Organocatalytic regiodivergent ring expansion of cyclobutanones for the enantioselective synthesis of azepino[1,2- a]indoles and cyclohepta[ b]indoles

Article abstract of DOI:10.1021/acs.orglett.0c01406

A regiodivergent organocatalytic enantioselective Michael addition/three-atom ring expansion sequence of electron-withdrawing group activated cyclobutanones with 2-nitrovinylindoles was developed. A series of azepino[1,2-a]indoles were obtained with exclusive regioselectivities and high diastereo- and enantioselectivities (up to >20:1 dr, 96% ee) with the application of the N1 nucleophilic site of the indole nucleus. Meanwhile, various cyclohepta[b]indoles could be accessed with high enantiopurity (up to 96% ee) through the Michael addition/boron-trifluoride-etherate-promoted indole C3-attack ring expansion process.

Full text of DOI:10.1021/acs.orglett.0c01406

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Letter
Organocatalytic Regiodivergent Ring Expansion of Cyclobutanones
for the Enantioselective Synthesis of Azepino[1,2‑a]indoles and
Cyclohepta[b]indoles
Wu-Lin Yang,* Wen Li, Zhong-Tao Yang, and Wei-Ping Deng*
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ABSTRACT: A regiodivergent organocatalytic enantioselective
Michael addition/three-atom ring expansion sequence of electron-
withdrawing group activated cyclobutanones with 2-nitrovinylin-
doles was developed. A series of azepino[1,2-a]indoles were
obtained with exclusive regioselectivities and high diastereo- and
enantioselectivities (up to >20:1 dr, 96% ee) with the application
of the N1 nucleophilic site of the indole nucleus. Meanwhile,
various cyclohepta[b]indoles could be accessed with high
enantiopurity (up to 96% ee) through the Michael addition/
boron-trifluoride-etherate-promoted indole C3-attack ring expan-
sion process.
hiral polycyclic indoles have found broad applications in
tioselective divergent synthesis of both azepino[1,2-a]indoles
and cyclohepta[b]indoles on the strength of the same strategy
remains unexplored and is highly desired.
C
medicines, pesticides, and other functional molecules.1
Among them, azepino[1,2-a]indoles and cyclohepta[b]indoles,
containing two privileged structures, indole and a seven-
membered ring, widely exist in many indole alkaloids and
endow a broad spectrum of biological activities (Figure 1).2
Recently, our group demonstrated 2-nitrovinylindoles as a
three-atom 3C partner in copper-catalyzed asymmetric (3 + 3)
annulations with azomethine ylides, which constructed
tetrahydro-γ-carboline skeletons with high diastereo- and
enantioselectivities (Scheme 1a).6 2-Nitrovinylindoles were
also identified as a nitrogen−carbon−carbon (NCC) synthon
in the enantioselective (3 + 2) annulations for the synthesis of
chiral pyrrolo[1,2-a]indoles.7 Considering the high value of
azepino[1,2-a]indole and cyclohepta[b]indole in medicinal
chemistry and drug discovery, we would like to develop a
straightforward procedure for the divergent synthesis of
enantiomerically pure azepino[1,2-a]indoles and cyclohepta[b]
indoles by using the N1 or C3 nucleophilicity and C2′
electrophilicity of 2-nitrovinylindoles. The challenges inherent
in such a strategy mainly include (1) the discovery of a suitable
four-atom building block, (2) the regioselectivity of the N1
and C3 positions of the indole nucleus, and (3) the control of
diastereo- and enantioselectivity.
In this context, cyclobutanones attracted our attention
because this class of reactants could undergo ring expansion via
a carbon−carbon bond cleavage process.8,9 However, the
Figure 1. Representative natural products and bioactive molecules
containing azepino[1,2-a]indoles and cyclohepta[b] indoles.
Received: April 23, 2020
Despite the fact that several typical catalytic enantioselective
approaches have been reported, including enantioselective
sequential reactions,3 (4 + 3) annulations,4 and the
intermolecular Rauhut−Currier reaction,5 all of these only
focus on constructing just one of the target products
(azepino[1,2-a]indoles and cyclohepta[b]indoles). The enan-
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© XXXX American Chemical Society
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Scheme 1. Synthesis of Polycyclic Indoles via the Catalytic
Enantioselective Reactions of 2-Nitrovinylindoles
Figure 2. Bifunctional catalysts investigated in this reaction.
After optimization of the reaction conditions, the substrate
scope for this diastereo- and enantioselective cascade reaction
was delved. As listed in Scheme 2, a wide spectrum of
cyclobutanones 2a−j bearing different N-aryl secondary amide
activating groups all proceeded smoothly, delivering the
corresponding azepino[1,2-a]indole products 3a−j in high
yields (71−95%) along with high diastereo- and enantiose-
lectivities (>20:1 dr, 88−96% ee). Noticeably, a slightly
decreased enantioselectivity was observed when using the β-
ketoamides 3g−j with electron-donating and neutral aryl
groups. This phenomenon could be attributed to the relatively
low acidity of the secondary amide N−H proton,13 which
exhibited an adverse effect on the first Michael step.
Significantly, the carboxylic-ester-activated cyclobutanone was
also compatible under this transformation, affording product
3k in high yield (90%) with an excellent level of diastereo- and
enantioselectivity (>20:1 dr, 98% ee). It should be noted that
this type of cyclobutanone was not presented in the previous
report.10
Then, we probed the reaction scope concerning the variation
of substitutions of 2-nitrovinylindoles 1 (Scheme 3). The
substituent on the C3 position of the indole ring showed an
adverse effect on the diastereoselectivity control, and product
3l was attained in high yield (88%) with high enantioselectivity
(92/85% ee) and moderate diastereoselectivity (6:1 dr).
Methyl, methoxy, fluoro, chloro, and bromo substituents at
the C5 or C6 position of the indole ring of 2-nitrovinylindoles
2 were all compatible in this cascade reaction, furnishing
azepino[1,2-a]indoles 3m−s in good to high yields (61−90%)
with excellent diastereo- and enantioselectivities (93−96% ee,
>20:1 dr). In addition, the cascade reaction with 2-nitro-
vinylpyrrole still proceeded smoothly, providing pyrrolo[1,2-
a]azepine 3t in 46% yield as a single diastereomer but with
modest enantioselectivity (42% ee).
enantioselective ring expansion of cyclobutanone derivatives
remains a challenging task in organic synthesis. Until recently,
Rodriguez, Coquerel, and coworkers reported an enantiose-
lective Michael addition/ring expansion cascade reaction of
amide activated cyclobutanones and ortho-amino nitrostyrenes
using bifunctional aminocatalysts,10 furnishing benzazocinone
products with high enantioselectivities and good to high
diastereoselectivities. Inspired by this elegant work, we
envisaged that chiral azepino[1,2-a]indoles and cyclohepta[b]-
indoles could be simultaneously formed via an enantioselective
Michael addition/ring expansion cascade reaction of cyclo-
butanones and 2-nitrovinylindoles (Scheme 1b). In this
process, two nucleophilic sites (N1 and C3 of indole) could
add to the carbonyl group after the Michael addition step,
which would deliver azepino[1,2-a]indoles and cyclohepta[b]-
indoles, respectively, via a spontaneous fragmentation. Herein
we report our results from this study.
To test this hypothesis, we began our study by evaluating the
reaction between 2-nitrovinylindoles 1a and 2-amide-sub-
stituted cyclobutanone 2a with Takemoto’s catalyst C111a
(Figure 2) in CH2Cl2 at ambient temperature (Table 1).
Pleasingly, the desired reaction proceeded smoothly, and
azepino[1,2-a]indole product 3a was isolated in 63% yield,
albeit with only 21% ee (entry 1). With this initial result in
hand, a series of chiral thiourea/squaramide aminocatalysts
were then screened (entries 2−9).11 To our delight, catalyst
C812 combining the 9-amino-quinine moiety with a N-
benzylsquaramide hydrogen-bond donor delivered the best
result (entry 8), and compound 3a was gained in excellent
yield (95%) with excellent diastereo- and enantioselectivity
(>20:1 dr, 96% ee). Next, the solvent effect in this reaction was
evaluated (see Table S1), and the chlorinated solvents
provided better results, with dichloromethane as the best
choice. When the catalyst loading was reduced to 5 mol %, the
reaction was incomplete, even after stirring for 4 days, and
product 3a was acquired in 63% yield with 94% ee (entry 10).
We note that the cyclohepta[b]indole product was not
detected in any case.
The absolute configuration of 3m was determined to be (9S,
10R) by single-crystal X-ray diffraction analysis. In accordance
with the stereochemical outcome and previous reports,10,14
a
plausible reaction pathway is depicted in Scheme 4. With the
dual activation of chiral bifunctional squaramide−tertiary
amine catalyst C8, the 2-carbamoyl cyclobutanones 2 are
enolized by the tertiary amine moiety. Meanwhile, the two
squaramide N−H bonds of catalyst activate the nitro group of
2-nitrovinylindole 1a through a hydrogen-bonding interaction.
The enolized cyclobutanones (Re-face) then add to the double
bond (Re-face) of 1a to favorably give intermediate A, which
B
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a
Table 1. Organocatalysts Screening
b
c
entry
catalyst
yield (%)
ee (%)
time (h)
1
2
3
4
5
6
7
8
9
C1
C2
C3
C4
C5
C6
C7
C8
C9
C8
63
93
48
24
66
74
54
95
95
63
−21
−58
−82
31
83
67
83
96
77
94
12
12
36
36
36
12
36
12
12
4 d
d
10
a
Unless others stated, reactions were carried out with 1a (0.20 mmol), 2a (0.22 mmol), and 10 mol % of catalyst in 2.0 mL of CH2Cl2 at room
b
c
1
temperature. Isolated yield after column chromatography. Determined by chiral HPLC analysis; >20:1 dr was determined by H NMR of the
crude product. Carried out with 5 mol % of C8.
d
Scheme 2. Substrate Scope of Cyclobutanones 2
Scheme 3. Substrate Scope of 2-Nitrovinylindoles 1
Unfortunately, azepino[1,2-a]indole product 3a, instead of
cyclohepta[b]indole product 4a, was observed in all cases. (See
Scheme S1.) To solve this problem, N-methyl-substituted 2-
nitrovinylindole 5a was used in the reaction. The strong Lewis
acid BF3·Et2O was directly added to the reaction mixture to
promote the cyclization/fragmentation process after the
Michael addition was completed (Scheme 5), and the two
diastereoisomers cis-6a and trans-6a of cyclohepta[b]indole
product were, respectively, obtained with high enantioselectiv-
ities (93% ee and 91% ee). Additionally, various substituent
groups on cyclobutanones and N-substituted 2-nitrovinylin-
doles were well-tolerated in the reaction under the optimal
conditions, and the corresponding cyclohepta[b]indole prod-
ucts 6b−g were provided in good yields with high
enantioselectivities (91−96% ee), albeit with modest diaster-
eoselectivities. Furthermore, cyclohepta[b] pyrrole derivative
6h was afforded in good yield with good enantioselectivities
(82% ee and 85% ee) by using N-methyl 2-nitrovinylpyrrole. It
should be noted that two diastereoisomers of cyclohepta[b]-
should be the crucial step for the enantioselectivity control.
The subsequent cyclization/fragmentation affords intermediate
C, and the protonation of amide enolate C would proceed
through thermodynamic control, furnishing products 3 with a
favorable cis configuration. Notably, this hypothesis for the
diastereoselectivity control is verified by the increased
diastereoselectivity after the cyclization/fragmentation/proto-
nation step of the Michael adduct (6:1 vs >20:1 dr; see
Scheme S1).
Subsequently, we would like to amplify the role of 2-
nitrovinylindoles 1 as 3C building blocks in the Michael
addition/ring expansion cascade process with the aim of
constructing cyclohepta[b]indoles. Interestingly, the cascade
process could be interrupted after the Michael addition step
when the reaction temperature was lowered to −40 °C, and
various additives were tested to promote the cyclization.
C
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Scheme 4. Proposed Reaction Pathway for the Cascade
Reaction
Scheme 6. Result of Cyclization/Fragmentation of Michael
Adduct Intermediate
configuration of trans-6g was assigned as (6R, 7R) by single-
crystal X-ray diffraction analysis, and the absolute configuration
of cis-6 was reasoned to be (6R, 7S).
To further evaluate the synthetic utility of the current
methodology (Scheme 7), the gram-scale synthesis of
azepino[1,2-a]indole product 3a was achieved while maintain-
ing the efficiency and the stereochemical outcome (90% yield,
>20:1 dr, 95% ee). Furthermore, several synthetic trans-
formations were explored. The nitro group of 3a could be
reduced in the presence of sodium borohydride/nickel(II)
chloride hexahydrate without the loss of stereochemical
integrity. The structurally novel tetracyclic indole compound
9 with 99% ee value could be facilely accessed via the
reduction/intramolecular aminolysis of product cis-6d. Mean-
while, the reduction/intramolecular aminolysis of product 3k
afforded 2-indolyl azepine derivative 10 with excellent
enantioselectivity (97% ee). We note that this class of 2-aryl
indoles in all cases could be easily separated by column
chromatography.
For the purpose of confirming the stereochemical
determined step in this reaction, both diastereoisomers of
Michael adduct intermediate 7a were isolated and used for the
next cyclization (Scheme 6), and the mixture of products cis-6a
and trans-6a was generated with similar diastereoselectivities
(2.3:1 dr vs 1.8:1 dr) as 7a or epi-7a. Therefore, by analogy to
the previous case (Scheme 4), the origin of the diaster-
eoselectivity should be derived from the protonation step of
the corresponding amide enolate, and the enantioselectivity
was determined by the Michael addition step. The absolute
Scheme 5. Enantioselective Synthesis of Cyclohepta[b]indoles via the One-Pot Sequence of N-Substituted 2-Nitrovinylindoles
5 and Cyclobutanones 2
D
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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.
Scheme 7. Demonstration of Synthetic Utility
AUTHOR INFORMATION
Corresponding Authors
■
Wu-Lin Yang − School of Pharmacy and Shanghai Key
Laboratory of New Drug Design, East China University of
Science and Technology, Shanghai 200237, China;
orcid.org/0000-0001-7985-5017; Email: yangwl@
ecust.edu.cn
Wei-Ping Deng − School of Pharmacy and Shanghai Key
Laboratory of New Drug Design, East China University of
Science and Technology, Shanghai 200237, China; Key
Laboratory of the Ministry of Education for Advanced Catalysis
Materials, Department of Chemistry, Zhejiang Normal
University, Jinhua 321004, China; orcid.org/0000-0002-
4232-1318; Email: weiping_deng@ecust.edu.cn
Authors
Wen Li − School of Pharmacy and Shanghai Key Laboratory of
New Drug Design, East China University of Science and
Technology, Shanghai 200237, China
Zhong-Tao Yang − School of Pharmacy and Shanghai Key
Laboratory of New Drug Design, East China University of
Science and Technology, Shanghai 200237, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01406
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the National Natural Science
Foundation of China (nos. 21572053 and 21772038) and the
China Postdoctoral Science Foundation (nos. 2018M632037
and 2019T120310). We greatly appreciate the Research
Center of Analysis and Test of East China University of
Science and Technology for the assistance with the MS and
NMR analysis.
azepine compound exhibits critical biological activities in
medicinal chemistry, such as neurokinin-1 receptor antago-
nistic activity and monoamine reuptake inhibitory activity.15
In summary, we have demonstrated a regiodivergent
enantioselective sequential Michael addition/three-atom ring
expansion reaction of cyclobutanone derivatives with 2-
nitrovinylindoles by controlling the regioselectivity of the N1
and C3 sites of the indole nucleus in the presence of chiral
bifunctional aminocatalysts. This protocol provides straightfor-
ward access to various enantiomerically pure azepino[1,2-
a]indoles and cyclohepta[b]indoles with high efficiency. The
salient features of the reaction include mild reaction
conditions, broad substrate scopes, easy scalability, and
versatile transformations of the products.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
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Experimental details, characterization of new com-
pounds 2, 3, and 6, crystallographic data of 3m and
trans-6g, and NMR and HPLC spectra (PDF)
Accession Codes
CCDC 1943765 and 1970016 contain the supplementary
crystallographic data for this paper. These data can be obtained
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