Atroposelective Construction of Axially Chiral Alkene-Indole Scaffolds via Catalytic Enantioselective Addition Reaction of 3-Alkynyl-2-indolylmethanols?

Article abstract of DOI:10.1002/cjoc.202100214

Atroposelective construction of axially chiral alkene-heteroaryl scaffolds is highly desired but challenging. In this work, we established an atroposelective construction of axially chiral alkene-indole scaffolds via the strategy of catalytic enantioselective addition reaction of 3-alkynyl-2-indolylmethanols with bulky nucleophiles. In this strategy, α-amido sulfones were used as competent nucleophiles and chiral phosphoric acid (CPA) acted as suitable chiral catalyst for this addition reaction. By this strategy, a new class of axially chiral acyclic alkene-indoles was synthesized in overall high yields (up to 86%), excellent (E/Z)-selectivity (all > 95 : 5) and good enantioselectivities (up to 92 : 8 er). This reaction represents the first catalytic enantioselective construction of axially chiral alkene-indole frameworks, which will add a new member to the family of atropoisomeric heterocycles, especially the family of axially chiral indole compounds.

Full text of DOI:10.1002/cjoc.202100214

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Accepted Article
Title: Atroposelective Construction of Axially Chiral Alkene-Indole Scaffolds via
Catalytic Enantioselective Addition Reaction of 3-Alkynyl-2-indolylmethanols
Authors: Jing-Yi Wang, Meng Sun, Xian-Yang Yu, Yu-Chen Zhang, Wei Tan* and Feng
Shi*
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Cite this paper: Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
Atroposelective Construction of Axially Chiral Alkene-Indole
Scaffolds via Catalytic Enantioselective Addition Reaction of
3-Alkynyl-2-indolylmethanols
Jing-Yi Wang,a Meng Sun,a Xian-Yang Yu,a Yu-Chen Zhang,a Wei Tan*,a and Feng Shi*,a
aSchool of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou, 221116, P. R. China
Keywords
Atropisomerism |Axial chirality | Asymmetric catalysis | Indole | Nucleophilic addition
Main observation and conclusion
Atroposelective construction of axially chiral alkene-heteroaryl scaffolds is highly desired but challenging. In this work, we established
an atroposelective construction of axially chiral alkene-indole scaffolds via the strategy of catalytic enantioselective addition reaction
of 3-alkynyl-2-indolylmethanols with bulky nucleophiles. In this strategy, α-amido sulfones were used as competent nucleophiles and
chiral phosphoric acid (CPA) acted as suitable chiral catalyst for this addition reaction. By this strategy, a new class of axially chiral acy-
clic alkene-indoles was synthesized in overall high yields (up to 86%), excellent (E/Z)-selectivity (all >95:5) and good enantioselectivi-
ties (up to 92:8 er). This reaction represents the first catalytic enantioselective construction of axially chiral alkene-indole frameworks,
which will add a new member to the family of atropoisomeric heterocycles, especially the family of axially chiral indole compounds.
Comprehensive Graphic Content
constructing axially chiral alkene-indole
Strategy for
scaffolds:
t-Bu
R2
H
R3
Nu
OH
R
t-Bu
B*-H
OH
Ar
R1
+
Ar
R1
Nu
N
H
Ar
Het
reaction
addition
R1
Ar
NH
3-alkynyl-2-
indolylmethanols
alkene-indoles
alkene-heteroaryls
Reaction for constructing axially chiral alkene-indole scaffolds:
new
A
member
for
the
H
t-Bu
R
SO2
family of axially chiral
heterocycles
t-Bu
OH
Ar
Ar
20 mol% CPA
15 oC
BocHN
Ar1
OH
Ar
Ar
+
R1
R1
p
R
SO2
-xylene,
NH
The
1st
atroposelective
of axially
N
H
2O
H
synthesis
chiral alkene-indoles
all >95:5 E/Z
to 86%
92:8
er
up
yield,
*E-mail: fshi@jsnu.edu.cn; wtan@jsnu.edu.cn
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Supporting Information
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
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through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
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First author et al.
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has not been established yet, which is much more challenging
because of the less hindered rotation around the axis (Scheme 2c).
To achieve this goal, we designed a strategy for constructing al-
kene-indole scaffolds by Brønsted acid (B*-H)-catalyzed enanti-
oselective addition reaction of nucleophiles (Nu) to
3-alkynyl-2-indolylmethanols. Nevertheless, there are some chal-
lenges to be overcome in this strategy, which mainly include: (1)
finding suitable bulky but reactive nucleophiles under B*-H cataly-
sis; (2) increasing the rotational barrier and configurational stabil-
ity of the acyclic alkene-indole scaffold; (3) controlling the
(Z/E)-selectivity and enantioselectivity of the addition reaction.
Background and Originality Content
Axially chiral aryl-based scaffolds are intriguing structures,
which exist in privileged chiral catalysts or ligands,[1] natural prod-
ucts[2] and bioactive molecules.[3] As a result, catalytic enantiose-
lective construction of axially chiral aryl-based scaffolds has be-
come an important area, which has absorbed great attention from
the synthetic chemists.[4-13] However, most of approaches have
been focused on catalytic enantioselective constructing axially
chiral (hetero)biaryls such as six-membered[4-8] or five-membered
(hetero)biaryls,[9-10] and this field has become well-developed
(Scheme 1a). In stark contrast, catalytic enantioselective construc-
tion of axially chiral alkene-arenes, a class of unique members of
atropoisomeric family, has seldom been reported and rather un-
derdeveloped (Scheme 1b). There are only very limited examples
on atroposelective synthesis of axially chiral styrenes or vinyl
arenes, which are based on six-membered aryls such as phenyl
and naphthyl scaffolds.[14-15] Among these approaches, Tan’s group
pioneered the synthesis of axially chiral styrene compounds via an
enantioselective nucleophilic reaction of substituted dio-
nes/ketone esters/malononitrile to alkynals under the catalysis of
a secondary chiral amine, which involved the strategy of iminium
activation.[14a] Nevertheless, the atroposelective construction of
axially chiral alkene-heteroaryl scaffolds is scarcely discovered in
previous reports and remains to be an unknown chemistry. This
result might be ascribed to the formidable challenges inherent in
axially chiral alkene-heteroaryl scaffolds such as lower rotational
barrier and less stable configuration. As a consequence, it is highly
desired to accomplish the atroposelective construction of axially
chiral alkene-heteroaryl scaffolds.
Scheme 2 Design and strategy for constructing axially chiral al-
kene-indole scaffolds
a new
class of axially chiral indole-based scaffolds
a) Designing
R2
R3
an
introducing
alkenyl
R3
R1
R
R2
group
R1
NH
NH
axially chiral alkene-indoles
axially chiral
aryl-indoles
Previous strategy for constructing
scaffold:
b)
aryl-alkene-indole
R2
t-Bu
OH
hindered
around
rotation
axis
R2
H
the
OH
B*-H
t-Bu
R1
O
Ar
(4+3) cyclization
N
Ar
Ar
H
R1
NH
Ar
3-alkynyl-2-
indolylmethanols
aryl-alkene-indoles
Scheme 1 Profile of catalytic enantioselective constructing axially chiral
This strategy
constructing alkene-indole
for
scaffold:
less hindered rotation
c)
aryl-based scaffolds
around
axis
the
t-Bu
Construction of axially chiral
Well-developed
a)
(hetero)biaryls:
H
Nu
t-Bu
OH
Ar
Ar
Ar
Ar
Het
Ar
OH
Het
Het
R1
Nu
R1
R1
R1
R
R1
R
B*-H
reaction
Ar
N
R1
NH
addition
Ar
R
R
H
Het
Ar
alkene-indoles
3-alkynyl-2-
more
indolylmethanols
challenging
six-membered
five-membered
(hetero)biaryls
(hetero)biaryls
Challenges:
Construction of axially chiral alkene-arenes: Underdeveloped
b)
reactive
increasing the rotational barrier
under B*-H catalysis
finding suitable
(1)
nucleophiles
and
stability
(2)
(3)
configurational
reaction
R3
R3
and
controlling the Z E
/
of
enantioselectivity the
(
)-
Challenges:
R4
R4
R2
R1
R2
X
R2
lower rotational barrier
R1
less stable
configuration
unknown chemistry
R1
Het
To solve these challenges in constructing axially chiral al-
kene-indole scaffolds, based on our experience in catalytic enanti-
oselective synthesis of indole derivatives,[24] we designed an enan-
tioselective addition reaction of 3-alkynyl-2-indolylmethanols with
α-amido sulfones in the presence of chiral phosphoric acid
(CPA).[25] It should be noted that Yan’s group utilized α-amino sul-
fones as competent nucleophiles to undergo conjugate addition
with vinylidene ortho-quinone methides in the presence of chiral
bifunctional organocatalysts, thus affording axially chiral styrene
compounds.[26] So, in this design (Scheme 3), α-amido sulfones
were selected as suitable nucleophiles considering their bulky size
and good reactivity under B*-H catalysis, which could act as sur-
rogates of sulfonyl groups. The bulky groups of sulfonyl and t-butyl
around the axis of alkene-indole products would increase the rota-
tional barrier and configurational stability of the acyclic al-
kene-indole scaffold. In the key step of the nucleophilic addition,
CPA would simultaneously activate both the allene-iminium in-
termediates[23] and α-amido sulfones via hydrogen-bonding inter-
action, thus controlling the (Z/E)-selectivity and enantioselectivity
=
vinyl
X
CHR,
O,
arenes
NR
or
styrenes
alkene-heteroaryls
In recent years, catalytic enantioselective construction of in-
dole-based axially chiral frameworks has become an emerging
area[16] because indole belongs to five-membered heteroaryls with
unique properties.[17] Synthetic chemists have designed innovative
strategies for constructing different axially chiral aryl-indoles such
as N-arylindoles,[18] 3-arylindoles,[19] 2-arylindoles[20] and bisin-
doles.[21] Based on these works, we conceived if an alkenyl group
was introduced to the indole moiety, axially chiral alkene-indoles
as a new class of atropoisomeric indole-based scaffolds would be
generated (Scheme 2a). However, the atroposelective construc-
tion of axially chiral alkene-indole scaffolds has scarcely been re-
ported. Recently, we designed 3-alkynyl-2-indolylmethanols as a
new class of indolylmethanols[22] and established their involved
catalytic enantioselective (4+3) cyclization, which afforded axially
chiral cyclic aryl-alkene-indoles due to the hindered rotation
around the axis (Scheme 2b).[23] In spite of this progress, catalytic
enantioselective construction of acyclic alkene-indole frameworks
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Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
of the addition reaction.
Table 1 Screening of catalysts and optimization of reaction conditionsa
G
G
Scheme 3 Design of the catalytic enantioselective addition reaction for
=
4a
4b
G
G
G
G
G
4-ClC6H4
,
,
=
=
=
=
=
=
2-
O
O
O
naphthyl
constructing axially chiral alkene-indole scaffolds
O
O
O
4c
,
P
1-
naphthyl
P
t-Bu
OH
4d
,
,
,
H
OH
9-phenanthrenyl
9-anthracenyl
4e
4f
SO2R
t-Bu
G
G
i-Pr) C H
2,4,6-(
SiPh3
G
3
6
2
G
,
OH
Ar
Ar
4g
=
OH
Ar
Ar
G
BocHN
Ar1
CPA
9-phenanthrenyl
5a
4
R
(
)-
+
R1
R
( )-
addition
R1
NH
SO2R
N
t-Bu
H
H
3-alkynyl-2-
α
axially chiral alkene-indoles
-amido sulfones
Ts
indolylmethanols
CPA
NHBoc
t-Bu
mol%
10
Cat.
Boc
CPA
N
+
OH
Ph
Ph
OH
Ph
Ph
Ar
Ts
=
25 o solvent
C,
Ar1
N
H
NH
3a
2a
Ar Ph
,
t-Bu
t-Bu
1a
=
2b
Ar 4-NO2C6H4
,
H
H
Ar1
RO2S
BocHN
NBoc
Ar1
entry
1
Cat.
4a
4b
4c
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
o-xylene
m-xylene
p-xylene
2
yield (%)b
41
erc
SO2R
OH
Ar
OH
H
R1
R1
N
N
H
Ar
Ar
Ar
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
64:36
63:37
67:33
76:24
68:32
55:45
51:49
76:24
77:23
80:20
81:19
78:22
82:18
90:10
90:10
92:8
O
O
H
O
O
P
P
2
35
*
*
allene-iminium
addition
nucleophilic
3
44
4
4d
4e
4f
48
5
48
Results and Discussion
6
44
Based on this design, we tried the reaction of
3-alkynyl-2-indolylmethanol 1a with α-amido sulfone 2a in the
presence of CPA 4a in toluene at 25 C (Table 1, entry 1). Gratify-
ingly, the addition reaction occurred as what we designed, and
axially chiral alkene-indole 3a was generated albeit with a low
yield of 41% and some extent of enantio-control (64:36 er). Nev-
ertheless, this preliminary result demonstrated the feasibility of
constructing axially chiral alkene-indole scaffolds via catalytic en-
7
4g
5a
5a
5a
5a
5a
5a
5a
5a
5a
26
8
52
o
9
40
10
11
12
13d
14d,e
15e,f
16e,f
52
54
mesitylene
p-xylene
p-xylene
p-xylene
p-xylene
36
antioselective
addition
reaction
between
65
3-alkynyl-2-indolylmethanols and α-amido sulfones. Then, to im-
prove the yield and the enantioselectivity of product 3a, a series
of CPAs 4b-4g bearing different 3,3’-substituents were screened
for this reaction (entries 2-7), and it was discovered that CPA 4d
bearing two 3,3’-(9-phenanthrenyl) groups could catalyze the re-
action in a higher enantioselectivity (76:24 er) than other CPAs
(entry 4 vs entries 1-3 and 5-7). Moreover, changing the backbone
of CPA 4d from BINOL to H8-BINOL, namely, using
H8-BINOL-derived CPA 5a as a catalyst led to a slightly improved
yield with retained enantioselectivity (entry 8 vs entry 4). So, CPA
5a was utilized as the optimal catalyst for this addition reaction.
The subsequent evaluation of toluene-type solvents (entries 9-12)
revealed that using p-xylene as the solvent could further enhance
the enantioselectivity from 76:24 er to 81:19 er (entry 11 vs entry
8). To improve the yield, a small amount of water was added to
the reaction mixture based on the consideration that water will
facilitate the generation of nucleophilic sulfonyl group from sub-
strate 2a. Indeed, using water as an additive in the reaction re-
sulted in an increased yield with a maintained enantioselectivity
(entry 13 vs entry 11). Subsequently, the reaction temperature,
catalyst loading and molar ratio of the reagents were carefully
adjusted (see the Supporting Information for details), which found
that the enantioselectivity of 3a could be elevated to 90:10 er in
64
73
68
aUnless otherwise indicated, the reaction was carried out on a 0.1 mmol
scale and catalyzed by 10 mol% Cat. under argon atmosphere in solvent (1
mL) at 25 oC for 24 h, and the molar ratio of 1a:2a was 1:1.2. bIsolated yield
and only the (E)-isomer was observed in all cases. cThe er value was deter-
mined by HPLC. dUsing H2O (5 μL) as an additive. eCatalyzed by 20 mol% 5a
at 15 oC and the molar ratio of 1a:2 was 1:1.5. Using H2O (50 μL) as an
additive.
f
After establishing the optimal reaction conditions, we investi-
gated the substrate scope of 3-alkynyl-2-indolylmethanols 1 in the
catalytic enantioselective addition reactions for the construction
of axially chiral alkene-indole frameworks. As shown in Table 2, a
series of 3-alkynyl-2-indolylmethanols 1 bearing different R\R1
substituents could smoothly participate in the addition reaction
with α-amido sulfone 2a or 2b under the standard conditions,
which afforded axially chiral alkene-indoles 3 in moderate yields
(53% to 76%) and good enantioselectivities (82:18 to 92:8 er).
Apart from substrate 1a (entry 1), it was discovered that C5-chloro
and C5-fluoro-substituted 3-alkynyl-2-indolylmethanols 1b-1c
were competent substrates, which delivered axially chiral products
3b-3c in higher enantioselectivities (entries 2-3). As to R1 substit-
uents, ortho-, meta- and para-substituted phenyl groups proved to
be suitable substituents for substrates 1, which could generate
substantial steric congestion around the axis for constructing axi-
ally chiral alkene-indole frameworks (entries 5-9).
o
the presence of 20 mol% 5a at 15 C with the molar ratio of 1:1.5
(entry 14). Furthermore, precisely modulating the amount of wa-
ter to 50 μL improved the yield of 3a to 73% (entry 15). Under
these conditions, other types of solvents were screened, but no
other solvents were better than p-xylene (see the Supporting In-
formation for details). Finally, changing α-amido sulfone from 2a
to 2b under these conditions led to a further enhanced enanti-
oselectivity of 92:8 er (entry 16). Thus, these conditions as illus-
trated in entries 15-16 were selected as the optimal reaction con-
ditions for generating axially chiral alkene-indole products.
Chin. J. Chem. 2021, 39, XXX－XXX
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First author et al.
Report
Table 2 Generality of 3-alkynyl-2-indolylmethanols 1a
4
5
6
7
8
9
p-FC6H4/Ph (2e)
m-BrC6H4/Ph (2f)
m-MeC6H4/Ph (2g)
Ph/Ph (2h)
3l
3m
3n
3o
3p
3q
56
80
75
72
80
86
85:15
82:18
88:12
87:13
90:10
84:16
t-Bu
H
Ts
NHBoc
t-Bu
mol%
5a
R
)-
20
(
+
OH
R1
OH
R1
R1
15 o
C
Ar
Ts
p
R
-xylene,
H2O
R1
N
R
NH
=
=
2a
,
Ar Ph
H
1
2b
Ar 4-NO2C6H4
,
2-Naphthyl/4-NO2C6H4 (2i)
3
Et/Ph (2j)
yield
(%)b
68
erc
entry
R\R1 (1)
2
3
aUnless otherwise indicated, the reaction was carried out on a 0.1 mmol
scale and catalyzed by 20 mol% (R)-5a under argon atmosphere in p-xylene
(1 mL) with water (50 μL) as an additive at 15 C for 24 h, and the molar
ratio of 1a:2 was 1:1.5. bIsolated yield and only the (E)-isomers of products
3 were observed in all cases. cThe er value was determined by HPLC.
o
1
2
3
4
5
6
7
8
9
H\Ph (1a)
5-Cl\Ph (1b)
5-F\Ph (1c)
2b
2b
2b
2a
2b
2b
2b
2b
2b
3a
3b
3c
3d
3e
3f
92:8
92:8
54
60
91:9
To investigate the effect of dialkyl groups in substrates 1 on the
reaction, we employed 3-alkynyl-2-indolylmethanol 1j bearing two
iso-propyl groups as a substrate in the reaction with α-amido sul-
fone 2i under the standard conditions (Scheme 4). It was discov-
ered that substrate 1j displayed a much lower capability in control-
ling the reactivity and the enantioselectivity than its di-
aryl-substituted counterparts because the reaction of 1j just af-
forded axially chiral alkene-indole 3r in 38% yield with 64:36 er. So,
this result implies that the diaryl groups in substrates 1 are neces-
sary for this reaction to achieve a high yield and good enantiose-
lectivity.
5-(tBu-ethynyl)\Ph (1d)
H\o-MeOC6H4 (1e)
H\m-MeC6H4 (1f)
H\p-FC6H4 (1g)
53
82:18
85:15
88:12
89:11
88:12
82:18
58
76
3g
3h
3i
64
H\p-MeC6H4 (1h)
H\p-PhC6H4 (1i)
71
70
aUnless otherwise indicated, the reaction was carried out on a 0.1 mmol
scale and catalyzed by 20 mol% (R)-5a under argon atmosphere in p-xylene
o
Scheme 4 Investigation on the effect of dialkyl groups in substrates 1
(1 mL) with water (50 μL) as an additive at 15 C for 24 h, and the molar
ratio of 1:2 was 1:1.5. bIsolated yield and only the (E)-isomers of products 3
were observed in all cases. cThe er value was determined by HPLC.
H
t-Bu
SO
22-Naphthyl
OH
t-Bu
NHBoc
mol%
5a
OH
i-Pr
i-Pr
20
R
)-
15 o
(
i-Pr
i-Pr
NH
+
Ar
SO
22-Naphthyl
Next, the substrate scope of α-amido sulfones 2 were studied by
the catalytic addition reaction with 3-alkynyl-2-indolylmethanol 1a
under the optimal reaction conditions. As listed in Table 3, a wide
range of α-amido sulfones 2 bearing various sulfonyl R groups
could serve as competent substrates for this reaction, which gen-
erated axially chiral alkene-indoles 3 in overall high yields and
good enantioselectivities. In detail, either para- (entries 1-4) or
meta-substituted (entries 5-6) phenyl groups could be utilized as
suitable sulfonyl R groups. In addition to phenyl group (entry 7),
2-naphthyl group could also serve as sulfonyl R group, and this
substrate 2i successfully took part in the addition reaction to give
axially chiral alkene-indole 3p in a high yield of 80% and consider-
able enantioselectivity of 90:10 er (entry 8). Notably, apart from
aryl groups, ethyl group as an aliphatic substituent could act as a
competent sulfonyl R group for substrate 2j, which smoothly un-
derwent the addition reaction to give alkene-indole 3q with axial
chirality in a good yield (entry 9). It should be noted that only the
(E)-isomers of products 3 were observed in all cases during the
investigation on the substrate scope, which demonstrated the
excellent (E/Z)-selectivity of the addition reaction.
p
C
-xylene,
H2O
N
=
Ar 4-NO2C6H4
3r
H
er
1j
38%
64:36
2i
yield,
The absolute configuration of alkene-indole product 3a was de-
termined to be (Sa) based on the X-ray diffraction analysis of its
single crystal (Figure 1).[27] Because all of the alkene-indole prod-
ucts 3 were synthesizing under the catalysis of CPA (R)-5a, the
absolute configurations of other products 3 were assigned as (Sa)
by analogy with that of 3a.
H
Ts
t-Bu
OH
Ph
Ph
NH
3a
Sa
)-
(
Figure 1 Absolute configuration of product 3a
To suggest a possible activation mode of CPA catalyst on the
substrates, we performed a control experiment to investigate the
role of NH group in 3-alkynyl-2-indolylmethanols. Namely,
N-methyl-protected 3-alkynyl-2-indolylmethanol 1k was utilized as
a substrate in the addition reaction with α-amido sulfone 2b under
standard conditions (Scheme 5a). In this case, N-methyl-protected
substrate 1k exhibited very low reactivity, which afforded al-
kene-indole 3s in an extremely low yield (13%) with a poor enan-
tioselectivity (56:44 er). This result indicated that the NH group of
3-alkynyl-2-indolylmethanols played an important role in control-
ling both the reactivity and the enantioselectivity of the addition
reaction, which might generate hydrogen-bonding interaction with
CPA catalyst. Based on this control experiment and our previous
theoretical calculations,[23] we suggested a possible reaction
pathway and activation mode for this CPA-catalyzed enantioselec-
tive addition reaction (Scheme 5b). Initially, activated by CPA
Table 3 Substrate scope of α-amido sulfones 2a
t-Bu
H
SO2R
t-Bu
NHBoc
mol%
5a
20
R
)-
15 o
(
OH
Ph
OH
Ph
Ph
+
Ar
p
C
SO2R
-xylene,
H2O
N
Ph
NH
H
2
1a
3
yield
(%)b
68
erc
entry
R/Ar (2)
3
1
2
3
p-MeC6H4/4-NO2C6H4 (2b)
p-tBuC6H4/4-NO2C6H4 (2c)
p-MeOC6H4/Ph (2d)
3a
3j
92:8
86:14
84:16
83
3k
83
(R)-5a
via
hydrogen-bonding
interaction,
www.cjc.wiley-vch.de
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
3-alkynyl-2-indolylmethanols 1 are easily transformed into al-
lene-iminium intermediates A. Then, the anion of CPA (R)-5a sim-
dration to generate a carbocation intermediate, which is readily
trapped by nucleophiles (Nu-H) to accomplish nucleophilic substi-
tutions (Scheme 7a). Based on this proposed reactivity, diphe-
nylphosphine oxide and indole were utilized as suitable nucleo-
philes to react with compound 3a (92:8 er) under the catalysis of
RPA in 1,2-dichloroethane (DCE), which afforded derivation prod-
ucts 6-7 in an excellent yield of 98% and retained enantioselectivi-
ty of 92:8 er (Scheme 7b). Interestingly, when we tried to reduce
compound 6 into its phosphine derivative under commonly used
conditions, the phosphine derivative was not obtained. Instead,
the functionality of diphenylphosphine oxide in compound 6 was
removed to generate product 8 with a nearly maintained enanti-
oselectivity, which provided an alternative method for the synthe-
sis of compound 8 from 3a.
ultaneously activated allene-iminium intermediates
A and
α-amido sulfones 2 via forming two hydrogen bonds, thus facili-
tating a nucleophilic addition between them to generate axially
chiral alkene-indoles (Sa)-3 with the release of imines B and CPA
(R)-5a.
Scheme 5 Control experiment and suggested activation mode
Control
experiment
a)
t-Bu
H
Ts
t-Bu
NHBoc
mol%
5a
20
R
OH
Ph
Ph
(
)-
15 o
+
OH
Ph
Ph
Ar
Ts
=
p
C
-xylene,
H2O
N
N
2b
Ar 4-NO2C6H4
,
Me
Me
1k
3s
er
13%
56:44
yield,
Scheme 7 Derivation of product 3a via nucleophilic substitutions
mode
activation
b) Suggested
Possible reactivity of
functionality in
3a
product
a)
2-indolylmethanol
t-Bu
H
H
t-Bu
H
Ts
Ts
t-Bu
H
Ph
Ph
t-Bu
OH
Ar
RPA
Ph
R1
5a
R
)-
O
OH
(
Ph
1
OH
R1
N
H
Nu
H
P
Ar
Ar
Nu
NH
3a
O
O
*
A
N
NH
Ar
H
O
1
P
5a
R
)-
(
allene-iminium
-
*
H2O
RPA
RPA
H
H
t-Bu
Ts
Ts
H
t-Bu
Ar1
Nu
H
t-Bu
RO2S
H
Ph
Ph
Ph
Nu
H
5a
SO2R
R
(
)-
O
P
NBoc
2
t-Bu
Ph
O
O
OH
2
R1
H
O
OH
Ar
N
NH
P
H
N
H
Ar
Ar
3a
3a
Boc
R1
NH
O
Ar
A
N
O
P
Ar1
B
substitutions of
3a
product
3
b)
Nucleophilic
Sa
)-
*
(
H
addition
H
nucleophilic
O
Ts
Ts
t-Bu
t-Bu
PHPh2
mol%
Ph
Ph
Furthermore, we investigated the stability and the rotational
Ph
Ph
HSiCl3
NEt3
20
RPA
barriers of this class of axially chiral alkene-indoles (Scheme 7). As
shown in Scheme 6a, product 3c with 91:9 er was stirred in iso-
propanol at 150 oC for five to eight hours. In spite of the high
temperature, compound 3c was recovered in 98% yield with
maintained enantioselectivity of 91:9 er, which implied that axially
chiral product 3c is very stable. To gain some insights into the ob-
served stability, the rotational barriers of compounds 3a and 3c
were theoretically calculated (see the Supporting Information for
details). As illustrated in Scheme 6b, the rotational barriers of
compounds 3a and 3c are 184.43 and 180.66 kJ mol-1, respectively.
Both of them are much larger than the rotational barrier (100 kJ
mol-1) to isolate the individual atropoisomers in the literature,[2f]
which are in accordance with the observed stability.
PPh2
DCE, 80 o
C
NH
toluene
NH
H
120 o
C
O
8
6
Ts
er
er
92:8
40%
91:9
98%
yield,
yield,
t-Bu
Ph
Ph
H
OH
Ts
NH
er
t-Bu
Ph
Ph
O
O
3a
N
H
RPA
P
92:8
OH
O
mol%
20
NH
NH
DCE, 50 o
C
7
RPA
er
92:8
98%
yield,
Conclusions
Scheme 6 Investigation on the stability and rotational barriers
In summary, we have established atroposelective construction
of axially chiral alkene-indole scaffolds via the strategy of catalytic
enantioselective addition reaction of 3-alkynyl-2-indolylmethanols
with bulky nucleophiles. In this strategy, α-amido sulfones were
used as competent nucleophiles and chiral phosphoric acid acted
as suitable chiral catalyst for this addition reaction. By this strategy,
a new class of axially chiral acyclic alkene-indoles was synthesized
in overall high yields (up to 86%), excellent (E/Z)-selectivity
(all >95:5) and good enantioselectivities (up to 92:8 er). This reac-
tion represents the first catalytic enantioselective construction of
axially chiral acyclic alkene-indole frameworks, which will add a
new member to the family of atropoisomeric heterocycles, espe-
cially the family of axially chiral indole compounds. In addition,
this approach provides a useful strategy for constructing axially
chiral alkene-indole scaffolds.
on
Investigation
the stability
a)
i-PrOH, 150 °C
3c
recovered
3c
er
91:9
t
h,
sealed tube
er
er
5 h
8 h
91:9
98%,
98%, 91:9
on
Investigation
the rotation barriers
b)
H
H
Ts
Ts
t-Bu
t-Bu
OH
Ph
OH
Ph
Ph
Ph
F
NH
NH
3c
3a
184.43
rotation barrier
(kJ/mol):
180.66
Finally, we tried the derivation of product 3a via nucleophilic
substitutions (Scheme 7). Because there is an indolylmethanol
functionality in the structure of product 3a, it is anticipated that
this functionality might be used for nucleophilic substitutions.
Namely, in the presence of an acid such as racemic phosphoric
acid (RPA), the indolylmethanol functionality can undergo dehy-
Experimental
General Procedure for the synthesis of products 3:
3-Alkynyl-2-indolylmethanol 1 (0.1 mmol), α-amido sulfone 2
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

First author et al.
Report
(0.15 mmol), chiral phosphoric acid (R)-5a (0.02 mmol) and H2O
(50 μL) were added to a sealed tube. Then, p-xylene (1.0 mL)
pre-cooled to 15 oC was added to the reaction mixture, which was
by Asymmetric Catalytic Reactions with Transition Metals. Coordin. Chem.
Rev. 2016, 308, 131–190; (d) Witzig, R. M.; Lotter, D.; Fäseke, V. C.; Sparr,
C. Stereoselective Arene-Forming Aldol Condensation: Catalyst-Controlled
Synthesis of Axially Chiral Compounds. Chem. Eur. J. 2017, 23, 12960–
12966; (e) Renzi, P. Organocatalytic Synthesis of Axially Chiral Atropiso-
mers. Org. Biomol. Chem. 2017, 15, 4506–4516; (f) Wang, Y.-B.; Tan, B.
Construction of Axially Chiral Compounds via Asymmetric Organocatalysis.
Acc. Chem. Res. 2018, 51, 534–547; (g) Bonne, D.; Rodriguez, J. Enanti-
oselective Syntheses of Atropisomers Featuring a Five-Membered Ring.
Chem. Commun. 2017, 53, 12385–12393; (h) Bonne, D.; Rodriguez, J. A
Bird's Eye View of Atropisomers Featuring a Five-Membered Ring. Eur. J.
Org. Chem. 2018, 2018, 2417–2531; (i) Zhang, S.; Liao, G.; Shi, B.-F. Enan-
tioselective Synthesis of Atropisomers Featuring Pentatomic Heteroaro-
matics. Chin. J. Org. Chem. 2019, 39, 1522–1528; (j) Da, B.-C.; Xiang, S.-H.;
Li, S.; Tan, B. Chiral Phosphoric Acid Catalyzed Asymmetric Synthesis of
o
stirred under argon atmosphere at 15 C for 24 h. After the com-
pletion of the reaction which was indicated by TLC, the reaction
mixture was purified through flash column chromatography on
silica gel to afford pure product 3.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2021xxxxx.
Acknowledgement
Axially
10.1002/cjoc.202000751.
Chiral
Compounds,
Chin.
J.
Chem.
2021,
DOI:
We are grateful for financial support from National Natural
Science Foundation of China (21772069 and 21831007), Post-
graduate Research & Practice Innovation Program of Jiangsu Prov-
ince (KYCX20_2235), and Natural Science Foundation of JSNU
(19XSRX013). We sincerely appreciate Prof. Yinchun Jiao for her
help in theoretical calculations.
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Manuscript received: XXXX, 2021
Manuscript revised: XXXX, 2021
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Entry for the Table of Contents
Atroposelective Construction of Axially Chiral Alkene-Indole Scaffolds via Catalytic Enantioselective Addition Reaction of
3-Alkynyl-2-indolylmethanols
Jing-Yi Wang, Meng Sun, Xian-Yang Yu, Yu-Chen Zhang, Wei Tan* and Feng Shi*
Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
The first
construction
axially chiral alkene-indole
of
frameworks
atroposelective
H
t-Bu
R
SO2
t-Bu
OH
CPA
BocHN
OH
Ar
Ar
+
Ar
reaction
addition
all >95:5 E/Z
to 86%
92:8
R1
Ar1
Ar
NH
R
SO2
R1
N
H
axially chiral
alkene-indoles
er
up
yield,
An atroposelective construction of axially chiral alkene-indole scaffolds has been established via the strategy of catalytic enantioselective addition
reaction of 3-alkynyl-2-indolylmethanols with α-amido sulfones in the presence of chiral phosphoric acid. By this strategy, a new class of axially chiral
acyclic alkene-indoles was synthesized in overall high yields (up to 86%), excellent (E/Z)-selectivity (all >95:5) and good enantioselectivities (up to 92:8
er). This reaction represents the first catalytic enantioselective construction of axially chiral alkene-indole frameworks.
www.cjc.wiley-vch.de
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, XXX－XXX