An Atropo-enantioselective Synthesis of Benzo-Linked Axially Chiral Indoles via Hydrogen-Bond Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b01828

A variety of axially chiral biaryldiols were synthesized in good yields with excellent atropo-enantioselectivities through construction of axially chiral indoles catalyzed by asymmetric hydrogen-bond donors. In addition, the new axially chiral compounds w

Full text of DOI:10.1021/acs.orglett.9b01828

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
An Atropo-enantioselective Synthesis of Benzo-Linked Axially Chiral
Indoles via Hydrogen-Bond Catalysis
Jin-Yu Liu,† Xie-Chao Yang,† Zhen Liu,† Yong-Chun Luo,† Hong Lu,‡ Yu-Cheng Gu,§ Ran Fang,†
and Peng-Fei Xu*,†
†State Key Laboratory of Applied Organic Chemistry, School of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000. P. R. China
‡Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry &
Materials Science, Northwest University, Xi’an 710069, P. R. China
§Syngenta Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, U.K.
S
* Supporting Information
ABSTRACT: A variety of axially chiral biaryldiols were synthesized in good yields with excellent atropo-enantioselectivities
through construction of axially chiral indoles catalyzed by asymmetric hydrogen-bond donors. In addition, the new axially chiral
compounds were proved to be efficient and practical catalysts for asymmetric catalysis. The strategy not only provides a novel
method to synthesize axially chiral compounds but also extends the scope of chiral catalysts.
ith the rapid development of chiral chemistry over the
past decade, axially chiral compounds1 have been
chirality of indoles in the carbocyclic ring. Consequently, the
construction of axial chirality through functionalization of
indoles in the carbocyclic ring is still an undiscovered area for
synthetic chemists.
W
extensively studied because of their widespread applications as
bioactive molecules,2 natural products,3 and chiral catalysts in
asymmetric catalysis.4 However, most of the axially chiral
compounds, especially commercially available catalysts, are
synthesized by chiral resolution, an inefficient method with a
yield of less than 50%.5 Some significant methods through
asymmetric metal catalysis have been reported to realize the
construction of axial chirality.3b,6 Compared with relatively
mature metal catalysis, asymmetric organocatalysis is a rising
star in the world of axial chirality,7 which includes phosphoric
acid catalysis,8 bifunctional catalysis,9 amine catalysis,10
ammonium salt catalysis11 and peptide catalysis.12 Notably,
to our knowledge, hydrogen-bond catalysis has never been
reported for the direct construction of axial chirality.13
The synthesis and modifications of indole scaffolds have
attracted much attention from organic chemists because of
their enormous potential and widespread applications.14
Particularly, most of the research has been focused on the
functionalization of indoles in the five-membered heterocyclic
ring.15 In recent years, some effective strategies via organo-
catalysis have been demonstrated to achieve the enantiose-
lective functionalization of indoles in the carbocyclic ring.16
However, all of these methods have constructed central
In 2018, our group successfully realized the asymmetric C−
H functionalization of indoles in the carbocyclic ring via
organocatalysis (Scheme 1a).16f The groups of Tan8h and Shi8d
reported effective strategies to construct axially chiral indoles
through functionalization of indoles in the five-membered
heterocyclic ring via phosphoric acid catalysis (Scheme 1b).
On the basis of the previous works and our interest in
asymmetric organocatalysis,17 we envisioned that the con-
struction of axial chirality through functionalization of indoles
in the carbocyclic ring might be achieved via hydrogen-bond
catalysis (Scheme 1c).
The study was initiated by testing the model reaction of 5-
hydroxyindole (1a) and iminoquinone derivative 2a in the
presence of hydrogen-bond donor I in CH2Cl2 (1 mL) at −20
°C, and the expected axially chiral product 3a was successfully
produced in moderate yield with an encouraging level of
atropo-enantioselectivity (Table 1, entry 1). In this model
Received: May 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01828
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
reaction, 5-hydroxyindole was used as the substrate instead of
4-hydroxyindole, which was used in our previous work to
achieve the asymmetric C−H functionalization of indole in the
carbocyclic ring, because of the higher rotation barrier. Various
hydrogen-bond donors (Figure 1) were then examined, and
Scheme 1. Construction of Axial Chirality through
Functionalization of Indoles in the Carbocyclic Ring
Figure 1. Catalysts investigated in the reaction.
chiral cyclohexanediamine-derived thiourea IV turned out to
be the optimal catalyst (Table 1, entries 1−7). Notably, the
bifunctional catalyst successfully produced the product, albeit
with modest enantioselectivity (Table 1, entry 8). However,
the chiral phosphoric acid, which has been commonly used to
construct axial chirality, could not promote the reaction (Table
1, entry 9). Adjusting the configuration of catalyst IV afforded
the product with opposite configuration (Table 1, entry 10).
Next, various solvents were screened, and toluene was found to
be optimal (Table 1, entries 11−15). THF and MeCN, which
are hydrogen-bond acceptors, inhibited the reaction (Table 1,
entries 13 and 14). Further study of the reaction temperature
indicated that low temperature could improve the enantiose-
lectivity (Table 1, entry 16), but a much lower temperature
was not better for the reaction because of reduced solubility of
the catalyst (Table 1, entry 17). Finally, the addition of 4 Å
molecular sieves did not affect the reaction (Table 1, entry 18),
and 1 equiv of substrate 1a was enough (Table 1, entry 19).
With the optimal reaction conditions established, various
hydroxyindoles 1 and iminoquinone derivatives 2 with
different electronic and steric properties were investigated for
the reaction (Table 2). All of the reactions proceeded
smoothly to afford the axially chiral products when substituted
5-hydroxyindoles were used as substrates (Table 2, 3a−e), and
2-methyl-5-hydroxyindole gave the best enantioselectivity
(Table 2, 3c).18 When the p-toluenesulfonyl substituent of
substrate 2 was changed to a methylsulfonyl group, the
reaction could also produce the product but with a relatively
low yield and enantioselectivity (Table 2, 3f vs 3a), probably
because of the weaker interaction between substrate 2 and the
catalyst. In addition, the electronic properties of substrates 2
had pronounced effects on the stereoselectivity and yield. In
general, substrates 2 with electron-donating substituents
(Table 2, 3g and 3h) or electron-rich aromatic rings (Table
2, 3i−l) exhibited higher reactivities compared with those with
electron-withdrawing substituents, which needed a higher
reaction temperature (Table 2, 3m). More electron-with-
drawing substituents (Br or NO2) inhibited the reaction.
Furthermore, halogen-monosubstituted quinone derivatives
were well-tolerated (Table 2, 3n and 3o), and substrates 2
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
catalyst
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
I
II
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
72
7
41
90
60
11
33
93
−37
−
−
45
−
−93
−93
−95
−7
−
−60
−97
−94
−97
−97
III
IV
V
VI
VII
VIII
IX
X
X
X
X
X
58
trace
trace
58
NR
91
>99
>99
54
trace
78
10
11
12
13
14
15
toluene
THF
MeCN
EtOAc
toluene
toluene
toluene
toluene
X
X
X
X
d
16
>99
91
>99
>99
e
17
18
df
,
dg
,
19
X
a
Conditions: the reactions were performed with 1a (0.15 mmol), 2a
(0.1 mmol), and the catalyst (20 mol %) in CH2Cl2 (1 mL) at −20
°C for 12 h. For detailed experimental procedures, see the Supporting
b
c
Information. Isolated yields. Determined by chiral-phase HPLC
d
e
f
g
analysis. At −40 °C. At −78 °C. 50 mg of 4 Å MS was added. 0.1
mmol of 1a was used.
B
DOI: 10.1021/acs.orglett.9b01828
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Table 2. Scope of the Asymmetric Synthesis of Axially
Chiral Biaryldiols
Scheme 2. Application of Axially Chiral Biaryldiol 3c
a
performed, and the hydrogen-bond catalyst was recycled
(Table 3). Fortunately, the reaction proceeded smoothly to
Table 3. Recovery of the Hydrogen-Bond Catalyst in Large-
Scale Reactions
no. of recovery
cycles
yield of catalyst
(%)
ee
(%)
entry
yield of 3c (%)
1
2
3
4
5
6
0
1
2
3
4
5
−
99
99
98
98
98
90
89
89
89
88
88
>99
>99
>99
>99
>99
>99
afford the axially chiral product with excellent results, and the
catalyst remained active even after five recycles (Table 3, entry
6).
NMR experiments on mixtures of substrates and catalysts
were conducted to explore the reaction mechanism (Figure 2).
The H NMR spectrum of the mixture revealed that the
catalyst interacted with quinone derivative 2a via hydrogen
bonding to generate a new activated complex. With the
stepwise addition of the catalyst, the 1H NMR spectrum of the
mixture showed that the signal of substrate 2a gradually
weakened and the signal of the new activated complex was
a
1
Conditions: the reactions were performed with 1 (0.1 mmol), 2 (0.1
mmol), and catalyst X (20 mol %) in toluene (1 mL) at −40 °C for
12 h. For detailed experimental procedures, see the Supporting
Information.
with relatively low reactivities showed more satisfactory results
when 2-methyl-5-hydroxyindole was used as the substrate
(Table 2, 3p−s). Unfortunately, naphthoquinone derivatives
could not produce the desired products, and the materials were
completely recycled.
To demonstrate the application of axially chiral biaryldiols as
asymmetric catalysts, an enantioselective allylboration of a
ketone catalyzed by the axially chiral product 3c was carried
out. The experimental results revealed that this new type of
axially chiral biaryldiol had more efficient catalytic activity and
stereocontrol ability than traditional binaphthols report
previously19 (Scheme 2). Notably, when the chiral biphenol,
which has a wider bite angle than BINOLs, was used as the
catalyst, the reaction could provide only the racemic products.
This result indicated that the Ts group and indole may play
important roles in the process.
To further explore the practicability of the axially chiral
product, a large-scale asymmetric synthesis of 3c was
Figure 2. Continuous NMR experiments.
C
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enhanced gradually (Figure 2). Additionally, when 0.5 equiv of
the catalyst was used (Figure 2), completely transformed 2a
(the signal of substrate 2a disappeared completely) demon-
strated a 1:2 binding interaction between the catalyst and 2a.
The hydroxyl group of substrate 1a was proved to have weak
interaction with the catalyst on the basis of the obvious
changes of the chemical shifts between the mixture and pure 5-
hydroxyindole (Figure 3), and the Lewis basic property of the
aromatization could be ruled out because the corresponding
product at C6 of the indole and the O-addition product of
imine were not observed (the materials were completely
recycled) when 4-fluoro-5-hydroxyindole was used as the
substrste (Scheme 3b).8c
In summary, we have developed a practical and efficient
approach for constructing axial chirality through functionaliza-
tion of indoles in the carbocyclic ring catalyzed by hydrogen-
bond donors, and a series of axially chiral biaryldiols with
asymmetric catalysis potential were obtained in moderate to
high yields with good atropo-enantioselectivities. Notably, the
axially chiral product showed more efficient catalytic activity
and stereocontrol ability than traditional binaphthols, com-
plementing and extending the scope of chiral catalysts.
Furthermore, mechanistic studies provided new insights into
the construction of axially chiral indoles via hydrogen-bond
catalysis. Further studies of applications of these compounds as
ligands and catalysts for asymmetric catalysis are currently
underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01828.
Figure 3. Exploration of the reaction mechanism.
Experimental details, characterization data, and HPLC
data for all compound derivatives (PDF)
sulfur atom was thought to play a role in the reaction. Further
experiment showed that 5-methoxyindole could not produce
the product because of the lack of the interaction between a
hydroxyl group and the catalyst (Scheme 3a).
Accession Codes
CCDC 1898795 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
Scheme 3. Control Experiments
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xupf@lzu.edu.cn.
ORCID
Yong-Chun Luo: 0000-0002-9567-7297
Ran Fang: 0000-0001-6804-6572
Peng-Fei Xu: 0000-0002-5746-758X
Notes
On the basis of our experimental results and previous
reports, a plausible reaction mechanism is proposed (Figure 4).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21871116, 21632003, and 21572087), The Key
Program of Gansu Province (17ZD2GC011), and the “111”
Program of the MOE of P. R. China for financial support. We
also gratefully acknowledge a Syngenta Postgraduate Fellow-
ship awarded to J.-Y.L.
Figure 4. Proposed mechanism.
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DOI: 10.1021/acs.orglett.9b01828
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