Cu(OTf)2 catalysed [6+2] cycloaddition reaction for the synthesis of highly substituted pyrrolo[1,2-a]indoles: Rapid construction of the yuremamine core

Article abstract of DOI:10.1039/c3cc40617b

Lewis acid catalysed [6+2] cycloaddition reaction for the synthesis of pyrrolo[1,2-a]indoles generating three contiguous stereocenters in a highly regio- and diastereoselective manner has been developed and further applied for the construction of the fully functionalized tricyclic core of yuremamine.

Full text of DOI:10.1039/c3cc40617b

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Cu(OTf)2 catalysed [6+2] cycloaddition reaction for the
synthesis of highly substituted pyrrolo[1,2-a]indoles:
rapid construction of the yuremamine core†‡
Cite this: Chem. Commun., 2013,
49, 3260
Received 24th January 2013,
Accepted 26th February 2013
Dattatraya H. Dethe,* Raghavender Boda and Saikat Das
DOI: 10.1039/c3cc40617b
www.rsc.org/chemcomm
Lewis acid catalysed [6+2] cycloaddition reaction for the synthesis
of pyrrolo[1,2-a]indoles generating three contiguous stereocenters
in a highly regio- and diastereoselective manner has been devel-
oped and further applied for the construction of the fully function-
alized tricyclic core of yuremamine.
Pyrrolo[1,2-a]indoles, the tricyclic indole derivatives, represent
key structural motifs in a variety of biologically active natural
products and pharmaceutical compounds.1 For example, mito-
mycin C 1 exhibits potent antibacterial and antitumoural
activity, which is now used as an anticancer drug in the
treatment of certain cancers.2 Another indole alkaloid flinderole
2 containing this moiety has shown selective antimalarial
properties.3 Recently another pyrroloindole natural product
isatisine A 3 has generated much interest among synthetic
chemists.4 In 2005, a new member of pyrrolo[1,2-a]indole
alkaloids, yuremamine 4, was isolated from the stem bark of
Mimosa hostilis and was found to have hallucinogenic and
psychoactive effects (Fig. 1).5
Fig. 1 Selected examples of natural products that contain the pyrrolo[1,2-a]-
indole framework.
All the strategies for synthesis of pyrrolo[1,2-a]indoles devel-
The structural features of 4 include a fused tricyclic frame- oped to date have focused on generating one or two stereo-
work containing a densely substituted pyrrolidine subunit, centers, however to the best of our knowledge there is no report
containing two phenyl ring substitutions. The challenging in the literature on synthesis of pyrrolo[1,2-a]indoles generat-
structural and stereochemical features of these natural pro- ing three contiguous stereocenters as required in yuremamine.
ducts combined with their interesting biological activities have You et al.7e in their approach towards the total synthesis of 4
fuelled several synthetic projects and many reports directed have developed an elegant route for the synthesis of the
toward the synthesis of pyrrolo[1,2-a]indoles have appeared so diastereomer of pentamethyl yuremamine.
far.6 The preliminary reports from the groups led by Kerr,7a
In this communication, we report our progress towards the
France,7b Shi7c and Chen7d have focused on the synthesis of the synthesis of 4, which has resulted in the discovery of [6+2]
pyrroloindole core present in 4. A total synthesis of yurem- cycloaddition reaction between a suitably substituted second-
amine has not been achieved so far. Generation of three ary benzylic alcohol and an a,b-unsaturated ester for the one
contiguous stereocenters with the required stereochemistry pot formation of pyrrolo[1,2-a]indoles with generation of three
has been a major impediment in the synthesis of yuremamine. contiguous stereocenters in a highly regio- and diastereoselective
manner.
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016,
India. E-mail: ddethe@iitk.ac.in; Fax: +91-512-2597436; Tel: +91-512-2596537
† This work is dedicated to Prof. Goverdhan Mehta on the occasion of his 70th
birthday.
According to our retrosynthetic analysis it was envisioned
that a [6+2] cycloaddition using suitably substituted indole
derivative 5 as a dipolarophile and cinnamate 6 as a dienophile
would lead to one pot construction of the yuremamine core,
which on further functional group transformation could be
converted to yuremamine 4. Compound 5 could be generated
‡ Electronic supplementary information (ESI) available: CCDC 917193 and
917194. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3cc40617b
c
3260 Chem. Commun., 2013, 49, 3260--3262
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Table 1 Optimization of [6+2] cycloaddition reaction
dr ratioa
Scheme 1 Retrosynthetic analysis for yuremamine.
Entry
Catalyst
Solvent
Yield %
1
2
3
4
5
6
7
8
TiCl4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CCl4
82
77
76
91
83
N.R.
86
83
93
82
77
89
82
56
62
81
54
74
11 : 1
14 : 1
25 : 2
25 : 1
9 : 1
N.A.
4 : 1
3 : 1
7 : 1
30 : 1
3 : 1
7 : 1
5 : 1
6 : 1
20 : 1
20 : 1
4 : 1
BF3ꢀOEt2
in situ from alcohol 7 (Scheme 1). The basis for our initial
expectation regarding the stereochemistry of the cyclization
step was based on the assumption that the ester group of
cinnamate 6 and the 2,4-dimethoxyphenyl ring would be trans
to each other to avoid steric interaction and generate a thermo-
dynamically more stable product.
p-TSA
CSA
CF3CO2H
CH3CO2H
FeCl3
AlCl3
ZnCl2
Cu(OTf)2
Yb(OTf)3
Sn(OTf)2
Sc(OTf)3
Fe(OTf)3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
9
10
11
12
13
14
15
16
17
18
To quickly check our strategy, we designed a model system
to check whether the cycloaddition of 5 and 6 is viable. The
synthesis was initiated (Scheme 2) by treatment of indole
aldehyde 9a3d with PhMgBr followed by deprotection of the
phenylsulfonyl group in 10a using Na/Hg to deliver alcohol 11a
in 96% yield. Having the key intermediate 11a in hand, the
stage was set for the key [6+2] cycloaddition reaction. To our
disappointment reaction of alcohol 11a with ethyl 3,4,5-
trimethoxy cinnamate 6 under various Lewis acid conditions
could not produce the desired cycloadduct; instead it resulted
in the formation of the unexpected product 12, through retro-
aldol type reaction as shown in Scheme 2. The structure of
compound 12 was deduced from its spectral data and was
further confirmed by matching the spectral data with the
literature report.8 Even other cinnamates such as ethyl cinna-
mate, p-methoxy ethyl cinnamate and p-bromo ethyl cinnamate
failed to undergo [6+2] cycloaddition reaction. Interestingly
after screening various catalysts (Table 1), we were gratified to
discover that reaction of alcohol 11a with the comparatively
more reactive ester 13a underwent smooth cyclization using
5 mol% Cu(OTf)2 in CH2Cl2 at 0 1C to give pyrroloindole 14a in
90% yield and with excellent regio- and diastereoselectivity.
Other Lewis acids gave poor diastereoselectivity (Table 1). The
structures of the compounds 14a and 14a0 were deduced from
their spectral data (1H, 13C, HRMS and NOESY). Formation of
14a0 suggests that the reaction is going through a stepwise
mechanism (see ESI‡). The reaction was equally efficient with
protected and free NH of indole ester 13a. Under optimized
DCE
Benzene
15 : 1
a
Diastereoselectivities determined from 1H NMR of the crude reaction
mixture.
Table 2 Substrate scope of the [6+2] cycloaddition reaction
Substrate (13) Product Yield
(R3/R4/R5) (14)
(%) drb
Entry Substrate (11) (R1/R2)
1
2
3
4
5
6
7
8
9
11a (Me/H)
11a (Me/H)
11a (Me/H)
11a (Me/H)
13a (H/H/H) 14a
13c (H/Me/H) 14b
13d (Me/H/H) 14d
13e (Me/H/Br) 14e
13d (Me/H/H) 14f
13e (Me/H/Br) 14g
13d (Me/H/H) 14h
13e (Me/H/Br) 14i
90
85
89
86
91
85
89
90
91
92
30 : 1
10 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
11b (Me/OMe)
11b (Me/OMe)
11c (CH2CH2OTBS/H)
11c (CH2CH2OTBS/H)
11d (CH2CH2OTBS/OMe) 13d (Me/H/H) 14j
11d (CH2CH2OTBS/OMe) 13e (Me/H/Br) 14k
10
b
Diastereoselectivities determined from 1H NMR of the crude reaction
mixture.
conditions we next examined the substrate scope of this reac-
tion and the results are shown in Table 2 and Scheme 3. Several
differently substituted pyrroloindoles 14a–14n were prepared in
a highly regio- and diastereoselective manner and in excellent
yields. It is worth mentioning that the scope of the reaction was
not limited to only the indole esters like 13a–13d, even styrene
derivatives underwent smooth cyclization to generate the
pyrroloindole derivatives (Table 3) in excellent yields, but the
diastereoselectivity was poor for these substrates, which
confirms the role of the ester group in controlling the stereo-
chemistry. Relative stereochemistry of the three contiguous
Scheme 2 Model study for [6+2] cycloaddition reaction.
c
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We thank Prof. Vinod K. Singh, Director, IISER, Bhopal,
for allowing us to use lab facilities. B.R. and S.D. thank CSIR,
New Delhi, for the award of research fellowships. We thank
Tapas Ghatak, Prasanjit Daw and Joydeb Goura from IIT
Kanpur for their help. Financial support from IIT Kanpur and
the CSIR sponsored network project CSIR-NCL-IGIB JRI pro-
gramme is gratefully acknowledged.
Scheme 3 Substrate scope of the [6+2] cycloaddition reaction.
Table 3 Substrate scope of the [6+2] cycloaddition reaction
Notes and references
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1
2
3
11a
11a
11a
13e (Me/OMe/Me)
13f (CH(Me)2/H/OMe)
13g (Me/OMe/OMe)
14l
14m
14n
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86
83
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Scheme 4 Synthesis of a yuremamine analogue.
stereocenters was unambiguously established by single crystal
X-ray analysis of compounds 14b and 14e.9
As a demonstration, the side chain at the 3-position of
indole derivatives 14g and 14h was converted to corresponding
dimethylamine derivatives 16a and 16b as present in yurem-
amine. Desilylation of compounds 14g and 14h using TBAF/THF
followed by oxidation and reductive amination of the resultant
aldehyde generated the dimethylamine derivatives 16a and 16b
(Scheme 4).
In summary, a novel approach for the synthesis of highly
substituted pyrrolo[1,2-a]indoles has been developed that
results in direct construction of the yuremamine core system
in a highly regio- and diastereoselective manner from readily
available starting materials. In a single transformation, three
stereochemical issues (C1, C2 and C3) have been addressed
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c
3262 Chem. Commun., 2013, 49, 3260--3262
This journal is The Royal Society of Chemistry 2013