Asymmetric Synthesis of β-Indolyl Cyclopentanones and Cyclopentylamides with an All-Carbon Quaternary Stereocenter via Chiral Phosphoric Acid Catalyzed Friedel-Crafts Alkylation Reactions

Article abstract of DOI:10.1021/acs.orglett.9b00963

The asymmetric Friedel-Crafts alkylation reactions of indoles with β-substituted cyclopentenimines enabled by chiral phosphoric acid catalysis has been developed, which affords adducts possessing an all-carbon stereocenter with high levels of enantioselectivities. Furthermore, the addition products could be readily converted into two types of useful but previously challenging chiral building blocks, such as β-alkyl-β-indolyl cyclopentanones and β-alkyl-β-indolyl cyclopentylamides, in one pot via in situ hydrolysis or reduction without erosion of chiral information.

Full text of DOI:10.1021/acs.orglett.9b00963

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Synthesis of β‑Indolyl Cyclopentanones and
Cyclopentylamides with an All-Carbon Quaternary Stereocenter via
Chiral Phosphoric Acid Catalyzed Friedel−Crafts Alkylation
Reactions
Wei Liu,†,‡ Subramani Rajkumar,† Weihu Wu,† Ziyu Huang,† and Xiaoyu Yang*,†
†School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
‡University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: The asymmetric Friedel−Crafts alkylation reac-
tions of indoles with β-substituted cyclopentenimines enabled by
chiral phosphoric acid catalysis has been developed, which affords
adducts possessing an all-carbon stereocenter with high levels of
enantioselectivities. Furthermore, the addition products could be
readily converted into two types of useful but previously
challenging chiral building blocks, such as β-alkyl-β-indolyl
cyclopentanones and β-alkyl-β-indolyl cyclopentylamides, in
one pot via in situ hydrolysis or reduction without erosion of
chiral information.
he indole nucleus is a prominent and privileged structure
in numerous natural products and synthetic compounds
to β-substituted cyclopentenones has been reported, probably
due to the relative low reactivity and challenge in terms of the
control of enantioselectivity in the conjugate additions of
cyclopentenones.6 Moreover, the racemic version of this
reaction has only recently been developed, and the desired
product was obtained only in 37% yield, demonstrating the low
reactivity of cyclopentenone upon indole addition (Figure
1c).7
With our continuous interest in asymmetric synthesis of β-
indolyl cyclopentanones and cyclopentenamide derivatives,8
our attention was drawn by this challenging asymmetric
reaction. With the well-known activation and stereoselectivity
control ability of imine substrates by chiral phosphoric acid
catalyst,9 we envision that the conjugate addition of indoles to
β-substituted cyclopentenimines under chiral phosphoric acid
catalysis would proceed efficiently and stereoselectively,10
establishing a protocol for asymmetric construction of chiral
all-carbon quaternary stereocenters. Subsequent facile hydrol-
ysis or reduction of the chiral imine products would yield two
types of valuable but previously challenging chiral building
blocks, namely β-alkyl-β-indolyl cyclopentanones and β-alkyl-
β-indolyl cyclopentylamides (Figure 1, bottom). Herein, we
report our success in achieving asymmetric construction of an
all-carbon stereocenter by asymmetric Friedel−Crafts alkyla-
tions of indoles with β-substituted cyclopentenimines under
chiral phosphoric acid catalysis.
T
with significant biological and pharmacological activities.1
Therefore, the synthesis of indole derivatives has been an
important research topic in organic and medicinal chemistry
for a long time. Direct enantioselective functionalization of
indoles is a straightforward and efficient approach to access
chiral indole derivatives. In the past two decades, a great
number of catalytic asymmetric indole functionalization
reactions have been developed by researchers,2 for which
asymmetric Friedel−Crafts alkylation represents as one of the
most powerful strategies. Numerous elegant methodologies
have been developed by enantioselective additions of indoles
to various electrophiles, such as activated alkenes, carbonyl
compounds, and imines. However, highly enantioselective 1,4-
additions of indoles to β,β-disubstituted activated alkenes
giving an all-carbon chiral quaternary stereocenter3 are
challenging4 due to the intrinsic steric hindrance. Recently,
some elegant methods have been developed on asymmetric
Friedel−Crafts alkylations of indoles with β,β-disubstituted
activated alkenes for construction of all-carbon stereocenters;
however, two electron-withdrawing groups are essentially
required to activate the alkenes5 (Figure 1, a). For this reason,
asymmetric construction of all-carbon stereocenters via
conjugate additions of indoles to cyclic electron-deficient
olefins is rare. A single example of asymmetric conjugate
addition of indole to β-substituted cyclohexenone has been
reported so far, which only provided the product with 74:26 er
upon chiral primary amine catalysis under high-pressure
conditions (Figure 1b).5a Furthermore, to the best of our
knowledge, no example of enantioselective addition of indoles
3-Methylcyclopentenone was chosen as a model cyclic
enone substrate that was converted into α,β-unsaturated
Received: March 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00963
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
R
cat.
sol
yield (%)
er
1
2
3
4
5
6
7
8
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-F-Ph
4-OMe-Ph
2-Me-Ph
tBu
4-OMe-Ph
4-OMe-Ph
4-OMe-Ph
A1
A2
A3
A4
A5
B1
B1
B1
B1
B1
B1
B1
B1
B1
B1
B1
toluene
toluene
toluene
toluene
toluene
toluene
DCM
90
52
84
89
70
74
66
64
43
87
95
92
94
81
65
70
54:46
65.5:34.5
54.5:45.5
54:46
72.5:27.5
76:24
67.5:32.5
65:35
67.5:32.5
66:34
76.5:23.5
65:35
53:47
90:10
90.5:9.5
93.5:6.5
CHCl3
Et2O
9
10
11
12
13
14
15
16
toluene
toluene
toluene
toluene
toluene
toluene
toluene
d
de
,
Figure 1. Asymmetric construction of chiral all-carbon quaternary
stereocenters by Friedel−Crafts alkylations of indoles.
e f
,
a
Reactions were performed with 1 (0.2 mmol), 2a (0.1 mmol),
catalyst (15 mol %), and 4 Å molecular sieves (30 mg) in solvent (1
ketimines 111 by condensation with various sulfonamides12
(Table 1). Initially, we tested reactions between N-Ts
cyclopentenimine (existed as 3:2 inseparable E/Z mixture,
0.2 mmol) with indole (2a, 0.1 mmol) in the presence of TRIP
catalyst (A1, 15 mol %) in toluene (1 mL) at ambient
temperature. After the mixture was stirred overnight, the
conjugate addition product β-indolyl cyclopentylimine was
obtained in high yield without detection of the 1,2-addition
product,13 which existed as an inseparable E/Z mixture of
imines as well. Further hydrolysis of the imines mixture with
basic alumina14 afforded β-indolyl-β-methyl cyclopentanone
(3a) in 90% yield, albeit with a negligible enantiomeric ratio
(er) (entry 1). Further screening of various chiral phosphoric
acid catalysts (entries 2−6) indicated the 3,3′-bis(1-naphthyl)
H8-BINOL derived catalyst (S)-B1 gave the best performance,
which afforded the product 3a with 76:24 er after hydrolysis.
Investigation of the solvents was also performed, and toluene
was chosen as the optimal solvent (entries 7−9). Next, we
studied the effect of arylsulfonyl groups (e.g., electron-donating
aryl groups, electron-withdrawing aryl groups and sterically
hindered aryl groups) attached at the imine site (entries 10−
12), which indicated p-methoxylphenylsulfonyl group sub-
stituted one (existed as 3:2 E/Z inseparable mixture) provided
the product with the best enantioselectivity and excellent yield.
Interestingly, the tert-butylsulfonyl-substituted substrate only
provided the product with negligible er (entry 13). With the
higher reactivity observed for the p-methoxylphenylsulfonyl
group substituted substrate, decreasing the reaction temper-
ature to −20 °C afforded the product 3a in 80% yield with
90:10 er (entry 14). Switching the concentration of the
reaction mixture from 0.1 to 0.05 M led to a minor
improvement in enantioselectivity (90.5:9.5 er, entry 15).
b
1
mL) at ambient temperature. Yields were determined by H NMR
c
using DME as internal standard. Enantiomeric ratio (er) was
d
determined by chiral HPLC analysis. Reactions were performed at
e
f
−20 °C. Reactions were performed in 2 mL of solvent. Reactions
were performed at −38 °C.
Finally, further lowering the reaction temperature to −38 °C
with longer reaction time (72 h) led to the optimal conditions
under which the product 3a could be obtained in 70% yield
with 93.5:6.5 er (entry 16). The absolute configuration of the
newly generated all-carbon quaternary stereocenter was
determined as R, which was unambiguously confirmed by X-
ray crystallography.12
With the optimal conditions in hand, we turned our
attention to exploring the substrate scope of this reaction.
Thus, the reactions of cyclopentenimine 1a (E/Z mixture)
with a range of substituted indoles under the optimal
conditions were investigated. As shown in Scheme 1, different
substitutions at the C-5 position of indoles were well tolerated,
including the electron-neutral −Me group (3b), electron-
donating −OMe group (3c), electron-withdrawing −F group
(3d), and diversifiable −Cl and −Br groups (3e and 3f).
Moreover, C-6-substituted indoles are also compatible
substrates, which provided the cyclopentanone products in
good yields and with high enantioselectivities (3g−k). It is
worth mentioning that reaction with C-6-COOMe-substituted
indole gave the product in almost enantiomeric pure form
(>99.5:0.5 er, 3l). The reactions between cyclopentenimine 1a
with other substituted indoles (2-, 4-, and 7-substituted ones)
were also attempted, however which gave poor perform-
ances.12 The tolerance of different substitutions at the C-3
position of cyclopentenimines 1 (e.g., ethyl and n-propyl
B
DOI: 10.1021/acs.orglett.9b00963
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Substrate Scope for β-Alkyl-β-indolyl
Cyclopentanones
Scheme 2. Substrate Scope for β-Alkyl-β-indolyl
a,b
a,
b
Cyclopentylamides
a
Reactions were performed with 1a (0.2 mmol), 2 (0.1 mmol),
catalyst B1 (0.015 mmol), 4 Å molecular sieve (30 mg) in toluene (2
mL) at −38 °C for 72 h, after which the reactions were cooled to −78
b
°C and reduced with L-Selectride (1.0 N, 1 mL) for 12 h. Isolated
yields. dr was determined by crude 1H NMR analysis. er was
determined by HPLC analysis using a chiral stationary phase.
indole addition step would provide β-indolyl cyclopentyla-
mides with a C-3 quaternary chiral center. As shown in Scheme
2, a variety of substituted indoles were investigated as
nucleophiles. After their conjugate additions with cyclo-
pentenimine 1a under the optimal conditions, the reaction
mixtures were subsequently cooled to −78 °C and subjected to
reduction with L-Selectride, which afforded the cyclopentyla-
mides with good diastereoselectivities and high enantioselec-
tivities (4a−e).
a
Reactions were performed with 1 (0.2 mmol), 2 (0.1 mmol), catalyst
(S)-B1 (0.015 mmol), and 4 Å molecular sieves (30 mg) in toluene
(2 mL) at −38 °C for 72 h, after which the reaction was stirred with
To further demonstrate the applications of these reactions,
the derivatizations of the chiral products were investigated
(Scheme 3). Stereoselective reduction of the carbonyl group in
b
basic alumina (1 g) for 8 h at rt. Isolated yield. er was determined by
HPLC analysis using a chiral stationary phase. Reactions were
performed at −30 °C. Reactions were performed at room
temperature.
c
d
Scheme 3. Derivatizations of the Chiral Products
groups) was also investigated. However, performing these
reactions under the optimal conditions (−38 °C) barely
afforded the desired products, again demonstrating the
vulnerability of these reactions to steric hindrance. The desired
products could only be obtained when these reactions were
performed at ambient temperature; however, the enantiomeric
ratios were only moderate (3m−o). The extension of these
conditions to β-methyl cyclohexenimine substrate was also not
successful, which provided the product in both low yield and
enantioselectivity.12
In addition to the synthesis of cyclopentanone derivatives,
we aimed to transform the addition products into β-indolyl
cyclopentylamines, which are a class of conformationally
restricted homotryptamine analogues with activity as selective
serotonin reuptake inhibitors (SSRIs) with potent activities.15
For instance, the (1S,3R)-5-CN indole substituted derivative 5
was shown to be 10-fold more active than the straight-chain
homotryptamine (Scheme 2). However, the biological
activities of β-indolyl cyclopentylamine analogues with a C-3
quaternary stereocenter have never been studied, probably due
to the lack of efficient methods for their asymmetric synthesis.
We envisioned that stereoselective reduction of the E/Z
mixture of the imine intermediates obtained in the asymmetric
3a with L-Selectride at −78 °C readily provided the
corresponding cyclopentanol 6a in 99% yield with 85:15 dr,
without any erosion in er. The relative stereochemistry of the
−OH group was assigned as cis to the indolyl moiety by NOE
analysis.12 The p-methoxylphenylsulfonyl group in cyclo-
pentylamide 4a could be facilely removed by treatment with
SmI2 to give cyclopentylamine 7a with a C-3 quaternary
stereocenter, whose relative configuration was also confirmed
by NOE analysis.
C
DOI: 10.1021/acs.orglett.9b00963
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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In conclusion, we have successfully established an
asymmetric protocol for the construction of a chiral all-carbon
quaternary center via asymmetric Friedel−Crafts reactions of
indoles with β-substituted cyclopentenimines under chiral
phosphoric acid catalysis. The chiral adducts could be readily
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β-alkyl-β-indolyl cyclopentylamides upon in situ hydrolysis or
reduction in one pot, respectively. With the success of applying
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ASSOCIATED CONTENT
■
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* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00963.
Experimental procedures, NMR spectra, HPLC traces,
and X-ray and analytical data for all new compounds
(PDF)
Accession Codes
CCDC 1902200 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 emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yangxy1@shanghaitech.edu.cn.
ORCID
́
(5) (a) Łyzwa, D.; Dudzinski, K.; Kwiatkowski, P. High-Pressure
̇
Xiaoyu Yang: 0000-0002-0756-0671
Notes
Accelerated Asymmetric Organocatalytic Friedel−Crafts Alkylation of
Indoles with Enones: Application to Quaternary Stereogenic Centers
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Xiang, B.; Yu, W.-B.; Han, L.; Jia, Y.-X. Highly Enantioselective
Construction of Trifluoromethylated All-Carbon Quaternary Stereo-
centers via Nickel-Catalyzed Friedel−Crafts Alkylation Reaction. J.
Am. Chem. Soc. 2013, 135, 2983−2986. (c) Chen, L.-A.; Tang, X.; Xi,
J.; Xu, W.; Gong, L.; Meggers, E. Chiral-at-Metal Octahedral Iridium
Catalyst for the Asymmetric Construction of an All-Carbon
Quaternary Stereocenter. Angew. Chem., Int. Ed. 2013, 52, 14021−
14025. (d) Arai, T.; Yamamoto, Y.; Awata, A.; Kamiya, K.; Ishibashi,
M.; Arai, M. A. Catalytic Asymmetric Synthesis of Mixed 3,3′-
Bisindoles and Their Evaluation as Wnt Signaling Inhibitors. Angew.
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Wu, L.; Xu, K.; Wu, H.; Liu, R.-R.; Gao, J.-R.; Jia, Y.-X. Asymmetric
Friedel−Crafts Alkylation of α-Substituted β-Nitroacrylates: Access to
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge NSFC (Grant No. 21702138),
Shanghai Pujiang Program (Grant No. 17PJ1406300),
“Thousand Talents Plan” Youth program, and the Shang-
haiTech University startup funding for financial support. Dr.
Na Yu (Analysis Center, School of Physical Science and
Technology, ShanghaiTech University) is acknowledged for
assistance with single-crystal crystallography. We thank Prof.
Baihua Ye for manuscript proofreading and helpful discussions.
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DOI: 10.1021/acs.orglett.9b00963
Org. Lett. XXXX, XXX, XXX−XXX