Synergistic Ir/Cu Catalysis for Asymmetric Allylic Alkylation of Oxindoles: Enantio- and Diastereoselective Construction of Quaternary and Tertiary Stereocenters

Article abstract of DOI:10.1002/chem.202101267

3,3-Disubstituted oxindoles bearing quaternary and tertiary stereogenic centers are privileged structural motifs, which widely exist in pharmaceutical and natural products. Herein, a highly regio-, enantio-, and diastereoselective allylic alkylation of 3-alkyl oxindoles through synergistic iridium and copper catalysis is described, which provides a series of 3,3-disubstituted oxindole derivatives containing adjacent quaternary and tertiary stereogenic centers in excellent yields, enantiomeric excess, and diastereomeric ratio (for 30 examples, up to 97 % yield, >99 % ee, and >20 : 1 dr). This method provides exclusive branched selectivity, excellent enantio- and diastereoselectivities, and good functional compatibility. Control experiments suggested that the chiral copper catalyst is required for achieving high reactivities and diastereoselectivities under mild reaction conditions.

Full text of DOI:10.1002/chem.202101267

Accepted Article
Accepted Article
Title: Synergistic Ir/Cu Catalysis for Asymmetric Allylic Alkylation of
Oxindoles: Enantio- and Diastereoselective Construction of
Quaternary and Tertiary Stereocenters
Authors: Tianhong Wang, Youbin Peng, Guanlin Li, Yicong Luo, Yong
Ye, Xiaohong Huo, and Wanbin Zhang
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202101267
Link to VoR: https://doi.org/10.1002/chem.202101267
01/2020

10.1002/chem.202101267
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Synergistic Ir/Cu Catalysis for Asymmetric Allylic Alkylation of
Oxindoles: Enantio- and Diastereoselective Construction of
Quaternary and Tertiary Stereocenters
Tianhong Wang,[a] Youbin Peng,[a] Guanlin Li,[a] Yicong Luo,[a] Yong Ye,[b] Xiaohong Huo,*[a]
and Wanbin Zhang*[a,b]
Abstract: 3,3-Disubstituted oxindoles bearing quaternary and
tertiary stereogenic centers are privileged structural motifs, which
widely exist in pharmaceutical and natural products. Herein, we
describe a highly regio-, enantio-, and diastereoselective allylic
alkylation of 3-alkyl oxindoles through synergistic iridium and copper
catalysis, providing a series of 3,3-disubstituted oxindole derivatives
containing adjacent quaternary and tertiary stereogenic centers in
excellent yields, enantiomeric excess, and diastereomeric ratio (for
30 examples, up to 97% yield, >99% ee, and >20:1 dr). This method
provides exclusive branched selectivity, excellent enantio- and
diastereoselectivities, and good functional compatibility. Control
experiments suggested that the chiral copper catalyst is required for
achieving high reactivities and diastereoselectivities under mild
reaction conditions.
Figure 1. Representative examples of bioactive molecules containing 3,3-
disubstituted oxindole frameworks.
As one of the most important structural motifs, optically active
3,3-disubstituted
oxindole
frameworks
are
frequently
encountered in biologically active natural products and
pharmaceuticals, as exemplified by antimitotic agents, a MDM2
inhibitor and anticancer agents (Figure 1).[1] The synthesis of
optically pure 3,3-disubstituted oxindoles has attracted much
attention from both medicinal chemists and organic chemists.[2]
Generally, readily available 3-substituted oxindoles are used as
prochiral nucleophiles for various catalytic asymmetric
transformations. Many elegant methods including the aldol
reaction,[3] azidation or amination,[4] the Michael reaction,[5] the
Mannich reaction,[6] fluorination,[7] and others,[8] have been
developed. Although important progress has been made, the
development of
a simple and efficient method for the
construction of enantiopure 3,3-disubstituted oxindoles
containing adjacent quaternary and tertiary stereogenic centers
represents a significant research topic but remains challenging
because of its inherent difficulty in the formation of an all-carbon
quaternary stereocenter and the control of diastereoselectivity.[9]
The iridium-catalyzed asymmetric allylic alkylation (AAA)
reaction has become one of the most efficient methods for the
enantioselective construction of carbon-carbon bonds.[10] Distinct
[a]
[b]
T. Wang, Y. Peng, G. Li, Y. Luo, X. Huo, W. Zhang
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs,
Frontiers Science Center for Transformative Molecules, School of
Chemistry and Chemical Engineering, Shanghai Jiao Tong
University
800 Dongchuan Road, Shanghai 200240 (China)
E-mail: wanbin@sjtu.edu.cn; huoxiaohong@sjtu.edu.cn
Y. Ye, W. Zhang
College of Chemistry, Zhengzhou University
75 Daxue Road, Zhengzhou 450052 (China)
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Synergistic Ir/Cu catalysis for AAA of 3-substituted oxindoles.
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from the Pd-catalyzed allylic substitution reactions,[11] Ir-
catalyzed AAA reactions typically give the branched products
with high to excellent branched/linear selectivity.[12] The
application of 3-substituted oxindoles as the prochiral
nucleophile in this reaction provides a simple and reliable
method for the construction of oxindole motifs containing
adjacent quaternary and tertiary stereogenic centers.[13]
However, the control of diastereoselectivity in this area has
always been a challenging problem when using a traditional
single catalyst system.[10h] Trost and co-workers achieved an
elegant transformation through a molybdenum-catalyzed allylic
alkylation reaction (Scheme 1a).[14] This molybdenum-catalyzed
reaction undergoes an inner-sphere process, in which the regio-,
enantio-, and diastereoselectivity determining step is the
“Claisen-like” rearrangement from the O-bound Mo enolate.[15]
It’s worth noting that the ratio of the O-bound and the C-bound
Mo enolate isomer is sensitive to the electronic and steric
circumstances of the nucleophile. And the (R,R)-products are
mainly formed via this inner-sphere mechanism. In an extension
of our work on synergistic catalysis including metal/organo[16]
and bimetallic catalysis,[17] we herein report the highly regio-,
enantio-, and diastereoselective AAA reaction of 3-substituted
oxindoles by the combination of a chiral iridium catalyst and a
chiral copper catalyst. We speculate that the chiral nucleophile
will be generated in situ from a chiral copper catalyst with the
oxindole under the assistance of base, which could improve the
facial selectivity during attack of the chiral electrophilic π-allyl-Ir
species. The complementary diastereomers of oxindole motifs
containing adjacent quaternary and tertiary stereogenic centers
might be obtained in high enantio- and diastereoselectivity
through an outer-sphere process (Scheme 1b).[18]
Table 1. Optimization of the reaction conditions.[a]
entry
1
base
L (Cu)
T (oC)
yield (%)[b]
dr[c]
ee (%)[d]
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
-
L1
-
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
NR
90
84
69
97
91
NR
63
75
87
95
91
83
76
87
73
trace
85
-
-
2
Cs2CO3
K2CO3
DBU
1.2:1
1.6:1
1.3:1
1.5:1
1.6:1
-
99/99
99/99
99/99
99/99
99/99
-
3
-
4
-
5
Et3N
-
6
DIPEA
NMM
NMM
NMM
NMM
NMM
NMM
NMM
NMM
NMM
NMM
NMM
NMM
-
7
-
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
1.8:1
4.0:1
2.0:1
18:1
2.3:1
4.6:1
1.6:1
2.0:1
5.0:1
ND
99/99
99/99
99/99
99
9
10
11
12
13
14
15
16
17
18
99/99
99/99
99/99
99/99
99
ND
2.5:1
99/99
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19
1a
1a
1b
1c
NMM
NMM
NMM
NMM
L12
L4
rt
0
0
0
NR
97
82
73
-
-
20[e]
21[e]
22[e]
>20:1
8:1
>99
98
99
L4
L4
10:1
[a] Reaction conditions: 1 (0.17 mmol, 1.0 equiv), 2a (1.2 equiv), 4 mol% Ir catalyst, 5 mol% Cu(OTf)2, 5 mol% L, base (1.2 equiv), THF (2 mL), rt, 12 h. DIPEA =
N,N-diisopropylethylamine, NMM = 4-methylmorpholine. [b] Isolated yield of all product diastereoisomers. NR = no reaction. ND = not detected. [c] Determined by
1H NMR integration of the crude product. [d] Determined by HPLC using a chiral column. [e] 24 h.
At the outset of this study, we chose Moc-protected 3-
methyloxindole (1a) and allylic carbonates (2a) as the model
substrates to investigate the feasibility of the AAA reaction in the
presence of 4 mol% Ir catalyst (Table 1). It was expected that a
bis-chelated enolate could be formed using the appropriate
copper catalyst. Initially, several control experiments were
conducted (entries 1-6). There is no conversion of starting
materials 1a without base (entry 1). It was found that high to
excellent
yields
and
enantioselectivities,
but
low
diastereoselectivities, were achieved using several classic
inorganic and organic bases including Cs2CO3, K2CO3, DBU,
Et3N and DIPEA (entries 2-6). Then, the weaker base, NMM,
was used and none of the product were detected (entry 7). To
our delight, the desired products (3aa) were smoothly produced
when Cu/L1 was added (entry 8). These results suggested that
the copper catalyst provides an important improvement with
regards to reactivity. To improve the diastereoselectivity,
different ligands containing a ferrocenyl framework were then
tested. The Josiphos-type ligands L4 gave the exclusive
branched product (S,R)-3aa in 95% yield, 99% ee and 18:1 dr
(entry 11). The screening of other chiral diphosphine ligands did
not give an improvement in yields and diastereoselectivities
(entries 16-19). In order to further improve the
o
diastereoselectivity, the reaction temperature was cooled to 0 C
and the dr value increased to >20:1 with 97% yield (entry 20).
The 3-methyloxindoles protected by Boc and Cbz were also
suitable to the optimal reaction conditions, affording the
corresponding products in high yields yet with decreased
diastereoselectivities (entries 21-22). That might be due to the
incompatibilities between the protecting group and the
synergistic Ir/Cu catalytic system.
Having established the optimal reaction conditions, we
began to investigate the suitability of the substrates under the
Ir/Cu catalyst system. As shown in Scheme 2, we first examined
the scope of the allyl methyl carbonates. The reaction conditions
tolerated a wide range of functional groups and the desired
products were smoothly obtained in high yields and with high to
excellent enantioselectivities and diastereoselectivities (up to
97% yield, >99% ee, and >20:1 dr). Electron-donating or -
withdrawing groups at the ortho-, meta-, or para-position of the
cinnamyl aryl rings have a negligible effect on this reaction,
giving the desired products in high yields and with excellent
stereoselectivities (3ab-3ao). It was noteworthy that allylic
carbonates bearing two substituents were also suitable for this
reaction, affording the corresponding products in high yields with
good stereoselectivities (3am-3ao, up to 93% yield, >20:1 dr
and >99% ee). Interestingly, allylic carbonates bearing two
chloro substituents gave the desired product in 92% yield with
decreased stereoselectivity (89% ee and 8:1 dr). To understand
this result, the allylic substrate 2o was conducted in the absence
of the copper catalyst. The corresponding product was also
Scheme 2. The substrate scope of allylic carbonates.
obtained in 46% yield with 99%/88% ee and 3:1 dr. Accordingly,
the background reaction without the chiral copper catalyst led to
the decreased stereoselectivity. Furthermore, an allylic
carbonate containing a naphthyl group was successfully applied
to this reaction, giving the product 3ap in high yield and with
excellent diastereoselectivity and enantioselectivity (93%
yield, >20:1 dr and 96% ee). Notably, allylic carbonates that
contain heteroaryl piperonyl and thiophene substituents
underwent allylation to give the corresponding products
smoothly (3aq and 3ar). A reaction with n-propyl-substituted allyl
methyl carbonate was also conducted, affording the product 3as
in 83% yield and with 2:1 diastereoselectivity and 87%/15%
enantioselectivity.
Next, we examined the substrate scope of the Ir/Cu catalyst
system with regard to oxindole nucleophile (Scheme 3).
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Scheme 4. Synthetic transformation of the allylated 3,3-disubstituted
oxindoles.
substitutions at the aromatic ring ranging from the 4-position to
6-position were investigated, delivering the allylation products
(3ea-3la) with moderate to high diastereoselectivities. Again,
excellent reactivities and enantioselectivities were maintained.
The oxindoles bearing electron-withdrawing substitutions at the
aromatic ring increased the acidity of oxindole, probably leading
to the obvious background reaction. Accordingly, the oxindoles
1g, 1h, and 1k gave the corresponding products with slightly
decreased diastereoselectivities. The absolute configuration of
the product (3fa) was determined to be (S,R) by X-ray diffraction
analysis.[19]
Having achieved the enantio- and diastereoselective allylic
alkylation of oxindoles, we were curious as to whether this Ir/Cu
catalytic system could be applied to the synthesis of the
complementary diastereomers of 3aa.[17a,c,e,g-i,20] It is interesting
to note that the enantiomer (R,S)-3aa, instead of
diastereoisomer (S,S)-3aa, was obtained when changing the
(Ra,R,R)-Ir-cat to (Sa,S,S)-Ir-cat (Table 2). Subsequently,
several chiral ligands were also explored to achieve the
stereodivergent synthesis (For more details, please see the
Supporting Information). The absolute configuration of the
quaternary carbon stereocenter could not be reversed. Although
the stereodivergent synthesis of 3aa was not realized in our
present Ir/Cu catalytic system, the chiral copper catalyst plays
an important role in improving both the reactivity and
diastereoselectivity.
Scheme 3. The substrate scope of 3-alkyl-2-oxindoles.
Substituents such as Et, Bn, i-Pr groups at the 3-position of the
oxindole were tolerated. An increase in the size of the alkyl
group resulted in a decrease in diastereoselectivity, while
maintaining high to excellent levels of reactivity and
enantioselectivities (3ba-3da). In the case of the oxindoles
substituted with an i-Pr group, the reaction afforded the product
3da in 82% yield and with 7:1 dr and >99% ee. Then, the
oxindoles bearing electron-donating or -withdrawing
In order to facilitate the further transformation of the
products 3aa, N-Moc group was removed with NaOH in MeOH.
The product 4 could be obtained in 99% yield, >99% ee and
>20:1 dr values without any loss of enantioselectivity and
diastereoselectivity (Scheme 4).
Table 2. Optimizing the reaction conditions for the synthesis of complementary
diastereoisomer 3aa.[a]
In summary, a dual Ir/Cu catalytic system has been
successfully developed for the regio-, enantio-, and
diastereoselective allylic alkylation of 3-substituted oxindoles
under mild reaction conditions. A series of oxindole motifs
containing adjacent all-carbon quaternary and tertiary
stereocenter were easily prepared in high yields and with high to
excellent stereoselectivities (up to >20:1 dr and >99% ee).
Further exploration of synergistic bimetallic catalysis for the
stereodivergent synthesis of oxindoles containing adjacent
stereocenters is currently underway in our laboratory.
entry
Ir-cat
L (Cu)
yield (%)[c]
dr
ee (%)
1
2
3
4
5
6
(Ra,R,R)
(Sa,S,S)
(Ra,R,R)
(Sa,S,S)
(Ra,R,R)
(Sa,S,S)
(Sp,R)-L4
(Sp,R)-L4
(R)-L9
97
68
73
63
85
83
>20:1
8:1
>99 (S,R)
99 (R,S)
99 (S,R)
99 (R,S)
99 (S,R)
99 (R,S)
5:1
(R)-L9
4:1
(R)-L11
(R)-L11
2.5:1
2.0:1
Acknowledgments
[a] Reaction conditions: 1a (0.17 mmol, 1.0 equiv), 2a (1.2 equiv), Ir catalyst (4
mol%), Cu(OTf)2 (5 mol%), L (5 mol%), NMM (1.2 equiv), THF (2 mL), 0 oC,
24 h.
This work was supported by the Shanghai Sailing Program
(19YF1421900), the Shanghai Municipal Education Commission
(201701070002E00030), and the National Natural Science
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Chem. Soc. 2010, 132, 1255-1257; c) F. Tan, L.-Q. Lu, Q.-Q. Yang, W.
Guo, Q. Bian, J.-R. Chen, W.-J. Xiao, Chem. Eur. J. 2014, 20, 3415-
3420; d) T.-R. Li, B.-Y. Cheng, S.-Q. Fan, Y.-N. Wang, L.-Q. Lu, W.-J.
Xiao, Chem. Eur. J. 2016, 22, 6243-6247; e) L. Wu, G. Yang, W. Zhang,
CCS Chem. 2019, 1, 623-631; f) L. Zhang, M. Wang, M. Zhou, Z.
Zhang, M. Muraoka, W. Zhang, Asian J. Org. Chem. 2019, 8, 1024-
1028; g) L. Wu, Q. Shao, L. Kong, J. Chen, Q. Wei, W. Zhang, Org.
Chem. Front. 2020, 7, 862-867.
Foundation of China (21831005, 21901158, and 21991112). We
also thank the Instrumental Analysis Center of SJTU for
characterization.
Keywords: Oxindoles; Asymmetric allylic alkylation; Bimetallic
catalysis; Quaternary stereogenic centers; Asymmetric catalysis
[9]
For selected reviews, see: a) K. Fuji, Chem. Rev. 1993, 93, 2037-2066;
b) J. Christoffers, A. Mann, Angew. Chem. Int. Ed. 2001, 40, 4591-4597;
Angew. Chem. 2001, 113, 4725-4732; c) I. Denissova, L. Barriault,
Tetrahedron 2003, 59, 10105-10146; d) C. J. Douglas, L. E. Overman,
Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5363-5367; e) B. M. Trost, C.
Jiang, Synthesis 2006, 2006, 369-396; f) J. P. Das, I. Marek, Chem.
Commun. 2011, 47, 4593-4623; g) K. Quasdorf, L. E. Overman, Nature
2014, 516, 181-191; h) Y. Liu, S.-J. Han, W.-B. Liu, B. M. Stoltz, Acc.
Chem. Res. 2015, 48, 740-751; i) X.-P. Zeng, Z.-Y. Cao, Y.-H. Wang, F.
Zhou, J. Zhou, Chem. Rev. 2016, 116, 7330-7396; j) J. Feng, M.
Holmes, M. J. Krische, Chem. Rev. 2017, 117, 12564-12580.
[1]
a) P. Chène, Nat. Rev. Cancer 2003, 3, 102-109; b) K. Deng, Z.
Nikolovska-Coleska, S. Qiu, Y. Ding, W. Gao, J. Stuckey, K. Krajewski,
P. P. Roller, Y. Tomita, D. A. Parrish, J. R. Deschamps, S. Wang, J.
Am. Chem. Soc. 2005, 127, 10130-10131; c) M. Zhang, W.-L. Wang,
Y.-C. Fang, T.-J. Zhu, Q.-Q. Gu, W.-M. Zhu, J. Nat. Prod. 2008, 71,
985-989; d) S. Peddibhotla, Curr. Bioact. Compd. 2009, 5, 20-38; e) J.
Dugal-Tessier, E. A. O’Bryan, T. B. H. Schroeder, D. T. Cohen, K. A.
Scheidt, Angew. Chem. Int. Ed. 2012, 51, 4963-4967; Angew. Chem.
2012, 124, 5047-5051; f) A. M. Swensen, J. Herrington, R. M.
Bugianesi, G. Dai, R. J. Haedo, K. S. Ratliff, M. M. Smith, V. A. Warren,
S. P. Arneric, C. Eduljee, D. Parker, T. P. Snutch, S. B. Hoyt, C.
London, J. L. Duffy, G. J. Kaczorowski, O. B. McManus, Mol.
Pharmacol. 2012, 81, 488-497; g) S.-S. Ma, W.-L. Mei, Z.-K. Guo, S.-B.
Liu, Y.-X. Zhao, D.-L. Yang, Y.-B. Zeng, B. Jiang, H.-F. Dai, Org. Lett.
2013, 15, 1492-1495; h) S.-Y. Zhu, H. Zhang, Q.-W. Ma, D. Liu, X.-P.
Hui, Chem. Commun. 2019, 55, 298-301; i) L.-M. Zhou, R.-Y. Qu, G.-F.
Yang, Expert Opin. Drug Discov. 2020, 15, 603-625.
[10] For selected reviews on Ir-catalyzed AAA reactions, see: a) R.
Takeuchi, S. Kezuka, Synthesis 2006, 2006, 3349-3346; b) G.
Helmchen, A. Dahnz, P. Dꢀbon, M. Schelwies, R. Weihofen, Chem.
Commun. 2007, 675-691; c) J. F. Hartwig, L. M. Stanley, Acc. Chem.
Res. 2010, 43, 1461-1475; d) J. F. Hartwig, M. J. Pouy, Top.
Organomet. Chem. 2011, 34, 169-208; e) W.-B. Liu, J.-B. Xia, S.-L.
You, Top. Organomet. Chem. 2012, 38, 155-207; f) P. Tosatti, A.
Nelson, S. P. Marsden, Org. Biomol. Chem. 2012, 10, 3147-3163; g) G.
Helmchen, Ir-catalyzed Asymmetric Allylic Substitution Reactions-
Fundamentals and Applications in Natural Products Synthesis, In
Molecular Catalysts, Wiley-VCH, Weinheim, 2014, p. 235; h) J. C.
Hethcox, S. E. Shockley, B. M. Stoltz, ACS Catal. 2016, 6, 6207-6213; i)
J. Qu, G. Helmchen, Acc. Chem. Res. 2017, 50, 2539-2555; j) Q.
Cheng, H.-F. Tu, C. Zheng, J.-P. Qu, G. Helmchen, S.-L. You, Chem.
Rev. 2019, 119, 1855-1969; k) S. L. Rꢁssler, D. A. Petrone, E. M.
Carreira, Acc. Chem. Res. 2019, 52, 2657-2672.
[2]
For selected reviews, see: a) K. Shen, X. Liu, L. Lin, X. Feng, Chem.
Sci. 2012, 3, 327-334; b) Z.-Y. Cao, Y.-H. Wang, X.-P. Zeng, J. Zhou,
Tetrahedron Lett. 2014, 55, 2571-2584; c) D. Cheng, Y. Ishihara, B.
Tan, C. F. Barbas, III ACS Catal. 2014, 4, 743-762; d) J.-R. Chen, X.-Y.
Yu, W.-J. Xiao, Synthesis 2015, 47, 604-629; e) N. Ye, H. Chen, E. A.
Wold, P.-Y. Shi, J. Zhou, ACS Infect. Dis. 2016, 2, 382-392; f) G.-J. Mei,
F. Shi, Chem. Commun. 2018, 54, 6607-6621; g) Z.-Y. Cao, F. Zhou, J.
Zhou, Acc. Chem. Res. 2018, 51, 1443-1454; h) A. D. Marchese, E. M.
Larin, B. Mirabi, M. Lautens, Acc. Chem. Res. 2020, 53, 1605-1619; i)
Y.-C. Zhang, F. Jiang, F. Shi, Acc. Chem. Res. 2020, 53, 425-446.
a) S. Ogawa, N. Shibata, J. Inagaki, S. Nakamura, T. Toru, M. Shiro,
Angew. Chem. Int. Ed. 2007, 46, 8666-8669; Angew. Chem. 2007, 119,
8820-8823; b) K. Shen, X. Liu, K. Zheng, W. Li, X. Hu, L. Lin, X. Feng,
Chem. Eur. J. 2010, 16, 3736-3742; c) S. Kato, M. Kanai, S.
Matsunaga, Heterocycles 2014, 88, 475-491.
[11] For selected reviews on Pd-catalyzed AAA reactions, see: a) B. M.
Trost, D. L. Van Vranken, Chem. Rev. 1996, 96, 395; b) G. Helmchen,
A. Pfaltz, Acc. Chem. Res. 2000, 33, 336; c) H. Miyabe, Y. Takemoto,
Synlett 2005, 2005, 1641; d) J. T. Mohr, B. M. Stoltz, Chem. Asian J.
2010, 2, 1476; e) Z. Lu, S. Ma, Angew. Chem. Int. Ed. 2008, 47, 258;
Angew. Chem. 2008, 120, 264; f) S. Oliver, P. A. Evans, Synthesis
2013, 45, 3179; g) N. A. Butt, W. Zhang, Chem. Soc. Rev. 2015, 44,
7929; h) U. Kazmaier, Transition Metal Catalyzed Enantioselective
Allylic Substitution in Organic Synthesis, Springer Verlag, Berlin and
Heidelberg, Germany, 2012.
[3]
[4]
a) T. Bui, M. Borregan, C. F. Barbas, III J. Org. Chem. 2009, 74, 8935-
8938; b) L. Cheng, L. Liu, D. Wang, Y.-J. Chen, Org. Lett. 2009, 11,
3874-3877; c) S. Mouri, Z. Chen, H. Mitsunuma, M. Furutachi, S.
Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2010, 132, 1255-1257; d)
K. Shen, X. Liu, G. Wang, L. Lin, X. Feng, Angew. Chem. Int. Ed. 2011,
50, 4684-4688; Angew. Chem. 2011, 123, 4780-4784; e) Q.-H. Deng, T.
Bleith, H. Wadepohl, L. H. Gade, J. Am. Chem. Soc. 2013, 135, 5356-
5359.
[12] For the mechanism study on the origin of branched regioselectivity in Ir-
catalyzed AAA reactions, see: a) D. Markovic, J. F. Hartwig, J. Am.
Chem. Soc. 2007, 129, 11680-11681; b) S. T. Madrahimov, D.
Markovic, J. F. Hartwig, J. Am. Chem. Soc. 2009, 131, 7228-7229; c) J.
A. Raskatov, S. Spiess, C. Gnamm, K. Brçdner, F. Rominger, G.
Helmchen, Chem. Eur. J. 2010, 16, 6601-6615; d) S. T. Madrahimov, J.
F. Hartwig, J. Am. Chem. Soc. 2012, 134, 8136-8147; e) S. T.
Madrahimov, Q. Li, A. Sharma, J. F. Hartwig, J. Am. Chem. Soc. 2015,
137, 14968-14981; f) S. L. Rꢁssler, S. Krautwald, E. M. Carreira, J. Am.
Chem. Soc. 2017, 139, 3603-3606.
[5]
[6]
a) T. Bui, S. Syed, C. F. Barbas, III J. Am. Chem. Soc. 2009, 131,
8758-8759; b) Y. Kato, M. Furutachi, Z. Chen, H. Mitsunuma, S.
Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 9168-9169; c)
R. He, S. Shirakawa, K. Maruoka, J. Am. Chem. Soc. 2009, 131,
16620-16621; d) M. Ding, F. Zhou, Y.-L. Liu, C.-H. Wang, X.-L. Zhao, J.
Zhou, Chem. Sci. 2011, 2, 2035-2039;
a) S. Kato, T. Yoshino, M. Shibasaki, M. Kanai, S. Matsunaga, Angew.
Chem. Int. Ed. 2012, 51, 7007-7010; Angew. Chem. 2012, 124, 7113-
7116; b) X. Chen, H. Chen, X. Ji, H. Jiang, Z.-J. Yao, H. Liu, Org. Lett.
2013, 15, 1846-1849; c) J. Shan, B. Cui, Y. Wang, C. Yang, X. Zhou, W.
Han, Y. Chen, J. Org. Chem. 2016, 81, 5270-5277.
[13] For the construction of a single stereocenter via Pd or Mo-catalyzed
AAA reactions, see: a) B. M. Trost, M. U. Frederiksen, Angew. Chem.
Int. Ed. 2005, 44, 308-310; Angew. Chem. 2005, 117, 312-314; b) B. M.
Trost, Y. Zhang, J. Am. Chem. Soc. 2006, 128, 4590-4591; c) B. M.
Trost, L. C. Czabaniuk, J. Am. Chem. Soc. 2010, 132, 15534-15536; d)
B. M. Trost, J. T. Masters, A. C. Burns, Angew. Chem. Int. Ed. 2013, 52,
2260-2264; Angew. Chem. 2013, 125, 2316-2320; e) A. Boucherif, S.-
W. Duan, Z.-G. Yuan, L.-Q. Lu, W.-J. Xiao, Adv. Synth. Catal. 2016,
358, 2594-2598; f) G.-Y. Ran, X.-X. Yang, J.-F. Yue, W. Du, Y.-C. Chen,
Angew. Chem. Int. Ed. 2019, 58, 9210-9214; Angew. Chem. 2019, 131,
9308-9312.
[7]
[8]
a) Y. Hamashima, T. Suzuki, H. Takano, Y. Shimura, M. Sodeoka, J.
Am. Chem. Soc. 2005, 127, 10164-10165; b) T. Ishimaru, N. Shibata, T.
Horikawa, N. Yasuda, S. Nakamura, T. Toru, M. Shiro, Angew. Chem.
Int. Ed. 2008, 47, 4157-4161; Angew. Chem. 2008, 120, 4225-4229.
a) T. Ishimaru, N. Shibata, J. Nagai, S. Nakamura, T. Toru, S.
Kanemasa, J. Am. Chem. Soc. 2006, 128, 16488-16489; b) S. Mouri, Z.
Chen, H. Mitsunuma, M. Furutachi, S. Matsunaga, M. Shibasaki, J. Am.
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[14] a) B. M. Trost, Y. Zhang, J. Am. Chem. Soc. 2007, 129, 14548-14549;
b) B. M. Trost, Y. Zhang, Chem. Eur. J. 2010, 16, 296-303.
[15] B. M. Trost, Org. Process Res. Dev. 2012, 16, 185-194.
[16] a) X. Zhao, D. Liu, F. Xie, Y. Liu, W. Zhang, Org. Biomol. Chem. 2011,
9, 1871-1875; b) X. Zhao, D. Liu, H. Guo, Y. Liu, W. Zhang, J. Am.
Chem. Soc. 2011, 133, 19354-19357; c) X. Huo, M. Quan, G. Yang, X.
Zhao, D. Liu, Y. Liu, W. Zhang, Org. Lett. 2014, 16, 1570-1573; d) X.
Huo, G. Yang, D. Liu, Y. Liu, I. D. Gridnev, W. Zhang, Angew. Chem.
Int. Ed. 2014, 53, 6776-6780; Angew. Chem. 2014, 126, 6894-6898.
[17] a) X. Huo, R. He, X. Zhang, W. Zhang, J. Am. Chem. Soc. 2016, 138,
11093-11096; b) X. Huo, R. He, J. Fu, J. Zhang, G. Yang, W. Zhang, J.
Am. Chem. Soc. 2017, 139, 9819-9822; c) R. He, P. Liu, X. Huo, W.
Zhang, Org. Lett. 2017, 19, 5513-5516; d) X. Huo, J. Fu, X. He, J. Chen,
F. Xie, W. Zhang, Chem. Commun. 2018, 54, 599-602; e) X. Huo, J.
Zhang, J. Fu, R. He, W. Zhang, J. Am. Chem. Soc. 2018, 140, 2080-
2084; f) P. Liu, X. Huo, B. Li, R. He, J. Zhang, T. Wang, F. Xie, W.
Zhang, Org. Lett. 2018, 20, 6564-6568; g) J. Zhang, X. Huo, B. Li, Z.
Chen, Y. Zou, Z. Sun, W. Zhang, Adv. Synth. Catal. 2019, 361, 1130-
1139; h) R. He, X. Huo, L. Zhao, F. Wang, L. Jiang, J. Liao, W. Zhang,
J. Am. Chem. Soc. 2020, 142, 8097-8103; i) L. Zhao, G. Li, R. He, P.
Liu, F. Wang, X. Huo, M. Zhao, W. Zhang, Org. Biomol. Chem. 2021,
19, 1955-1959.
[18] For selected reviews on bimetallic catalysis, see: a) D. R. Pye, N. P.
Mankad, Chem. Sci. 2017, 8, 1705-1718; b) J. Fu, X. Huo, B. Li, W.
Zhang, Org. Biomol. Chem. 2017, 15, 9747-9759; c) Y. Nakao, General
Principles of Metal/Metal Dual Catalysis in Dual Catalysis in Organic
Synthesis, Thieme, Stuttgart, Germany, 2019, p 3; d) Y. Wu, X. Huo, W.
Zhang, Chem. Eur. J. 2020, 26, 4895-4916; e) U. B. Kim, D. J. Jung, H.
J. Jeon, K. Rathwell, S.-G. Lee, Chem. Rev. 2020, 120, 13382-13433.
[19] The absolute configurations of 3fa were determined by X-ray analysis.
For more details, please see the Supporting Information.
[20] For selected reviews on stereodivergent synthesis, see: a) C. S.
Schindler, E. N. Jacobsen, Science 2013, 340, 1052-1053; b) M. T.
Oliveira, M. Luparia, D. Audisio, N. Maulide, Angew. Chem. Int. Ed.
2013, 52, 13149-13152; Angew. Chem. 2013, 125, 13387-13390; c) S.
Krautwald, E. M. Carreira, J. Am. Chem. Soc. 2017, 139, 5627-5639; d)
L. Lin, X. Feng, Chem. Eur. J. 2017, 23, 6464-6482; e) I. P. Beletskaya,
C. Nꢂjera, M. Yus, Chem. Rev. 2018, 118, 5080-5200; f) Y. Wang, S.
Luo, Chin. J. Org. Chem. 2020, 40, 2161-2163; For selected works on
stereodivergent bimetallic catalysis, see: g) X. Jiang, P. Boehm, J. F.
Hartwig, J. Am. Chem. Soc. 2018, 140, 1239-1242; h) L. Wei, Q. Zhu, S.
Xu, X. Chang, C.-J. Wang, J. Am. Chem. Soc. 2018, 140, 1508-1513; i)
S. Xu, L. Wei, C. Shen, L. Xiao, H. Tao, C. Wang, Nat. Commun. 2019,
10, 5553; j) Z. He, X. Jiang, J. F. Hartwig, J. Am. Chem. Soc. 2019, 141,
13066-13073; k) Q. Zhang, H. Yu, L. Shen, T. Tang, D. Dong, W. Chai,
W. Zi, J. Am. Chem. Soc. 2019, 141, 14554-14559; l) H.-M. W, Z.
Zhang, F. Xiao, L, Wei, X.-Q. Dong, C.-J. Wang, Org. Lett. 2020, 22,
4852-4857; m) M. Zhu, Q. Zhang, W. Zi, Angew. Chem. Int. Ed. 2021,
60, 6545-6552; Angew. Chem. 2021, 133, 6619-6626.
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Tianhong Wang, Youbin
Peng, Guanlin Li, Yicong
Luo, Yong Ye, Xiaohong
Huo,* and Wanbin Zhang*
Page No. – Page No.
Synergistic Ir/Cu
Catalysis for Asymmetric
Allylic Alkylation of
Oxindoles: Enantio- and
Diastereoselective
Construction of
Synergistic Ir/Cu Catalysis: a highly regio-, enantio-, and diastereoselective allylic alkylation of 3-
alkyl oxindoles was developed through synergistic iridium and copper catalysis, providing a series of
3,3-disubstituted oxindole derivatives containing adjacent quaternary and tertiary stereogenic centers
in excellent yields, enantiomeric excess, and diastereomeric ratio (for 30 examples, up to 97% yield,
>99% ee, and >20:1 dr).
Quaternary and Tertiary
Stereocenters
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