DOI: 10.1002/chem.201500368
Communication
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Cyclodepsipeptides
Divergent Solid-Phase Synthesis of Natural Product-Inspired
Bipartite Cyclodepsipeptides: Total Synthesis of Seragamide A
Hans-Dieter Arndt,*[a, b] Stefano Rizzo,[a] Christina Nçcker,[a] Vijay N. Wakchaure,[a] Lech-
Gustav Milroy,[a, c, d] Vanessa Bieker,[a, c] Abram Calderon,[a, c] Tuyen T. N. Tran,[a, c] Silke Brand,[a]
Leif Dehmelt,[a, c] and Herbert Waldmann*[a, c]
employed as efficient tools for the study of biology[1,2] and de-
termine a major fraction of the marketed drugs.[2]
Abstract: Macrocyclic natural products (NPs) and ana-
logues thereof often show high affinity, selectivity, and
metabolic stability, and methods for the synthesis of NP-
like macrocycle collections are of major current interest.
We report an efficient solid-phase/cyclorelease method for
the synthesis of a collection of macrocyclic depsipeptides
with bipartite peptide/polyketide structure inspired by the
very potent F-actin stabilizing depsipeptides of the jaspla-
kinolide/geodiamolide class. The method includes the as-
sembly of an acyclic precursor chain on a polymeric carri-
er, terminated by olefins that constitute complementary
fragments of the polyketide section and cyclization by
means of a relay-ring-closing metathesis (RRCM). The
method was validated in the first total synthesis of the
actin-stabilizing cyclodepsipeptide seragamide A and the
synthesis of a collection of structurally diverse bipartite
depsipeptides.
Numerous bioactive natural products are macrocyclic, but in
synthetic drugs macrocycles are underrepresented which at
least in part is due to their structural complexity and the corre-
sponding synthetic challenges. However, very recently macro-
cycles have increasingly been recognized as advantageous syn-
thesis targets for research programs in drug discovery[3] and
chemical biology, because macrocyclization often results in in-
creased affinity, selectivity and metabolic stability.[4] Therefore,
the development of enabling technology to efficiently access
structurally and stereochemically diverse, NP-like collections of
macrocycles is of major current interest.
The jasplakinolide/geodiamolide class of cyclodepsipeptides
(Scheme 1) features a characteristic bipartite architecture, that
is, they embody a peptide and a polyketide section.[5] They
very potently stabilize the F-actin polymer which results in and
correlates to cytotoxicity in tumor cell lines (IC50 values in the
10–30 nm range). We[6] and others[7] have shown that for this
bioactivity amino acid configuration and side chain constitu-
tion are crucial and allow for modulation of bioactivity. This
effect enabled the development of efficient tools for biological
imaging, in particular for the study of dynamics of the actin cy-
toskeleton in living cells.[6–8]
Natural products (NPs) are secondary metabolites with privi-
leged scaffolds selected in evolution to bind to multiple pro-
teins.[1] Due to their biological relevance, natural products as
well as derivatives and analogues thereof have been widely
Given this pronounced activity and relevance of the jasplaki-
nolide/geodiamolide class of cyclodepsipeptides we set out to
develop a flexible and efficient method for the synthesis of
a geodiamolide/jasplakinolide-inspired compound collection.
We now report an efficient solid-phase/cyclorelease method
for the synthesis of jasplakinolide/geodiamolide analogues and
its validation in the first total synthesis of the actin-stabilizing
cyclodepsipeptide seragamide.
[a] Prof. Dr. H.-D. Arndt, Dr. S. Rizzo, M. Sc. C. Nçcker, Dr. V. N. Wakchaure,
Dr. L.-G. Milroy, B. Sc. V. Bieker, Dr. A. Calderon, Dr. T. T. N. Tran,
Dr. S. Brand, Dr. L. Dehmelt, Prof. Dr. H. Waldmann
Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11
44227 Dortmund (Germany)
Fax: (+49)3641948212
To establish an enabling, flexible strategy for the synthesis
of cyclodepsipeptide scaffolds we envisioned to assemble an
acyclic precursor chain on a polymeric carrier, terminated by
an olefin fragment that represents part of the polyketide struc-
ture of the cyclodepsipeptide (Scheme 1). Cyclization would be
achieved by means of a ring-closing metathesis (RCM) reaction
with a double bond integrated into the linker to the solid sup-
port, that otherwise constitutes the complementary fragment
of the polyketide section.[9] To direct the catalyst’s activity to
the intended break point, a kinetically highly reactive[10] allylic
1,6-diene handle was chosen to initiate RCM precursor carbene
formation in the sense of a relay-ring-closing metathesis
(RRCM, Scheme 1b,c).[11] Macrocyclization to the cyclodepsi-
[b] Prof. Dr. H.-D. Arndt
Friedrich-Schiller-Universitꢀt
Institute of Organic and Macromolecular Chemistry
Humboldtstrasse 10, 07743 Jena (Germany)
[c] Dr. L.-G. Milroy, B. Sc. V. Bieker, Dr. A. Calderon, Dr. T. T. N. Tran,
Dr. L. Dehmelt, Prof. Dr. H. Waldmann
TU Dortmund, Faculty of Chemistry and Chemical Biology
Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
Fax: (+49)2132499
[d] Dr. L.-G. Milroy
Eindhoven University of Technology, Division of Molecular Bioengineering &
Molecular Imaging, PO box 513, 5600 MB Eindhoven (The Netherlands)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500368.
Chem. Eur. J. 2015, 21, 1 – 7
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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