Enantioselective [4 + 2] Cycloaddition/Cyclization Cascade Reaction and Total Synthesis of cis-Bis(cyclotryptamine) Alkaloids

Article abstract of DOI:10.1021/acs.orglett.1c00260

The asymmetric catalytic synthesis of 3-cyclotryptamine substituted oxindoles through formal [4 + 2] cycloaddition/cyclization cascade is described. A wide range of cyclotryptamine derivatives were obtained in enantioenriched form under mild reaction conditions and were found to have potential anticancer activity. The strategy enables ready assembly of cyclotryptamine subunits at the C3a-C3a′ positions with two quaternary stereogenic centers in cis-selectivity, leading to the concise synthesis of optically active cis-bis(hexahydropyrroloindole) and others of the cyclotryptamine alkaloid family.

Full text of DOI:10.1021/acs.orglett.1c00260

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Letter
Enantioselective [4 + 2] Cycloaddition/Cyclization Cascade Reaction
and Total Synthesis of cis-Bis(cyclotryptamine) Alkaloids
Jian Xu, Runze Li, Nian Xu, Xiaohua Liu,* Fei Wang,* and Xiaoming Feng*
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ABSTRACT: The asymmetric catalytic synthesis of 3-cyclotrypt-
amine substituted oxindoles through formal [4 + 2] cycloaddition/
cyclization cascade is described. A wide range of cyclotryptamine
derivatives were obtained in enantioenriched form under mild
reaction conditions and were found to have potential anticancer
activity. The strategy enables ready assembly of cyclotryptamine
subunits at the C3a−C3a′ positions with two quaternary stereogenic
centers in cis-selectivity, leading to the concise synthesis of optically active cis-bis(hexahydropyrroloindole) and others of the
cyclotryptamine alkaloid family.
yclotryptamine alkaloids which comprise two or more
hexahydropyrroloindole (HPI) units or others represent
precursors, such as homo- or heterobisoxindoles,3 hexahy-
dropyrroloindole derivatives,4 and indole-substituted oxin-
doles5 (Figure 1b). Thus, these strategies have enabled concise
access to the total synthesis of optically active alkaloid natural
products, including chimonanthine, calycanthidine, hodgkin-
sine, etc.6
In fact, most reported approaches have paid much attention
to the optically active trans-isomers where homotype alkaloids
are involved. Actually, several pyrroloindoline alkaloids,
including desmethyl meso-chimonanthine and others, bearing
a pseudo C2-symmetric backbone have also been isolated.1,2
Enantioselective construction of nonsymmetrical meso-ana-
logues is elusive and interesting.4g,i,7 Starting with meso-
chimonanthine, asymmetric Heck cyclization to desymmetriza-
tion allows the total synthesis of a variety of cyclotryptamine
alkaloid oligomers by Overman8 and Wills.9 Dalko and co-
workers had realized the synthesis of desymmetrized dimeric
meso-pyrrolidinoindoline alkaloids10 by using s tandem [4 + 2]
cycloaddition route, which was inspired by Funk for the total
synthesis of perophoramidine,5c,11 and communesin F as
well.12
C
a set of structurally and biologically interesting natural
products.1,2 The simplest member of this family, for example,
chimonanthine, consists of two same cyclotryptamine subunits
fused at the C3a and C3a′ positions, forming chiral or meso-
isomers (Figure 1a). This core structure could be extended
into optically active hodgkinsine B, quadrigemine C, and
others upon appending an additional HPI subunit at the C7′-
position. Asymmetric assembly of such molecules featured with
vicinal quaternary all-carbon centers drew much attention over
the past decades. Many elegant routes have been discovered,
starting from the enantioselective construction of the key
In view of the structural and stereoversatility of such
architecture and the challenge of catalytic asymmetric
construction of the sterically congested vicinal all-carbon
quaternary stereocenters in these structures, herein we
performed an asymmetric catalytic [4 + 2] cycloaddition/
cyclization cascade reaction between tryptamine derivatives
Received: January 22, 2021
Published: February 23, 2021
Figure 1. Representative asymmetric catalytic strategies for the
construction of hexahydropyrroloindole alkaloid natural products.
https://dx.doi.org/10.1021/acs.orglett.1c00260
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1856−1861
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and indol-2-ones in situ generated from 3-bromooxindoles.
Then, a number of enantiomerically enriched cyclotryptamine-
substituted oxindole derivatives were prepared (82−99% yield,
>19:1 dr, 88−99% ee). As a continuation of our research on
the enantioselective synthesis of HPI alkaloids,3f the employ-
ment of a similar nickel complex of chiral N,N′-dioxides as the
catalyst in the synthesis of trans-bisoxindoles from 3-
bromooxindoles, stereoselective reversal synthesis of cis-
chimonanthine analogues, and the related derivatives were
established in this case. This kind of [4 + 2] cycloaddition and
sequential transformations could be extended to the con-
struction of piperidinoindoline scaffolds. Biological activity
evaluation indicates that some new cyclotryptamine-substi-
tuted oxindole derivatives have promising anticancer property.
At the outset of this study, we chose tryptamine derivative
1a and 3-methyl-3-bromooxindole 2a as model substrates to
optimize the reaction conditions (Table 1). Cs2CO3 was
With the optimal conditions in hand (Table 1, entry 9), the
scope of tryptamine derivatives was explored in the cascade
reaction with 2a (Scheme 1). It was found that the reaction
a
Scheme 1. Substrate Scope of Tryptamine Derivatives
a
Table 1. Optimization of the Reaction Conditions
b
c
c
entry
metal salt
base
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
Mg(OTf)2
Zn(OTf)2
Cu(OTf)2
Fe(OTf)3
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
Ni(BF4)2·6H2O
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Et3N
DIPEA
nPr3N
nPr3N
82
46
50
34
82
84
84
89
89
>19:1
90:10
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
5
3/47
25
0
84
94
95
96
a
Unless otherwise noted, all reactions were carried out with 1 (0.10
d
9
96
mmol), 2 (1.2 equiv), L3-PiMe3/Ni(BF4)2·6H2O (1:1, 10 mol %),
nPr3N (1.2 equiv) in DCM (1.0 mL) at 20 °C for 6−8 h. Yield of
a
Unless otherwise noted, all reactions were carried out with 1a (0.10
mmol), 2a (0.12 mmol), L3-PiPr2/metal salt (1:1, 10 mol %), base
(0.12 mmol) in DCM (1.0 mL) at 20 °C for 8−10 h. Yield of
isolated product. Determined by chiral HPLC. Ligand was replaced
1
isolated product, dr values were determined by H NMR, and ee
b
values were determined by HPLC analysis.
c
d
by L3-PiMe3.
tolerated tryptamines with various carbamate functions at the
side chain nitrogen, affording the related products 3ba−3da in
eminent results (91−95% yield, 95−96% ee). Either electron-
donating groups or electron-withdrawing groups at the 5- or 6-
position of the indole ring of tryptamines had no significant
impact on the outcomes, providing the corresponding
pyrroloindolines 3ea−3ia in outstanding results (84−99%
yield, 93−96% ee). Examination of the possible substitution on
the indolic nitrogen demonstrated that a range of alkyl
protecting groups are compatible; for example, N-methyl, N-
benzyl, and N-allyl-substituted tryptamines underwent cycliza-
tion in good yield and enantiocontrol (3ja−3la; 82−87% yield,
88−92% ee). Moreover, N-H based tryptamine derivative 1m
could react with indol-2-one of 2d to afford the related product
3md in 96% yield with 99% ee. Next, we considered utilizing
this methodology for the construction of a variant of the cyclic
core structure. It seemed likely that the formation of
tetrahydrofuran (3na; 99% yield, 92% ee) and piperidinyl
indoline (3oa; 90% yield, 96% ee) was readily available with
initially selected as the base to generate indol-2-one
intermediate from 2a. First, a variety of metal salts combined
with chiral ligand N,N′-dioxide L3-PiPr2 were tested in DCM
at 20 °C (entries 1−5). It was found although the desired
hexahydropyrroloindole derivative 3aa could be isolated in
moderate to good yield, the enantioselectivity was poor by the
use of many typical Lewis acids, such as Mg(OTf)2, Zn(OTf)2,
Cu(OTf)2, or Fe(OTf)3. In comparison, Ni(BF4)2·6H2O
provided promising results as 82% yield with >19:1 dr and
84% ee (entry 5). Then, different bases were explored to
minimize base-accelerated racemic reaction.10 An obviously
increased enantioselectivity was observed when organic bases
n
were used (entries 6−8), and sterically hindered Pr3N could
give the best results in 89% yield with >19:1 dr and 96% ee
(entry 8). Moreover, when the ligand was changed to L3-
PiMe3, which is much easier to be prepared, the excellent
outcomes could be retained (entry 9).
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great enantiocontrol upon using tryptophol or indole
propionamide substrate.
We next turned to the intramolecular variant of this cascade
reaction to 3-alkyl-3-bromoindolin-2-ones (Scheme 2). For
Furthermore, the synthetic utility of this reaction was
investigated. A gram-scale reaction between tryptamine 1a and
methyl carbamate 3-bromooxindole 2g was performed,
furnishing the product 3ag in nearly quantitative yield, >19:1
dr, 97% ee (Scheme 3a). Reducing of 3ag by red-Al at high
Scheme 2. Substrate Scope of 3-Substituted-3-
Bromooxindoles
a
Scheme 3. Gram Scale-Up and Synthetic Utility
temperature via a reductive amination/cyclization of oxindole
moiety generated the final alkaloid 4 as cis-(−)-calycanthidine
in 85% yield. Accordingly, the asymmetric total synthesis cis-
(+)-chimonanthidine 5 was efficiently obtained from azide-
containing product 3ad upon methylation and reducing after a
one-column purification with 86% overall yield (Scheme 3b).
The presence of multiple low-energy conformations around
the vicinal quaternary carbon of these alkaloids leads to
difficulty in crystalline samples for X-ray analysis.6a After
acidification with hydrochloric acid, the structure of cis-
(+)-chimonanthidine 5 was unambiguously and first assigned
by X-ray crystallographic analysis (Scheme 3b).13 The C3a−
a
Standard conditions.
example, indolinones with 3-alkyl substituent ranged from
methyl to isobutyl with increased steric hindrance gave rise to
the desired products in remarkable yield and enantioselectivity
(3ab, 90% yield with 93% ee; and 3ac, 95% yield with 96% ee).
Moreover, a range of functional groups at the terminal position
of the 3-alkyl chain, such as azide, iodine, ether, methyl
carbamate, allyl, or ester, were introduced, and they could
indeed be accomplished to deliver the products 3ad−3ai with
perfect enantioselectivities (94−99% ee), which will play
promising roles in further transformations. Moreover, the
reaction was amenable to other benzyl or heteroaromatic
groups, including the furyl, thienyl or 1-naphthyl group (3aj,
3ak, 3am). We also employed 3-benzyl-3-bromooxindoles
containing electron-donating or electron-withdrawing groups
at different positions on the benzyl moiety, and the reaction
afforded the corresponding products (3an-3at) with admirable
results (89−97% yield, 95−97% ee).
C
3a′ σ-bond is 1.55 Å in the salt of the compound 5, indicating
steric congestion in this kind of diastereoisomer. Similarly, cis-
(+)-N-desmethyl-chimonanthine 7 and cis-(+)-N-allyl-chimo-
nanthine 8 could be synthesized by reductive cyclization of the
product 3md and 3lg respectively in high yields (Scheme 3c
and d).4g Taken together, these syntheses highlight the
versatility of this method and suggest that its use in even
more complex contexts might prove feasible (for example,
hodgkinsine B).8,9,14
Considering the importance of these indole-based structures,
we investigated the bioactivity of several cyclotryptamine-
oxindole products 3. The in vitro cytotoxicity against human
colorectal carcinoma (HCT-116), renal carcinoma (ACHN),
and hepatocellular carcinoma (HCCLM3) cells were eval-
uated. IC50 values ranged from 11.79 to 68.18 μM, which are
listed in Figure 2. The effects are moderate, but two are more
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indol-2-one could be activated after coordinating to the N,N′-
dioxide/NiII complex. The Si-face of the indol-2-one is
shielded by the amide unit of the ligand, and the tandem [4
+ 2] cyclization/addition with tryptamine 1a occurs preferen-
tially from the Re-facial of indol-2-one. There might be
stabilizing π−π stacking interaction between the two indoline
rings of the two substrates, and the nucleophilicity of the C3
position of the tryptamine enables the addition to the less-
electron-rich C3 carbon of indol-2-one in an endo-selective
cycloaddition manner.16c The primary cycloadduct Int A was
unstable, and it could spontaneously rearrange into the cyclic
imine Int B, which in turn could be trapped by the nucleophilic
side chain of tryptamine to give the desired pyrrolidinoindoline
skeleton.
Based on the understanding of the reaction process, we
carried out tandem reaction between 3-bromoindolin-2-one 2d
and N-H free indole derivative 1p (Scheme 4b), which has
been reported by Wang and co-workers for the enantiose-
lective total synthesis of perophoramidine.5c The asymmetric
formal [4 + 2] cycloaddition/rearrangement process occurred
smoothly under the standard condition, delivering the imine
product 9 in excellent diastereo- and enantioselectivity. After
reduction and crossover cyclization, a piperidinolindoline
scaffold 10 was constructed with high yield and stereo-
selectivity, which is the key subunit of the dihydropsycho-
triadine, the elusive scaffold of bis(cyclotryptamine) alka-
loids.17
In summary, we have developed an efficient route to the
synthesis of cyclotryptamine-oxindole architectures bearing
vicinal quaternary carbon stereocenters via asymmetric
catalytic [4 + 2] cycloaddition/cyclization cascade reactions.
The endo- and enantioselective cycloaddition process following
late-stage C−N bond formation enabled the formation of cis-
bis(cyclotryptamine) units, which represent an important
framework of the hexahydropyrroloindole alkaloid family.
These cyclotryptamine derivatives showed promising biological
activity. Additional applications of this methodology are
underway.
Figure 2. Bioactivities of some cyclotryptamine-oxindole products.
sensitive than the natural products against HCT-116, including
(−)-chimonanthine and meso-chimonanthine (see the Sup-
porting Information for details).15 These synthesized cyclo-
tryptamine-oxindole derivatives and the stereoisomers of the
natural products might be promising compounds for
discovering more applications in medicinal chemistry.
The stereocontrol of this coupling reaction was considered
based on the previous study of the catalyst structure16 and the
outcome of this reaction process. The stereoarrangement at C3
position of oxindole products in the current case is a reversal to
the oxindole derivative synthesized via nucleophilic addition of
3-substituted oxindoles with 3-bromoindolin-2-ones in our
previous work,3f even in the presence of the same chiral
catalyst. We propose that this appearance is due to a different
activation manner although the same electrophile is involved.
A different diastereo- and enantioselective nucleophilic attack
model (Scheme 4a) was suggested.10−12 The in situ generated
Scheme 4. (a) Proposed Mechanism and Stereoselectivity
Control. (b) Enantioselective Synthesis of Piperidindoline
Derivative
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spectra (PDF)
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AUTHOR INFORMATION
■
Corresponding Authors
Xiaohua Liu − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0001-9555-0555; Email: liuxh@scu.edu.cn
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Asymmetric Construction of Vicinal All-Carbon Quaternary Stereo-
centers and its Application to the Synthesis of Cyclotryptamine
Alkaloids. Angew. Chem., Int. Ed. 2013, 52, 9176−9181. (c) Chen, D.-
F.; Zhao, F.; Hu, Y.; Gong, L.-Z. C-H Functionalization/Asymmetric
Michael Addition Cascade Enabled by Relay Catalysis: Metal
Carbenoid Used for C-C Bond Formation. Angew. Chem., Int. Ed.
2014, 53, 10763−10767. (d) Ghosh, S.; Bhunia, S.; Kakde, B. N.; De,
S.; Bisai, A. Enantioselective construction of vicinal all-carbon
quaternary centers via catalytic double asymmetric decarboxylative
allylation. Chem. Commun. 2014, 50, 2434−2437. (e) Chen, S.-K.;
Ma, W.-Q.; Yan, Z.-B.; Zhang, F.-M.; Wang, S.-H.; Tu, Y.-Q.; Zhang,
X.-M.; Tian, J.-M. Organo-Cation Catalyzed Asymmetric Homo/
Heterodialkylation of Bisoxindoles: Construction of Vicinal All-
Carbon Quaternary Stereocenters and Total Synthesis of (−)-Chi-
monanthidine. J. Am. Chem. Soc. 2018, 140, 10099−10103. (f) Xu, J.;
Zhong, Z. W.; Jiang, M. Y.; Zhou, Y. Q.; Liu, X. L.; Feng, X. M.
Asymmetric Catalytic Concise Synthesis of Hetero-3,3′-Bisoxindoles
for the Construction of Bispyrroloindoline Alkaloids. CCS Chem.
2020, 2, 1894−1902.
Fei Wang − Center for Natural Products Research, Chengdu
Institute of Biology, Chinese Academy of Sciences, Chengdu
610041, China; Email: wangfei@cib.ac.cn
Xiaoming Feng − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0003-4507-0478; Email: xmfeng@scu.edu.cn
Authors
Jian Xu − Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan
University, Chengdu 610064, China
Runze Li − Center for Natural Products Research, Chengdu
Institute of Biology, Chinese Academy of Sciences, Chengdu
610041, China
Nian Xu − Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan
University, Chengdu 610064, China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21625205, U19A2014, and 21921002) for financial
support. The authors wish to acknowledge Professor Pengchi
Deng (Analytical & Testing Center, Sichuan University) for
NMR support.
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