Dearomative indole [5+2] cycloaddition reactions: Stereoselective synthesis of highly functionalized cyclohepta[b]indoles

Article abstract of DOI:10.1002/anie.201406278

The first dearomative indole [5+2] cycloaddition reaction with an oxidopyrylium ylide resulted in efficient and diastereoselective construction of some highly functionalized and synthetically challenging oxacyclohepta[b]indoles. The protocol proceeds unde

Full text of DOI:10.1002/anie.201406278

Angewandte
Chemie
DOI: 10.1002/anie.201406278
Heterocycle Synthesis
Dearomative Indole [5+2] Cycloaddition Reactions: Stereoselective
Synthesis of Highly Functionalized Cyclohepta[b]indoles**
Guangjian Mei, Hao Yuan, Yueqing Gu, Wei Chen, Lung Wa Chung, and Chuang-chuang Li*
Abstract: The first dearomative indole [5+2] cycloaddition
reaction with an oxidopyrylium ylide resulted in efficient and
diastereoselective construction of some highly functionalized
and synthetically challenging oxacyclohepta[b]indoles. The
protocol proceeds under very mild reaction conditions, thus
enabling high functional-group tolerance and unique endo
selectivity.
has been of long-standing interest to organic chemists.[11]
However, there are few known facile preparations of cyclo-
hepta[b]indole skeletons bearing a quaternary stereogenic
carbon center at the C*-position (Figure 1).[11c]
Indoles undergo [3+2][12,13] and [4+2][6g–i,14] cycloaddition
reactions to generate cyclopenta[b]indoles and hydrocarba-
zoles, respectively. However, to the best of our knowledge,
there has been no report in the literature concerning [5p+2p]
cycloaddition reactions[15] where the 2p component is derived
D
earomatization of indoles has been a powerful and
=
potentially versatile strategy to construct many unprece-
dented complex alkaloids from structurally simple sub-
strates.[1] Some dearomative strategies have been developed,
including iminium catalysis,[2] allylation,[3] alkylation,[4] aryla-
tion,[5] and cycloaddition.[6] Dearomative cycloaddition of the
from the C2 C3 bond of an indole. Seven-membered cyclo-
hepta[b]indoles are difficult to access by direct cyclization
reactions because of the combination of entropic factors and
the development of nonbonding interactions in the transition
state. These difficulties can be overcome if a cycloaddition
rather than a cyclization approach is used, whereby two of the
bonds in the cyclic framework might be formed simultane-
ously or almost simultaneously.[16] Herein, we report the
unusual intramolecular and intermolecular dearomative
=
C2 C3 bond of electron-rich aromatic indoles represents an
attractive, straightforward, and atom-economic approach to
building fused indoline compounds. Moreover, indolines with
a fused seven-membered ring at the C2- and C3-positions
(cyclohepta[b]indoles) are privileged scaffolds which are
present in many pharmaceuticals and natural products, such
as ajmaline (1),[7] kopsifoline D (2),[8] ambiguine D isonitrile
(3)[9] (Figure 1). These compounds have been reported to
exhibit a broad range of biological activities. In particular,
ajmaline (1) is a class Ia antiarrhythmic drug with potent
sodium-channel-blocking effects and possesses a very short
half-life, thus making it useful for acute intravenous treat-
ments.[10] Consequently, the development of synthetic meth-
ods for the preparation of functionalized cyclohepta[b]indoles
Figure 1. Alkaloids featuring the cyclohepta[b]indole core.
[*] G. Mei, H. Yuan, Y. Gu, W. Chen, Prof. Dr. C.-C. Li
Laboratory of Chemical Genomics, School of Chemical Biology
andBiotechnology, Peking University Shenzhen Graduate School
Shenzhen 518055 (China)
indole [5+2] cycloaddition reactions with an oxidopyrylium
ylide. These straightforward transformations afford a series of
densely functionalized cyclohepta[b]indole skeletons contain-
ing two adjacent quaternary carbon centers.
E-mail: chuangli@pku.edu.cn
Prof. Dr. L. W. Chung, Prof. Dr. C.-C. Li
Department of Chemistry, South University of Science and-
Technology of China, Shenzhen 518055 (China)
E-mail: ccli@sustc.edu.cn
Our group has been interested in 1,3-dipolar cycloaddi-
tion reactions to access complex natural heterocycles.[17] In
particular, we were intrigued by the intramolecular [3+2]
dipolar cycloaddition reaction of 4, as developed by Padwa
et al.,[13] for the rapid assembly of the complex oxapolycyclic
indoline 5 (Figure 2). Remarkably, the reaction proceeded
with simultaneous formation of multiple bonds. Furthermore,
Homepage: http://www.ligroup.com.cn
[**] This work was supported by the opening foundation from the State
Key Laboratory of Bioorganic and Natural Products Chemistry of
SIOC, the national 973 Program (Grant nos. 2011CB512002 and
2010CB833201), the Natural Science Foundation of China (Grants
no. 21172009 and 20902007), and the Shenzhen Basic Research
Program (Grants no. JCYJ20130329180259934 and
=
this transformation involved the efficient use of the C2 C3
bond of an indole as the 2p component in an intramolecular
cycloaddition reaction with a push-pull carbonyl ylide.[13c,d]
Based on these studies, it was envisaged that the push-pull
nature of oxidopyrylium ylide 6 could enable an intramolec-
JC201005260097A). We would also like to thank Dr. Tao Wang at
PKUSZ for his help with the X-ray crystallographic analysis, Prof. Z.
Yang and Prof. Z. Wang at PKUSZ and Prof. G. Dong at UT, Austin
for helpful discussions, as well as the National Supercomputing
Center in Shenzhen for computational facilities.
=
ular [5+2] dipolar cycloaddition reaction with the C2 C3
bond of an indole to generate synthetically challenging oxa-
cyclohepta[b]indole skeletons, such as 7 (Figure 2). It is
noteworthy, however, that the driving force for the facial
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406278.
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Figure 2. Intramolecular [3+2] and [5+2] dipolar cycloaddition reac-
tions of indoles.
Figure 3. Intramolecular [5+2] cycloaddition of a methoxy oxidopyry-
lium ylide and an indole. TBS=tert-butyldimethylsilyl, Tf=trifluorome-
thanesulfonyl.
selectivity of this dipolar cycloaddition reaction remained
unclear.
lium ylide 12 using a fluoride source (Figure 3). It was
envisaged that the use of this approach would enable the
[5+2] cycloaddition reaction to proceed smoothly under very
mild reaction conditions. The key challenge of this strategy,
however, would be the development of a method capable of
accessing a methoxy pyrylium salt through methylation in the
presence of an electron-rich indole system (when R = alkyl
group or H).
With the indole kojic acid derivative 14a in hand (see the
Supporting Information for details), we proceeded to inves-
tigate the intramolecular [5+2] cycloaddition reaction of the
methoxy oxidopyrylium ylide and indole using the group-
transfer strategy (Table 1). Treatment of 14a with MeOTf at
Our initial attempts focused on the synthesis of acetox-
ypyranone 8 (Scheme 1; see the Supporting Information for
details), which was identified as an important precursor for
the oxidopyrylium ylide 9. Pleasingly, the intramolecular
[5+2] dipolar cycloaddition of the oxidopyrylium ylide and
indole moieties in 9 occurred when 8 was treated with Et3N in
CH3CN at 1508C in a sealed tube, and the compound 10 was
formed as the sole product in 70% yield. The pentacyclic
structure of 10 was unambiguously confirmed by X-ray
crystallographic analysis, which showed the intramolecular
[5+2] cycloaddition reaction proceeded with exclusive endo
selectivity.
Table 1: Optimization of the reaction conditions.
Entry
MeOTf (equiv)
Solvent
Yield [%]
1
2
3
4
5
6
7
1.0
1.5
2.0
2.0
2.0
2.0
2.0
CH2Cl2
CH2Cl2
CH2Cl2
THF
DMF
MeCN
DCE
16[a]
60[a]
80[a]
0
0
41[b]
26[b]
Scheme 1. Synthesis of the pentacyclic core 10 by intramolecular [5+2]
cycloaddition.[22] Ts =4-toluenesulfonyl.
[a] Yield of isolated product. [b] Determined by 1H NMR spectroscopy.
DCE=1,2-dichoroethane, DMF=N,N-dimethylformamide, THF=tetra-
hydrofuran.
While effective, the high temperature required to form the
oxidopyrylium ylide would limit the overall scope and utility
of this reaction. With this in mind, we sought inspiration from
the group-transfer strategy developed by Wender and Mas-
careÇas.[18] This involves the use of MeOTf as a methylating
reagent to form the methoxy pyrylium salt of kojic acid (11) at
a low temperature, followed by generation of the oxidopyry-
408C resulted in methylation to yield the corresponding
methoxy pyrylium salt, which was treated with CsF in CH2Cl2/
DMF[18] at 258C to generate the oxidopyrylium ylide. When
1 equivalent of MeOTf was used in CH2Cl2, the yield for the
adduct 15a was low (16%), thus suggesting that only small
quantities of the oxidopyrylium ylide were generated under
2
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Table 2: Scope of the intramolecular [5+2] cycloaddition reaction.
these reaction conditions (entry 1). Gratifyingly, the use of
1.5 equivalents of MeOTf in CH2Cl2 led to a significant
improvement in the yield of 15a to 60% (entry 2). Solvent
effects were also investigated for the reaction. The results of
these screening experiments revealed that the reaction
performed poorly when it was conducted in DMF and THF
(entries 4 and 5). When MeCN and DCE were used as the
reaction solvent, the yield of 15a was low (entries 6 and 7).
Based on these results, CH2Cl2 was chosen as the optimal
solvent. Under the optimized reaction conditions, 15a was
obtained in 80% yield using 2 equivalents of MeOTf
(entry 3).
Entry[a]
Substrate
Product
Yield
[%][b]
1
80
73
2
With the optimized reaction conditions in hand, we
proceeded to explore the scope of the intramolecular [5+2]
cycloaddition reaction using a variety of different substrates
(Table 2). Pleasingly, the reaction performed well with
a variety of indole systems bearing electron-donating or
electron-withdrawing substituents at C5 and N1 positions.
Furthermore, these reaction conditions worked well with the
electronically matched and mismatched oxidopyrylium ylides
(i.e., the OTBS group was placed at different positions;
entries 1 and 2, 7 and 8, 9 and 10). Indoles bearing an electron-
donating group provided higher yields, under the optimized
reaction conditions (entries 1, 2, 5, 6, 7, and 8), than those
bearing an electron-withdrawing group (entries 3, 9, 10, and
11). Pleasingly, the reaction conditions were tolerant of the N-
unprotected indoles (entry 4) as well as the indoles bearing
a benzyl, allyl, or tosyl group at N1 (entries 5, 6, and 3). The
structure of 15c, which demonstrated exclusive endo selec-
tivity, was determined unambiguously by X-ray crystallo-
graphic analysis (see the Supporting Information),[19] which
showed that the intramolecular dearomative indole [5+2]
cycloaddition reactions in Table 2 proceeded with exclusive
endo selectivity.
DFT (M06-2X/6-31G*) calculations both the [5+2] endo-
and exo-cycloaddition reactions as proceeding through a con-
certed mechanism,[20] and the endo pathway was calculated as
having a 15.6 kcalmolÀ1 lower free-energy barrier than the
asynchronic exo pathway (Figure 4; see the Supporting Infor-
mation for details). A stepwise pathway[20b] is prohibited by
the tether of the substrate. Notably, the endo-cycloaddition
product is much more stable than the exo-cycloaddition
product by 22.9 kcalmolÀ1, and is in agreement with the
observed exclusive production of the endo-cycloaddition
product in our experiments. In addition, our preliminary
calculations suggested that the reaction barrier, in the absence
of the tether, is slightly increased.
3
64
63
81
4[c]
5
6
74
7
90
85
40
45
8
9
10
To our delight, under similar reaction conditions,[18b,21] the
intermolecular dearomative [5+2] cycloaddition reaction of
1-methyl-indole (17a) and maltol (18) occurred smoothly to
give the tetracyclic core 19a as the sole product in 61% yield
(Scheme 2). Pleasingly, the reaction performed well with
a variety of indole systems (17b, 17c, 17d, 17e). The structure
of 19a was determined by two-dimensional NMR spectros-
copy (see the Supporting Information), which showed that the
cycloaddition had proceeded regioselectively with exclusive
endo selectivity. Our DFT calculations also showed that the
free-energy barrier for the intermolecular endo cycloaddition
is slightly lower than that of the the exo-cycloaddition by
11
43
[a] Reaction conditions: 1) The substrate and MeOTf (2.0 equiv) in
CH2Cl2 were reacted at 408C for 12 h; 2) CsF (5.0 equiv) in CH2Cl2/DMF
(1:1) were added at 258C for 7 h. [b] Yield of isolated product. [c] MeOTf
(1.5 equiv), CsF (5.0 equiv).
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ular cycloadditions proceeded under very mild reaction
conditions with exclusive endo selectivity. Furthermore,
DFT calculations have provided some mechanistic insight
into the [5+2] reaction. The application of this methodology
to the synthesis of selected natural bioactive indole alkaloids
and pharmaceutically active agents is currently underway.
Received: June 16, 2014
Published online: && &&, &&&&
Keywords: cycloaddition · diastereoselectivity · heterocycles ·
.
synthetic methods · ylides
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Communications
Heterocycle Synthesis
G. Mei, H. Yuan, Y. Gu, W. Chen,
L. W. Chung, C.-C. Li*
&&&& — &&&&
Dearomative Indole [5+2] Cycloaddition
Reactions: Stereoselective Synthesis of
Highly Functionalized
Bridge construction: The title reaction
with an oxidopyrylium ylide resulted in
efficient and diastereoselective construc-
tion of highly functionalized oxacyclo-
hepta[b]indoles. The protocol proceeded
under very mild reaction conditions, thus
enabling high functional-group tolerance
and endo selectivity. TBS=tert-butyldi-
methylsilyl, Tf=trifluoromethanesul-
fonyl.
Cyclohepta[b]indoles
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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