Regio- and Enantioselective (3+3) Cycloaddition of Nitrones with 2-Indolylmethanols Enabled by Cooperative Organocatalysis

Article abstract of DOI:10.1002/anie.202011267

The regio- and enantioselective (3+3) cycloaddition of nitrones with 2-indolylmethanols was accomplished by the cooperative catalysis of hexafluoroisopropanol (HFIP) and chiral phosphoric acid (CPA). Using this approach, a series of indole-fused six-membered heterocycles were synthesized in high yields (up to 98 %), with excellent enantioselectivities (up to 96 % ee) and exclusive regiospecificity. This approach enabled not only the first organocatalytic asymmetric (3+3) cycloaddition of nitrones but also the first C3-nucleophilic asymmetric (3+3) cycloaddition of 2-indolylmethanols. More importantly, theoretical calculations elucidated the role of the cocatalyst HFIP in helping CPA control the reactivity and enantioselectivity of the reaction, demonstrating a new mode of cooperative catalysis.

Full text of DOI:10.1002/anie.202011267

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Regio- and Enantioselective (3+3) Cycloaddition of Nitrones with
2-Indolylmethanols Enabled by Cooperative Organocatalysis
Authors: Tian-Zhen Li, Si-Jia Liu, Yu-Wen Sun, Shuang Deng, Wei
Tan, Yingchun Jiao, Yu-Chen Zhang, and Feng Shi
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
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
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202011267
Link to VoR: https://doi.org/10.1002/anie.202011267

10.1002/anie.202011267
Angewandte Chemie International Edition
RESEARCH ARTICLE
Regio- and Enantioselective (3+3) Cycloaddition of Nitrones with
2-Indolylmethanols Enabled by Cooperative Organocatalysis
Tian-Zhen Li,[a] Si-Jia Liu,[a] Yu-Wen Sun,[a] Shuang Deng,[b] Wei Tan,[a] Yingchun Jiao,*[b] Yu-Chen
Zhang*[a] and Feng Shi*[a]
Dedicated to those who are committed to advocating diversity in chemistry
[a]
[b]
T.-Z. Li, S.-J. Liu, Y.-W. Sun, Dr. W. Tan, Prof. Dr. Y.-C. Zhang, Prof. Dr. F. Shi
School of Chemistry and Materials Science
Jiangsu Normal University
Xuzhou, 221116, China
E-mail: fshi@jsnu.edu.cn; zhangyc@jsnu.edu.cn
Website: https://www.x-mol.com/groups/Shi_Feng
S. Deng, Prof. Dr. Y. Jiao
School of Chemistry and Chemical Engineering
Hunan University of Science and Technology
Xiangtan, 411201, China
E-mail: yinchunjiao@hnust.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract: The regio- and enantioselective (3+3) cycloaddition of
nitrones with 2-indolylmethanols was accomplished by the
cooperative catalysis of hexafluoroisopropanol (HFIP) and chiral
phosphoric acid (CPA). Using this approach, a series of indole-fused
six-membered heterocycles were synthesized in high yields (up to
98%), with excellent enantioselectivities (up to 96% ee) and
exclusive regiospecificity. This approach enabled not only the first
organocatalytic asymmetric (3+3) cycloaddition of nitrones but also
the first C3-nucleophilic asymmetric (3+3) cycloaddition of 2-
indolylmethanols. More importantly, theoretical calculations
elucidated the role of the cocatalyst HFIP in helping CPA control the
reactivity and enantioselectivity of the reaction, demonstrating a new
mode of cooperative catalysis.
alkenyl gold complexes.[1e,8] However, despite these rapid
developments, the organocatalytic asymmetric (3+3)
cycloaddition of nitrones has not yet been achieved and remains
unexplored (Scheme 1d).[10] There are some challenging issues
for this type of transformation. The first issue is that nitrones are
difficult to activate with organocatalysts, and there are very few
examples of the activation of nitrones by chiral
organocatalysts.[5-6] The second issue is the identification of
suitable three-atom reaction partners that can be easily
activated by chiral organocatalysts to undergo asymmetric (3+3)
cycloaddition with nitrones. The final issue is the identification of
effective chiral organocatalysts that can control the reactivity and
enantioselectivity of the (3+3) cycloaddition. Therefore, the
development of organocatalytic asymmetric (3+3) cycloadditions
of nitrones is a challenging task.
Introduction
Nitrones are basic materials and important intermediates
in organic synthesis that have attracted intense attention from
the chemistry community.[1] In particular, nitrones can act as
three-atom building blocks in catalytic asymmetric (3+n)
cycloadditions, providing a useful tool for the synthesis of
enantioenriched heterocyclic compounds (Scheme 1).[2-9]
Nitrones are suitable 1,3-dipoles for constructing optically pure
five-membered
isoxazolidine
frameworks
via
catalytic
asymmetric (3+2) cycloadditions (Scheme 1a).[2-6] Notably, most
asymmetric (3+2) cycloadditions of nitrones are catalyzed by
metal/chiral ligands (L*),[2-3] and only a small fraction of the
transformations are enabled by chiral organocatalysts.[4-6] In
addition to well-developed (3+2) cycloadditions, catalytic
asymmetric (3+3)[7-8] and (3+4)[9] cycloadditions of nitrones have
been rapidly developed, but all of these transformations are
enabled by metal catalysts (Scheme 1b-1c). In particular, the
catalytic asymmetric (3+3) cycloaddition of nitrones is a powerful
method for the enantioselective construction of six-membered
heterocyclic scaffolds, and the reaction partners are mainly
cyclopropanes, trimethylenemethanes, vinyldiazoacetate, and
Scheme 1. Profile of catalytic asymmetric cycloadditions of nitrones
In this context, we wondered whether 2-indolylmethanols
could serve as suitable three-atom reaction partners to undergo
organocatalytic asymmetric (3+3) cycloaddition with nitrones.
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202011267
Angewandte Chemie International Edition
RESEARCH ARTICLE
This consideration is based on our understanding of the
chemistry of 2-indolylmethanols (Scheme 2).[11-13] In recent
years, 2-indolylmethanols have proven to be versatile reactants
in organocatalytic asymmetric reactions due to their unique
property of C3 electrophilicity,[11] and they have been widely
used in catalytic asymmetric C3-electrophilic substitutions[14] and
cycloadditions[15] (Scheme 2a). However, in sharp contrast, the
C3 nucleophilicity of 2-indolylmethanols has scarcely been
reported, and the catalytic asymmetric C3-nucleophilic reactions
of 2-indolylmethanols are rather underdeveloped (Scheme 2b).
To date, only one report in the literature has described the
asymmetric C3-nucleophilic (4+3) cycloaddition of 2-
indolylmethanols catalyzed by a chiral Brønsted acid (B*-H).[16]
Despite this progress, other types of catalytic asymmetric C3-
nucleophilic reactions of 2-indolylmethanols are still unknown
(Scheme 2c), most likely due to the intrinsic challenges involved
in conducting these reactions. For example, how can the
reactivity of 2-indolylmethanols be controlled to exhibit C3
nucleophilicity instead of the predominant C3 electrophilicity?
Additionally, how can the regioselectivity and enantioselectivity
of the reaction caused by the different reactivities of 2-
indolylmethanols be controlled? Thus, it is highly valuable to
devise innovative strategies toward realizing catalytic
asymmetric C3-nucleophilic reactions of 2-indolylmethanols.
nucleophilic
indolylmethanols.
asymmetric
(3+3)
cycloaddition
of
2-
However, another reaction between 2-indolylmethanols and
nitrones with different regioselectivity also appears to be
possible (Scheme 3b). Namely, in the presence of CPA, 2-
indolylmethanols 1 can transform into a delocalized carbocation
via dehydration. Due to the well-established C3 electrophilicity of
the delocalized carbocation, in principle, the oxygen anion of
nitrones 2 can attack the C3 position of the indole ring, thus
undergoing asymmetric (3+3) cycloaddition to give products 3’
with different regioselectivity.
Therefore, controlling the reactivity, regioselectivity and
enantioselectivity is a key factor for achieving the (3+3)
cycloaddition of nitrones with 2-indolylmethanols that we
designed. Herein, we report our investigation in detail.
Scheme 3. Our designed reaction and another possible reaction with different
regioselectivity
Scheme 2. Profile of the catalytic asymmetric reactions of 2-indolylmethanols
To develop organocatalytic asymmetric (3+3) cycloadditions
of nitrones and to realize catalytic asymmetric C3-nucleophilic
reactions of 2-indolylmethanols, we designed a chiral phosphoric
acid[17] (CPA)-catalyzed asymmetric (3+3) cycloaddition of
nitrones with 2-indolylmethanols (Scheme 3a). The choice of
CPA as an organocatalyst was based on the consideration that
CPA can simultaneously activate both 2-indolylmethanols 1 and
nitrones 2 via hydrogen-bonding interactions, causing the C3
position of 2-indolylmethanols to become nucleophilic and attack
the imine group of nitrones, thus accomplishing an
enantioselective C3-nucleophilic (3+3) cycloaddition to give
chiral products 3. This design realizes the first organocatalytic
asymmetric (3+3) cycloaddition of nitrones and the first C3-
Results and Discussion
Based on the design mentioned above, we attempted to react
2-indolylmethanol 1a with nitrone 2a in the presence of the CPA
catalyst 4a in toluene at 30 °C (Table 1, entry 1). As expected,
1a exhibited C3 nucleophilicity, undergoing (3+3) cycloaddition
with 2a to afford the desired product 3aa with exclusive
regioselectivity, and regioisomer 3aa’ was not observed,
demonstrating the feasibility of our design. However, the yield
and enantioselectivity of 3aa were extremely low (26% yield,
11% ee), demonstrating the great challenge of controlling the
reactivity and enantioselectivity of the designed C3-nucleophilic
(3+3) cycloaddition. To tackle this challenge, we considered the
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202011267
Angewandte Chemie International Edition
RESEARCH ARTICLE
strategy of the cooperative catalysis of CPA with another
cocatalyst because cooperative catalysis involving CPAs has
proven to be a powerful strategy for achieving unprecedented
enantioselective reactions that are inaccessible or disfavored in
the presence of a single catalyst.[18-19] Therefore, we tentatively
added hexafluoroisopropanol (HFIP) to the reaction system as a
cocatalyst due to its special effects on organic reactions.[20]
enantioselectivity of 3aa (Table 1, entry 9). Then, the effect of
the amount of the cocatalyst HFIP on the reaction was
investigated (see the SI for details), and it was discovered that
as little as 20 mol% of HFIP promoted the reaction, affording a
good yield and enantioselectivity (Table 1, entry 11), and that 60
mol% of HFIP delivered the best results for the reaction (Table 1,
entry 12). Considering the low cost of HFIP, 60 mol% of HFIP
was used in the subsequent condition optimization (see the SI
for details). Briefly, the evaluation of different solvents revealed
that toluene controlled the reactivity and enantioselectivity better
than any other solvent (Table 1, entries 13-17 vs entry 12). The
addition of sodium sulfate as an additive improved the
enantioselectivity to a good level of 91% ee, with a high yield of
95% (Table 1, entry 18). It was discovered that diluting the
reaction concentration (from 1 mL toluene to 8 mL toluene)
further improved the enantioselectivity from 91% ee (Table 1,
entry 18) to 94% ee, albeit with a decreased yield of 73% (Table
1, entry 19). Finally, a suitable modulation of the reagent ratio
with a prolonged reaction time led to a high yield of 95% and an
excellent enantioselectivity of 95% ee (Table 1, entry 20).
Notably, the regioisomer 3aa’ was not observed during the
optimization of the conditions, demonstrating the high
regioselectivity of the (3+3) cycloaddition. Therefore, the two
sets of conditions given in entry 20 (conditions A) and entry 18
(conditions B) were selected as the optimal conditions for the
subsequent investigation of the substrate scope of nitrones 2
and 2-indolylmethanols 1.
Table 1. Optimization of the reaction conditions[a]
entry
Cat.
solvent
y
yield (%)[b]
ee (%)[c]
1
2
4a
4a
4b
4c
4d
4e
4f
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
0
26
64
11
45
41
27
68
53
67
13
73
13
72
75
48
-
50
50
50
50
50
50
50
50
50
20
60
60
60
60
60
60
60
60
60
3
93
4
92
5
95
6
95
Table 2. Substrate scope of nitrones 2[a]
7
94
8
4g
5a
6a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
46
9
95
10
11
12
13
14
15
16
17
18[d]
19[d,e]
20[d,e,f]
75
75
95
entry
R/R1 (2)
3
yield (%)[b]
ee (%)[c]
93
EtOAc
CH3CN
THF
N.R.
91
1
2
Ph/Me (2a)
4-FC6H4/Me (2b)
4-ClC6H4/Me (2c)
4-BrC6H4/Me (2d)
4-IC6H4/Me (2e)
4-MeC6H4/Me (2f)
4-PhC6H4/Me (2g)
3-ClC6H4/Me (2h)
3-BrC6H4/Me (2i)
3-MeOC6H4/Me (2j)
2-MeC6H4/Me (2k)
2-naphthyl/Me (2l)
2-furyl/Me (2m)
Et/Me (2n)
3aa
3ab
3ac
3ad
3ae
3af
95
96
98
83
95
98
64
66
81
67
96
96
83
52
26
95
93
92
91
94
90
91
91
89
93
78
95
91
85
86
<5
-
N.R.
N.R.
95
3
acetone
toluene
toluene
toluene
-
4
91
94
95
5
73
6
95
7
3ag
3ah
3ai
8
[a] The reaction was performed on a 0.1 mmol scale in a solvent (1 mL) for 12
h, and the molar ratio of 1a:2a was 1.2:1. [b] Isolated yield of 3aa. [c] The
enantiomeric excess (ee) of 3aa was determined by HPLC. [d] Na2SO4 (100
mg) was used as an additive. [e] The volume of toluene was 8 mL. [f]
Catalyzed by 10 mol% 5a for 48 h at a 1a:2a molar ratio of 2:1. N.R. = no
reaction.
9
10
11[d]
12
13[d]
14[d]
15[d]
3aj
3ak
3al
3am
3an
3ao
Gratifyingly, the addition of HFIP indeed greatly improved
the yield and enantioselectivity (Table 1, entry 2 vs entry 1),
demonstrating that HFIP was a good cocatalyst for CPA. Then,
under the cooperative catalysis of HFIP and CPA, several CPAs
4b-4g were evaluated for this reaction (Table 1, entries 3-8),
and it was discovered that 4d bearing 3,3’-di-9-phenanthrenyl
groups was superior to the others (Table 1, entry 5 vs entries 2-
4 and 6-8) in controlling the enantioselectivity. The change in the
backbone of 4d from BINOL to H8-BINOL and SPINOL (Table 1,
entries 9-10) revealed that H8-BINOL-derived CPA 5a was the
optimal chiral catalyst for this reaction with regard to the
Ph/Ph (2o)
[a] Conditions A: The reaction was performed on a 0.1 mmol scale and
catalyzed by 10 mol% (R)-5a and 60 mol% HFIP in toluene (8 mL) with
Na2SO4 (100 mg) as an additive at 30 °C for 48 h, and the molar ratio of 1a:2
was 2:1. The absolute configuration of 3aa was determined to be (S) by
single-crystal X-ray analysis.[21] [b] Isolated yield. [c] The ee was determined by
HPLC. [d] Reaction time of 4 days.
First, we investigated the substrate scope of nitrones 2
(Table 2). As shown in entries 1-12, a variety of nitrones 2a-2l
bearing different R substituents, such as para-, meta-, or ortho-
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202011267
Angewandte Chemie International Edition
RESEARCH ARTICLE
substituted phenyl groups (Table 2, entries 1-11) and a 2-
naphthyl group (Table 2, entry 12), smoothly participated in the
reaction to give products 3aa-3al in overall high yields with
excellent enantioselectivities. More importantly, nitrones 2m-2n
bearing heteroaromatic (2-furyl) and aliphatic (ethyl) R groups
successfully underwent enantioselective (3+3) cycloaddition with
2-indolylmethanol 1a in moderate to good yields with high
enantioselectivities (Table 2, entries 13-14). In addition, the R1
group of the nitrones could be changed from a methyl to a
phenyl group (Table 2, entry 15), and although this substrate 2o
exhibited much lower reactivity, it ultimately participated in the
reaction to afford product 3ao with good enantioselectivity. It
should be noted that in all cases, regioisomers 3’ were not
observed.
Then, the substrate scope of 2-indolylmethanols 1 in the
catalytic asymmetric (3+3) cycloaddition was studied by reaction
with nitrone 2a (Table 3). As shown in entries 2-7, a series of 2-
indolylmethanols 1b-1g bearing electronically different Ar groups
with para-, meta- or ortho-substitutive patterns served as
suitable substrates in the reaction, delivering products 3ba-3ga
in moderate to high yields with excellent enantioselectivities.
Moreover, 2-indolylmethanols 1h-1n bearing either electron-
donating or electron-withdrawing groups at different positions of
the indole ring acted as suitable reaction partners, undergoing
(3+3) cycloaddition with nitrone 2a to generate products 3ha-
3na in generally high yields with good enantioselectivities.
Clearly, C5-substituted 2-indolylmethanols 1i-1m exhibited
higher reactivities and gave higher enantioselectivities than C6-
and C4-substituted 2-indolylmethanols (1h and 1n) (Table 3,
entries 9-13 vs entries 8 and 14). In all cases, regioisomers 3’
were not observed, demonstrating the exclusive regiospecificity
of the (3+3) cycloaddition.
More importantly, we further extended the substrate scope of
this reaction to different types of 2-indolylmethanols 1o-1r and
ether 1a’ substrates (Scheme 4). Under standard conditions B,
indolylmethanols 1o-1p bearing two different aryl groups could
successfully participate in the (3+3) cycloaddition to give
products 3oa[21] and 3pa in good yields with high
diastereoselectivities and excellent enantioselectivities (Scheme
4a-4b).
However,
when
dibenzofuryl-substituted
2-
indolylmethanol 1q and dimethyl-substituted 2-indolylmethanol
1r were used as the substrates, few products could be obtained
because these indolylmethanols easily decomposed into a
complex mixture. After modulating the reaction conditions such
as by greatly increasing the amount of indolylmethanols 1q-1r
and HFIP, these indolylmethanols could smoothly participate in
the (3+3) cycloaddition to give products 3qa and 3rb in
moderate to good results (Scheme 4c-4d). Interestingly, ether
1a’ was suitable for (3+3) cycloaddition, affording product 3aa in
a good yield with a high enantioselectivity (Scheme 4e). In all
cases, regioisomers 3’ were not observed.
Table 3. Substrate scope of 2-indolylmethanols 1[a]
entry
R/Ar (1)
3
yield (%)[b]
ee (%)[c]
1
2
H/Ph (1a)
H/p-ClC6H4 (1b)
H/p-MeC6H4 (1c)
H/m-FC6H4 (1d)
H/m-ClC6H4 (1e)
H/m-MeC6H4 (1f)
H/o-MeC6H4 (1g)
6-Cl/Ph (1h)
3aa
3ba
3ca
3da
3ea
3fa
95
51
98
98
93
98
53
54
98
89
85
98
98
53
91
92
90
93
89
90
90
84
91
90
90
92
93
75
3
4
Scheme 4. Further extension of the substrate scope
5
To examine the utility of the catalytic asymmetric (3+3)
cycloaddition, we performed a one-mmol-scale reaction and
some synthetic transformations of the products (Scheme 5). As
illustrated in Scheme 5a, the one-mmol-scale reaction of 2-
indolylmethanol 1k with nitrone 2a successfully proceeded to
give product 3ka in a retained high yield of 86% with an
excellent enantioselectivity of 92% ee, and these results were
comparable to those of the small-scale reaction (Table 3, entry
11). In addition, product 3aa was transformed into chiral
6
7
8[d]
3ga
3ha
3ia
9
5-F/Ph (1i)
10
11
12
13
14[e]
5-Cl/Ph (1j)
3ja
5-Br/Ph (1k)
3ka
3la
5-Me/Ph (1l)
5-OMe/Ph (1m)
4-Me/Ph (1n)
3ma
3na
phosphane
7
in
a
high yield with almost maintained
enantioselectivity (Scheme 5b). Moreover, 3aa underwent a
ring-opening reaction to produce compound 8 with nearly the
same enantioselectivity (Scheme 5c), and 3ka smoothly
underwent a Suzuki coupling reaction with arylboronic acid to
generate compound 9 with no decrease in the enantioselectivity
(Scheme 5d).
[a] Conditions B: The reaction was performed on a 0.1 mmol scale and
catalyzed by 5 mol% (R)-5a and 60 mol% HFIP in toluene (1 mL) with Na2SO4
(100 mg) as an additive at 30 °C for 12 h, and the molar ratio of 1:2a was
1.2:1. [b] Isolated yield. [c] The ee was determined by HPLC. [d] Catalyzed by
20 mol% (R)-5a in toluene (8 mL) for 4 days using a 1h:2a molar ratio of 2:1.
[e] Reaction time of 48 h.
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202011267
Angewandte Chemie International Edition
RESEARCH ARTICLE
cycloaddition, which might be due to the effect of the fluorine
atoms in these alcohols.
Table 4. Control experiments to investigate the role of HFIP[a]
yield
(%)[b]
ee
(%)[c]
entry
CPA
cocatalyst
1
2
3
4
5
6
7
5 mol% (R)-5a
5 mol% (R)-5a
none
60 mol% HFIP
none
95
12
91
59
-
10 mol% HFIP
10 mol% HFIP
60 mol% TFE
60 mol% i-PrOH
60 mol% t-BuOH
N.R.
30
5 mol% (R)-5a
5 mol% (R)-5a
5 mol% (R)-5a
5 mol% (R)-5a
86
86
-
48
trace
trace
-
[a] Conditions B: The reaction was carried out at a 0.1 mmol scale and was
catalyzed by CPA and a cocatalyst in toluene (1 mL) with Na2SO4 (100 mg) as
an additive at 30 °C for 12 h, and the molar ratio of 1a:2a was 1.2:1. [b]
Isolated yield of 3aa; regioisomer 3aa’ was not observed in all cases. [c] The
ee was determined by HPLC.
Scheme 5. One-mmol-scale reaction and synthetic transformations
To gain some insights into the role of HFIP as a cocatalyst in
the catalytic asymmetric (3+3) cycloaddition, some control
experiments were carried out (Table 4). As listed in entry 1,
when cooperatively catalyzed by 5 mol% (R)-5a and 60 mol%
HFIP (standard conditions B), the (3+3) cycloaddition of 2-
indolylmethanol 1a with nitrone 2a afforded product 3aa in a
high yield of 95%, with an excellent enantioselectivity of 91% ee
(see also Table 3, entry 1). When the same reaction was
performed in the absence of HFIP (Table 4, entry 2), the
reaction was very sluggish and afforded 3aa in an extremely low
yield of 12%, with a moderate enantioselectivity of 59% ee. This
phenomenon indicated that the single chiral catalyst (R)-5a
catalyzed the (3+3) cycloaddition but in a rather inefficient
manner, and the cocatalyst HFIP not only greatly improved the
yield but also enhanced the enantioselectivity of the reaction
(Table 4, entry 1 vs 2). When the reaction was performed in the
absence of (R)-5a (Table 4, entry 3), no reaction occurred. This
result showed that as a single catalyst, HFIP could not catalyze
the (3+3) cycloaddition, and it acted as an important cocatalyst
for this reaction. In addition, the effect of the cocatalyst loading
of HFIP on the reaction was investigated. It was discovered that
the addition of only 10 mol% HFIP evidently improved the yield
and enantioselectivity (Table 4, entry 4 vs entry 2), but the best
results for the reaction were obtained with 60 mol% HFIP (Table
4, entry 1). Furthermore, some other alcohols were employed as
cocatalysts instead of HFIP under the standard conditions
(Table 4, entries 5-7). It was revealed that the addition of
trifluoroethanol (TFE), another fluorinated alcohol, to the
reaction system also increased the yield and enantioselectivity
to some extent (Table 4, entry 5 vs entry 2). This result implied
that TFE could also act as a cocatalyst for this reaction, but its
catalytic efficacy was lower than that of HFIP (Table 4, entry 5
vs entry 1). However, nonfluorinated alcohols such as
isopropanol and tertiary butanol failed to act as cocatalysts for
this reaction (Table 4, entries 6-7). These results demonstrated
the superiority of fluorinated alcohols, particularly HFIP, as
cocatalysts for this CPA-catalyzed asymmetric (3+3)
To obtain some insight into the reaction pathway, we
monitored the reaction process of 2-indolylmethanol 1a with
nitrone 2a, but no intermediate products were isolated.
Nevertheless, we tried to use HRMS to detect the signals of
some possible intermediates. As illustrated in Scheme 6a, after
performing the reaction for 2 h, a weak signal ([M−H]− m/z
1141.4320) possibly due to the complex of intermediate A with
(R)-5a was detected. In addition, a strong signal ([M−H]− m/z
1123.4251) that was likely due to the complex of carbocation B
with the (R)-5a anion was detected. Thus, the HRMS study
supported the generation of possible reaction intermediates and
indicated that the (3+3) cycloaddition proceeded via a stepwise
process involving the C3-nucleophilic addition of 2-
indolylmethanol 1a to nitrone 2a and subsequent intramolecular
cyclization. Moreover, N-Me-protected 2-indolylmethanol 1s
failed to participate in the reaction (Scheme 6b), which implied
that the NH group of the indole ring formed a hydrogen bond
with the catalysts.
Scheme 6. Study of the possible reaction intermediates and activation mode
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202011267
Angewandte Chemie International Edition
RESEARCH ARTICLE
To better understand the role of HFIP and the reaction
mechanism, based on the experimental results, we performed
theoretical calculations on the possible reaction pathways of the
catalytic asymmetric (3+3) cycloaddition of 2-indolylmethanol 1a
with nitrone 2a (Scheme 7). First, the calculation revealed that
barriers (9.46 kcal‧mol-1) of this step supported the conclusion
that pathway A occurs more readily than pathway B. In addition,
the energy barrier of TS-2 (3.93 kcal‧mol-1) was 4.09 kcal‧mol-1
lower than that of TS-2’ (8.02 kcal‧mol-1), and the energy barrier
of TS-3 (4.70 kcal‧mol-1) was 12.38 kcal‧mol-1 lower than that of
TS-3’ (17.08 kcal‧mol-1). Moreover, the overall energy barrier of
pathway A was 8.41 kcal‧mol-1 (from the starting point to TS-2),
which was much lower than the overall energy barrier of
pathway B (19.21 kcal‧mol-1, from the starting point to TS-3’). All
these results demonstrated that the addition of HFIP to the
reaction as a cocatalyst lowered the energy barriers of the key
transition states as well as the overall energy barrier.
To better understand how HFIP worked with (R)-5a to
control the reactivity and enantioselectivity, we compared the
structures of the key TSs in pathways A and B (see the SI for
details). A comparison of TS-1 and TS-1’ in the two pathways is
shown in Figure 1. In TS-1, HFIP formed four hydrogen bonds
with the other reagents. In detail, the OH group of HFIP not only
formed a hydrogen bond (1.559 Å) with the anion of (R)-5a but
also interacted with the prochiral CH of the protonated nitrone
via hydrogen bonding (2.154 Å). More importantly, two fluorine
atoms of HFIP formed C-H···F hydrogen-bonding interactions[22]
(2.420 Å and 2.462 Å, in red ellipses) with the phenyl C-H
groups of the protonated nitrone and 2-indolylmethanol,
respectively. In addition, the P=O group of the (R)-5a anion
formed two hydrogen bonds (1.692 Å and 1.698 Å) with the NH
and OH groups of 2-indolylmethanol. Therefore, in the
cocatalytic system, HFIP and the (R)-5a anion formed multiple
hydrogen bonds with the two substrates, similar to a crab's
pincers tightly binding the substrates, thus fixing the steric
orientation of the substrates during the nucleophilic addition and
controlling the enantioselectivity of this key step. Moreover, the
multiple hydrogen-bonding interactions resulted in the stability of
TS-1. By contrast, in TS-1’, the anion of (R)-5a only generated
three hydrogen bonds with the substrates, and the nonbonding
interactions between the catalyst and substrates were much
weaker than those in TS-1, leading to the large difference in the
energy barriers (9.46 kcal‧mol-1) of TS-1 and TS-1’.
nitrone 2a can easily transform into intermediate
C via
protonation in the presence of (R)-5a (Scheme 7a). This
interaction between 2a and (R)-5a made the reaction pathway
for regioisomers 3’ (in Scheme 3b) less possible due to the
absence of both the oxygen anion of the nitrone and the
delocalized carbocation generated from 2-indolylmethanol.
Therefore, this finding explained the exclusive formation of
regioisomers 3. In fact, attempts were made to reverse the
regioselectivity, but regioisomer 3aa' was not observed in all
cases (see the SI for details).
Second, the reaction pathway involving the cooperative
catalysis of (R)-5a and HFIP was studied. After exploring a
series of possible activation modes of the substrates in the
cocatalytic system (see the SI for details), we found the most
stable structures for related intermediates (INT) and transition
states (TS). As illustrated in pathway A (Scheme 7b), in INT-1,
HFIP and the CPA (R)-5a anion simultaneously activated both 2-
indolylmethanol 1a and intermediate C by forming multiple
hydrogen bonds, thus facilitating their enantioselective
nucleophilic addition via TS-1 to give chiral INT-2. Then, INT-2
rapidly transformed into INT-3 via TS-2. The subsequent
dehydration of INT-3 via TS-3 generated carbocation INT-4,
which underwent intramolecular addition via TS-4 to give final
product (S)-3aa. Notably, the theoretical calculations revealed
that excess HFIP also had some effect on the processes of TS-2
and TS-3 after the generation of the chiral center (TS-1). In brief,
the OH group of HFIP formed a hydrogen bond with the P=O
group of CPA, and the combined catalytic system cooperatively
activated the substrates via hydrogen-bonding interactions in
TS-2 and TS-3. Therefore, the calculation results revealed that
HFIP played an important role in the whole reaction pathway.
In addition, pathway B was investigated in the presence of
the single catalyst CPA (R)-5a (Scheme 7c). In all the
calculated structures (INT-1’ to INT-4’, TS-1’ to TS-4’), the
substrates were only activated by CPA via a single mode. For
example, in INT-1’, only the (R)-5a anion activated 2-
indolylmethanol 1a and intermediate C via TS-1’ to give chiral
INT-2’. The subsequent transformation of INT-2’ through TS-2’
to TS-4’ gave rise to product (S)-3aa.
Similar observations were also made when comparing TS-2
with TS-2’ and TS-3 with TS-3’ (see the SI for details). Namely,
in TS-2 and TS-3, not only did the OH group of HFIP form a
hydrogen bond with the P=O group of (R)-5a but also one
fluorine atom of HFIP formed N-H···F or C-H···F hydrogen-
bonding interactions with the substrates. In TS-2’ and TS-3’,
these nonbonding interactions were not generated in the
absence of HFIP, resulting in much weaker interactions between
the catalyst and substrates and the observed higher energy
barriers.
Therefore, the theoretical calculations elucidated the role
of the cocatalyst HFIP in helping CPA stabilize the key transition
states and create a chiral environment to control the reactivity
and enantioselectivity of the (3+3) cycloaddition between 2-
indolylmethanols and nitrones.
To explain the role of HFIP in the reaction, the calculated
free energy profiles of pathways A and B are summarized and
compared in Scheme 7d. Obviously, the energy barriers of all
the transition states of pathway A (TS-1 to TS-4) and pathway B
(TS-1’ to TS-4’) were remarkably different. In most of the steps,
the energy barrier of pathway A was much lower than that of
pathway B. Specifically, it is clear that the energy barrier of TS-1
in pathway A (20.39 kcal‧mol-1) was much lower than that of TS-
1’ in pathway B (29.85 kcal‧mol-1). Because this step was the
key step for initiating the C3-nucleophilic (3+3) cycloaddition and
generating the chiral center, the large difference in the energy
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202011267
Angewandte Chemie International Edition
RESEARCH ARTICLE
Scheme 7. Calculated reaction pathways and free energy profiles for understanding the role of HFIP and the reaction mechanism
7
This article is protected by copyright. All rights reserved.

10.1002/anie.202011267
Angewandte Chemie International Edition
RESEARCH ARTICLE
Keywords: nitrone • indolylmethanol • cooperative catalysis •
organocatalysis • enantioselectivity • cycloaddition
[1] For some recent reviews: a) L. L. Anderson, Asian J. Org. Chem. 2016, 5,
9; b) L. L. Anderson, M. A. Kroc, T. W. Reidl, J. Son, J. Org. Chem. 2016,
81, 9521; c) D. B. Huple, S. Ghorpade, R.-S. Liu, Adv. Synth. Catal. 2016,
358, 1348; d) P. Merino, T. Tejero, I. Delso, R. Matute, Org. Biomol. Chem.
2017, 15, 3364; e) S.-I. Murahashi, Y. Imada, Chem. Rev. 2019, 119, 4684.
[2] For a review: T. Hashimoto, K. Maruoka, Chem. Rev. 2015, 115, 5366.
[3] For early examples on metal-catalyzed asymmetric (3+2) cycloadditions of
nitrones: a) K. V. Gothelf, K. A. Jørgensen, J. Org. Chem. 1994, 59, 5687;
b) J.-P. G. Seerden, A. W. A. Scholte op Reimer, H. W. Scheeren,
Tetrahedron Lett. 1994, 35, 4419; c) K. Hori, H. Kodama, T. Ohta, I.
Furukawa, Tetrahedron Lett. 1996, 37, 5947; d) S. Kobayashi, M.
Kawamura, J. Am. Chem. Soc. 1998, 120, 5840; e) S. Kanemasa, Y.
Oderaotoshi, J. Tanaka, E. Wada, J. Am. Chem. Soc. 1998, 120, 12355; f)
K. B. Simonsen, P. Bayꢀn, R. G. Hazell, K. V. Gothelf, K. A. Jørgensen, J.
Am. Chem. Soc. 1999, 121, 3845.
[4] For early examples on chiral amine-catalyzed asymmetric (3+2)
cycloadditions of nitrones: a) W. S. Jen, J. J. M. Wiener, D. W. C. MacMillan,
J. Am. Chem. Soc. 2000, 122, 9874; b) S. Karlsson, H.-E. Hꢁgberg, Eur. J.
Org. Chem. 2003, 2782; c) A. Puglisi, M. Benaglia, M. Cinquini, F. Cozzi, G.
Celentano, Eur. J. Org. Chem. 2004, 567.
Figure 1. Comparison between TS-1 and TS-1’ of the two pathways
[5] For examples on chiral thiourea-catalyzed asymmetric (3+2) cycloadditions
of nitrones: a) A. Wittkopp, P. R. Schreiner, Chem. Eur. J. 2003, 9, 407; b)
W. Du, Y. K. Liu, L. Yue, Y. C. Chen, Synlett 2008, 2997.
Finally, considering the importance of the constructed
oxacarboline scaffold in chemical biology,[23] we investigated the
possible bioactivity of the oxacarboline products 3. The in vitro
cytotoxicities of some selected products 3 against the human
prostatic carcinoma PC-3 cell line were evaluated. The tested
products 3 exhibited moderate to strong cytotoxicity against the
PC-3 cell line, and the IC50 values ranged from 40.08 to 222.65
μg/mL (see the SI for details). Therefore, these results of the
cytotoxic evaluation demonstrated the importance of this class of
oxacarboline products 3, which exhibited moderate to strong
anticancer activity against the PC-3 cell line and are promising
compounds for discovering more applications in medicinal
chemistry.
[6] For examples on chiral Bronsted acid-catalyzed asymmetric (3+2)
cycloadditions of nitrones: a) P. Jiao, D. Nakashima, H. Yamamoto, Angew.
Chem. Int. Ed. 2008, 47, 2411; Angew. Chem. 2008, 120, 2445; b) Y. Jin, Y.
Honma, H. Morita, M. Miyagawa, T. Akiyama, Synlett 2019, 30, 1541.
[7] For recent reviews: a) X. Xu, M. P. Doyle, Acc. Chem. Res. 2014, 47, 1396;
b) Y. Deng, Q.-Q. Cheng, M. P. Doyle, Synlett 2017, 28, 1695.
[8] For catalytic asymmetric (3+3) cycloadditions of nitrones: a) M. P. Sibi, Z.
Ma, C. P. Jasperse, J. Am. Chem. Soc. 2005, 127, 5764; b) Y.-B. Kang, X.-
L. Sun, Y. Tang, Angew. Chem. Int. Ed. 2007, 46, 3918; Angew. Chem.
2007, 119, 3992; c) R. Shintani, S. Park, W.-L. Duan, T. Hayashi, Angew.
Chem. Int. Ed. 2007, 46, 5901; Angew. Chem. 2007, 119, 6005; d) F. Liu, D.
Qian, L. Li, X. Zhao, J. Zhang, Angew. Chem. Int. Ed. 2010, 49, 6669;
Angew. Chem. 2010, 122, 6819; e) X. Wang, X. Xu, P. Y. Zavalij, M. P.
Doyle, J. Am. Chem. Soc. 2011, 133, 16402; f) X. Xu, P. J. Zavalij, M. P.
Doyle, Chem. Commun. 2013, 49, 10287; g) M. Chen, Z.-M. Zhang, Z. Yu,
H. Qiu, B. Ma, H.-H. Wu, J. Zhang, ACS Catal. 2015, 5, 7488; h) Q.-Q.
Cheng, J. Yedoyan, H. Arman, M. P. Doyle, J. Am. Chem. Soc. 2016, 138,
44; i) P.-W. Xu, J.-K. Liu, L. Shen, Z.-Y. Cao, X.-L. Zhao, J. Yan, J. Zhou,
Nat. Commun. 2017, 8, 1619; j) K. O. Marichev, F. G. Adly, A. M. Carranco,
E. C. Garcia, H. Arman, M. P. Doyle, ACS Catal. 2018, 8, 10392; k) F. G.
Adly, K. O. Marichev, J. A. Jensen, H. Arman, M. P. Doyle, Org. Lett. 2019,
21, 40; l) L. Zhou, B. Xu, D. Ji, Z.-M. Zhang, J. Zhang, Chin. J. Chem. 2020,
38, 577.
Conclusion
In summary, we have established the regio- and
enantioselective (3+3) cycloaddition of nitrones with 2-
indolylmethanols enabled by the cooperative organocatalysis of
HFIP and CPA. Using this approach, a series of indole-fused
six-membered heterocycles were synthesized in high yields with
excellent enantioselectivities and exclusive regiospecificity. This
design realized not only the first organocatalytic asymmetric
(3+3) cycloaddition of nitrones but also the first C3-nucleophilic
asymmetric (3+3) cycloaddition of 2-indolylmethanols. More
importantly, theoretical calculations elucidated the role of the
cocatalyst HFIP in helping CPA stabilize the key transition state
and create a chiral environment, thus controlling the reactivity
and enantioselectivity. This study not only enriches the
chemistry of nitrones and 2-indolylmethanols but also advances
the research field of cooperative asymmetric catalysis.
[9] For catalytic asymmetric (3+4) cycloadditions of nitrones: a) J.-L. Hu, L.
Wang, H. Xu, Z. Xie, Y. Tang, Org. Lett. 2015, 17, 2680; b) Y. Zhang, J.
Zhang, Chem. Commun. 2012, 48, 4710.
[10] For a sole example using in situ generated nitrones: Y. Liu, J. Ao, S.
Paladhi, C. E. Song, H. Yan, J. Am. Chem. Soc. 2016, 138, 16486.
[11] For recent reviews: a) G.-J. Mei, F. Shi, J. Org. Chem. 2017, 82, 7695; b)
Y.-C. Zhang, F. Jiang, F. Shi, Acc. Chem. Res. 2020, 53, 425; c) M. Petrini,
Adv. Synth. Catal. 2020, 362, 1214.
[12] For selected examples on catalytic asymmetric reactions of
indolylmethanols from other groups: a) Q.-X. Guo, Y.-G. Peng, J.-W. Zhang,
L. Song, Z. Feng, L.-Z. Gong, Org. Lett. 2009, 11, 4620; b) F.-L. Sun, M.
Zeng, Q. Gu, S.-L. You, Chem. Eur. J. 2009, 15, 8709; c) C. Guo, J. Song,
J.-Z. Huang, P.-H. Chen, S.-W. Luo, L.-Z. Gong, Angew. Chem. Int. Ed.
2012, 51, 1046; Angew. Chem. 2012, 124, 1070; d) J. Song, C. Guo, A.
Adele, H. Yin, L.-Z. Gong, Chem. Eur. J. 2013, 19, 3319; e) S. Qi, C.-Y. Liu,
J.-Y. Ding, F.-S. Han, Chem. Commun. 2014, 50, 8605; f) K. Bera, C.
Schneider, Org. Lett. 2016, 18, 5660; g) K. Bera, C. Schneider, Chem. Eur.
J. 2016, 22, 7074; h) I. Kallweit, C. Schneider, Org. Lett. 2019, 21, 519; i) X.
Acknowledgements
This work was supported by NSFC (21772069 and 21831007)
and Natural Science Foundation of Jiangsu Province. We are
grateful for Prof. Shu Zhang for her help in biological evaluation.
8
This article is protected by copyright. All rights reserved.

10.1002/anie.202011267
Angewandte Chemie International Edition
RESEARCH ARTICLE
Li, J. Sun, Angew. Chem. Int. Ed. 2020, 59, 17049; Angew. Chem. 2020,
132, 17197; j) F. Gꢁricke, C. Schneider, Org. Lett. 2020, 22, 6101.
[13] For selected examples on catalytic asymmetric reactions of
indolylmethanols from our group: a) C.-S. Wang, J.-L. Wu, C. Li, L.-Z. Li, G.-
J. Mei, F. Shi, Adv. Synth. Catal. 2018, 360, 846; b) J.-L. Wu, J.-Y. Wang, P.
Wu, J.-R. Wang, G.-J. Mei, F. Shi, Org. Chem. Front. 2018, 5, 1436; c) Y.-N.
Lu, C. Ma, J.-P. Lan, C. Zhu, Y.-J. Mao, G.-J. Mei, S. Zhang, F. Shi, Org.
Chem. Front. 2018, 5, 2657; d) C. Ma, F. Jiang, F.-T. Sheng, Y. Jiao, G.-J.
Mei, F. Shi, Angew. Chem. Int. Ed. 2019, 58, 3014; Angew. Chem. 2019,
131, 3046; e) C.-S. Wang, T.-Z. Li, S.-J. Liu, Y.-C. Zhang, S. Deng, Y. Jiao,
F. Shi, Chin. J. Chem. 2020, 38, 543.
[14] For catalytic asymmetric C3-electrophilic substitutions of 2-
indolylmethanols: a) H.-H. Zhang, C.-S. Wang, C. Li, G.-J. Mei, Y. Li, F. Shi,
Angew. Chem. Int. Ed. 2017, 56, 116; Angew. Chem. 2017, 129, 122; b) Z.-
Q. Zhu, Y. Shen, J.-X. Liu, J.-Y. Tao, F. Shi, Org. Lett. 2017, 19, 1542; c)
M.-M. Xu, H.-Q. Wang, Y.-J. Mao, G.-J. Mei, S.-L. Wang, F. Shi, J. Org.
Chem. 2018, 83, 5027.
[15] For catalytic asymmetric C3-electrophilic cycloadditions of 2-
indolylmethanols: a) Z.-Q. Zhu, Y. Shen, X.-X. Sun, J.-Y. Tao, J.-X. Liu, F.
Shi, Adv. Synth. Catal. 2016, 358, 3797; b) X.-X. Sun, H.-H. Zhang, G.-H. Li,
Y.-Y. He, F. Shi, Chem. Eur. J. 2016, 22, 17526; c) M.-M. Xu, H.-Q. Wang,
Y. Wan, S.-L. Wang, F. Shi, J. Org. Chem. 2017, 82, 10226; d) J. Mao, H.
Zhang, X.-F. Ding, X. Luo, W.-P. Deng, J. Org. Chem. 2019, 84, 11186.
[16] M. Sun, C. Ma, S.-J. Zhou, S.-F. Lou, J. Xiao, Y. Jiao, F. Shi, Angew.
Chem. Int. Ed. 2019, 58, 8703; Angew. Chem. 2019, 131, 8795.
[17] For some reviews: a) T. Akiyama, Chem. Rev. 2007, 107, 5744; b) M.
Terada, Chem. Commun. 2008, 2008, 4097; c) M. Terada, Synthesis 2010,
2010, 1929; d) A. Zamfir, S. Schenker, M. Freund, S. B. Tsogoeva, Org.
Biomol. Chem. 2010, 8, 5262; e) J. Yu, F. Shi, L.-Z. Gong, Acc. Chem. Res.
2011, 44, 1156; f) D. Parmar, E. Sugiono, S. Raja, M. Rueping, Chem. Rev.
2014, 114, 9047; g) H. Wu, Y.-P. He, F. Shi, Synthesis 2015, 47, 1990; h) F.
E. Held, D. Grau, S. B. Tsogoeva, Molecules 2015, 20, 16103; i) Z.-L. Xia,
Q.-F. Xu-Xu, C. Zheng, S.-L. You, Chem. Soc. Rev. 2020, 49, 286; For
recent highlights: j) L. Liu, J. Zhang, Chin. J. Org. Chem. 2019, 39, 3308; k)
B. Tan, Chin. J. Org. Chem. 2020, 40, 1404.
[18] For early examples: a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew.
Chem. Int. Ed. 2004, 43, 1566; Angew. Chem. 2004, 116, 1592; b) D.
Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356; For selected
recent examples: c) K. Mori, T. Itakura, T. Akiyama, Angew. Chem. Int. Ed.
2016, 55, 11642; Angew. Chem. 2016, 128, 11814; d) D. Qian, L. Wu, Z. Lin,
J. Sun, Nat. Commun. 2017, 8, 567; e) M. Chen, Y. Han, D. Ma, Y. Wang, Z.
Lai, J. Sun, Chin. J. Chem. 2018, 36, 587; f) R. Zhang, W. Guo, M. Duan, K.
N. Houk, J. Sun, Angew. Chem. Int. Ed. 2019, 58, 18055; Angew. Chem.
2019, 131, 18223; g) D. Ma, C.-B. Miao, J. Sun, J. Am. Chem. Soc. 2019,
141, 13783; h) H. Osakabe, S. Saito, M. Miyagawa, T. Suga, T. Uchikura, T.
Akiyama, Org. Lett. 2020, 22, 2225.
[19] For reviews on cooperative catalysis involving CPAs: a) D.-F. Chen, Z.-Y.
Han, X.-L. Zhou, L.-Z. Gong, Acc. Chem. Res. 2014, 47, 2365; b) P.-S.
Wang, D.-F. Chen, L.-Z. Gong, Top. Curr. Chem. 2020, 378, 9; For some
recent examples on cooperative catalysis involving CPAs: c) H.-C. Lin, P.-S.
Wang, Z.-L. Tao, Y.-G. Chen, Z.-Y. Han, L.-Z. Gong, J. Am. Chem. Soc.
2016, 138, 14354; d) F. Goericke, C. Schneider, Angew. Chem. Int. Ed.
2018, 57, 14736; Angew. Chem. 2018, 130, 14952; e) J. Meng, L.-F. Fan,
Z.-Y. Han, L.-Z. Gong, Chem. 2018, 4, 1047; f) A. Suneja, H. J. Loui, C.
Schneider, Angew. Chem. Int. Ed. 2020, 59, 5536; Angew. Chem. 2020,
132, 5580; g) H.-J. Jiang, X.-M. Zhong, Z.-Y. Liu, R.-L. Geng, Y.-Y. Li, Y.-D.
Wu, X.-H. Zhang, L.-Z. Gong, Angew. Chem. Int. Ed. 2020, 59, 12774;
Angew. Chem. 2020, 132, 12874.
[20] X.-D. An, J. Xiao, Chem. Rec. 2020, 20, 142.
[21] CCDC 2023109 for 3aa, 2035664 for 3oa. see the Supporting Information.
[22] a) J. R. Loader, S. Libri, A. J. H. M. Meijer, R. N. Perutzb, L. Brammer,
CrystEngComm, 2014, 16, 9711; b) Q.-X. Zhang, Y. Li, J. Wang, C. Yang,
C.-J. Liu, X. Li, J.-P. Cheng, Angew. Chem. Int. Ed. 2020, 59, 4550; Angew.
Chem. 2020, 132, 4580.
[23] P. Agarwa, J. van der Weijden, E. M. Sletten, D. Rabuka, C. R. Bertozzi,
Proc. Natl. Acad. Sci. USA, 2013, 110, 46.
9
This article is protected by copyright. All rights reserved.

10.1002/anie.202011267
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
The regio- and enantioselective (3+3) cycloaddition of nitrones with 2-indolylmethanols has been established under the cooperative
catalysis of hexafluoroisopropanol (HFIP) and chiral phosphoric acid (CPA). This approach not only realized the first organocatalytic
asymmetric (3+3) cycloaddition of nitrones and the first C3-nucleophilic asymmetric (3+3) cycloaddition of 2-indolylmethanols but also
revealed a new mode of cooperative catalysis.
10
This article is protected by copyright. All rights reserved.