ORGANIC
LETTERS
2011
Vol. 13, No. 8
2090–2093
Total Synthesis and Biological Evaluation
of (-)-9-Deoxy-englerin A
†
Dmitry B. Ushakov, Vaidotas Navickas, Markus Strobele,
†
§
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Cacilia Maichle-Mossmer, Florenz Sasse, and Martin E. Maier*
^
‡
,†
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Institut fu€r Organische Chemie, Universitat Tubingen, Auf der Morgenstelle 18, 72076
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Tu€bingen, Germany, Abteilung fu€r Festkorperchemie und Theoretische Anorganische
€
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Chemie, Institut fu€r Anorganische Chemie, Universitat Tubingen, Ob dem Himmelreich
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7, 72074 Tu€bingen, Germany, Institut fu€r Anorganische Chemie, Universitat Tubingen,
Auf der Morgenstelle 18, 72076 Tu€bingen, Germany, and Abteilung Chemische Biologie,
Helmholtz-Zentrum fu€r Infektionsforschung, Inhoffenstrasse 7, 38124 Braunschweig,
Germany
Received February 23, 2011
ABSTRACT
An effective total synthesis of (-)-9-deoxy-englerin (4), an analogue of the natural guaiane sesquiterpene englerin A (1), has been achieved. The
synthesis features a transannular epoxide opening to construct the 5,7-fused ring system followed by transannular ether formation with
mercury(II) trifluoroacetate.
The guaiane sesquiterpene englerin A (1) was isolated
from the plant extract of Phyllanthus engleri by Beutler
et al. (Figure 1).1 This novel guaianolide showed very high
selectivity and potency against various cell lines that
are involved in renal cancer. As a result of its remark-
able activity englerin A (1) has attracted significant
interest within the synthetic community.2-4 Recently,
the Chen group published the synthesis and biological
evaluation of englerin analogues. It turned out that
modifications in the cinnamic acid part are tolerated,
whereas substantial deviations from the glycolic acid at
9-OH diminish the cytotoxicity.5 Because other oxygen-
brigded guaiane-type sesquiterpenes, like orientalol F6,7 (5),
are known, it might be of interest to convert some of them to
englerin analogues. In addition, simpler englerin analogues
should reveal key structure-activity relationships. We
therefore targeted 9-deoxy-englerin (4). In this context we
also wanted to explore a novel route to the guaianolide core
structure.8,9
†
€
€
Institut f€ur Organische Chemie, Universitat Tubingen.
§
€
Abteilung f€ur Festkorperchemie und Theoretische Anorganische Chemie,
€
Institut f€ur Anorganische Chemie, Universitat T€ubingen.
^
€
Institut f€ur Anorganische Chemie, Universitat T€ubingen.
‡ Abteilung Chemische Biologie, Helmholtz-Zentrum f€ur Infektions-
forschung, Braunschweig.
(1) Ratnayake, R.; Covell, D.; Ransom, T. T.; Gustafson, K. R.;
Our retrosynthetic plan for 9-deoxy-englerin (4) fea-
tured a transannular ether formation leading to azulene
Beutler, J. A. Org. Lett. 2009, 11, 57–60.
(2) For total syntheses of englerin A, see: (a) Willot, M.; Radtke, L.;
€
€
Konning, D.; Frohlich, R.; Gessner, V. H.; Strohmann, C.; Christmann,
M. Angew. Chem., Int. Ed. 2009, 48, 9105–9108. (b) Zhou, Q.; Chen, X.;
Ma, D. Angew. Chem., Int. Ed. 2010, 49, 3513–3516. (c) Molawi, K.;
Delpont, N.; Echavarren, A. M. Angew. Chem., Int. Ed. 2010, 49, 3517–
3519. (d) Nicolaou, K. C.; Kang, Q.; Ng, S. Y.; Chen, D. Y.-K. J. Am.
Chem. Soc. 2010, 132, 8219–8222.
(3) Formal total synthesis: Xu, J.; Caro-Diaz, E. J. E.; Theodorakis,
E. A. Org. Lett. 2010, 12, 3708–3711.
(4) Synthetic studies: (a) Navickas, V.; Ushakov, D. B.; Maier, M. E.;
(5) Chan, K. P.; Chen, D. Y.-K. ChemMedChem. 2011, 6, 420–423.
(6) Peng, G.-P.; Tian, G.; Huang, X.-F.; Lou, F.-C. Phytochemistry
2003, 63, 877–881.
(7) Total synthesis: Jimenez-Nunez, E.; Molawi, K.; Echavarren,
A. M. Chem. Commun. 2009, 7327–7329.
(8) For a recent review, see: Foley, D. A.; Maguire, A. R. Tetrahedron
2010, 66, 1131–1175.
€
Strobele, M.; Meyer, H.-J. Org. Lett. 2010, 12, 3418–3421. (b) Sun,
B.-F.; Wang, C.-L.; Ding, R.; Xu, J.-Y.; Lin, G.-Q. Tetrahedron Lett.
2011, 52, in press, doi: 10.1016/j.tetlet.2010.11.087.
(9) For a recent case, see: Parmar, D.;Price, K.;Spain, M.;Matsubara,
H.; Bradley, P. A.; Procter, D. J. J. Am. Chem. Soc. 2011, 133,
2418–2420.
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10.1021/ol200499t
Published on Web 03/17/2011
2011 American Chemical Society