[3 + 2] Annulations between indoles and α,β-unsaturated ketones: Access to pyrrolo[1,2-a]indoles and model reactions toward the originally assigned structure of yuremamine

Article abstract of DOI:10.1039/c5ra11904a

A direct [3 + 2] annulation reaction between indoles and α,β-unsaturated ketones is reported, which allows for the efficient assembly of densely substituted, highly functionalized pyrrolo[1,2-a]indoles. Model reactions toward the originally assigned structure of yuremamine are also described, leading to the successful construction of the core with required functionality.

Full text of DOI:10.1039/c5ra11904a

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DOI: 10.1039/C5RA11904A
The efficient assembly of densely substituted, highly functionalized pyrrolo[1,2-a]indoles by the direct annulation
of indoles and α, β-unsaturated ketones is reported.

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DOI: 10.1039/C5RA11904A
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[3+2] Annulations between Indoles and α, β-Unsaturated
Ketones: Access to Pyrrolo[1,2-a]indoles and Model Reactions
Toward the Originally Assigned Structure of Yuremamine
Received 00th January 20xx,
Accepted 00th January 20xx
Haokun Li,a Zhonglei Wanga and Liansuo Zua
DOI: 10.1039/x0xx00000x
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A direct [3+2] annulation reaction between indoles and α, β-
unsaturated ketones is reported, which allows the efficient
assembly of densely substituted, highly functionalized pyrrolo[1,2-
a]indoles. Model reactions toward the originally assigned
structure of yuremamine were also described, leading to the
successful construction of the core with required functionality.
Scheme 1. Synthetic strategy toward the originally assigned
structure of yuremamine
The efficient transformations of simple starting materials into
complex structures that resemble the core of natural products and
medicinally important molecules are of great significance in organic
synthesis. Pyrrolo[1,2-a]indole tricyclic ring system1 is a basic
nucleus of a number of complex natural products and biologically
important molecules. For example, mitomycins and mitosenes
containing the pyrrolo[1,2-a]indole core have received considerable
attention of synthetic chemists and medicinal chemists because of
their intricate structures and potent biological activeties.2
Yuremamine, a new member of pyrroloindole alkaloids, was
isolated from the stem bark of Mimosa hostiles in 2005 by Callaway
and co-workers and shown to have hallucinogenic and psychoactive
effects.3 The originally assigned structure of yuremamine (1)
features a densely decorated pyrrolo[1,2-a]indole core, three
contiguous stereogenic centers and the polyphenolic rings. Since its
isolation, several synthetic strategies toward the core structure
have been developed by Kerr, Shi, Dethe, Chen, France and You.4
While these approaches are significant and have led to the
successful construction of the pyrroloindole core, none of them
could allow for the complete incorporation of all
substituents/functionality in a single step that are positioned for
the eventual chemical synthesis of 1. Very recently, Sperry and co-
Our synthetic strategy was inspired by the intricate molecular
architecture of 1 without realizing that the structure of the natural
product was mis-assigned when we started our study. Our approach
to 1 is depicted in Scheme 1. We conceived that this pyrroloindole
alkaloid (1) could be derived from pyrrolo[1,2-a]indole A involving
functional group transformations and structural isomerization. The
densely decorated pyrrolo[1,2-a]indole A could in turn be produced
by the direct [3+2] annulation between a tryptamine derivative and
the corresponding multi-substituted α, β-unsaturated ketone. One
appealing feature of the synthetic design is that the pyrrolo[1,2-
a]indole core (A), which bears useful substituents/functionality as
required by the structure of 1, could be efficiently assembled from
readily available starting materials in a single step operation.
workers reported
a concise biomimetic total synthesis of
yuremamine, leading to its structural revision from the
pyrroloindole (1) to the flavonoidal indole (2), which was initially
hypothesized as a biosynthetic intermediate (Scheme 1).5
While the reactions between indoles and α, β-unsaturated
carbonyls to furnish the alkylated products at N1 or C2 or C3 via
conjugate addition have been widely investigated,6 the annulation
process to form a new ring is rare.7 Particularly, the related
reactions of tryptamine derivatives with α, β-unsaturated ketones,
a. Department of Pharmacology and Pharmaceutical Sciences, School of Medicine,
Tsinghua University, Beijing, 100084 China.
Email: zuliansuo@biomed.tsinghua.edu.cn
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Scheme 2. The substrate scope of the [3+2] annulation reactions
as depicted in our synthetic design (Scheme 1), have been well
studied for the preparation of fused indolines in the presence of
organocatalysts and organometallic reagents.8 We envisioned that
under suitable dehydrative conditions at elevated temperature, the
thermodynamically more stable pyrrolo[1,2-a]indoles (A) could be
formed, and thus the frame work of 1 could be assembled in a
highly efficiently manner.
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DOI: 10.1039/C5RA11904A
A model reaction between 3a and 4a was carried out first to
identify the optimized reaction conditions (Table 1). Gratifyingly, a
variety of acids, both bronsted acids and Lewis acids, could be
utilized to catalyze the transformation, producing 5a with moderate
to good yields. The best result (87% yield) was obtained using 20
mol% p-TsOH.H2O as the catalyst and toluene as the reaction media.
As expected, high reaction temperature was essential for the
formation of 5a, indicating that the pyrrolo[1,2-a]indole should be
the thermodynamically more stable product.
Table 1. Optimization of reaction conditions a
entry acid
yield of 3a (%) b
1
2
3
4
5
6
7
none
Benzoic acid
AcOH
TFA
p-TsOH.H2O
FeCl3
0
47
38
50
87
57
50
ZnCl2
a
Reaction conditions: To a solution of 3a (62.8 mg, 0.2 mmol) and
4a (49.0 mg, 0.24 mmol) in toluene was added the specified acid.
The resulting mixture was heated to 110 oC for 2 h. b Isolated yield
after silica gel chromatography.
The substrate scope of the [3+2] annulations was next
investigated (Scheme 2). Under optimized reaction conditions, a
variety of 3-substituted indoles and α, β-unsaturated ketones
proved to be suitable substrates, delivering the pyrrolo[1,2-
a]indoles with good to excellent yields. Indoles with different
tethered nucleophiles at 3-position as well as an alkyl bromide side
chain were well tolerated, furnishing the desired products with
different functionalized side chains (5a-h). A series of α, β-
unsaturated ketones with different substitution patterns turned out
to be efficient substrates, generating the pyrrolo[1,2-a]indoles
bearing useful functionality. The electron withdrawing group R3
could be varied (5j, 5k), but is not required for the reaction to occur
(5n). When R2 is aliphatic, the annulation reaction also proceeded
with high efficiency (5i). It should be noted that a variety of
functional groups (protected amine, alcohol, alkyl bromide, ketone,
ester, and amide) were compatible with the reaction conditions.
Finally, two complex pyrrolo[1,2-a]indoles (5o, 5p) that contain the
substituents/functionality for the chemical synthesis of 1 were
successfully constructed.
Next, we turned our attention to the construction of the core
of 1. Our first model reaction involved the Curtius rearrangement of
the related carboxylic acid 6 with the hypothesis that the in situ
generated isocyanate B could be hydrolyzed and isomerized to
deliver ketone 7 (Scheme 3). The saponifcation of 5l underwent well
using potassium hydroxide, affording 6 with good yield. The Curtius
rearrangement initiated cascade sequence presumably involving B
and C as the intermediates proceeded smoothly, producing ketone
7 in 89% yield. Unfortunately, when the similar synthetic sequence
was applied to a more advanced substrate 8, the formation of
ketone 9 was not observed. Under certain forcing reaction
conditions, the generated isocyanate intermediate D was trapped
by the nearby phenyl ring via Friedel-Crafts acylation reaction.
Considering that the 1 contains more nucleophilic polyphenolic
rings, which would attack the isocyanate intermediate more readily,
we turned to an alternative approach as depicted in Scheme 4.
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PleaseRdSoCnoAtdavdajunsctems argins
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Scheme 3. Model reactions via Curtius rearrangement
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was realized by carrying out the reaction under N2 and adding
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sodium boron hydride to the reaction tDoOIr:e1d0u.1c0e39/tCh5eRAi1n190si4tAu
generated ketone. By doing this, alcohol 13 was generated in good
yields as a mixture of three diastereomeric isomers. Although the
diastereoselectivity of the reduction need to be further improved,
the structure of 13 contains the side chain and correct substitution
pattern, which resembles the key structural features of the
originally assigned structure of yuremamine (1).
Conclusions
In conclusion, we have developed a direct annulation reaction
between indoles and α, β-unsaturated ketones, which allows for
the rapid assembly of densely substituted, highly functionalized
pyrrolo[1,2-a]indoles in a single step. Model reactions toward the
originally assigned structure of yuremamine were carried out,
leading to the successful construction of the core with required
functionality and the discovery of several interesting synthetic
transformations.
Notes and references
1
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Scheme 4. Model reactions via Baeyer-Villiger oxidation
2
3
4
J. J. Vepsalainen, S. Auriola, M. Tukiainen, N. Ropponen, J.
Callaway, Planta Med. 2005, 71, 1053.
The second model reaction for the synthesis of the core of 1
centered on the Baeyer-Villiger oxidation of aldehyde 10 and
related structural isomerization (Scheme 4). Compound 10 was
produced in good yield by a two step synthetic manipulation from
5g involving DIBAl-H reduction of the ester followed by Dess-Martin
oxidation of the resulted alcohol. The Baeyer-Villiger oxidation of 10
proceeded well in the presence of oxone, delivering 11 in 69% yield.
Under basic conditions, the deprotection and structural
isomerization of 11 did not occur to afford the desired ketone, but
instead 2, 3-disubstituted indole 12 was isolated as the major
product, presumably because that the electron rich system was
further oxidized by molecular oxygen. A solution to this problem
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For indoline synthesis by direct annulation: Q. Cai, S. L. You,
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