Construction of Chiral Tricyclic Indoles through a Rhodium-Catalyzed Asymmetric Arylation Protocol

Article abstract of DOI:10.1021/acs.orglett.6b03585

A rhodium/diene complex catalyzed asymmetric 1,4-addition of arylboronic acids to indole-derived α,β-unsaturated esters to access highly enantioenriched 3-(1H-indol-2-yl)-3-arylpropanoates has been developed. By taking advantage of the nucleophilic character of indole at C3 and N1 positions, construction of a series of valuable chiral tricyclic indole frameworks such as 2,3-dihydro-1H-pyrrolo[1,2-a]indoles and cyclopenta[b]indoles can be efficiently achieved.

Full text of DOI:10.1021/acs.orglett.6b03585

Letter
pubs.acs.org/OrgLett
Construction of Chiral Tricyclic Indoles through a Rhodium-Catalyzed
Asymmetric Arylation Protocol
Chun-Yan Wu, Yue-Na Yu, and Ming-Hua Xu*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, China
University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: A rhodium/diene complex catalyzed asymmetric 1,4-addition of arylboronic acids to indole-derived α,β-
unsaturated esters to access highly enantioenriched 3-(1H-indol-2-yl)-3-arylpropanoates has been developed. By taking
advantage of the nucleophilic character of indole at C3 and N1 positions, construction of a series of valuable chiral tricyclic indole
frameworks such as 2,3-dihydro-1H-pyrrolo[1,2-a]indoles and cyclopenta[b]indoles can be efficiently achieved.
olycyclic indoles constitute an important and unique class of
Pfused heterocycles that are widely found in diverse
biologically active natural products and pharmaceutical com-
pounds.1 Among them, 2,3-dihydro-1H-pyrrolo[1,2-a]indoles
and -cyclopenta[b]indoles are especially attractive due to their
vital roles in medicinal chemistry and organic synthesis. For
example, flinderole C (1) was identified as having selective
antimalarial activity;1a yuremamine (2) was isolated from
Mimosa hostilis and was found to have hallucinogenic and
psychoactive effects;1b isatisine A (3) bearing a 2,3,9,9a-
tetrahydro-1H-pyrrolo[1,2-a]indole skeleton exhibits strong
antiviral activity;1c compound 4 displays effects for treatment
of cardiovascular and renal disorders and recently has also been
tested as a psychotropic drug;1d yeuhchukene (5) displays potent
anti-implantation activity;1e and MK-05241f is a selective
prostaglandin D2 receptor antagonist used for the prevention
of niacin-induced flushing (Figure 1).
Figure 1. Examples of polycyclic indole-based bioactive compounds.
generally could only lead to the formation of either pyrrolo-
[1,2-a]indoles or cyclopenta[b]indoles. To the best of our
knowledge, there are no reports describing a versatile asymmetric
approach capable of the convenient construction of both
structural motifs. We therefore devised a viable strategy that
would be flexible enough to allow rapid assembly of both chiral
pyrrolo[1,2-a]indoles and cyclopenta[b]indoles in a highly
stereoselective manner.
Rhodium-catalyzed asymmetric 1,4-addition of arylboron
reagents to electron-deficient olefins represents one of the
most practical methods to obtain enantioenriched compounds.4
Over the past two decades, significant advances have been made
Because of this great importance, development of efficient
methods for the highly stereoselective synthesis of various chiral
polycyclic indoles from readily available materials is in particular
demand. In the past few years, a number of valuable studies was
conducted for the construction of chiral 2,3-dihydro-1H-
pyrrolo[1,2-a]indoles2 and -cyclopenta[b]indoles3 by use of a
chiral auxiliary or asymmetric catalysis approach to incorporate
the stereogenic center(s). The key ring-closing strategy mainly
involves Friedel−Crafts alkylation,3b−e N-alkylation/acylation/
hemiacetalization,2b−f and C−H activation.2a,j,3a In general, most
of these methodologies rely on the use of rationally designed
indole substrates with C3 and/or N1 position(s) blocked or
prefunctionalized. While these methods are efficient, they
Received: December 1, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03585
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Letter
in the development of highly effective catalyst systems.5 We have
also demonstrated that a series of simple chiral olefins including
hybrid sulfur−olefins and phosphorus−olefins as well as dienes
are superior ligands for the Rh-catalyzed reactions over a broad
variety of substrates.6 Inspired by the success of these
achievements, we reasoned that the proper combination of
indole and α,β-unsaturated ester elements might allow us to
design a new type of potential substrates, 2-indolyl acrylates, for
rhodium-catalyzed enantioselective 1,4-addition (Scheme 1). By
ester group from bulky tert-butyl to sterically less hindered
methyl or ethyl resulted in a significant decrease of
enantioselectivity (Table 1, entries 1−3). Interestingly, when
a
Table 1. Substrate Evaluation and Conditions Optimization
Scheme 1. Synthetic Strategies to Chiral Tricyclic Indoles
b
c
d
entry
7
solvent
additive
yield (%)
ee (%)
1
7a
7b
7c
7d
7e
7f
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
DCE
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
KOH
96
59
96
76
81
94
96
77
-
2
3
76
4
98
5
94
6
50
taking advantage of the inherent nucleophilic character of indole
at nonsubstituted N1/C3 positions and the ester functionality,
the resulting products could be expected to undergo site-
selective cyclization for flexible construction of chiral 2,3-
dihydro-1H-pyrrolo[1,2-a]indoles and cyclopenta[b]indoles.
Herein, we present our successful development of a highly
efficient approach for the synthesis of chiral tricyclic indoles
through Rh/diene-catalyzed asymmetric 1,4-addition.
7
7a
7a
7a
7a
7a
7a
7a
7a
trace
84
8
K2HPO4
KF
96
96
96
89
88
95
96
9
92
10
11
12
13
KHF2
NEt3
75
22
K3PO4
K3PO4
K3PO4
85
94
e
14
dioxane
86
The 2-indolyl acrylate substrates could be readily prepared
from indole-2-carboxylic acid through reduction and Witting
olefination.7 We began our work by studying the reaction
between tert-butyl free-(NH)-2-indolyl acrylate 7a and p-
methoxyphenylboronic acid 8a in K3PO4 (1.5 M)/dioxane at
60 °C in the presence of 2.5 mol % of [Rh(COE)2Cl]2 and 5 mol
% of various chiral ligands (L1−L6) that are available in our
laboratory. As shown in Scheme 2, reactions with our typical
a
The reaction was carried out with 0.2 mmol of unsaturated indole
esters 7, 2.0 equiv of p-methoxyphenylboronic acid 8a in the presence
of 5.0 mol % of [Rh], 5.0 mol % of L3, and K3PO4 (1.5 M, 3.0 equiv)
in 2.0 mL of solvent at 60 °C for 15 h. Unless noted, 3.0 equiv of
additive (1.5 M) was used. Isolated yield. Determined by Chiral
b
c
d
e
HPLC. 3 mol % of [Rh] and L3 was employed.
N-substituted indoles 7d−f were subjected to the reaction, no
better ee’s were obtained, and with N-Boc substrate 7f,
surprisingly, even lower yield and ee were afforded (entry 6).
These results suggested that the N-protection of the indole is
dispensable. Further investigation on reaction parameters such as
additive, solvent, and catalyst loading was also conducted.
Among the various additives screened (entries 7−11), K3PO4
was found to be the best. Varying the solvent did not furnish
better results (entries 12 and 13). In addition, lowering the
catalyst loading would lead to somewhat diminished yield while
still maintaining the enantioselectivity (entry 14).
Scheme 2. Ligand Screening
With the optimized conditions in hand, the substrate scope of
the reaction was explored (Table 2). We were pleased to find that
the catalyst system applies to various arylboronic acids with
either electron-donating or -withdrawing group(s) on the phenyl
ring at different positions. In all cases, good to excellent
enantioselectivities (92−99% ee) could be obtained. Notably,
methyl substitution at the ortho-position could give the product
with extremely high enantioselectivity (99% ee); however, the
yield dropped significantly due to obvious steric reasons.
Accordingly, reactions with other sterically less bulky or
unencumbered arylboronic acids generally proceeded well.
Moreover, 2-indolyl acrylates having substituents on the indole
phenyl ring were found to be equally suitable substrates,
furnishing products 9q−v in 93−97% ee. Unfortunately, the
reaction failed to give product with more challenging
alkenylboronic acids such as styrylboronic acid.
sulfinamide−olefin ligands6e,g L1 and L2 produced the desired
product 9a in low yields with modest enantioselectivities (81%
and 55% ee), while almost no reaction was observed with
phosphite−olefin ligand6h L4 and BINAP (L5). Gratifyingly, the
two chiral diene ligands L3 and L6 both exhibited great catalytic
reactivity and enantioselectivity, providing 9a with excellent
yields and enantiomeric excesses. Among them, our previously
developed [3.3.0]diene6a,b L3 gave the highest ee (96%).
We next investigated the structural influence of substrate
under the above identified reaction conditions. Changing the
The absolute configuration of the newly formed chiral center
was unequivocally determined to be R by X-ray crystallographic
B
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Letter
a
Table 2. Asymmetric Arylation of 2-Indolylacrylate
Scheme 3. Asymmetric Arylation of Other Structurally Similar
Acrylates
b
c
entry
R
Ar
9
yield (%)
ee (%)
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-MeOC6H4
Ph
9a
9b
9c
9d
9e
9f
96
99
95
92
96
78
96
98
92
36
98
98
95
90
94
91
94
97
98
89
94
96
96
96
96
97
97
97
95
96
98
99
92
95
95
96
94
96
95
95
97
95
94
94
2
3
4-MeC6H4
4-FC6H4
4
5
4-ClC6H4
4-BrC6H4
3-MeOC6H4
3-MeC6H4
3-FC6H4
6
7
9g
9h
9i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
2-MeC6H4
2-naphthyl
4-PhC6H4
4-tBuC6H4
4-MOMOC6H4
3,5-(Me)2C6H3
3,4-O2CH2C6H3
Ph
9j
arylation product in 88% yield with 78% ee. In this case, Hayashi
diene L6 was found to be more effective, delivering 13b in high
yield (94%) with largely improved enantioselectivity (94% ee)
under the same conditions. These results indicate that the
current method showcases a broad-scope application potential in
asymmetric synthesis.
Following the original plan, we next turned our attention to
the feasibility of the site-selective cyclization for construction of
chiral pyrrolo[1,2-a]indole and cyclopenta[b]indole frame-
works. As represented by 9b in Scheme 4, the synthesis of a
9k
9l
9m
9n
9o
9p
9q
9r
9s
9t
5-F
5-MeO
5-F
Ph
4-MeOC6H4
4-MeOC6H4
Ph
5-MeO
6-Cl
9u
9v
Scheme 4. Construction of Chiral Polycyclic Indoles
6-Me
Ph
a
The reaction was carried out with 0.2 mmol of unsaturated indole
esters 7, 2.0 equiv of arylboronic acid 8 in the presence of 5.0 mol % of
[Rh], 5.0 mol % of ligand L3, and K3PO4 (1.5 M, 3.0 equiv) in 2.0 mL
b
c
of dioxane at 60 °C for 15 h. Isolated yield. Determined by Chiral
HPLC.
analysis of the adduct 9f (Figure 2). Assuming an analogous
reaction mechanism, the same absolute configurations of the
obtained products could be assigned.
Figure 2. X-ray structure of (R)-9f.
series of chiral tricyclic indole-based heterocycles was carried out.
LAH reduction of the tert-butyl ester 9b and N-Bn-9b gave
alcohol intermediates 14a and 14b. Exposure of 14a under
Mitsunobu reaction conditions smoothly provided the N-
cyclized product 15 in 81% yield without loss of enantiopurity.
In the other case, treatment of 14a with the oxidant TPAP and
NMO9 at 40 °C furnished the corresponding tricyclic ketone
product 16. In considering the different cyclization from the
indole C3 site, we initially attempted to carry out a direct
intramolecular Friedel−Crafts alkylation or acylation. However,
we found that the benzylic carbon stereocenter was quite
sensitive to the acidic conditions, and the attempts were not
successful. Fortunately, bromination and iodination of the
alcohol 14b, followed by nBuLi-mediated intramolecular
Encouraged by the above success, we explored the utility of
this catalyst system in asymmetric arylation of other structurally
analogous α,β-unsaturated esters. To our delight, under the
standard conditions, benzofuran- and benzothiophene-derived
acrylates 10a and 10b could also serve as appropriate Michael
acceptors to form the addition products 11a and 11b in high
yields (96% and 99%) and with excellent enantioselectivities
(93% and 96% ee) (Scheme 3). Surprisingly, unlike tert-butyl
free-(NH)-2-indolyl acrylate, tert-butyl free-(NH)-3-indolyl
acrylate 12a could not undergo efficient 1,4-addition. Never-
theless, it is interesting to note that the reaction using N-Cbz-
protected acrylate 12b was smooth,8 affording the desired
C
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Letter
substitution,10 afforded the expected cyclic product 4-benzyl-3-
phenyl-1,2,3,4-tetrahydrocyclopenta[b]indole 18 in good yield
over three steps. Oxidative dehydrogenation of the resulting 18
with DDQ in THF/H2O successfully provided its tricyclic
ketone 19 in moderate yield. It should be noted that no ee
erosion was observed in all these transformations. Thus, as
anticipated, we were able to flexibly construct all four interesting
types of indole-based tricyclic chiral heterocycle structures in a
highly enantioenriched manner through simple site-selective
cyclization of the aforementioned arylation products 9.
Importantly, these heterocycles might be further elaborated to
access more functionalized or complicated polycyclic molecules
that are useful in medicinal chemistry.
In summary, we have developed a highly effective rhodium/
diene catalytic system for the asymmetric 1,4-addition of
arylboronic acids to α,β-unsaturated N1/C3-free 2-indolyl
acrylates to afford the corresponding arylation products in high
yields with excellent enantioselectivities (92−99% ee). The
method is applicable to α,β-unsaturated benzofuran- and
benzothiophene-derived acrylates as well as N-protected 3-
indolyl acrylates. By taking advantage of the nucleophilic
character of indole at N1/C3 positions and the ester
functionality, the synthetic utility of the arylation products in
the flexible and facile construction of four different types of
indole-based tricyclic structural motifs through site-selective
intramolecular cyclization was demonstrated. Given the unique
presence of polycyclic indoles in a wide variety of natural
products and biologically active compounds, we believe that this
protocol should find an attractive application in related biological
and drug discovery studies.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03585.
Experimental procedures and spectroscopic data of all new
compounds (PDF)
X-ray crystal structure data for (R)-9f (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xumh@simm.ac.cn.
ORCID
Ming-Hua Xu: 0000-0002-1692-2718
Notes
(7) Zaghdane, H.; Boyd, M.; Colucci, J.; Simard, D.; Berthelette, C.;
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Hamel, M.; Stocco, R.; Sawyer, N.; Sillaots, S.; Gervais, F.; Gallant, M.
Bioorg. Med. Chem. Lett. 2011, 21, 3471.
The authors declare no competing financial interest.
(8) The same conjugate addition to the corresponding N-Boc-
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(9) Maki, B. E.; Scheidt, K. A. Org. Lett. 2009, 11, 1651.
(10) Smith, A. B.; Cui, H.-F. Org. Lett. 2003, 5, 587.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation of China (21325209,
21472205, 81521005) and the Shanghai Municipal Committee
of Science and Technology (Program of Shanghai Academic
Research Leader, 14XD1404400) for financial support.
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