Tandem Mannich/Diels-Alder reactions for the synthesis of indole compound libraries

Article abstract of DOI:10.1039/c6ra08786h

A tandem Mannich/Diels-Alder sequence for the synthesis of small-molecule libraries with an indolyl-octahydro-3a,6-epoxy-isoindole core structure is demonstrated in this study. Representative diversification examples based on this scaffold were performed, and a library is being produced within the European Lead Factory (ELF) Consortium.

Full text of DOI:10.1039/c6ra08786h

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Tandem Mannich/Diels–Alder reactions for the
synthesis of indole compound libraries†
Cite this: RSC Adv., 2016, 6, 46654
a
a
a
a
Peng Wu,‡ Michael A˚ xman Petersen,‡ Rico Petersen, Thomas Flagstad,
b
b
b
ac
Rachel Guilleux, Martin Ohsten, Remy Morgentin, Thomas E. Nielsen*
and Mads H. Clausen*
Received 5th April 2016
Accepted 2nd May 2016
´
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DOI: 10.1039/c6ra08786h
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A tandem Mannich/Diels–Alder sequence for the synthesis of small- exploitation of new chemical space represented by these new
molecule libraries with an indolyl-octahydro-3a,6-epoxy-isoindole scaffolds will be associated with novel physico-chemical prop-
11
core structure is demonstrated in this study. Representative diversifi- erties and potentially useful biological effects.
cation examples based on this scaffold were performed, and a library is
The synthesis of biologically active and structurally diverse
12–14
being produced within the European Lead Factory (ELF) Consortium.
small molecule libraries is a current focus of our group.
As
1
5
a continuation of our efforts to synthesize indole derivatives,
the amine protected compounds 1 with an indolyl-hexa-
hydroepoxyisoindole core was designed. This scaffold has
A large portion of pharmaceutically active compounds and
1
approved drugs, including all small-molecule kinase inhibitors
previously been synthesized employing an intramolecular
2,3
approved by the FDA so far, are structurally dependent on
16–18
Diels–Alder reaction
and is virtually unexplored biologically.
4
heterocyclic scaffolds. The indole core structure is embedded
We envisioned its formation through a convenient tandem
Mannich/Diels–Alder reaction sequence. Subsequent cycles of
deprotection and functionalization lead to indole compounds 3
with an octahydro-3a,6-epoxyisoindole core and three sites for
diversication: one introduced intrinsically by the indole
component, in addition to a primary amine and a secondary
amine for further decoration (Fig. 1). In the present work, we
describe the synthesis of a small-molecule library based on this
indolyl-octahydroepoxyisoindole scaffold (3), which combines
a bicyclic aromatic indole with a tricyclic aliphatic 3a,6-epoxy-
in a plethora of compounds, which exhibit a broad range of
5
6
biological activities, such as anticancer, antibacterial, anti-
7
8
inammatory, and anti-HIV, and is clearly one of the most
intensively studied heterocyclic scaffolds. In fact, indole or
9
fused indole moieties are present in more than 50 FDA-
approved small-molecule drugs and countless biologically
active compounds currently in clinical or preclinical develop-
1
ment. Due to the fact that present drug discovery efforts tend to
focus on a limited number of scaffolds, there is a growing
interest within the chemical and pharmaceutical communities
to develop synthetic approaches towards small-molecule
10
libraries that also incorporate new scaffolds. Properties
3
relating to lipophilicity, fraction of sp -hybridised carbon
atoms, ratio of chiral/non-chiral centers, and drug-likeness
parameters differentiate these newly sought-aer scaffolds
from most traditional aromatic scaffolds. It is expected that the
a
Department of Chemistry, Technical University of Denmark, DK-2800, Kgs. Lyngby,
Denmark. E-mail: ten@kemi.dtu.dk; mhc@kemi.dtu.dk
b
EDELRIS, 115 Avenue Lacassagne, 69003 Lyon, France
c
Singapore Centre on Environmental Life Science Engineering, Nanyang Technological
University, 637551, Singapore
d
Center for Nanomedicine and Theranostics, Technical University of Denmark, DK-
2
800, Kgs. Lyngby, Denmark
†
Electronic supplementary information (ESI) available: General methods,
experimental procedures including the two deprotection steps, characterization
1
13
data, H and C NMR spectra. See DOI: 10.1039/c6ra08786h
Fig. 1 Production of indole compounds 3 through cycles of depro-
‡
Authors contributed equally.
tection and functionalization.
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3
isoindole ring, the latter displaying a high Fsp value and Table 1 One-pot Mannich/Diels–Alder reaction
several chiral centers.
The synthesis of substrate 4 for the Mannich/Diels–Alder
reaction was achieved by protection of furfurylamine 5, followed
by formylation using phosphoryl chloride in DMF to give alde-
19
hyde 8, which readily reacted with allylamine to afford the
Schiff base 4 in high yield (Fig. 2).
In initial experiments with the one-pot Mannich/Diels–Alder
reaction sequence, indole was employed as the C-nucleophile in
ꢀ
THF at 70 C, together with CBzCl, to give the amino-protected
compound 1b in 56% yield (entry 1, Table 1). This process is
easily applicable to other indole nucleophiles, substituted with
either electron-withdrawing or electron-donating groups,
affording the corresponding tricyclic 3a,6-epoxyisoindole
derivatives 1a and 1c–e in good yields ranging from 59 to
a
b
Entry
Nucleophile
Product 1
Yield
7
2% (Table 1, entries 1 and 3–6). Attempts to use other
1
2
3
4
5
6
7
8
9
N-Methylindole
Indole
1a
1b
1c
1d
1e
1f
1g
1h
1i
59%
56%
62%
72%
60%
C-nucleophilic aromatic systems, such as 1,3-dimethox-
ybenzene, 1H-pyrrolo[2,3-b]pyridine, 1H-indazole, and thio-
phene, in this one-pot process led to intractable mixtures with
little or no trace of Diels–Alder product (Table 1, entries 6–9).
The reaction was monitored by LC-MS, where Mannich inter-
6-Fluoroindole
5-Methoxy-indole
5-Fluoroindole
1,3-Dimethoxybenzene
1H-Pyrrolo[2,3-b]pyridine
1H-Indazole
c
—
c
—
—
c
mediates 9a–e could be observed, as detected by a signicant [M
+
c
+
Thiophene
—
Na ] peak, while the Diels–Alder products 1a–e were charac-
+
a
b
terized by a signicant [M + H ] peak. The relative stereo-
chemistry was determined by NOESY analysis. Although
compounds 1 were obtained as racemates, it is noteworthy to
mention the possibility of accessing both enantiomers, through
either chiral preparative HPLC or enantioselective Diels–Alder
4 equiv. of nucleophile was added in the reaction. Isolated yield aer
c
column chromatography. Intractable mixture.
simply isolated by concentration in vacuo and used directly in
the next steps, since any attempts to purify it by column chro-
matography failed probably due to poor stability of the free
amines.{
20,21
reactions,
during lead optimization of identied hits.
Removal of the phthalimido protecting group of 1a–e with
hydrazine and hydrochloric acid in methanol afforded the cor-
responding compounds with a primary amine handle, which was
subjected to a subsequent round of diversication steps.§
Selected modication examples include sulfonylation with 4-
The secondary amino handle was then subject to another
round of diversication steps. For example, the deprotected
(triuoromethyl)benzene sulfonyl chloride to give 2a, TBTU-
mediated acylation with cyclopropanecarboxylic acid to give 2b,
urea-formation using phenyl isocyanate to give 2c, and acylation
with cyclohexanecarbonyl chloride to give 2d (Fig. 3).
Cbz-deprotection of 2a–d was carried out under reducing
condition using 10% Pd/C and a hydrogen atmosphere.
However, except in the case of N-methyl indole substituted
compound 2a, epimerization at the 3-CH-indole position with
varied ratio ranging from 9 : 1 to 3 : 2 was observed during the
deprotection for compounds 2b–d. The crude compound was
Fig. 3 Examples of functionalized compounds 2 after the first step. *
ꢀ
Fig. 2 Synthesis of substrate 4 for the Mannich/Diels–Alder reaction. Deprotection condition: hydrazine, 2 M HCl (aq.), MeOH, 21 C, 1 h.
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product of sulfonamide 2a was converted to the bissulfonamide
3a, alkylated compound 3b, and urea 3c. The deprotected
product of amide 2b was functionalized to give sulfonylated
compound 3d and acylated compound 3e through a sulfonyla-
tion reaction and a TBTU-coupling reaction, respectively, and
the free amine derived from urea compound 2c was further
functionalized to give sulfonylated compound 3f and amide 3g
(Fig. 4).
All of the functionalized compounds 3a–g were puried by
direct preparative HPLC, which underpin the subsequent
production of a screening compound library. Based on the steps
of phthalimido deprotection, functionalization of primary
amine, Cbz deprotection, and functionalization of the
secondary amine for the synthesis of compounds with an
indolyl-octahydroepoxyisoindole core, a collection of 120
compounds that resemble the structural features of compounds
Fig.
5
Physical chemical property analysis of the produced
compounds (red dots) vs. enumerated compounds in library (blue
dots).
3a–c have been produced as a part of a small-molecule
screening library under the ELF consortium. All produced
compounds and most of the enumerated compounds are
compliant with Lipinski's Rule of Five in terms of clog P values
and MW (Fig. 5).
Effectively, the production focused on nal compounds in
N-methyl indole series since no epimerization at the 3-CH-
indole position occurred during the Cbz-deprotection step.
reproducible on a 0.1 mol scale with yields comparable to those
shown in Table 1. To expand the library, future productions will
involve additional N-substituted indoles. A systematic relative
conguration assignment method could also be approached
with the aim to include both diastereomers from N-unsub-
stituted indoles series in the library, since most of these dia-
stereomers could be separated by preparative LCMS (C18-
Noteworthy,
the
Mannich/Diels–Alder
reaction
was
ꢀ
Fig. 4 Examples of validated compounds for library synthesis. * Deprotection condition: 10% Pd/C (10 mol%), H
2
, MeOH, DMF, 21 C, overnight.
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phase). The goal is to access new, biologically relevant chemical
scaffolds that are not represented in existing screening
collections.
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7
An efficient protocol for the rapid assembly of indolyl-hexahy-
dro-3a,6-epoxyisoindole via a tandem Mannich/Diels–Alder
synthesis sequence has been developed in the reported study.
Diversication of the indolyl-octahydroepoxyisoindole core
through amino group functionalization has led to the validation
of 120 compounds which will be incorporated in a small-
molecule library under the ELF consortium.
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Acknowledgements
This research was done within the European Lead Factory and
has received support from the Innovative Medicines Initiative
Joint Undertaking (grant no. 115489), with nancial contribu-
tion from the European Union's Seventh Framework Pro-
gramme (FP7/2007–2013) and EFPIA companies' in-kind
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2
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