Total synthesis and absolute configuration of the guaiane sesquiterpene englerin A

Article abstract of DOI:10.1002/anie.200905032

Catnip craze: Nepetalactone, the psychoactive ingredient of catmint, was selected as starting material for the first enantioselective synthesis of englerin A. This cytotoxic guaiane sesquiterpene is a highly selective inhibitor (1-87 nM) of several renal

Full text of DOI:10.1002/anie.200905032

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
under http://dx.doi.org/10.1002/anie.200905032.
Angew. Chem. Int. Ed. 2009, 48, 9105 –9108
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9105

Communications
Scheme 2. Oxidation of nepetalactones 7 and 9. mCPBA=meta-
chloroperbenzoic acid.
Scheme 5. Epimerization at C5. pTsOH=para-toluenesulfonic acid,
IBX=2-iodoxybenzoic acid, DMSO=dimethylsulfoxide, DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene, nBuLi=n-butyllithium.
Acetalization of the vicinal hydroxy groups (15!16a)
was then followed by an IBX oxidation of the primary alcohol
to give aldehyde 17a (Scheme 5). In contrast to the bicyclic
form, the C5 epimer was now accessible by epimerization
with DBU, giving the diastereomer 17b in 70% yield in a ratio
of 3:1. Compound 17b was then converted into diene 18 using
a Wittig olefination.
Scheme 3. Tentative mechanism for the ring contraction.
Diene 18 was subjected to the conditions of olefin
metathesis[21] (Scheme 6) using the Grubbs II catalyst[22]
(20 mol%), giving the desired guaiane 19, which had the
Scheme 4. Attachment of the side-chain. THF=tetrahydrofuran.
glycosidation)[16] with inversion of configuration at the
anomeric center (10a!12).[17]
After the starting material had been set up, in just two
steps, for the crucial coupling reaction, an allylation was
envisaged to install the remaining carbon framework. The
Grignard reagent of allyl bromide 13[18] is relatively unstable
and prone to homocoupling (Wurtz reaction). The analogous
Barbier reaction[19] with aldehyde 11 proceeded smoothly to
give homoallylic alcohol 14 in 93% yield (d.r. 5:1). We
assume that this selectivity results from a minimization of
dipole–dipole interactions in the aldehydeꢀs reactive confor-
mation. The relative as well as the absolute configuration of
14 was confirmed by X-ray crystallography (Scheme 4). The
reduction[20] with LiAlH4 furnished the crystalline triol 15.
Scheme 6. Ring-closing metathesis and formation of the glycolate
ester 20. Mes=mesityl, Cy=cyclohexyl, TBS=tert-butyldimethylsilyl.
formally E-configured trisubstituted double bond.[23] After
transacetalization of the acetonide (19!4) using methanol,
the secondary hydroxy group was acylated with (tert-butyldi-
methylsilyloxy)acetyl chloride.[24]
The subsequent epoxidation using mCPBA afforded the
desired epoxide 3 with a moderate selectivity of 2.3:1. We
observed that an NMR sample of 3 in CDCl3 was smoothly
9106 www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 9105 –9108

Angewandte
Chemie
converted into 2 by a transannular epoxide opening.[25] This
process could be accelerated by heat, resulting in quantitative
conversion. The secondary alcohol 2 was converted into the
cinnamate ester 21 using a Yamaguchi esterification.[26]
Finally, the TBS ether was removed using TBAF in THF to
give englerin A (1) in 91% yield (Scheme 7). The spectro-
[3] R. M. Wilson, S. J. Danishefsky, J. Org. Chem. 2006, 71, 8329 –
8351.
[4] For a excellent example, see: C. F. Bender, F. K. Yoshimoto,
C. L. Paradise, J. K. De Brabander, J. Am. Chem. Soc. 2009, 131,
11350 – 11352.
[5] R. M. Wilson, S. J. Danishefsky, J. Org. Chem. 2007, 72, 4293 –
4305.
[6] For a short review, see: M. Christmann, Angew. Chem. 2008, 120,
2780 – 2783; Angew. Chem. Int. Ed. 2008, 47, 2740 – 2742.
[7] For selected examples, see: a) M. S. Chen, M. C. White, Science
2007, 318, 783 – 787; b) K. Chen, P. S. Baran, Nature 2009, 459,
824 – 828; c) S. Kasuya, S. Kamijo M. Inoue, Org. Lett. 2009, 11,
3630 – 3632; d) N. D. Litvinas, B. H. Brodsky, J. Du Bois, Angew.
Chem. 2009, 121, 4583 – 4586; Angew. Chem. Int. Ed. 2009, 48,
4513 – 4516.
[8] For an example using (R)-cryptone from eucalyptus oil, see: J.
Becker, K. Bergander, R. Frꢁhlich, D. Hoppe, Angew. Chem.
2008, 120, 1678 – 1681; Angew. Chem. Int. Ed. 2008, 47, 1654 –
1657.
[9] Nepetalactone can be obtained by distillation of commercially
available catnip oil (ca. 0.45 US$/g). For an excellent protocol
for the separation of nepetalactones 7 and 9, see: K. R. Chauhan,
A. Zhang„ US 7,375,239, 2008.
[10] Nepetalactones induce effects of a buzz or sexual arousal in cats:
a) R. B. Bates, C. W. Sigel, Experientia 1963, 19, 564 – 565; b) K.
Sakurai, K. Ikeda, K. Mori, Agric. Biol. Chem. 1988, 52, 2369 –
2371.
[11] For an elegant application of a combination of allylation/RCM in
sesquiterpene synthesis, see: M. S. Dowling, C. D. Vanderwal, J.
Am. Chem. Soc. 2009, 131, 15090 – 15091. For a gold caralyzed
synthesis of the guaiane ring system, see: b) E. Jimꢂnez-Nfflæez,
K. Molawi, A. E. Echavarren, Chem. Commun. 2009, DOI:
10.1039/B920119J.
Scheme 7. Completion of the total synthesis. 4-DMAP=4-dimethylami-
nopyridine, TBAF=tetra-n-butylammonium fluoride.
[12] I. Liblikas, E. M. Santangelo, J. Sandell, P. Baeckstrꢁm, M.
Svensson, U. Jacobsson, C. R. Unelius, J. Nat. Prod. 2005, 68,
886 – 890.
[13] This compound was obtained in diastereomerically pure form as
a gift from Symrise GmbH. The measured optical rotation of 9
{½aꢁ2D0 = + 19.9 (c = 1.71, Et2O)} was essentially identical to that
reported from Mori and co-workers {½aꢁ2D0 = + 20.6 (c = 0.24,
Et2O)} for material obtained by asymmetric synthesis (referen-
ce [10b]).
[14] CCDC 749796 (8a), 749797 (8b), 749798 (10b), 750007 (12), and
749799 and 750121 (14) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. See the Supporting Infor-
mation for additional details on the X-ray crystallographic
analyses.
[15] H. L. Gordon, S. Freeman, T. Hudlicky, Synlett 2005, 2911 – 2914.
[16] S. J. Danishefsky, M. T. Bilodeau, Angew. Chem. 1996, 108,
1482 – 1522; Angew. Chem. Int. Ed. Engl. 1996, 35, 1380 – 1419.
[17] Product of the acid-catalyzed epoxide-opening with methanol:
scopic data (1H NMR, 13C NMR, UV) exactly matched with
those reported.[2a] However, the optical rotation {½aꢁ2D0 = + 51
(c = 0.58, MeOH)} of the synthetic material was opposite to
that found for the natural product {½aꢁ2D0 = ꢀ63 (c = 0.13,
MeOH)}, thereby establishing the previously unknown abso-
lute configuration of natural (ꢀ)-englerin A.
We have completed the first total synthesis of (+)-
englerin A and determined its absolute configuration. The
key steps involve an epoxylactone rearrangement, a diaste-
reoselective Barbier reaction, and a ring-closing metathesis.
The ease of the transannular epoxide opening supports our
working hypothesis of a biomimetic process. The synthesis of
(ꢀ)-englerin A and the biological evaluation of both enan-
tiomers will be subject of future reports from this laboratory.
Received: September 8, 2009
Published online: October 30, 2009
Keywords: antitumor agents · natural products ·
.
rearrangements · terpenes · total synthesis
[1] G. M. Cragg, P. G. Grothaus, D. J. Newman, Chem. Rev. 2009,
109, 3012 – 3043.
[2] a) R. Ratnayake, D. Covell, T. T. Ransom, K. R. Gustafson, J. A.
Beutler, Org. Lett. 2009, 11, 57 – 60; b) J. A. Beutler, R.
Ratnayake, D. Covell, T. R. Johnson, WO 2009/088854, 2009.
Angew. Chem. Int. Ed. 2009, 48, 9105 –9108
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
9107

Communications
[18] a) D. H. R. Barton, T. Shioiri, D. A. Widdowson, J. Chem. Soc. C
[22] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1,
953 – 957.
1971, 1968 – 1974.
[19] a) B. M. Trost, J. R. Corte, M. S. Gudiksen, Angew. Chem. 1999,
111, 3945 – 3947; Angew. Chem. Int. Ed. 1999, 38, 3662 – 3664;
b) C. Pꢂtrier, J. Einhorn, J. L. Luche, Tetrahedron Lett. 1985, 26,
1449 – 1452.
[20] J. Mulzer, B. List, J. W. Bats, J. Am. Chem. Soc. 1997, 119, 5512 –
5518.
[21] a) A. Gradillas, J. Pꢂrez-Castells, Angew. Chem. 2006, 118, 6232 –
6247; Angew. Chem. Int. Ed. 2006, 45, 6086 – 6101; b) C. Hamel,
E. V. Prusov, J. Gertsch, W. B. Schweizer, K.-H. Altmann,
Angew. Chem. 2008, 120, 10235 – 10239; Angew. Chem. Int. Ed.
2008, 47, 10081 – 10085.
[23] M. E. Krafft, E.-H. Song, R. J. Davoile, Tetrahedron Lett. 2005,
46, 6359 – 6362.
[24] M. Leemhuis, J. H. van Steenis, M. J. van Uxem, C. F. van Nos-
trum, W. E. Hennink, Eur. J. Org. Chem. 2003, 3344 – 3349.
[25] M. Yoshikawa, Y. Fukuda, S. Hatakeyama, N. Tanaka, H.
Matsuda, J. Yamahara, N. Murakami, Chem. Pharm. Bull. 1993,
41, 1194 – 1196.
[26] a) J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi,
Bull. Chem. Soc. Jpn. 1979, 52, 1989 – 1993; b) T. Nagamitsu, D.
Takano, T. Fukuda, K. Otoguro, I. Kuwajima, Y. Harigaya, S.
Omura, Org. Lett. 2004, 6, 1865 – 1867.
9108 www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 9105 –9108