Consecutive isocyanide-based multicomponent reactions: Synthesis of cyclic pentadepsipeptoids

Article abstract of DOI:10.3762/bjoc.10.101

The synthesis of six cyclic depsipeptoids inspired by the natural depsipeptide sansalvamide A is described. An efficient and fast synthetic strategy was developed using a combination of consecutive isocyanide-based multicomponent reactions (Ugi and Passerini reactions). This methodology can be used to access a variety of cyclic oligodepsipeptoids.

Full text of DOI:10.3762/bjoc.10.101

Consecutive isocyanide-based multicomponent
reactions: synthesis of cyclic pentadepsipeptoids
Angélica de Fátima S. Barreto1, Otilie E. Vercillo2, Ludger A. Wessjohann3
and Carlos Kleber Z. Andrade*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1017–1022.
1Laboratório de Química Metodológica e Orgânica Sintética, Instituto
de Química, Universidade de Brasília, CP 4478, 70910-970
doi:10.3762/bjoc.10.101
Brasília-DF, Brazil, 2Faculdade UnB Planaltina, Área Universitária Nº
1, Vila Nossa Senhora de Fátima, Planaltina, 73300-000, Brasília, DF,
Brazil and 3Department of Bioorganic Chemistry, Leibniz Institute of
Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany
Received: 13 February 2014
Accepted: 07 April 2014
Published: 05 May 2014
This article is part of the Thematic Series "Multicomponent reactions II"
and is dedicated to Prof. Ronaldo A. Pilli on the occasion of his 60th
anniversary.
Email:
Carlos Kleber Z. Andrade* - ckleber@unb.br
* Corresponding author
Guest Editor: T. J. J. Müller
Keywords:
© 2014 Barreto et al; licensee Beilstein-Institut.
License and terms: see end of document.
depsipeptoids; multicomponent reactions; Passerini reaction;
sansalvamide A; Ugi reaction
Abstract
The synthesis of six cyclic depsipeptoids inspired by the natural depsipeptide sansalvamide A is described. An efficient and fast
synthetic strategy was developed using a combination of consecutive isocyanide-based multicomponent reactions (Ugi and
Passerini reactions). This methodology can be used to access a variety of cyclic oligodepsipeptoids.
Introduction
Peptoids are an interesting class of non-natural compounds that efficiently produce complex molecules with a reduced number
have recently received much attention due to their wide range of of steps and short reaction times [15-18].
biological activities, which makes them attractive candidates for
drug discovery [1-7]. This family of oligomers comprising Depsipeptides are polymeric natural compounds, analogues of
poly-N-substituted glycines mimics the primary natural struc- peptides, being formed by amino acids and hydroxy acids
ture of peptides and exhibits greater proteolytic stability and linked together by amide and ester bonds. These natural prod-
increased cellular permeabilities in comparison to peptides ucts show promising biological activities, especially regarding
[5-7]. A powerful synthetic tool for the preparation of a peptoid their therapeutic potential in cancer treatment [19]. An example
backbone is the Ugi four-component reaction (U-4CR) [8-14]. of a cyclic depsipeptide is sansalvamide A (San A, Figure 1)
It has been demonstrated that the combination of multicompo- [20-29], which was isolated from a marine fungus (Fusarium
nent reactions with the use of microwave irradiation is able to spp.) [20] and exhibits antitumor activity against multiple
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Beilstein J. Org. Chem. 2014, 10, 1017–1022.
cancer cell lines. It is cytotoxic against colon (HCT-116) toid analogues of San A based on a strategy developed in our
[20,23,25,26], pancreatic (S2-013 and AsPC-1) [22,28,29], groups for the synthesis of cyclic RGD pentapeptoids [44]. This
prostate (PC-3), breast (MDA-MB231) and melanoma cancers strategy was adapted by a combination of microwave-assisted
(WM-115) [24]. It has been reported that substitution of an ester Ugi and Passerini reactions. It is also important to highlight that
group by an amide in the structure of a peptide provides an effi- the synthesis of cyclic depsipeptoids had not been explored yet.
cient way to evaluate the role of protein hydrogen bonding [30- In this paper, we describe the synthesis of six pentadepsipep-
34]. Recent works have discovered that some analogues of San toid analogues of San A (Figure 3).
A inhibit Hsp 90, a key protein that enables many proteins
involved in tumor progression [35-39].
The synthetic route for the synthesis of cyclic pentadepsipep-
toids via consecutive Ugi reactions allows only three side
The Passerini three-component reaction (P-3CR) allows an easy chains connected to three nitrogen atoms. The pentapeptide of
access to depsipeptides using a convergent approach. It has San A has in its structure five side chains attached to the α
become a powerful tool in combinatorial synthesis [40-43] and carbon atoms: one isopropyl, one benzyl and three isobutyl
can be used strategically for the synthesis of depsipeptoids. By groups. To generate the pentapeptoid analogues of San A, the
analogy to peptides and peptoids, a depsipeptoid would be a side chain groups isobutyl, isopropyl and benzyl linked to the α
peptoid bearing an ester group instead of an amide group. carbon atom present in the peptide were moved to the nitrogen
Differences between peptide, peptoid, depsipeptide and atoms. It was decided to keep at least one benzyl group in the
depsipeptoid structures are outlined in Figure 2.
structure of the peptoids and vary the isopropyl and isobutyl
groups, thus maintaining a greater similarity with the structure
of the San A depsipeptide.
Results and Discussion
In continuing our research on the synthesis of peptoids with
potential pharmacological activity [12,17,18,44,45] and using a The retrosynthetic analysis of the depsipeptoids (Scheme 1)
fast and efficient microwave-assisted synthesis of peptoids shows that the proposed compounds can be achieved using a
[15,17,18], we decided to carry out the synthesis of depsipep- strategy based on: (a) formation of a peptoid via Ugi reaction;
Figure 1: Sansalvamide A (1) and its depsipeptoid analogues (2).
Figure 2: Generic structures of (a) peptide, (b) peptoid, (c) depsipeptide and (d) depsipeptoid.
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Beilstein J. Org. Chem. 2014, 10, 1017–1022.
Figure 3: Structures of six pentadepsipeptoid analogues of San A.
Scheme 1: Retrosynthetic analysis of the cyclic depsipeptoids.
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Beilstein J. Org. Chem. 2014, 10, 1017–1022.
(b) ester hydrolysis; (c) formation of an acyclic depsipeptoid 92–100% yield. Acid 8 was then employed in a Passerini reac-
scaffold through a Passerini reaction; (d) deprotection of the tion with isobutyraldehyde (9a) or isovaleraldehyde (9b) and
amine/acid groups and (e) a macrocyclization step via an tert-butyl isocyanoacetate (3b), in a MW reactor (20 min at
intramolecular Ugi reaction.
80 °C) in THF, affording the acyclic depsipeptoids 10a and 10b
in 70% and 66% yield, respectively. Removal of the Boc
The general strategy for the synthesis of cyclic pentadepsipep- protecting group and ester hydrolysis were achieved after treat-
toids is depicted in Scheme 2. The synthesis of analogues 2 was ment of the acyclic depsipeptoids 10a,b with TFA in CH2Cl2,
initiated by an Ugi 4-component reaction (U-4CR) using methyl giving the corresponding amino acids 11a,b as TFA salt in
isocyanoacetate (3a), paraformaldehyde (4), benzylamine (5) quantitative yields.
and N-Boc-glycine (6) in MeOH (Scheme 2) in a microwave
(MW) reactor (3 min at 80 °C) to provide the peptoid 7 in In the last step, the depsipeptoid amino acid salts 11a,b were
77–87% yield. Peptoid 7 was subjected to hydrolysis in the subjected to an Ugi three-component four-center reaction
presence of LiOH (THF/H2O, 0 °C, 2.5 h) followed by treat- (U-3C4CR) (Scheme 3). Compounds 11a,b were added under
ment with 2 M NaHSO4 providing the corresponding acid 8 in pseudo-high dilution conditions (addition rate: 0.6 mL/h; addi-
Scheme 2: Synthesis of acyclic depsipeptoids 11a,b.
Scheme 3: Synthesis of macrocycles 2a-f.
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paraformaldehyde 4, triethylamine, sodium sulfate and iso-
propyl/isobutyl/tert-butyl isocyanide 12a–c in methanol to yield
the target cyclic pentadepsipeptoids 2a–f after purification by
column chromatography (yields ranged from 33–49%
depending on the substrate). The structures of the final prod-
ucts obtained are shown in Figure 3.
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In summary, the approach developed herein allows the syn-
thesis of a wide range of cyclic depsipeptoids. Different struc-
tures can be obtained by changes in the amine component in the
first Ugi reaction, in the carbonyl component in the Passerini
reaction or in the isocyanide and carbonyl components in the
macrocyclization step. The general route and procedure devel-
oped allows an easy access to complex molecules with a signifi-
cantly reduced number of steps in short reaction times, and high
yields in most of the steps. The strategic combination of two
isocyanide-based multicomponent reactions and microwave ir-
radiation makes this a very useful and attractive protocol. The
obtained depsipeptoids will be tested for different biological
activities.
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Supporting Information
Supporting Information File 1
General procedures, NMR and mass spectra of all
compounds.
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Acknowledgements
The authors thank the Instituto de Química, Universidade de
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