthetic Methodologies via Catalytic Enantiose-
lective Synthesis of 3,3-Disubstituted Oxindoles. Acc. Chem. Res. 2018,
51, 1443−1454.
(13) (a) Wong, W. H.; Lim, P. B.; Chuah, C. H. Oxindole Alkaloids
from Alstonia Macrophyllaz. Phytochemistry 1996, 41, 313−315.
(b) Wright, C. W.; Allen, D.; Cai, Y.; Phillipson, J. D.; Said, I. M.;
Kirby, G. C.; Warhurst, D. C. Zn Vitro Antiamoebic and
Antiplasmodial Activities of Alkaloids Isolated from Alstonia
angustifolia Roots. Phytother. Res. 1992, 6, 121−124. (c) Mayerl, F.;
Hesse, M. Macrocarpamin, ein neues Bisindolalkaloid aus Alstonia
macrophylla WALL. Helv. Chim. Acta 1978, 61, 337−351.
(14) Harada, M.; Ozaki, Y. Effect of Gardneria Alkaloids on
Ganglionic Transmission in the Rabbit and Rat Superior Cervical
Ganglia in Situ. Chem. Pharm. Bull. 1978, 26, 48−52.
(15) For selected reviews, see: (a) Liu, X. H.; Lin, L. L.; Feng, X. M.
Chiral N,N’-Dioxides: New Ligands and Organocatalysts for Catalytic
Asymmetric Reactions. Acc. Chem. Res. 2011, 44, 574−587. (b) Liu,
X. H.; Lin, L. L.; Feng, X. M. Chiral N,N’-dioxide ligands: synthesis,
coordination chemistry and asymmetric catalysis. Org. Chem. Front.
2014, 1, 298−302. (c) Liu, X. H.; Zheng, H. F.; Xia, Y.; Lin, L. L.;
Feng, X. M. Asymmetric Cycloaddition and Cyclization Reactions
Catalyzed by Chiral N,N’-Dioxide−Metal Complexes. Acc. Chem. Res.
2017, 50, 2621−2631. (d) Liu, X. H.; Dong, S. X.; Lin, L. L.; Feng, X.
M. Chiral Amino Acids-Derived Catalysts and Ligands Chin. Chin. J.
Chem. 2018, 36, 791−797.
(6) Song, G. Y.; Chen, D.; Su, Y.; Han, K. L.; Pan, C. L.; Jia, A. Q.;
Li, X. W. Isolation of Azomethine Ylides and Their Complexes:
Iridium(III)-Mediated Cyclization of Nitrone Substrates Containing
Alkynes. Angew. Chem., Int. Ed. 2011, 50, 7791−7796.
(7) Yeom, H.-S.; Lee, J.-E.; Shin, S. Gold-Catalyzed Waste-Free
Generation and Reaction of Azomethine Ylides: Internal Redox/
Dipolar Cycloaddition Cascade. Angew. Chem., Int. Ed. 2008, 47,
7040−7043.
(8) Jeong, J.; Yeom, H. S.; Kwon, O.; Shin, S. Auxiliary-Controlled
Asymmetric [3 + 2]-Dipolar Cycloaddition of Azomethine Ylides
Generated from Au-Catalyzed Intramolecular Redox Reaction of
Nitronyl Alkynes. Chem. - Asian J. 2011, 6, 1977−1981.
(9) Du, Y. L.; Zhu, Y. F.; Han, Z. Y. Pd(II)-Catalyzed
Cycloisomerization/Dipolar Cycloaddition Cascade of N-Arylnitrone
Alkynes with Olefins. J. Org. Chem. 2015, 80, 7732−7738.
(16) For selected examples, see: (a) Zhang, D.; Lin, L. L.; Yang, J.;
Liu, X. H.; Feng, X. M. Asymmetric Synthesis of Tetrahydroindoli-
zines by Bimetallic Relay Catalyzed Cycloaddition of Pyridinium
Ylides. Angew. Chem., Int. Ed. 2018, 57, 12323−12327. (b) Chen, Y.
S.; Dong, S. X.; Xu, X.; Liu, X. H.; Feng, X. M. Bimetallic
Rhodium(II)/Indium(III) Relay Catalysis for Tandem Insertion/
Asymmetric Claisen Rearrangement. Angew. Chem., Int. Ed. 2018, 57,
16554−16558. (c) Li, J.; Lin, L. L.; Hu, B. W.; Zhou, P. F.; Huang, T.
E
https://dx.doi.org/10.1021/acs.orglett.9b04572
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Y.; Liu, X. H.; Feng, X. M. Gold(I)/Chiral N,N’-Dioxide−Nickel(II)
Relay Catalysis for Asymmetric Tandem Intermolecular Hydro-
alkoxylation/Claisen Rearrangement. Angew. Chem., Int. Ed. 2017, 56,
885−888. (d) Jia, Z. J.; Shan, G.; Daniliuc, C. G.; Antonchick, A. P.;
Waldmann, H. Enantioselective Synthesis of the Spirotropanyl
Oxindole Scaffold through Bimetallic Relay Catalysis. Angew. Chem.,
Int. Ed. 2018, 57, 14493−11497. (e) Hu, B. W.; Li, J.; Cao, W. D.;
Lin, Q. C.; Yang, J.; Lin, L. L.; Liu, X. H.; Feng, X. M. Asymmetric
Synthesis of Fused Bicyclic N,O- and O,O-Acetals via Cascade
Reaction by Gold(I)/N,N’-Dioxide-Nickel(II) Bimetallic Relay
Catalysis. Adv. Synth. Catal. 2018, 360, 2831−2835. (f) Li, J.; Lin,
L. L.; Hu, B. W.; Lian, X. J.; Wang, G.; Liu, X. H.; Feng, X. M.
Bimetallic Gold(I)/Chiral N,N’-Dioxide Nickel(II) Asymmetric Relay
Catalysis: Chemo- and Enantioselective Synthesis of Spiroketals and
Spiroaminals. Angew. Chem., Int. Ed. 2016, 55, 6075−6078. (g) Ge, S.
L.; Cao, W. D.; Kang, T. F.; Hu, B. W.; Zhang, H.; Su, Z. S.; Liu, X.
H.; Feng, X. M. Bimetallic Catalytic Asymmetric Tandem Reaction of
b-Alkynyl Ketones to Synthesize 6,6-Spiroketals. Angew. Chem., Int.
Ed. 2019, 58, 4017−4021.
(17) CCDC 1946247 and CCDC 1971929 contain the supple-
mentary crystallographic data for this paper. These data are provided
free of charge by The Cambridge Crystallographic Data Centre.
F
https://dx.doi.org/10.1021/acs.orglett.9b04572
Org. Lett. XXXX, XXX, XXX−XXX