Communications
DOI: 10.1002/anie.201007790
Natural Products
Total Synthesis and Biological Evaluation of (À)-Englerin A and B:
Synthesis of Analogues with Improved Activity Profile**
Lea Radtke, Matthieu Willot, Hongyan Sun, Slava Ziegler, Stephanie Sauerland,
Carsten Strohmann, Roland Frꢀhlich, Peter Habenberger, Herbert Waldmann, and
Mathias Christmann*
Dedicated to Professor Dieter Enders on the occasion of his 65th birthday
Although successful in many types of cancer, chemotherapy
has shown at best moderate effectiveness in the treatment of
renal cell carcinoma.[1] Currently approved therapies target
the downstream signaling that leads to an over-expression of
angiogenic factors such as VEGF and PDGF and include
tyrosine kinase inhibitors (sorafenib, sutinib) as well as
mTOR inhibitors (temsirolimus, everolimus). Owing to
severe side effects and other drawbacks of the above-
mentioned treatments, the identification of novel inhibitors
Scheme 1. Strategy for the diverted synthesis of englerin A derivatives
of kidney cancer signaling pathways remains highly desirable.
Toward this end, a collection of plant extracts was screened
against an NCI 60-cell panel containing renal cancer cell lines
along with eight other organ panels. Selecting for specific
inhibitors of renal cancer cell lines led to the identification of
englerin A and B, metabolites of Phyllanthus engleri, which is
a plant indigenous to the East African countries of Tanzania
and Zimbabwe. Englerin A (1) is a densely functionalized
guaiane sesquiterpenoid with an oxatricyclic core flanked by
two opposing ester side chains (Scheme 1). Following Beu-
tlerꢀs initial report[2] on the strong and selective activity of 1
against six of eight renal cancer cell lines, both compounds
from intermediate 2 (green box) or earlier intermediates (red box).
TBS=tert-butyldimethylsilyl.
received immediate attention from the synthetic community.
In 2009, our research group established the previously
unknown absolute configuration of englerin A by total syn-
thesis of its (+)-enantiomer.[3] Shortly after, the groups of
Ma[4] and Echavarren[5] reported independent total syntheses
of (À)-1 using elegant gold-catalyzed cyclization cascade
reactions of open-chain precursors. A fourth synthesis of
englerin was published by Nicolaou, Chen, and co-workers[6]
and features an intermolecular rhodium-catalyzed
[4+3] cycloaddition strategy and progress reports from
other groups[7] are harbingers of ongoing interest.
Herein, we report a reliable and scalable route to
englerinꢀs natural enantiomer (À)-1 via intermediate 2,
encompassing englerinꢀs complete guaiane core (2). This
material fuelled an extensive SAR study[8] aimed to clarify the
role of englerinꢀs two ester side chains (green boxes).
Diverting the synthesis[9] at an earlier intermediate allowed
us to probe the influence of the isopropyl group (red box).
When devising a strategy for a total synthesis program, it is
mandatory to plan for the preparation of both enantiomers
when the absolute configuration is unknown. The monoter-
pene nepetalactone possesses an iridoid substructure that is
primed for olefin oxidation leading to englerinꢀs oxidation
pattern. While (+)-nepetalactone is readily available in bulk
quantities from essential oil companies, the (À)-enantiomer 3
can be synthesized from (+)-citronellal on multigram scale
following Schreiberꢀs protocol.[10] In our initial total synthesis,
the absolute configuration of englerin A was deduced from
natural (+)-nepetalactone. For the biological evaluation of
the natural product and key analogues, we had to start from
synthetic nepetalactone 3 and thus taking advantage of the
previously developed chemistry.[3a] This material was con-
[*] L. Radtke, Dr. M. Willot, S. Sauerland, Prof. C. Strohmann,[+]
Prof. H. Waldmann, Prof. M. Christmann
TU Dortmund University, Faculty of Chemistry
Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
Fax: (+49)231-755-5363
E-mail: mathias.christmann@tu-dortmund.de
Dr. R. Frꢀhlich[+]
University of Mꢁnster, Institute of Organic Chemistry
Corrensstrasse 40, 48149 Mꢁnster (Germany)
Dr. H. Sun, Dr. S. Ziegler, Prof. H. Waldmann
Department of Chemical Biology
Max-Planck-Institute of Molecular Physiology
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
Dr. P. Habenberger
Lead Discovery Center GmbH
Emil-Figge-Strasse 76a, 44227 Dortmund (Germany)
[+] X-ray crystal structure analysis.
[**] We thank the Fonds der Chemischen Industrie (Dozentenstipen-
dium to M.C.), the Alexander von Humboldt Foundation for
postdoctoral fellowships (to M.W. and H.S.) and finally, we thank
Takasago International Corporation for generous donation of (+)-
citronellal.
Supporting information for this article is available on the WWW
3998
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 3998 –4002