Communications
DOI: 10.1002/anie.201005530
Structure Elucidation
Gephyronic Acid, a Missing Link between Polyketide Inhibitors of
Eukaryotic Protein Synthesis (Part I): Structural Revision and Stereo-
chemical Assignment of Gephyronic Acid**
Lionel Nicolas, Timo Anderl, Florenz Sasse,* Heinrich Steinmetz, Rolf Jansen, Gerhard Hꢀfle,
Sabine Laschat,* and Richard E. Taylor*
Culture supernatants of Archangium gephyra
strain Ar 3895 demonstrated antibiotic activity,
leading to the isolation of a novel polyketide,
gephyronic acid (1), as a separable mixture of
keto and hemiketal isomers.[1] Their structures
(Scheme 1) were included in a single publica-
tion describing their isolation and biological
activity, but spectroscopic data were not
included. Initial biological analyses revealed
selective inhibition of eukaryotic protein syn-
thesis along with a nanomolar cytostatic effect
against a range of mammalian cell lines. For
example, keto-1 exhibits an IC50 value of
10 ngmLÀ1 against HeLa (human cervix carci-
noma) and K-562 (human myelogenous leuke-
mia) cell lines, and similar activity was observed
with hemiketal-1, suggesting that equilibration
occurs under assay conditions.[1]
Scheme 1. Originally proposed structure of gephyronic acid and structures of myriapor-
Previous efforts in the Taylor lab resulted in
an asymmetric total synthesis of myriapor-
ones 3 and 4 (2a and 2b, respectively) and
one isomers and tedanolides.
provided confirmation of their absolute and relative config-
uration (Scheme 1).[2] Moreover, detailed biological analyses
of the synthetic material demonstrated that the myriaporones
are potent eukaryote-selective cytostatic agents.[3,4]
[*] L. Nicolas, Prof. R. E. Taylor
Department of Chemistry & Biochemistry
University of Notre Dame, 251 Nieuwland Science Hall
Notre Dame, IN 46556-5670 (USA)
Fax: (+1)574-631-6652
Owing to intriguing biological and structural similarities
between the myriaporones and gephyronic acid, we initiated a
follow-up effort to unambiguously assign the relative and
absolute configuration of gephyronic acid, which is crucial for
its subsequent total synthesis and further biological studies.
The full spectroscopic data presented herein, including 1H and
13C NMR, COSY, ROESY, J-HMBC, HSQC-HECADE, and
GBIRD-HSQMBC experiments[5] along with fragment syn-
thesis, support not only a structural reassignment but also the
unambiguous reassignment of the configuration of gephyr-
onic acid, which has been confirmed by total synthesis.[6]
In the original paper, Sasse et al. described gephyronic
acid as a separable mixture of open keto-alcohol and closed
hemiketal forms. In a more recent investigation a third
component was isolated and identified as an anomer of the
hemiketal form.
E-mail: taylor.61@nd.edu
T. Anderl, Prof. S. Laschat
Institut fꢀr Organische Chemie, Universitꢁt Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
Fax: (+49)711-685-64285
E-mail: sabine.laschat@oc.uni-stuttgart.de
Dr. F. Sasse, H. Steinmetz, Dr. R. Jansen, Prof. G. Hꢂfle
Abteilung Chemische Biologie und Arbeitsgruppe Mikrobielle
Wirkstoffe, Helmholtz-Zentrum fꢀr Infektionsforschung
Inhoffenstrasse 7, 38124 Braunschweig (Germany)
Fax: (+49)531-6181-3499
E-mail: florenz.sasse@helmholtz-hzi.de
[**] This work was supported by the National Science Foundation, the
Deutsche Forschungsgemeinschaft (CHE-0924351 for R.E.T. and
F.S.), the Deutsche Akademische Austauschdienst (fellowship for
T.A.), the Ministerium fꢀr Wissenschaft, Forschung und Kunst des
Landes Baden-Wꢀrttemberg (Landesgraduierten fellowship for
T.A.), and the Fonds der Chemischen Industrie. We thank Prof. M.
Kalesse for a generous gift of tedanolide and Dr. J. Zajicek for his
assistance in NMR measurements.
Based on our previous experience with myriaporones 2
and tedanolides 3, we quickly identified spectroscopic incon-
sistencies with the originally reported structure. Further, a
new high-resolution mass spectrum (HREIMS) of keto-1,
which provided a [M+Na]+ ion at m/z 493.3148 as well as ions
at [2M+Na]+ and [3M+Na]+, indicated a molecular formula
Supporting information for this article is available on the WWW
938
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 938 –941