C(sp2)-H Bond Multiple Functionalization in Air for Construction of Tetrahydrocarbazoles with Continuous Quaternary Carbons and Polycyclic Diversification

Article abstract of DOI:10.1021/acs.orglett.0c00145

The C(sp²)-H function of indole ketone with diazo compound via a rhodium(II)-catalyzed intramolecular electrophilic trapping reaction under mild conditions in air was demonstrated. The established methodology provided a highly efficient approach for direct synthesis of mutisubstituted tetrahydrocarbazoles with continuous quaternary carbons. The resulting products facilitate further modification to conveniently construct tetrahydrocarbazoles with additional fused heterocyclic rings. By phenotypic screening, several products exhibit good anticancer bioctivities in osteosarcoma cell lines.

Full text of DOI:10.1021/acs.orglett.0c00145

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Letter
C(sp2)−H Bond Multiple Functionalization in Air for Construction of
Tetrahydrocarbazoles with Continuous Quaternary Carbons and
Polycyclic Diversification
Longlong Song, Dan Ni, Shikun Jia, Rou Pi, Suzhen Dong, Fan Yang, Jie Tang,* and Shunying Liu*
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ABSTRACT: The C(sp2)−H function of indole ketone with diazo compound via a rhodium(II)-catalyzed intramolecular
electrophilic trapping reaction under mild conditions in air was demonstrated. The established methodology provided a highly
efficient approach for direct synthesis of mutisubstituted tetrahydrocarbazoles with continuous quaternary carbons. The resulting
products facilitate further modification to conveniently construct tetrahydrocarbazoles with additional fused heterocyclic rings. By
phenotypic screening, several products exhibit good anticancer bioctivities in osteosarcoma cell lines.
etrahydrocarbazoles1 consist of structurally diverse indole
Scheme 2. Strategies for Constructing Tetrahydrocarbazole
Cores Containing Quaternary Carbons
T
alkaloid scaffolds2 present in a range of drug candidates
and bioactive natural products. As shown in Scheme 1,
Scheme 1. Natural Products and Bioactive Compounds
Containing the Tetrahydrocarbazole Scaffold
tetrahydrocarbazoles have been employed as important
rogens.3 Owing to their remarkable significance, developing
highly efficient methodologies to construct tetrahydrocarbazole
cores has attracted attention in the synthesis and pharmaceu-
tics communities. Considerable well-designed strategies for
synthesis of tetrahydrocarbazoles by transition-metal catalysts
were developed,4 such as a cascade reaction at the C2 position
of the Diels−Alder reaction with the C3 position of indole and
the Friedel−Crafts alkylation at the C3 position in indole
(Scheme 2a−c).5 Notably, the structural characteristics of
these active tetrahydrocarbazole derivatives (Scheme 1) are a
fused heterocycle ring typically fused with a C ring in the
tetrahydrocarbazole core scaffold.6
Received: January 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00145
© XXXX American Chemical Society
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A

Organic Letters
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Letter
a
Among these methodologies, those used to build tetrahy-
drocarbazole core structures containing quaternary carbons are
highly limited, and only several efficient examples have been
reported. You and co-workers innovatively synthesized
enantiomeric tetrahydrocarbazoles containing a quaternary
carbon by iridium-catalyzed allylic dearomatization, followed
by acid-catalyzed stereospecific migration of indole at the C2
position (Scheme 2a).7a Widenhoefer et al. established an
operational method to offer single quaternary carbon
tetrahydrocarbazoles by platinum-catalyzed intramolecular
alkylation of indoles at the C3 position with olefins (Scheme
1b).7b Recently, Williams and co-workers demonstrated
unparalleled biosynthetic tetrahydrocarbazoles with quaternary
carbons catalyzed by the reductase-dependent Diels−Alderase
(Scheme 1c).7c However, these well-established elegant
methods cannot construct continuous quaternary carbons
and are also difficult to use for further introduction of an
additional fused ring at the C ring. To the best of our
knowledge, no example was developed to construct tetrahy-
drocarbazole cores coupled with continuous quaternary
carbons at the C ring, which may be attributed to a great
steric hindrance effect and functional group limitations. Thus,
developing a robust and generally applicable method for the
preparation of tetrahydrocarbazoles containing continuous
quaternary carbons has been considered a formidable
challenge.
In the past years, transition-metal-catalyzed carbene
reactions including X−H (X = O, N, and C) insertion cascade
sequences8 have been used as convenient artificial tools for
diverse heterocyclic molecules. Many chemists have made
outstanding contributions toward construction of useful
molecules by carbene chemistry, including Doyle,9 Davis,10
Zhou,11 Feng,12 Wang,13 Xu,14 and Hu.15 Recently, we also
developed a rhodium(I)-catalyzed carbene reaction to
construct asymmetric 3,3-disubstituted oxindoles.16 Based on
the elegantly developed C−H functionalization of indole
heterocycles with diazoalkanes,17 we envision that if a carbene
intermediate is trapped by the ketone at C3 in indole, it will
provide a convenient approach to construct a C ring with
quaternary carbons (Scheme 2d) to overcome the above-
mentioned synthetic gap. Continuous quaternary carbons with
multifunctional substituents at the C ring will facilitate further
cyclization to generate an additional fused ring with he C ring,
which will afford bioactive compounds with structural diversity
for drug discovery. Here, we report a method via carbene
intermediates from indoles for synthesis of tetrahydrocarbazole
core scaffolds containing continuous quaternary carbons,
which are demonstrated to be readily for further diverse
cyclization.
Table 1. Optimization of the Reaction Conditions
b
T
(°C)
yield
(%)
dr (syn/
c
entry
catalyst
R1
solvent
anti)
1
2
3
4
Rh2(OAc)4
Cu(OTf)2
Rh2(esp)2
[Rh(C2H4)
Cl]2
Boc
Boc
Boc
Boc
DCM
DCM
DCM
DCM
40
40
40
40
45
trace
41
71:29

61:39
53:47
<10
5
6
7
8
[Ir(cod)Cl]2
[Pd(allyl)Cl]2
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Boc
Boc
Boc
Boc
Cbz
Bn
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
toluene
DCE
40
40
30
0
<10
44
49
56
51
82
92
99
82
77
85
85
52:48
65:35
68:32
54:46
69:31
92:8
>20:1
>20:1
82:18
90:10
93:7
9
40
40
rt
10
11
12
13
14
15
16
d
Bn
Me
Me
Me
Me
Me
rt
rt
rt
rt
rt
CHCl3
e
DCM
95:5
a
Reactions performed by adding 2 (0.05 mmol) in 1 mL of solvent to
the mixture of 1 (0.1 mmol) and catalyst in 1 mL of solvent via
syringe pump over 1 h. Isolated yield. Determined by H NMR of
the crude products. rt = room temperature. Without 4 Å molecular
sieves in air. DCE: dichloroethane. DCM: dichloromethane.
b
c
1
d
e
poor diastereoselectivity. On the base of the electrical effects of
substituents on the N atom in 3-diazooxindoles, various
substituents were tested, such as Cbz, Bn, and Me groups.
Indeed, electron-donating groups markedly increased the yield
and diastereoselectivity (Table 1, entry 10) up to 82% and
92:8, respectively. A lower temperature also played a positive
role in the investigational results to give 92% yield (Table 1,
entry 11), and the N-Me group substituted 2 offered a nearly
quantitative yield (Table 1, entry 12), which may be benefit
from lower steric hindrance. Further exploration of solvent
effect shows that DCM is an optimal choice (Table 1, entries
13−15). Surprisingly, the reaction proceeded smoothly in air,
but with a slightly decreasing diastereoselectivity (95:5)
without 4 Å molecular sieves (Table 1, entry 16). The
reaction was conducted at 25 °C with 4 Å molecular sieves in
air using DCM as solvent to obtain the optimized results.
The substrate scope of this reaction was then explored. A
series of 3-diazooxindoles were subjected to 1e and gave the
corresponding products in admirable yields (Scheme 3).
Substituents such as F, Cl, and OMe (3b−n) in the N-Me
or N-Bn group protected 3-diazooxindoles were also well-
tolerated. However, the substituent at the para-position in Bn-
protected 3-diazooxindoles did not afford supreme diaster-
eoselectivity (3i,j), which demonstrates a steric limitation in
this reaction process. The reaction was further efficiently
extended to 2-arylindolyl and 2-alkylindolyl ketones (3f, 3h,
3o−p). The relative stereochemical configuration of 3m was
confirmed by single-crystal X-ray crystallography (inset in
Scheme 3). Gram-scale reaction of 1b with 2a proceeded,
affording 3a with satisfactory results (5.0 mmol scale, 1.56 g,
90%).
At the launch of exploration, N-methylindole alkyl ketone 1
and 3-diazooxindole 2 were employed at 40 °C under the
conditions of Rh2(OAc)4 as catalyst and with 4 Å molecular
sieves as additives under N2 atmosphere. It was delightful that
anticipated product 3 was afforded in 45% yield, but with a
poor diastereoselective ratio (71:29; Table 1, entry 1).
Cu(OTf)2, Rh2(esp)2, [Ir(cod)Cl]2, [Rh(cod)Cl]2, and [Pd-
(allyl)Cl]2 were also used to test the reaction (Table 1, entries
2−6). Apart from Rh2(esp)2 and [Pd(allyl)Cl]2, Cu(OTf)2,
[Rh(cod)Cl]2, and [Ir(cod)Cl]2 failed to build tetrahydrocar-
bazole products. The yields were increased to 56% by
decreasing reaction temperature from 40 to 0 °C (Table 1,
entries 7 and 8). Differently N-substituted diazooxindole 2
(Table 1, entry 9) generated a good yield and improved the
B
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Scheme 3. Substrate Scope for the
Tetrahydrospirocarbazole Synthesis
Scheme 4. Substrate Scope for the Tetrahydrocarbazole
a
a
Synthesis
a
Reactions performed by adding 2 (0.4 mmol) in 1 mL of DCM to
the mixture of 1 (0.2 mmol) and catalyst in 1 mL of DCM via syringe
pump for 1 h at 25 °C
The asymmetric reaction version was explored in the
presence of metal catalysts and chiral ligands.18 An extensive
selection of reaction conditions (Table S1) such as 1 mol % of
Rh2(OAc)4, 5 mol % of (R)-3,3-bis(2,4,6-iPr3C6H2)-binol
phosphoric acid (IIa), and −10 °C temperature in DCM gave
a moderate enantioselectivity of syn- (63:37 er) and anti-
tetrahydrospirocarbazoles (94:6 er).
In order to explore the possibility of the additional fused
heterocycle to the C ring of the tetrahydrocarbazole core
structure from the resulting products, phenyldiazoacetate 4 was
used instead of 3-diazooxindole 2 to run the reaction with N-
methylindolealkyl ketone 1 under optimized conditions
(Scheme S2). The tested results showed the reaction by
using phenyldiazoacetates conducted at 40 °C with 4 Å
molecular sieves in DCM to afford the best result. A range of
phenyldiazoacetates were well tolerated in this reaction
(Scheme 4). All desired products were delivered in moderate
to good yields and excellent diastereoselectivities when
phenyldiazoacetate bearing F, Cl, Br, OMe, and Me at the
meta-position or para-position of aromatic rings (5a−i, 5m−q)
was used. Additionally, phenyldiazoesters derived from
androstrone, L-menthol, and diacetone-D-glucose (5v−x)
underwent the reaction to afford the resultant tetrahydrocar-
bazole products, respectively.
a
Reactions performed by adding 4 (0.4 mmol) in 1 mL of DCM to
the mixture of 1 (0.2 mmol) and catalyst in 1 mL of DCM via syringe
pump over 1 h at 40 °C.
in 36% yield (Scheme 5a). Following esterification of 5aa to
give a lactone derivative 5ab in 90% yield, which is the
essential scaffold in many pharmaceutical molecules, such as
palmostalin B, hymeglusin, and orlistat.19 Furthermore, 5ba
can be transformed to polycyclicbenzofuroindolines20 5ca in
42% yield through a formal [4 + 2] annulation. Dearomatiza-
tion and cyclopropanation of 5dd was also conducted at 0 °C
to afford 5ca in 45% yield.
Ondansetron21 was also totally synthesized through this
strategy (Scheme 5b). Compound 1a was treated with 5w
under the standard conditions to deliver 5da in 80% yield.
Then dehydration22a of 5da at the C5 position to afford 5db,
which followed by elimination22b at 60 °C and oxidation22c
under mild conditions to afford 5dd. Then 5dd was reacted
with imidazole through an intermolecular addition22d to
generate ondansetron in 41% overall yield.
A number of primary mechanistic studies were conducted to
understand this C−H functionalized reaction pathway.
Initially, C−H insertion products 7a and 7b were prepared
and then reacted in succession under the critical conditions
(IS, Scheme S3). No desired tetrahydrocarbazole products
were observed, which excludes a stepwise C−H insertion/aldol
addition pathway and verifies a direct trapping pathway of a
To demonstrate the practicality for construction of an
additional ring to C ring via this strategy, a range of further
cyclizations of tetrahydrocarbazole derivatives has been carried
out. The tetrahydrocarbazole 5aa was obtained by 10% Pd/C
to reduce the Bn group from 5p in 99% yield, and 5aa also can
be obtained from demethylation of 5s under alkalic conditions
C
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favored in a zwitterion capture step (Scheme 6) can be
explained by the chelation between an enolate rhodium and
carbonyl group of indole 1 in the syn-conformation which
stabilize the transition state.
Scheme 5. Synthetic Applications of Tetrahydrocarbazoles
Scheme 6. Plausible Mechanism
zwitterioinc intermediate. In addition, operando IR spectros-
copy was used to further explore the interaction mechanism
(Figure 1). Compound 2a was added to a solution of 1e in
Considering the possible bioactivities of tetrahydrocarbazole
core scaffolds, we explored the biologic activity of the resulting
tetrahydrocarbazole products in MG63, HOS, 143B, and
MNNG/HOS cell lines24 by phenotypic screening (Table 2
and Table S2). It is noted that 3h exhibited excellent inhibition
against all tested osteosarcoma cell lines. Compound 3j
showed a selected inhibition against MNNG/HOS compared
other osteosarcoma cell lines. Compound 3i exhibited a better
selective inhibition against the HOS cell line. These results
show that the resulting compounds are promising for use as hit
compounds for the search fro an antiosteosarcoma cancer drug
for target therapy. Presently, there is no target therapeutic
treatment for osteosarcoma.
In summary, a highly efficient routine to directly construct
tetrahydrocarbazole with consecutive quaternary carbon
centers in up to quantitative yields and excellent diaster-
eoselectivities has been achieved under mild conditions in air.
Results show this reaction has a wide range of substrates and
achieves a moderate degree of chiral control. The resulting
products have good stability, and gram-scale reactions
succeeded. The products are readily used to construct diverse
tetrahydrocarbazole core scaffolds with an additional fused ring
to the C ring. The developed method was also applicable to
build ondansetron. Additionally, the bioactive analysis
illustrates that the synthetic tetrahydrocarbazole product 3h
is a new potential antiosteosarcoma hit compound. Further
enantioselective optimization of those tetrahydrocarbazoles
and medicinal chemistry are currently ongoing in our
laboratory.
Figure 1. Three-dimensional Fourier transform IR (3DFTIR) profiles
of 1e and 2a.
DCM and monitored at the same concentration. Typical
stretching vibration signals of the CO and CN2 group in
2a were observed at 1605 and 1691 cm−1, respectively,23 which
rapidly disappeared with the decomposition of diazos by
Rh(II) catalyst. The CO signal of 1e gradually disappeared
with the reaction process. Three new peaks attributed to the
CO, OH, and phenyl group signals in 3a were gradually
increased and observed at 1605, 1697, and 1685 cm−1
respectively. Significantly, not the diazo decomposition but
the capture process was a rate-limiting step for this reaction.
According to the experimental results, we propose a
plausible mechanism. Primarily, 4/2 is catalyzed by
Rh2(OAc)4 to form a carbene I/II, which then reacts with 1
to form zwitterioninc intermediates TSI and TSII. The active
TSI and TSII are subsequently capped by ketones and
respectively yield products 3 or 5. The syn-stereochemistry
D
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Table 2. Inhibitory Activity of the Representative Resulting Compounds against MG63, HOS, 143B, and MNNG/HOS Cell
a
Lines
inhibition (%)
entry
no.
MG63
HOS
143B
MNNG/HOS
1
2
3
4
5
6
7
8
9
3a
3b
3h
3i
100.1 4.7
62.5 1.5
25.9 3.4
112.3 0.8
92.2 4.4
98.6 3.7
118.0 3.3
62.0 5.8
114.1 1.5
105.4 0.7
104.8 0.2
53.8 3.1
4.0 0.4
26.1 0.2
52.9 1.7
49.9 2.3
100.8 1.0
55.9 0.8
98.0 2.4
102.8 1.8
105.5 8.4
73.6 1.3
8.3 0.5
49.3 0.6
72.7 0.8
41.8 2.3
69.7 4.1
37.3 2.0
79.4 1.2
80.6 2.7
95.9 2.1
61.5 0.6
1.4 0.2
95.5 2.1
28.9 6.4
78.4 1.2
110.3 0.9
98.2 1.1
105.2 0.6
47.1 2.8
3j
3k
5o
5v
5n
5g
10
a
Proliferation is presented as inhibition (%). Inhibition (%) of M G63, HOS, 143B, and MNNG/HOS was produced by the tested compounds at
100 μM.
Suzhen Dong − Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, School of
Chemistry and Molecular Engineering, East China Normal
University, Shanghai 200062, China
Fan Yang − Shanghai Engineering Research Center of Molecular
Therapeutics and New Drug Development, School of Chemistry
and Molecular Engineering, East China Normal University,
Shanghai 200062, China
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00145.
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Experimental procedure and spectroscopic data for all
compounds (PDF)
Accession Codes
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00145
CCDC 1482623 and 1958479 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
AUTHOR INFORMATION
Corresponding Authors
■
Financial support from NSFC (21672066) is greatly acknowl-
edged.
Jie Tang − Shanghai Engineering Research Center of Molecular
Therapeutics and New Drug Development, School of Chemistry
and Molecular Engineering, East China Normal University,
Shanghai 200062, China; Email: jtang@chem.ecnu.edu.cn
Shunying Liu − Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, School of
Chemistry and Molecular Engineering, East China Normal
University, Shanghai 200062, China; orcid.org/0000-
0002-3894-757X; Email: syliu@sist.ecnu.edu.cn
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Authors
Longlong Song − Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, School of
Chemistry and Molecular Engineering, East China Normal
University, Shanghai 200062, China
Dan Ni − Shanghai Engineering Research Center of Molecular
Therapeutics and New Drug Development, School of Chemistry
and Molecular Engineering, East China Normal University,
Shanghai 200062, China
Shikun Jia − Shanghai Engineering Research Center of Molecular
Therapeutics and New Drug Development, School of Chemistry
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Shanghai 200062, China
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