Nickel-Catalyzed Asymmetric Reductive Carbo-Carboxylation of Alkenes with CO2

Article abstract of DOI:10.1002/anie.202102769

Reductive carboxylation of organo (pseudo)halides with CO₂ is a powerful method to provide carboxylic acids quickly. Notably, the catalytic reductive carbo-carboxylation of unsaturated hydrocarbons via CO₂ fixation is a highly challenging but desirable approach for structurally diverse carboxylic acids. There are only a few reports and no examples of alkenes via transition metal catalysis. We report the first asymmetric reductive carbo-carboxylation of alkenes with CO₂ via nickel catalysis. A variety of aryl (pseudo)halides, such as aryl bromides, aryl triflates and inert aryl chlorides of particular note, undergo the reaction smoothly to give important oxindole-3-acetic acid derivatives bearing a C3-quaternary stereocenter. This transformation features mild reaction conditions, wide substrate scope, facile scalability, good to excellent chemo-, regio- and enantioselectivities. The method highlights the formal synthesis of (?)-Esermethole, (?)-Physostigmine and (?)-Physovenine, and the total synthesis of (?)-Debromoflustramide B, (?)-Debromoflustramine B and (+)-Coixspirolactam A; thereby, opening an avenue for the total synthesis of chiral natural products with CO₂.

Full text of DOI:10.1002/anie.202102769

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Asymmetric Synthesis
Hot Paper
Nickel-Catalyzed Asymmetric Reductive Carbo-Carboxylation of
Alkenes with CO2
Xiao-Wang Chen, Jun-Ping Yue, Kuai Wang, Yong-Yuan Gui, Ya-Nan Niu, Jie Liu, Chuan-
Kun Ran, Wangqing Kong,* Wen-Jun Zhou, and Da-Gang Yu*
Dedicated to Professor Peter Kꢀndig and Professor Gerhard Erker on the occasion of their 75th birthdays
Abstract: Reductive carboxylation of organo (pseudo)halides
with CO2 is a powerful method to provide carboxylic acids
quickly. Notably, the catalytic reductive carbo-carboxylation of
unsaturated hydrocarbons via CO2 fixation is a highly chal-
lenging but desirable approach for structurally diverse carbox-
ylic acids. There are only a few reports and no examples of
alkenes via transition metal catalysis. We report the first
asymmetric reductive carbo-carboxylation of alkenes with CO2
via nickel catalysis. A variety of aryl (pseudo)halides, such as
aryl bromides, aryl triflates and inert aryl chlorides of
particular note, undergo the reaction smoothly to give impor-
tant oxindole-3-acetic acid derivatives bearing a C3-quaternary
stereocenter. This transformation features mild reaction con-
ditions, wide substrate scope, facile scalability, good to
excellent chemo-, regio- and enantioselectivities. The
method highlights the formal synthesis of (À)-Esermethole,
(À)-Physostigmine and (À)-Physovenine, and the total syn-
thesis of (À)-Debromoflustramide B, (À)-Debromoflustr-
amine B and (+)-Coixspirolactam A; thereby, opening an
avenue for the total synthesis of chiral natural products with
CO2.
developed.[4–7] Particularly, the transition metal-catalyzed
reductive carboxylation of organo (pseudo)halides with CO2
attracts much attention because of its high step economy, easy
operation and good compatibility by avoiding pregeneration
and handing moisture-sensitive organometallic reagents.[8,9]
Besides the widely-investigated ipso-carboxylation of carbon-
(pseudo)halides,[9,10] the transition metal-catalyzed reductive
carbo-carboxylation of unsaturated hydrocarbons via remote
CO2 fixation has become a highly desirable approach to
generate structurally diverse carboxylic acids with complex
structure.[11,12] As it is much more challenging considering the
rate competition in reactions of organometallic intermediates,
which are generated via oxidative addition of carbon-
(pseudo)halide to low-valent transition metals, with unsatu-
rated bond and CO2, the reported methods are still limited to
the use of highly reactive alkynes or allenes.[11] For example, in
2015 Martin realized the first nickel-catalyzed divergent
cyclization/carboxylation of alkyl halides-tethered alkynes
with CO2 to give tetrasubstituted acrylic acids with carbocy-
clic skeletons (Figure 1A, top).[11a,b] More recently, the same
group has also reported a highly selective remote carboxyla-
2
À
tion of C(sp ) H bonds via catalytic 1,4-Ni migration with
Introduction
alkynes (Figure 1A, middle).[11d] Besides, Sato also realized
an elegant palladium-catalyzed intramolecular arylative car-
boxylation of allenes with Et2Zn as a reductant (Figure 1A,
bottom).[11c] However, there is no report on transition metal-
catalyzed reductive carbo-carboxylation of alkenes with CO2,
which might arise from a more facile reaction of nucleophilic
organometallic intermediate with CO2 than alkenes. With our
continuous interest in the carboxylation of unsaturated bonds
with CO2,[12b,13] we aim to resolve such a challenge by
developing an efficient transition metal-catalytic system for
reductive carbo-carboxylation of alkenes with CO2. If suc-
Carbon dioxide (CO2) has been regarded as an ideal C1
synthon in organic synthesis because of its abundance, non-
toxicity, and renewability.[1] In the past decades, CO2 chemis-
try has rapidly developed for transferring waste to treasure.[2]
As carboxylic acids are ubiquitous motifs that do not only
exist widely in drug molecules and natural products but also
act as bulk feedstocks in the synthesis of fine chemicals and
materials,[3] the generation of carboxylic acids from CO2 is
particularly attractive and a variety of strategies have been
[*] X.-W. Chen, J.-P. Yue, Dr. Y.-Y. Gui, Y.-N. Niu, J. Liu, C.-K. Ran,
Prof. Dr. W.-J. Zhou, Prof. Dr. D.-G. Yu
Dr. Y.-Y. Gui
College of Chemistry and Materials Science
Sichuan Normal University
Chengdu 610068 (P. R. China)
Key Laboratory of Green Chemistry & Technology of Ministry of
Education, College of Chemistry, Sichuan University
29 Wangjiang Road, Chengdu 610064 (P. R. China)
E-mail: dgyu@scu.edu.cn
Prof. Dr. W.-J. Zhou
College of Chemistry and Chemical Engineering
Neijiang Normal University
K. Wang, Prof. Dr. W. Kong
The Center for Precision Synthesis
Institute for Advanced Studies
Wuhan University
Wuhan 430072 (P. R. China)
E-mail: wqkong@whu.edu.cn
Neijiang 641100 (P. R. China)
Prof. Dr. D.-G. Yu
Beijing National Laboratory for Molecular Sciences
Beijing 100190 (P. R. China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102769.
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carbo-carboxylation of aryl (pseudo)halides-tethered acryl-
amides using inexpensive transition-metal catalyst and non-
toxic CO2 as carboxyl source. To realize this transformation,
several challenges need to be resolved. First, the transition
metal-catalyzed reductive ipso-carboxylation of aryl halides
has been widely studied in good efficiency,[8–10] which is highly
competitive to the desired insertion of alkenes into reactive
carbon-transition metal species, thus arising a chemoselectiv-
À
ity issue. Second, the insertion of alkenes into carbon metal
bonds must be achieved in high regio- and enantioselective
fashion. Third, as CO2 is a relatively inert electrophile, the
final capture of the alkyl-metal species by CO2 should be
efficient to prevent side reactions,[20a,b] including protonation
and homopolymerization. Herein, we report the first nickel-
catalyzed asymmetric reductive carbo-carboxylation reaction
of aryl halides-tethered alkenes and CO2 under mild reaction
conditions (Figure 1B). Notably, as the oxindole-3-acetic acid
derivatives bearing a C3-quaternary stereocenter, which are
generated in high chemo-, regio-, enantioselectivities, could
transform into pyrroloindolines and spirolactam, privileged
scaffolds widely existing in bioactive alkaloids, this strategy
opens an avenue for the CO2-involved enantioselective
synthesis of biologically active natural products, including
formal synthesis of (À)-Esermethole, (À)-Physostigmine and
(À)-Physovenine, as well as the total synthesis of
(À)-Debromoflustramide B, (À)-Debromoflustramine B and
(+)-Coixspirolactam A.
Figure 1. Transition metal-catalyzed reductive carbo-carboxylation of
unsaturated hydrocarbons with CO2.
cessful, we could construct structurally diverse carbo/hetero-
cyclic skeletons bearing carboxylic acids functional groups.
More significantly, we might be able to synthesize high value-
added enantiomerically pure carboxylic acids through chiral Results and Discussion
ligands-induced asymmetric reductive alkene carbo-carbox-
ylation reaction, which has not been disclosed yet.[14,15]
Indoline- and oxindole-3-acetic acid derivatives bearing
a C3-quaternary stereocenter are not only widely found in
bioactive molecules and natural products but also serve as key
precursors to construct complex molecules (Figure 2).[16]
Although some approaches,[17] such as Pd-catalyzed asym-
metric carbonylation with CO as the carbonyl source,[17a,f,g]
have been reported to obtain these core structures, it is highly
desirable to seek more cost-efficient catalysts and user-
friendly carbonyl source. Inspired by recent great progress
on reductive cross couplings,[18–21] we hypothesized whether
we could synthesize these structures via asymmetric reductive
Our study was initiated by employing the N-benzyl-N-
(2-bromophenyl)methacrylamide 1a as the model substrate,
NiBr2·DME as nickel-precatalyst, zinc power as reductant,
LiOtBu as the base and MgCl2 as Lewis acid to activate inert
CO2 (Table 1). We hypothesized that ligands might play an
important role in achieving selective cyclo over ipso carbox-
ylation. Several chiral ligands were first investigated at room
temperature (entries 1–8). The reaction using electron-defi-
cient (S)-CF3-iPr-Pyrox (L1) gave the 5-exo product 2a-Me in
27% yield and 51% ee; however, the ratio of 5-exo- (2a-Me),
6-endo- (2a’), to ipso-carboxylation (2a’’) was low to 47:18:35
(entry 1). Replacing L1 with relatively more electron-rich
(S)-iPr-Phox (L2) could afford the product with higher
enantioselectivity than L1 (entry 2). Bisoxazoline ligand L3
did not show any activity in this reaction (entry 3). Moreover,
the reaction using bipyridyl ligand L5 with central and axial
chirality character afforded 2a with 74% ee and 73:7:20 ratio
(entry 5). To our delight, when a chiral phosphine-oxazoline
ligand linked with ferrocene scaffold L4 was employed, the
undesired ipso carboxylation and 6-endo cyclization were
suppressed, the enantioselectivity dramatically elevated to
91% and showed 95% 5-exo cyclo-selectivity (entry 4). Other
diphosphine ligands L6–L8 also exhibited higher cyclo-
selectivity than electron-deficient ligand L1, albeit with low
enantioselectivity (entries 6–8). The investigation of nickel
pre-catalysts showed that Ni(COD)2 (entry 11) gave a slightly
higher yield than NiBr2·DME and Ni(acac)2 (entry 10). When
15 mol% of L4 was used, the desired product 2a was isolated
Figure 2. Bioactive indoline- and oxindole-3-acetic acid derivatives
bearing a C3-quaternary stereocenter.
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Table 1: Optimization of the reaction conditions.[a]
Notably, acrylamides with N-allyl groups, such as 2-methyl
propenyl (1i), prenyl (1j), cinnamyl (1k), which might
undergo potential competitive 5-exo cyclization, also showed
comparable reactivity and selectivity (55–89% yields, 84–
94% ee).
Next, the diversity of alkene motifs was also explored.
Comparing with the alkenes bearing methyl group, those with
more hindered alkyl groups, such as ethyl (1l), prenyl (1m),
benzyl (1n–1o), 1-naphthalene methyl (1p), silyl ether (1q)
and alkyl ether (1r) groups, could also react well to give
desired products 2l–2q in good yields (62–98%) and ex-
cellent enantioselectivities (90–96% ee). When the ent-L4
was used as ligand, ent-2m can be obtained with a 96% yield
and 93% ee. When the methyl group on the alkene moiety
was replaced with phenyl group, only 6-endo product was
detected.
Furthermore, we investigated the scope of aryl bromides.
The substrate with 1-bromonaphthalene (1s) afforded the
product 2s in distinct yield (87%) and near optical purity
(> 99.8% ee). The methyl group at meta and para position
(1t–1u) did not affect the reaction. However, the methyl
Entry
L*
[Ni]
Yield[b]
[%]
ee[c]
[%]
2a-Me:2a’:2a’’[d]
1
2
3
4
5
6
7
8
9
10
11
12[e]
13
14
15[f]
16[g]
17[h]
L1
L2
L3
L4
L5
L6
L7
L8
L4
L4
L4
L4
L4
–
NiBr2·DME
NiBr2·DME
NiBr2·DME
NiBr2·DME
NiBr2·DME
NiBr2·DME
NiBr2·DME
NiBr2·DME
NiCl2·DME
Ni(acac)2
Ni(COD)2
Ni(COD)2
w/o [Ni]
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
27
11
trace
83
54
<5
44
23
70
78
85
51
90
–
91
74
–
À2
À39
92
92
92
94
–
47:18:35
20:17:63
–
95:2:3
73:7:20
67:20:13
92:2:6
85:2:13
96:2:2
96:2:2
95:2:3
95:2:3
–
88
À
group (1v) and carbon fluoro bond (1w) at ortho position
N.R.
trace
N.R.
60
induced slightly lower ee value (85–85.5% ee), which might
arise from the steric hindrance. Besides, substrates bearing
methoxy (1x–1z), trifluoromethoxy (1aa) groups and oxy-
genated heterocycles (1ab) reacted well to give good to
excellent cyclo-selectivity and enantioselectivities. But the
bromoarene bearing strong electron-withdrawing groups,
such as CN, CO2Me and CF3 groups, led to poor selectivity.
The chemical structure and absolute configuration of (R)-2g
(CCDC 2030840) and (R)-2n (CCDC 2030841) were further
assigned by single-crystal X-ray diffraction analysis.[22] The
stereochemistry of other compounds was assigned by analogy.
Considering the similar reactivity of aryl sulfonates to
halides, we further tested aryl triflates in this transformation
(Table 3). Indeed, the desired products 2 could be obtained
with high enantiopurities. The moderate yields arise from
competitive protonation.
–
–
94
94
–
–
L4
L4
L4
94:4:2
95:2:3
41
[a] Conditions: 1a (0.2 mmol), NiBr2·DME (5 mol%), chiral ligand L*
(10 mol%), Zn (2 equiv), LiOtBu (2 equiv), MgCl2 (2 equiv) in solvent
(4 mL) at room temperature (RT) for 48 h. [b] The isolated yields of 2a-
Me after column chromatography purification on silica gel. [c] Enantio-
meric excess (ee) values were determined by chiral high performance
liquid chromatography (HPLC) analysis. [d] Determined with gas
chromatography (GC). [e] 15 mol% of L4 was used. Isolated as acid after
treating with 2 M HCl. [f] Without Zn. [g] Without LiOtBu. [h] Without
MgCl2. DME=Dimethoxyethane. COD=1,5-cyclooctadiene. N.R.=No
reaction. DMSO=Dimethyl Sulfoxide.
Encouraged by these results, we further explored more
accessible but challenging aryl chlorides, which show lower
reactivity and have been rarely investigated in asymmetric
reductive difunctionalization of unsaturated bonds.[20a,g] To
our delight, these aryl chlorides-tethered acrylamides reacted
smoothly with CO2 under the same reaction conditions
(Table 4). Moreover, the reaction of aryl chloride 4a gave
2a in a higher yield of 96% and a slightly better ee value of
95% than the result (88% yield, 94% ee) of corresponding
bromide 1a. Changing the N-protecting group with methyl
(4b) and geranyl (4c) also gave the product with high yields
and enantioselectivities. An array of aryl chlorides with
different functional groups, such as methyl (4d–4 f), methoxy
(4g–4h), fluoro (4i), trifluoromethyl (4j) reacted well to
generate the desired products in good to excellent yields and
enantioselectivities (85–95% ee). Swapping the methyl group
on the alkene motif with the benzyl group (4l, 4m) provided
the carbo-carboxylation products with commendable yields
and enantioselectivities (90% yield, 94–95% ee). A challeng-
in 94% ee and 88% yield (entry 12). Further systematical
investigation of bases and solvents failed to give superior
results than entry 12 (see the Supporting Information for
details). Control experiments showed that Ni-catalyst, ligand
and Zn were all indispensable in this reductive transformation
(entries 13–15). Furthermore, the basic LiOtBu and Lewis
acidic MgCl2 additive were also important for this trans-
formation to achieve high yield (entries 16–17).
After establishing the optimal reaction conditions, we first
examined several N-protecting groups of acrylamides. As
shown in Table 2, various kinds of N-alkyl groups with
different electronic properties could be well tolerated.
À
ing substrate 4k, in which the C Cl bond is deactivated with
electron-donating methoxyl group at the ortho position, could
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Table 2: Substrate scope of aryl bromides.[a]
[a] Conditions: substrate 1 (0.3 mmol), Ni(COD)2 (5 mol%), L4 (15 mol%), Zn (2 equiv), LiOtBu (2 equiv), MgCl2 (2 equiv) in 6 mL DMSO at RT.
Isolated yields are given and ee values were determined by chiral HPLC analysis. [b] Ni(COD)2 (10 mol%), L4 (30 mol%). [c] NiBr2·DME (10 mol%),
L4 (30 mol%).
also react well to give the desired product in 74% yield albeit
with 80% ee.
Table 3: Substrate scope of aryl triflates.[a]
The synthetic utility of this protocol was first demon-
strated by the scale-up reaction of 1m in a 3 mmol scale. With
(R,Rp)-iPr-FOXAP as the ligand, the desired product ent-2m
could be obtained in 72% yield and 93% ee along with 18%
starting material recovery (Scheme 1A). Additionally, selec-
tive C5- bromination of 2a took place smoothly to give 6 in
94% yield and 91% ee. Moreover, 2a could be reduced by
BH3·SMe2 in high efficiency to generate useful chiral indoline
7 with a C3 quaternary stereocenter, which is a key inter-
mediate for MNKS inhibitors synthesis (Scheme 1B).[23]
[a] Conditions: substrate 3 (0.3 mmol), Ni(COD)2 (5 mol%), L4
(15 mol%), Zn (2 equiv), LiOtBu (2 equiv), MgCl2 (2 equiv) in 6 mL
DMSO at RT. Isolated yields are given and ee values were determined by
chiral HPLC analysis.
To highlight the utility of this methodology, we sought to
employ it in the synthesis of bioactive natural products.
As (À)-Debromoflustramine B, (À)-Esermethole, (À)-Phys-
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Table 4: Substrate scope of aryl chlorides.[a]
ovenine show remarkable bioactivity, such as cholinesterase
inhibition.[24] Several groups have realized the asymmetric
total synthesis.[17] However, many methods suffer from the use
of precious metal catalysts or toxic reagents. Therefore, we
aimed to develop a concise route to the valuable nature
product by using the nickel-catalyzed asymmetric carbo-
carboxylation as a key step. First, ent-2m could undergo
efficient esterification to give compound 8 in 90% yield with
TMSCHN2. Second, the ammonolysis of ester 8 in the
presence of methylamine afforded amide 9 with 86% yield,
which took part in the reductive cyclization in the presence of
LiAlH4 to give (À)-Debromoflustramide B 10. Moreover,
further reduction of 10 yielded bioactive (À)-Debromoflus-
tramine B 11, which showed 7500 times more potent than its
dextro-enantiomer in biological testing.[24c] This process went
through four steps with 68% total yield and the enantiose-
lectivity maintained well (Scheme 1C). Similarly, the product
ent-2y can be easily transformed to amide 12, which is a key
intermediate in the facile synthesis of (À)-Esermethole and
(À)-Physostigmine.[17g] Besides, ent-2y can also be trans-
formed to furoindoline scaffold 13, which is a key intermedi-
ate to the synthesis of (À)-Physovenine (Scheme 1D).[17a]
Furthermore, successively treating 2q with TBAF and TFA
yielded spironolactone 14. The following debenzylation of 14
gave the natural product (+)-Coixspirolactam A 15 with 57%
total yield from 2q in 3 steps (Scheme 1E).
[a] Conditions: substrate 3 (0.3 mmol), Ni(COD)2 (5 mol%), L4
(15 mol%), Zn (2 equiv), LiOtBu (2 equiv), MgCl2 (2 equiv) in 6 mL
DMSO at RT. Isolated yields are given and ee values were determined by
chiral HPLC analysis.
To gain more insight into this selective reductive carbo-
carboxylation, stoichiometric reactions using equivalent
Scheme 1. Synthetic utility. A) Scale-up reaction of 1m. B) Facile transformations of 2a. C) Synthesis of (À)-Debromoflustramide B and
(À)-Debromoflustramine B. D) Synthesis of the key intermediate for (À)-Esermethole and (À)-Physovenine. E) Synthesis of (+)-Coixspirolactam A.
a) TMSCHN2 (4 equiv), MeOH/Et2O, 08C–RT; b) MeNH2 (33 wt% in EtOH), 608C; c) LiAlH4 (10 equiv), THF, 08C–RT; d) LiAlH4 (10 equiv), THF,
reflux. e) NaH (2.5 equiv), THF, 08C–RT; then LiAlH4 (4 equiv), 08C–RT. f) TBAF (4 equiv), THF, 08C–RT. g) TFA (1 drop), DCM, 08C–RT. h) TfOH
(15 equiv), toluene, 1208C.
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Table 5: Control experiments.[a]
cyclization to afford alkyl-NiIIL* intermediate V, which could
be reduced by Zn to yield the intermediate IV (path B).
Subsequent nucleophilic attack of IV to CO2 gave NiI-
carboxylate VI. Further reduction and transmetalation could
yield the carboxylate VII and regenerate reactive Ni0L* I.
Final workup of the reaction with hydrolysis of VII gave the
desired product VIII. Additionally, Ar-NiIIL* species II might
proceed 6-endo cyclization to form relative stable NiIIL*
enolate species IX, which could form the byproduct X. The
ipso-carboxylation byproduct XI might result from the
nucleophilic attack of Ar-NiIL* species III to CO2 according
to previous reports.[9b,10b]
Entry
x
4aa [%]
4ab [%]
4ac [%]
4ad [%]
1
2
3
4
5
0
2
3
5
10
6
8
13
52
56
36
38
34
23
31
<5
<5
<5
<5
<5
17
<5
<5
<5
<5
[a] GC yields.
Conclusion
Ni(COD)2 were conducted under N2 to determine the
possible intermediates (Table 5). In the absence of Zn, 36%
of 6-endo product 4ab was obtained along with 17% of b-H
elimination product 4ad and < 5% of 4ac formation.
Interestingly, the expected 5-exo product 4aa was formed in
just only 6% yield. By increasing the loading of Zn reductant
from 0 to 10 equivalents, we observed the yield of 5-exo
product 4aa improved a lot. These control experiments
indicated that Ar-NiIIL* generated from oxidative addition
might favor 6-endo cyclization but the Ar-NiIL*, which is
formed in situ through single-electron reduction of Ar-NiIIL*
by Zn, might favor a 5-exo cyclization. This investigation
provides new insight into the Ni-catalyzed reductive cycliza-
tion.
In conclusion, we have developed the first nickel-
catalyzed asymmetric reductive carbo-carboxylation of al-
kenes using sustainable CO2 as the carboxyl source, which
provides an efficient approach to the synthesis of versatile
oxindole-3-acetic acid derivatives bearing a C3-quaternary
stereocenter. Aside from aryl bromides, other aryl electro-
philes, such as triflates and chlorides, are also amenable in this
reaction. This transformation features mild reaction condi-
tions, wide substrate scope, facile scalability, with good
chemo-, regio- and enantioselectivity. The utility of this
methodology is highlighted by the formal synthesis of
(À)-Esermethole, (À)-Physostigmine and (À)-Physovenine,
as well as the total synthesis of (À)-Debromoflustramide B,
(À)-Debromoflustramine B and (+)-Coixspirolactam A,
opening an avenue for the total synthesis of chiral natural
products with CO2.
Based on the experimental observation and previous
reports, the possible mechanism was proposed in Figure 3.
À
First, the oxidative addition of carbon (pseudo)halides bonds
to Ni0L* I gave Ar-NiIIL* species II, which might undergo
a Zn-mediated single electron reduction to give a Ar-NiIL*
species III (path A). The following enantioselective 5-exo
cyclization would afford an alkyl-NiIL* intermediate IV.[20d]
Meanwhile, Ar-NiIIL* species II might also go through 5-exo
Acknowledgements
Financial support provided by the National Natural Science
Foundation of China (91956111, 21822108, 21702149),
Figure 3. Proposed mechanism.
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accounts.1c00135.
Sichuan Science and Technology Program (20CXTD0112),
Fundamental Research Funds from Sichuan University
(2020SCUNL102), and the Fundamental Research Funds
for the Central Universities. We thank Xiaoyan Wang from
the Analysis and Testing Center of Sichuan University and the
comprehensive training platform of the Specialized Labora-
tory in the College of Chemistry at Sichuan University for
compound testing. We also thank Wen-Hao Yu from College
of Chemistry and Materials Science, Sichuan Normal Uni-
versity for single-crystal X-ray diffraction analysis.
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Conflict of interest
On March 29, 2021, a Chinese Patent on this work was applied
for with the number (202110330170.6).
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Keywords: alkenes · carbo-carboxylation · carbon dioxide ·
nickel
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Manuscript received: February 23, 2021
Accepted manuscript online: April 1, 2021
Version of record online: && &&
,
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&&&&
These are not the final page numbers!

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Research Articles
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Research Articles
Asymmetric Synthesis
X.-W. Chen, J.-P. Yue, K. Wang, Y.-Y. Gui,
Y.-N. Niu, J. Liu, C.-K. Ran, W. Kong,*
W.-J. Zhou, D.-G. Yu*
&&&& — &&&&
Nickel-Catalyzed Asymmetric Reductive
Carbo-Carboxylation of Alkenes with CO2
A strategy is presented for nickel-cata-
lyzed asymmetric reductive carbo-car-
boxylation of alkenes with CO2. A variety
of aryl (pseudo)halides react to produce
oxindole-3-acetic acid derivatives bearing
a C3-quaternary stereocenter. Notably,
synthesis of a range of bioactive pyrro-
loindolines was achieved.
&&&&
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Angew. Chem. Int. Ed. 2021, 60, 2 – 10
These are not the final page numbers!