Angewandte
Chemie
DOI: 10.1002/anie.200905032
Natural Product Synthesis
Total Synthesis and Absolute Configuration of the Guaiane
Sesquiterpene Englerin A**
Matthieu Willot, Lea Radtke, Daniel Kꢀnning, Roland Frꢀhlich, Viktoria H. Gessner,
Carsten Strohmann, and Mathias Christmann*
Plants are a valuable source of new bioactive molecules.[1] In
an NCI 60-cell panel screening, extracts from Phyllanthus
engleri, belonging to the genus Euphorbiaceae (spurge
family), stood out because of their high selectivity and
activity against renal cancer cells. By using bioassay-guided
fractionation, Beutler and co-workers isolated the active
component and elucidated its structure except for the
absolute configuration.[2] The guaiane sesquiterpene engler-
in A (1) selectively inhibits the growth of renal cancer cell
lines with GI50 values ranging from 1–87 nm (Scheme 1). This
promising biological activity coupled with the appealing
molecular architecture led us to pursue a synthetic approach
toward englerin A with the goal of investigating the structural
space beyond natural product derivatives.[3] Retrosynthetic
removal of the cinnamate side chain in 1 leads to the
protected glycolate ester 2, which may be obtained—possibly
in a biomimetic fashion—by a transannular epoxide-opening.
Epoxide precursor 3 is accessible from the alkene 4 through a
sequence involving a kinetically controlled acylation and a
subsequent diastereoselective oxidation. At this juncture, it
seemed appropriate to ponder on a suitable starting material.
In our understanding of synthetic efficiency, the minimization
ꢀ
of C C bond-forming reactions through the identification of
large and readily accessible fragments[4] of the carbon frame-
work is the key objective in synthesis planning.[5] By using
computer-guided substructure searches, it is relatively easy to
identify molecules that partially overlap with the target
structure, differing only in the oxidation state or the degree of
ꢀ
unsaturation. As a result of rapid progress in oxidative C H
functionalizations,[6,7] terpenes from plant oil[8] will gain
importance as sustainable feedstock in synthesis.
Guided by such consideration, we selected the mono-
terpene trans,cis-nepetalactone (7)[9,10] as a suitable starting
material for our synthesis. In addition to providing the
correctly configured trisubstituted cyclopentane, its alkene
moiety appears susceptible to an oxidative rearrangement to
ꢀ
ꢀ
give aldehyde 6. Consequently, C6 C7 and C8 C9 of 4 were
identified as strategic bonds, which in the synthetic direction
may be formed by an addition of the allylmetal compound 5
to the aldehyde 6 and a subsequent ring closing metathesis.[11]
Depending on the catmint (Nepeta) species, the active
ingredient nepetalactone exists as a mixture of varying
amounts of four diastereomers, which can all be obtained in
pure form.[12] The oxidation of trans,cis-nepetalactone (7) with
mCPBA (Scheme 2) afforded 8b with the undesired config-
uration at C10 as the major isomer (d.r. 7:1). Fortunately, the
epoxidation of cis,trans-nepetalactone (9)[13] installed the
correct configuration at C10 for the major isomer 10a
(d.r. 1.5:1).[14] Despite the necessity of a late-stage epimeriza-
tion at C5, we selected this material for use in the course of
our synthesis.
Scheme 1. Retrosynthetic analysis of englerin A (1). RCM=ring-closing
metathesis, TBS=tert-butyldimethylsilyl.
[*] Dr. M. Willot, Dipl.-Chem. L. Radtke, Dipl.-Chem. D. Kꢀnning,
Prof. Dr. M. Christmann
TU Dortmund University, Organic Chemistry
Otto-Hahn-Str. 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
Corrensstr. 40, 48149 Mꢁnster (Germany)
Dr. V. H. Gessner,[+] Prof. Dr. C. Strohmann[+]
TU Dortmund University, Inorganic Chemistry
Otto-Hahn-Str. 6, 44227 Dortmund (Germany)
Treatment of 10a with NaOMe led to a rapid ring
contraction of the epoxylactone moiety into the formyl
lactone 11 (Scheme 3). Interestingly, the initially envisaged
rearrangement of 8a into the aldehyde 6 did not take place,
possibly resulting from the strain of the trans-bicyclo-
[3.3.0]octane scaffold.[15] For the very same reason, an
epimerization from the cis-annulated form is energetically
disfavored. Under acidic reaction conditions, the epoxide 10a
was opened with MeOH (in analogy to the Danishefsky
[+] X-ray crystallography
[**] We thank the Fonds der Chemischen Industrie for a Dozentensti-
pendium (M.C.), the DAAD for a research fellowship (M.W.),
Symrise GmbH und Co. KG (Holzminden) for a generous donation
of nepetalactone, and Dr. Hans-Dieter Arndt for support and helpful
discussions.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2009, 48, 9105 –9108
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9105