Enantioselective Dearomative Arylation of Isoquinolines

Article abstract of DOI:10.1021/acscatal.6b01693

The C1-substituted tetrahydroisoquinolines and 1,2-dihydroisoquinoline constitute an important group and are interesting structural motifs found in many natural products and pharmaceuticals. In this context, a phosphoric-acid-catalyzed enantioselective dearomative arylation of isoquinolines was realized, providing the chiral dihydroisoquinolines with indole substituents at the C1-position in good results (up to >99% yield and 97% ee). The reaction features mild reaction conditions and operational simplicity, which make it an attractive approach to the discovery of biologically interesting α-indolisoquinolines.

Full text of DOI:10.1021/acscatal.6b01693

Letter
pubs.acs.org/acscatalysis
Enantioselective Dearomative Arylation of Isoquinolines
Ming Zhang,‡,§ Wangsheng Sun,‡,§ Gongming Zhu,‡ Guangjun Bao,‡ Bangzhi Zhang,‡ Liang Hong,*,†
Min Li,*,† and Rui Wang*,†,‡
†School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
‡Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, 730000, China
S
* Supporting Information
ABSTRACT: The C1-substituted tetrahydroisoquinolines and 1,2-dihydroisoquinoline constitute an important group and are
interesting structural motifs found in many natural products and pharmaceuticals. In this context, a phosphoric-acid-catalyzed
enantioselective dearomative arylation of isoquinolines was realized, providing the chiral dihydroisoquinolines with indole
substituents at the C1-position in good results (up to >99% yield and 97% ee). The reaction features mild reaction conditions
and operational simplicity, which make it an attractive approach to the discovery of biologically interesting α-indolisoquinolines.
KEYWORDS: enantioselective, isoquinolines, dearomative arylation, indole, chiral phosphoric acid
and used for the treatment of overactive bladder with urge
soquinolines, found abundantly in the plant kingdom, are
Ithe largest family of naturally occurring alkaloids with a wide incontinence.4
range of pharmacological activities.1 Among them, the C1-
substituted tetrahydroisoquinolines and 1,2-dihydroisoquino-
line constitute an important group and are interesting structural
motifs found in many natural products and pharmaceuticals
(Figure 1). For example, Crispine, isolated from the Carduus
crispus plant, exhibits a promising cytotoxic activity and
antidepressant-like activity.2 Noscapine, a benzylisoquinoline
alkaloid from plants of the poppy family, has been used as an
antitussive drug and recently discovered as an antiangiogenic
drug that induces apoptosis in cancer cells.3 The α-phenyl-
isoquinoline solifenacin is a medicine of the antimuscarinic class
Owing to this importance, many methods have been
developed to construct the chiral C1-substituted hydro-
isoquinolines, including catalytic enantioselective Reissert-type
reaction,5 asymmetric hydrogenation of isoquinolines,6 and
enantioselective oxidative cross-dehydrogenative couplings,7
among others. The developed methods focused on the
enantioselective alkylation of isoquinolines and tetrahydroiso-
quinolines, while the asymmetric synthesis of C1-aromatic
isoquinolines are by far less well developed. Wanner et al.
stereoselectively introduced the aryl group to isoquinolines by
using a chiral auxiliary group at the nitrogen atom (Scheme
1a).8 Qiu and Lee reported the synthesis of C1-indol
isoquinolines from chiral sulfinimine substrates in multisteps
(Scheme 1b).9 Therefore, there is an urgent requirement to
develop novel enantioselective arylation of isoquinolines.
Recently, the α-indolisoquinolines like IBR2 analogues have
been identified as novel small molecule RAD51 inhibitors,
which could inhibit the proliferation of triple-negative human
breast cancer cells.10 They could also effectively inhibit the NF-
κB activation by blocking IκBα degradation.11 Further study
shows that both enantiomers vary greatly in inhibition
activities.12 The traditional methods for the synthesis of α-
indolisoquinolines include the Ag-catalyzed nucleophilic
Received: June 15, 2016
Revised: July 8, 2016
Figure 1. Representative examples.
© XXXX American Chemical Society
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Scheme 1. Routes to Chiral C1-Aromatic Isoquinolines
a
and limited scope of substrates, which hinder its practical
application (Scheme 1b). Consequently, the development of a
simple, mild, and direct method for the synthesis of α-
indolisoquinolines, especially in enantioselective version, is the
current focus in medicinal organic chemistry.
Table 1. Optimization of the Reaction Conditions
Inspired by the recent enantioselective dearomatization of
(iso)quinolines and pyridines,5,14 we became interested in how
to catalytically install indoles at the C1 position of isoquino-
lines. Following our interests in tetrahydroisoquinoline and
indole functionalization7d,e,h,15 and the recent advances in chiral
anion catalysis,16 we envisioned that an effective chiral
induction could be achieved by the interaction of an ion-pair
between the ionic isoquinoline substrates and the chiral anion
catalyst (Scheme 1c). Herein, we reported a highly
enantioselective dearomatization of isoquinoliniums with
indoles.
We initially explored the dearomatization of isoquinoline 1a
in the presence of chiral phosphoric acid catalyst 3a (Table 1).
Pleasingly, the reaction proceeded smoothly to afford the
dearomatized product 4a in 35% yield and 63% ee. Further
screening other phosphoric acids showed that the 3,3′-
substituents played a significant role on the reaction outcome.
Among them, the catalyst 3f gave the best enantioselectivity of
95%, albeit with a slight lower yield of 38%. We then chose 3f
in further optimization studies aimed at improving the reaction
yield. The amount of substrate isoquinoline 1a had an
important impact on the yield. Increasing the amount to 2.0
equiv could significantly improve the yield to 72%, and could be
further increased to 84% when 3.0 equiv of 1a was used.
Subsequent screening of solvents revealed that the solvents
impacted the outcome, and p-xylene was the most ideal for the
reaction, affording 4a in 98% yield and 97% ee.17
b
c
entry
cat. 3
1a:2a
solvent
yield (%)
ee (%)
1
3a
3b
3c
3d
3e
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
1:1
1:1
1:1
1:1
1:1
1:1
2:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
THF
35
48
5
63
92
95
76
90
95
96
96
59
95
93
96
96
97
97
2
3
4
35
24
38
72
84
24
83
54
98
98
98
89
5
6
7
8
9
10
11
12
13
14
15
Et2O
o-xylene
m-xylene
p-xylene
mesitylene
a
Unless otherwise specified, the reaction was carried out in 0.1 mmol
scale in 1 mL of solvent under room temperature within 48 h.
Isolated yield. Determined by chiral HPLC on a Chiralcel IA
b
c
With the established optimal conditions, we next investigated
the substrate scope of the reaction (Scheme 2). In general, a
wide range of indoles 2 with different substituents could
participate in the reaction smoothly to afford the desired
products in moderate to excellent yields (41−99%) and
excellent enantioselectivities (93−97%). 4-Methylindole af-
forded the corresponding product in 45% yield and 96% ee
(Scheme 2, 4b). The methyl, methoxy and fluoro group at the
C5-, and C6-position gave excellent yields (84−99%) and
column.
addition of indoles to ortho-alkynylaryl aldimines, base-
promoted addition to N-acylisoquinolinium salts, and three-
component coupling reactions.13 Qiu et al. have tried the
enantioselective synthesis by using chiral sulfinimine substrate.8
However, this method needs the use of stoichiometric amount
of chiral source and suffers the inefficient multistep synthesis
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Scheme 2. Scope of the Reaction
a
Unless otherwise specified, the reaction was carried out in 0.1 mmol scale in 1 mL of p-xylene under room temperature, with the ratio of 1/2/3f =
b
c
3.0/1.0/0.1. The ee values were determined by HPLC on a chiral phase (Chiralcel column). Cat. 3b was used. The reaction was carried out under
60 °C, and the ee was determined after deprotection of TBS.
enantioselectivities (94−95% ee) (Scheme 2, 4c−4e and 4h−
4j), whereas chloro and bromo substituents led to the lower
yields (41−75%) with no difference on the enantioselectivities
(94−97% ee) (Scheme 2, 4f,g and 4k,l). In the case of C7-
substituted indoles, methyl and methoxy substituents showed
excellent efficiency (99% yields, 93−95% ee) (Scheme 2, 4m,
n), while fluoro substituent reduced the reaction yield (42%
yield, 97% ee) (Scheme 2, 4o). Substituted isoquinolines 1
were also tested for the reaction. Isoquinolines with different
Scheme 3. Scope of Other Arylating Reagents
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Scheme 4. Transformation of the Products
Scheme 5. Proposed Mechanism
substituents led to the corresponding dearomatized products in
good yields and enantioselectivities (Scheme 2, 4p−s).18
As a limitation of this catalytic system, the current catalytic
system was not suitable for other arylating reagents. We have
tried other arenes and heteroarenes like N-benzyl-pyrrole, N-
TBS-pyrrole, furan, thiophene, and 1,3,5-trimethoxybenzene.
Under the employed catalytic conditions, the N-benzyl-pyrrole
could afford the corresponding racemic product in 40% yield,
but the others showed no reactivity even with longer reaction
time or higher reaction temperature (Scheme 3).
We also carried out some derivatizations of the products to
demonstrate the synthetic utility of this method (Scheme 4).
The deprotection of the TBS group could proceed with high
efficiency using TBAF to form 5 and 6, respectively. The
absolute configuration of 5 was determined to be (S) at the
newly formed stereocenter by X-ray analysis.18 Moreover, the
double bonds on the 1,2-dihydroisoquinoline moiety of the
products could be reduced by Raney nickel under a H2 atm.
Additionally, the N−H free α-indoltetrahydro-isoquinoline 8
could be prepared by a two-step reduction/deprotection
sequence.
plausible mechanism for this transformation. The intermediate
9 is generated first. Subsequently, with the help of phosphoric
t
acid, intermediate 9 releases a molecule of BuOH to generate
the iminium ion 10, which could be trapped by a nucleophile
indole to give the product (Scheme 5).
In summary, we have developed a new dearomative arylation
method, which represents a simple and direct access to chiral α-
indoldihydroisoquinolines with excellent enantiomeric purity.
The mild reactions and the operational simplicity make this
reaction an attractive approach to the discovery of biologically
interesting α-indolisoquinolines. Further work will be directed
toward the biological evaluation of these synthesized
compounds.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.6b01693.
■
S
Details of experimental procedure, data, HPLC and
NMR spectra of all compounds (PDF)
Crystallographic data of 5 (CIF)
To shed more light on the mechanism of this reaction, we
prepared the intermediate 9 by mixing isoquinoline and
Boc2O,19 and then we exposed the mixture to the standard
reaction conditions, which delivered the desired product in 97%
ee. Based on this result and previous study,16,20 we proposed a
AUTHOR INFORMATION
Corresponding Authors
*E-mail for L.H.: hongliang@sysu.edu.cn.
■
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ACS Catalysis
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*E-mail for R.W.: wangrui@lzu.edu.cn.
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Author Contributions
§These authors contributed equally (M.Z. and W.S.).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We are grateful for the financial support from the NSFC
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