Cascade annulation of malonic diamides: A concise synthesis of polycyclic pyrroloindolines

Article abstract of DOI:10.1039/c2cc33129b

A concise synthesis of polycyclic pyrroloindolines from simple malonic diamides via an intramolecular oxidative coupling/condensative cyclization cascade process is reported. The reaction provides an efficient method to construct polycyclic pyrroloindolines in good to excellent yields, which should be useful in the synthesis of natural products and pharmaceutical molecules.

Full text of DOI:10.1039/c2cc33129b

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COMMUNICATION
Cascade annulation of malonic diamides: a concise synthesis of polycyclic
pyrroloindolinesw
Feng Fan,a Weiqing Xie*b and Dawei Ma*ab
Received 1st May 2012, Accepted 7th June 2012
DOI: 10.1039/c2cc33129b
A concise synthesis of polycyclic pyrroloindolines from simple
malonic diamides via an intramolecular oxidative coupling/
condensative cyclization cascade process is reported. The reaction
provides an efficient method to construct polycyclic pyrroloindolines
in good to excellent yields, which should be useful in the synthesis of
natural products and pharmaceutical molecules.
As a part of our ongoing program on the intramolecular oxidative
coupling of tryptamine derived precursors, we have already applied
this strategy in the total synthesis of the communesin family of
alkaloids.10 To evaluate the feasibility of designing a cascade
reaction initiating with oxidative coupling, we recently reported
an efficient synthesis of polycyclic spiroindolines from simple
tryptamine keto-amides via an oxidative coupling/condensative
cyclization cascade process.12 The reaction took advantage of the
nucleophilicity of the oxygen atom of the enolate to facilitate
capture of the imine resulting from oxidative coupling and enabled
the construction of tetracyclic spiroindoline in a one-pot reaction.
Since an increasing number of polycyclic pyrroloindoline
natural products have been isolated with potent biological
activities,2 we turned our attention to designing a new cascade
reaction to construct polycyclic pyrroloindoline scaffolds,
which would provide quick access to a series of polycyclic
pyrroloindolines 4 from malonic diamides 1 (Fig. 1). When
malonic diamide 1 is subjected to the cascade reaction conditions
that we previously developed,12 a trianion 2 would be first generated
by deprotonation in the presence of excessive base. An intra-
molecular oxidative coupling of the enolate with the indole moiety
mediated by I2 will ensue to form a spiroindolenine 3, which would
further cyclize to furnish a polycyclic pyrroloindoline 4 through
nucleophilic attack of the resulting imine by nitrogen. Although
intramolecular oxidative coupling of dianions had been well studied
in our previous reports,10,12 site selective intramolecular oxidative
Pyrroloindolines have a fused indole framework that is widely
found in both natural products and medicinal molecules
with promising biological activities.1 Due to their structural
complexity and biological activities, numerous methods have
been developed for the synthesis of such a motif.2 Besides
simple pyrroloindoline alkaloids such as physostigmine,3 poly-
cyclic pyrroloindolines (e.g. minfiensine4) have attracted much
more attention from the chemical community due to the
synthetic challenges posed by their structural complexity.
To establish polycyclic pyrroloindoline scaffolds, multiple
synthetic steps are usually needed,3,4 which prevents them
from being applied in diverse synthesis. From the standpoint
of medicinal chemistry, a simple synthetic method for the
synthesis of a collection of natural product-like molecules is a
powerful tool in the search for biologically active compounds.5
Taking into consideration both atom economy and synthetic
efficiency in chemical synthesis, a concise and practical approach
for the construction of polycyclic pyrroloindolines with chemical
diversity is still highly desirable for chemical biology and medicinal
chemistry research.
Oxidative coupling is an important method for C–C bond
formation.6,7 Although extensive studies have been devoted to
oxidative homocoupling,6 oxidative heterocoupling has received
little attention due to competitive homocoupling side-reactions.7
In consequence, oxidative coupling has rarely been applied in the
total synthesis of natural products until the recent work from
the Baran group,8 Overman group,9 our group,10 and others.11
a School of Pharmacy, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237, China
b State Key Laboratory of Bioorganic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
China. E-mail: xiewq@mail.sioc.ac.cn, madw@mail.sioc.ac.cn;
Fax: +86-21-64166128; Tel: +86-21-54925341
w Electronic supplementary information (ESI) available: General
experimental procedure and spectra data of starting materials and
products. CCDC 879839 and 879840. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2cc33129b
Fig. 1 Oxidative coupling/condensative cyclization of malonic diamides.
Chem. Commun., 2012, 48, 7571–7573 7571
c
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Table 2 Substrate scope of the cascade annulation reactionc
Table 1 The influence of the protecting group of the amide on the
cascade annulation reactionc
Entry Product (yield) Entry Product (yield)
1
8
Entry
Substrate, R2
Product, yielda
1
2
3
4
5
1a, H
1b, Ph
1c, Bn
1d, CO2Me
1e, Ts
5a, 21%b
6, 43%
5c, 59%
5d, 80%
5e, 80%
2
3
4
9
a
b
c
Isolated yield. 30% dimerization product was isolated. General
conditions: malonic diamide 1 (1.0 equiv.), LiHMDS (3.3 equiv.), I2
(1.1 equiv.).
coupling of trianion 2 remained a challenge. With this uncertainty
in mind, we initiated our study by applying the previous oxidative
coupling conditions12 to malonic diamide 1 except that one
more equivalent of base was employed to ensure the genera-
tion of trianion 2.
10
Aware that the nucleophilicity of nitrogen was influenced by
the attached protecting group, we first began to screen the
protecting groups on the appendant amide. As shown in
Table 1, a low yield was obtained (21%) when no protecting
group was present on nitrogen (Table 1, entry 1). Isolation of
the dimerization product of diamide 1a indicated that the
intramolecular oxidative coupling reaction had slowed down,
probably due to the decreased acidity of the malonic methylene
proton, which was consistent with our previous observations.10,12
Better results were achieved by using phenyl or benzyl groups as
the protecting group (entries 2 and 3). Although no starting
material was observed in the reaction mixtures, oxidative coupling
products without formation of the second ring were monitored by
TLC but were too unstable to be isolated. Interestingly, when the
phenyl protected substrate 1b was subjected to the standard
conditions, the oxidative product 6 was produced, presumably
via air oxidation of the cyclization product. Gratifyingly, the yields
were significantly improved when electron-withdrawing groups
such as methyl carbamate and tosyl were attached on the nitrogen
(entries 4 and 5), which both gave comparable yields. It should be
noted that only a single stereoisomer was detected in all the
reaction mixtures and the relative configuration of the products
was established by crystallographic analysis of 5d.
11
5
12
6
13
Subsequently, we evaluated the substrate scope of the cascade
annulation reaction. A series of malonic diamides with various
substituents on the indole were synthesized and submitted to the
reaction conditions. Gratifyingly, both malonic diamides with
electron-donating and withdrawing groups on the indole ring
gave the corresponding products in good yields (Table 2, entries
1 to 11), which showed good functional group tolerance of the
cascade annulation reaction. Remarkably, substrates embedded
with 2-substituted indole also afforded products with contiguous
quaternary carbon centers in good yields (entries 10 and 11).
We also prepared a-substituted malonic diamides to make
contiguous quaternary carbon centers via intramolecular oxidative
coupling. However, a-methyl malonic diamide with methyl
7
14
a
b
50% starting material was recovered. 7% starting material was
c
recovered. General conditions: malonic diamide 1 (1.0 equiv.),
LiHMDS (3.3 equiv.), I2 (1.1 equiv.).
c
7572 Chem. Commun., 2012, 48, 7571–7573
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carbamate on the appendant amide was unreactive under the
standard conditions (entry 12, 5q). A switch of the protecting
group to tosyl afforded the annulation product 5r in only 25%
yield. The yield was greatly improved (71%) when a phenyl
group was present on the a position of the malonic diamide
(entry 13). These results further confirmed that the intramolecular
oxidative coupling reaction may be related to the pKa of the two
oxidative coupling partners. Interestingly, when two substituents
were present at the same time (2-methyl indole and a-phenyl
malonic diamide), three contiguous quaternary carbon centers
could be generated albeit in a low yield (21%, entry 14).
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In conclusion, a concise and efficient protocol for the
construction of polycyclic pyrroloindolines was reported.
Starting from malonic diamides embedded with an indole,
tetracyclic products were formed in one pot via an intra-
molecular oxidative coupling/condensative cyclization cascade
process with moderate to good yields. In this reaction, two
rings and at least one quaternary carbon center, in some cases
two or three continuous quaternary carbon centers, could be
formed, which showed the capability and efficiency of this
cascade annulation reaction. Furthermore, the structures of
the annulation products highly resembled those of natural
products and those compounds could be used as candidates in
medicinal chemistry. Application of this method to the total
synthesis of natural products and assays of biological activities
of polycyclic pyrroloindoline products are currently being
pursued in our lab.
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c
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Chem. Commun., 2012, 48, 7571–7573 7573