Enantioselective Construction of Functionalized Tetrahydrocarbazoles Enabled by Asymmetric Relay Catalysis of Gold Complex and Chiral Br?nsted Acid

Article abstract of DOI:10.1021/acs.orglett.6b00012

An intramolecular hydroamination/Michael addition cascade is realized using a combination of gold(I) complex and chiral BINOL-phosphoric acid, affording fused-tetrahydrocarbazole scaffolds in excellent yields and high enantioselectivities.

Full text of DOI:10.1021/acs.orglett.6b00012

Letter
pubs.acs.org/OrgLett
Enantioselective Construction of Functionalized
Tetrahydrocarbazoles Enabled by Asymmetric Relay Catalysis of
Gold Complex and Chiral Brønsted Acid
Feng Zhao,† Nan Li,† Yi-Fan Zhu,† and Zhi-Yong Han*,†,‡
†Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei 230026, P. R. China
‡High Magnetic Field Laboratory, Hefei Institutes of Physical Science, CAS, Hefei 230031, P. R. China
S
* Supporting Information
ABSTRACT: An intramolecular hydroamination/Michael addi-
tion cascade is realized using a combination of gold(I) complex and
chiral BINOL−phosphoric acid, affording fused-tetrahydrocarba-
zole scaffolds in excellent yields and high enantioselectivities.
hiral tetrahydrocarbazoles (THCs) have been recognized
as very important structural motifs due to their frequent
occurrence in a variety of natural products and pharmacolog-
ically active compounds, and many of their synthetic analogues
often exhibit potential biological activities (Figure 1).1 For
Friedel−Crafts-type alkylation of alkenylindoles has proven to
be a preeminent strategy for THC synthesis (Scheme 1a).2
These methods include intramolecular hydroarylations of
indole-substituted alkenes, allenes or α,β-unsaturated aldehydes
catalyzed by chiral scandium(III),2b platinum(II),2a,d,f and
gold(I)2c,e,g complexes and organocatalysts,2h respectively. In
addition, the catalytic stereoselective Diels−Alder reactions
C
Scheme 1. Asymmetric Catalytic Approaches to Chiral THCs
Figure 1. Selected examples of compounds containing tetrahydro-
carbazole motifs.
instance, (−)-alloaristoteline and (+)-aristoteline are two
natural alkaloids existing in Aristotelia chilensis leaves that are
used in Chilean folk medicine to treat pain and inflamma-
tion;1a,d ambiguine indole alkaloid fischambiguine B displays
strong inhibitory activity against Mycobacterium tuberculosis;1c
and alstilobanine A has been reported to possess modest
relaxant activity against phenylephrine-induced contractions of
thoracic rat aortic rings with endothelium.1f The medicinal
relevance of THCs has pushed forward the rapid development
of synthetic methods to construct such chiral scaffolds.
Over the past decades, catalytic asymmetric approaches for
the synthesis of optically active THCs have been well
developed, rendering it possible to access these important
compounds from a variety of readily available starting
materials.2−5 In these endeavors, the catalytic intramolecular
Received: January 3, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00012
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
have also provided a number of efficient and straightforward
protocols by using 2-vinylindoles,3b,c,i 3-vinylindoles,3a,e,h or
heterocyclic ο-quinodimethanes generated in situ3d,f,g acting as
diene substrates (Scheme 1b). Recently, List and co-workers
established catalytic asymmetric Fischer indolizations, generat-
ing 3-substituted chiral THCs in high yields and excellent levels
of enantioselectivities (Scheme 1c).4 Cascade processes with
properly designed indole derivatives as substrates have also
provided successful approaches to THCs with high optical
purity.5 Obviously, the known methods to access tetrahy-
drocarbazole motifs are mostly performed by employing
substituted indoles as substrates, which are normally prepared
via stepwise procedures. Instead, asymmetric Fischer indoliza-
tion opened up a unique strategy for constructing chiral THCs,
adopting phenylhydrazones as substrates. Therefore, the
development of alternative transformations to optically pure
THCs from more extensive starting materials is still challenging
and highly desirable.
Table 1. Optimization of Catalysts and Reaction
Conditions
a
b
c
entry
3
solv
temp (°C)
yield (%)
ee (%)
1
3a
3b
3c
3d
3e,
3f
DCE
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
>99
94
45
48
3
2
DCE
3
DCE
>99
97
Recently, gold/chiral Brønsted acid6 relay catalysis has
evolved into a general strategy, allowing for the creation of a
large number of transformations,7a−h and thus been recognized
as a robust tool for building up molecular and stereochemical
complexity.7,8 With a proper substrate design, we envisioned
that this catalytic system might also contribute to the
construction of chiral THCs (Scheme 1d). Substituted 2-
ethynylanilines 1 were selected as substrates, which can be
easily prepared through Sonogashira coupling. The relay
catalytic process consists of a gold-catalyzed indole-formation
step and subsequent intramolecular cyclization to give
tetracyclic compounds 4 with two adjacent stereocenters in
one operation.
The initial investigation of the proposed strategy was
performed with 2-ethynylaniline derivative 1a in the presence
of a combined catalyst system consisting of an achiral gold
complex 2 (5 mol %) and a chiral phosphoric acid 3a (5 mol
%) in DCE at 25 °C. The transformation proceeded smoothly
and afforded polycyclic compound 4a quantitatively (>99%
yield) with moderate enantioselectivity (45% ee, Table 1, entry
1). Later on, various structurally diverse chiral phosphoric acids
3a−i were evaluated to identify the best orgnaocatalyst (entry
1−9). Among them, the phosphoric acid 3f bearing planar
anthryl substituents at 3,3′-positions turned out to be the
preeminent catalyst and was able to provide the tetracycle 4a
quantitatively with 74% ee (entry 6). Further decreasing or
increasing the size of the plannar substituents was not able to
improve the enantioselectivity (entries 7−9). A survey of
solvents showed that medium polar solvents (i.e., halogenated
hydrocarbons) were beneficial for the stereocontrol and DCE
proved to be the optimal one (entry 10−16). With a prolonged
reaction time, the reaction could be performed at 0 °C, giving
quantitative yield and slightly increased stereoselectivity (entry
17). The enantioselectivity was finally improved to 80% ee in
the presence of 5 mol % of IPrAu(MeCN)SbF6 2 and 10 mol %
of 3f at −30 °C (entry 18).
4
DCE
46
47
74
57
54
56
68
65
68
72
66
61
67
75
80
5
DCE
>99
>99
98
6
DCE
7
3g
3h
3i
DCE
8
DCE
77
9
DCE
>99
95
10
11
12
13
14
15
16
3f
benzene
toluene
MeCN
DCM
CHCl3
dioxane
MeNO2
DCE
3f
83
3f
91
3f
83
3f
93
3f
98
3f
>99
>99
>99
d
17
3f
d,e
18
3f
DCE
−30
a
Unless indicated otherwise, all reactions were carried out for 12 h at
b
c
0.05 M concentration. Isolated yield. Determined by chiral HPLC.
d
e
The reaction time was 4 days. 10 mol % of 3 was used.
substituent on the benzene ring exhibited significant effect on
the enantioselectivity. For instance, substrates with a
substituent at the 3-position gave higher enantioselectivities
than those with one at other positions (4n vs 4b, 4g, 4q; 4l vs
4e; 4p vs 4i and 4o vs 4h). The electron effect of the
substituents varied depending on their positions. The electron-
withdrawing substituent at the 2-position had a positive effect
on the enantioselectivities (4c−j), while substituents at the 3-
position showed an ambiguous influence (4k−p). The absolute
configuration of 4o was determined by X-ray crystallographic
analysis (see the Supporting Information for details).
To better understand the mechanism of this relay catalytic
process, the reaction of 1a in the presence 2 and 3f in CDCl3 at
1
room temperature was monitored by H NMR spectroscopy.
As shown in Figure 2, a broad singlet at 8.06 ppm was observed
when the reaction began. As the reaction proceeded forward,
the signal of Ha decayed with the concomitant appearance of
Hb and Hc from the final product 4a. This indicates that Ha
probably belongs to the key intermediate of this reaction. The
chemical shift and splitting pattern of Ha are consistent with
N−H from the indole ring of compound 5a. This confirmed
our proposed reaction pathway as shown in Scheme 2. It is
noteworthy that intermediate 5a cannot be isolated due to its
high reactivity to transform into the final product. It could
undergo a background reaction to form racemic product or a
chiral phosphoric acid-catalyzed process leading to optically
With the optimized reaction conditions in hand, the
generality of the protocol for different substituted substrates
was investigated (Table 2). All substrates underwent clean
reactions to afford the corresponding products 4b−q in high
yields (79 to >99% yield) and with moderate to excellent
enantioselectivities (76−93% ee). As most substituted sub-
strates showed lower reactivity than 1a, an increased temper-
ature was required to allow the reactions to be finished within
an acceptable reaction time. Notably, the position of the
B
DOI: 10.1021/acs.orglett.6b00012
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
infeasible, and on the other hand, it can be easily realized by the
relay catalytic strategy described here.
Table 2. Substrate Scope
While intermediate 5a was difficult to isolate, compound 5l,
bearing a more electron-deficient indole motif and thus being
less reactive for the intramolecular Michael addition, was
successfully isolated (eq 1). Compound 5l was then applied for
the chiral phosphoric acid catalyzed asymmetric Friedel−Crafts
reaction. As anticipated, this reaction provided the desired
product 4l with quantitative yield and higher enantioselectivity
(97% ee), further confirming the existence of background
reaction (eq 2).
a
All reactions were carried out at 0.05 M concentration until full
conversion of 1 (4−7 d).
In summary, we have disclosed an intramolecular hydro-
amination/Michael addition cascade enabled by gold(I)
complex/chiral phosphoric acid relay catalysis leading to chiral
tetrahydrocarbazoles bearing two adjacent stereocenters with
excellent yields and high enantioselectivities. This strategy
provided a novel and efficient alternative to known methods to
access highly enantioenriched THCs and holds great potential
for applications in the synthesis of polycyclic natural products.
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.6b00012.
Complete description of methods and additional results;
spectroscopic data for all new compounds; synthesis
procedures for substrates (PDF)
1
Figure 2. Monitoring of intermediates by H NMR spectroscopy.
Scheme 2. Proposed Mechanism for the Tandem Reaction
X-ray crystal data for 4o (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hanzy2014@ustc.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSFC
(21502183), the SRG-HSC (2015SRG-HSC044), and the
Fundamental Research Funds for the Central Universities
(WK2060190041).
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