Total synthesis of the cytotoxic 1,10-seco-eudesmanolides britannilactone and 1,6-O,O-diacetylbritannilactone

Article abstract of DOI:10.1002/chem.201002927

A natural boost! The first synthetic access to the bioactive title compounds was achieved from the dienyl carboxylic acid 1 (see scheme), which in turn is readily available by using sultone chemistry. The enantioselective route developed here also confirms the relative and absolute configuration of these sesquiterpene lactones. Copyright

Full text of DOI:10.1002/chem.201002927

DOI: 10.1002/chem.201002927
Total Synthesis of the Cytotoxic 1,10-seco-Eudesmanolides Britannilactone
and 1,6-O,O-Diacetylbritannilactone
Jçrn Merten, Yuzhou Wang, Tilo Krause, Olga Kataeva, and Peter Metz*[a]
Dedicated to Professor Alberto Brandi on the occasion of his 60th birthday
Britannilactone (1a), 1-O-acetylbritannilactone (1b), and
1,6-O,O-diacetylbritannilactone (1c) are members of the
1,10-seco-eudesmanolide family of sesquiterpene lactones,
which have been isolated from the plant Inula britannica
syn. Inula japonica; a traditional Chinese medicinal herb
(xuan fu hua) used for the treatment of bronchitis and in-
flammation (Scheme 1).[1,2] Compounds 1a–1c display inter-
esting bioactivities such as cytotoxicity in cancer cells.[3,4]
Moreover, compound 1b and particularly 1c are anti-inflam-
matory agents;[5] compound 1c effects cell-cycle arrest at the
G2+M phase and also affects the polymerization of microtu-
bules.[3b] Herein, we report the first total synthesis of 1a and
1c by using the readily available carboxylic acid 2, which
has already served as an important intermediate in the syn-
thesis of the more highly oxygenated 1,10-seco-eudesmano-
lides (ꢀ)-eriolanin (3a) and (ꢀ)-eriolangin (3b).[6] Since the
absolute configuration of 2 was unambiguously established,
our synthetic access to 1a and 1c has also proved the abso-
lute configuration of these natural products.
Carboxylic acid 2 was treated with bis(sym-collidine)iodi-
ne(I) hexafluorophosphate[7] in toluene followed by reduc-
tion[8,9] of the intermediate allyl iodides in a one-pot proce-
dure to give
a 4.8:1 mixture of e-lactones 4 and 5
(Scheme 2). Since separation was not accomplished at this
stage, the mixture was reduced with lithium borohydride to
give triol 6, which was easily isolated as the major product.
Chemoselective tritylation of the primary alcohol and subse-
quent Dess–Martin oxidation[10] of the resultant tritylether 7
afforded ketone 8. X-ray diffraction analysis of 8 (using
anomalous scattering) provided further independent proof
of its absolute configuration.[11] Mild desilylation[12] of 8 led
to the b-hydroxy ketone 9, which was subjected to a hydrox-
yl-directed[13] reduction with sodium bis(2-methoxyethoxy)-
AHCTUNGTREGaNNNU luminum hydride (Red-Al) to give the desired 6a (eudes-
mane numbering) allyl alcohol 10. Next, the modified
Tamao–Fleming oxidation[6,14] of 10 was used to give triol 11
(Scheme 2). This sequence enables the formation of the
completely oxygenated skeleton of the target molecules
with the correct configuration at all stereogenic centers, as
confirmed by X-ray diffraction analysis.[11]
Scheme 1. Structures and retrosynthesis of the cytotoxic 1,10-seco-eudes-
manolides 1a, 1b, and 1c. TBS=tert-butyldimethylsilyl.
N-chlorosuccinimide (NCS)[15] proved to be a better coox-
idant than bisacetoxyiodobenzene[6,16] for the TEMPO-medi-
ated chemoselective oxidation of triol 11 to give the hydroxy
g-lactone 12 (Scheme 3). After protection of the secondary
alcohol, a one-step a-methylenation of lactone 13 succeeded
with sodium hydride and paraformaldehyde. Although the
original methodology[17] for attachment of the requisite
a-methylene unit did not work well for 13, changing the sol-
vent from THF to DMF allowed a fast methylenation at
room temperature, and following desilylation, lactone 14
was isolated. Detritylation to give 1a proceeded uneventful-
ly to give (+)-britannilactone, which proved to be identical
to the natural product by comparison of the spectral and op-
[a] Dr. J. Merten, Dr. Y. Wang, Dr. T. Krause,+ Dr. O. Kataeva,+
Prof. Dr. P. Metz
Fachrichtung Chemie und Lebensmittelchemie
Organische Chemie I, Technische Universitꢀt Dresden
Bergstrasse 66, 01069 Dresden (Germany)
Fax : (+49)351-463-33162
E-mail: peter.metz@chemie.tu-dresden.de
[+] X-ray diffraction analysis
Supporting information for this article (including full experimental
details and compound characterization) is available on the WWW
under http://dx.doi.org/10.1002/chem.201002927.
3332
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 3332 – 3334

COMMUNICATION
Acknowledgements
Financial support of this work by the
Deutsche Forschungsgemeinschaft is
gratefully acknowledged. We thank
Prof. Dr. M. M. Rafi, Rutgers Univer-
sity, New Brunswick, USA, for
a
sample of natural 1,6-O,O-diacetylbri-
tannilactone (1c).
Keywords: antitumor agents ·
natural products
·
structure
elucidation · terpenoids · total
synthesis
[1] For the isolation of 1a–1c, see:
a) B.-N. Zhou, N.-S. Bai, L.-Z.
Ling, G. A. Cordell, Phytochemis-
try 1993, 34, 249–252; b) F. Jeske,
S. Huneck, J. Jakupovic, Phyto-
chemistry 1993, 34, 1647–1649.
Scheme 2. Synthesis of triol 11 from carboxylic acid 2. a) i) IACHTNUGTRNE(UNG col)2PF6, toluene, 08C, ii) Bu3SnH, AIBN, tolu-
ene, 758C, 73% 4/5 (4.8:1); b) LiBH4, THF, 08C!RT, 82% (2 steps); c) TrCl, DMAP, pyridine, CH2Cl2, RT,
100%; d) Dess–Martin periodinane, pyridine, CH2Cl2, RT, 98%; e) Bu4NF, AcOH, THF, RT, 100%; f) Red-
Al, CH2Cl2, toluene, ꢀ208C!RT, 83 %; g) i) Bu4NF, MS (4 ꢂ), THF, 858C (sealed tube) ii) KF, H2O2,
NaHCO3, THF, MeOH, 858C (sealed tube), 91%. Tr=triphenylmethyl, col=sym-collidine, AIBN=azobisiso-
butyronitrile, DMAP=4-(N,N-dimethylamino)pyridine, Red-Al=sodium bis(2-methoxyethoxy)aluminum hy-
dride, MS=molecular sieves.
[2] For the relative configuration of 1
illustrated in Scheme 1, see
Ref. [1b], as well as the depicted
crystal structures of 1b in: a) A.-
R. Han, W. Mar, E.-K. Seo, Nat.
Prod. Sci. 2003, 9, 28–30; b) S.
Liu, H. Liu, W. Yan, L. Zhang, N.
Bai, C.-T. Ho, Bioorg. Med.
Chem. Lett. 2004, 14, 1101–1104.
[3] a) C. Yang, C.-M. Wang, Z.-J. Jia,
Planta Med. 2003, 69, 662–666;
b) C.-T. Ho, M. Rafi, R. S. Dipao-
la, G. Ghai, R. T. Rosen, N. Bai,
US 6627623 B2, 2003; c) M. M.
Rafi, N.-S. Bai, C.-T. Ho, R. T.
Rosen, E. White, D. Perez, R. S.
Dipaola, Anticancer Res. 2005, 25,
313–318; d) S. Liu, H. Liu, W.
Yan, L. Zhang, N. Bai, C.-T. Ho,
Bioorg. Med. Chem. 2005, 13,
2783–2789; e) N. Bai, C.-S. Lai,
K. He, Z. Zhou, L. Zhang, Z.
Quan, N. Zhu, Q. Y. Zheng, M.-
H. Pan, C.-T. Ho, J. Nat. Prod.
2006, 69, 531–535; f) C.-M.
Wang, Z.-J. Jia, R.-L. Zheng,
Scheme 3. Completion of the synthesis of 1a and 1c. a) TEMPO (50 mol%), NCS, Bu4NCl (10 mol%),
CH2Cl2, H2O, pH 8.6, RT, 77%; b) TMSCl, imidazole, CH2Cl2, 08C, 100%; c) NaH, paraformaldehyde, DMF,
RT; d) Bu4NF, THF, 08C, 35% (2 steps); e) TsOH, MeOH, RT, 100%; f) Ac2O, pyridine, RT, 67%. TEMPO=
2,2,6,6-tetramethylpiperidine-1-oxyl (free radical), NCS=N-chlorosuccinimide, TMSCl=Trimethylsilyl chlo-
ride , TsOH=toluenesulfonic acid.
tical rotation data.[18] To determine without any doubt if the
Planta Med. 2007, 73, 180–184.
relative configuration of (+)-britannilactone depicted in the
literature[1a] should be revised to that of 1a, we repeated the
published procedure for isolation[1a] of this sesquiterpene
lactone from Inula britannica flowers.[19] As anticipated, the
X-ray diffraction analysis of natural 1a obtained in this way
unambiguously verified the 6a orientation of the secondary
hydroxyl group.[11] Finally, conversion of synthetic 1a to the
diacetate also gave (ꢀ)-1c, which, by comparison of the
spectral and optical rotation data, was also found to be iden-
tical to the natural product.[20]
[4] Recently, a non-natural acyl derivative of 1b (ABL-N) was shown
to induce apoptosis in breast cancer cells and cause significant inhib-
ition of tumor growth in vivo: B. Liu, M. Han, J.-J. Wang, Y.-P.
Zhang, D.-Q. Zhang, J.-K. Wen, Breast Cancer Res. 2010, 12, R9.
[5] a) K.-H. Je, A.-R. Han, H.-T. Lee, W. Mar, E.-K. Seo, Arch. Pharm.
Res. 2004, 27, 83–85; b) M. Han, J.-K. Wen, B. Zheng, D.-Q. Zhang,
Life Sci. 2004, 75, 675–684; c) Y.-P. Liu, J.-K. Wen, B. Zheng, D.-Q.
Zhang, M. Han, Eur. J. Pharmacol. 2007, 577, 28–34; d) B. Liu, M.
Han, J.-K. Wen, J. Pharmacol. Exp. Ther. 2008, 324, 292–298; e) Y.-
P. Liu, J.-K. Wen, Y.-B. Wu, J. Zhang, B. Zheng, D.-Q. Zhang, M.
Han, Phytomedicine 2009, 16, 156–160.
[6] a) J. Merten, R. Frçhlich, P. Metz, Angew. Chem. 2004, 116, 6117–
6120; Angew. Chem. Int. Ed. 2004, 43, 5991–5994; b) J. Merten, A.
Hennig, P. Schwab, R. Frçhlich, S. V. Tokalov, H. O. Gutzeit, P.
Metz, Eur. J. Org. Chem. 2006, 1144–1161.
[7] B. Simonot, G. Rousseau, J. Org. Chem. 1994, 59, 5912–5919.
[8] F. Homsi, G. Rousseau, J. Org. Chem. 1998, 63, 5255–5258.
[9] W. P. Neumann, Synthesis 1987, 665–683.
In conclusion, a short enantioselective route to britanni-
lactone (1a) and 1,6-O,O-diacetylbritannilactone (1c) has
been developed that also confirmed the relative and abso-
lute configuration of these bioactive natural products.
Chem. Eur. J. 2011, 17, 3332 – 3334
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3333

P. Metz et al.
[10] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277–7287.
[11] CCDC-794897 (8), 794895 (11), and 794896 (natural 1a) contain the
supplementary crystallographic 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.
[12] a) J. S. Debenham, R. Rodebaugh, B. Fraser-Reid, J. Org. Chem.
1997, 62, 4591–4600; b) D. L. Boger, R. M. Borzilleri, S. Nukui,
R. T. Beresis, J. Org. Chem. 1997, 62, 4721–4736.
[13] Review: A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993,
93, 1307–1370.
[14] H.-J. Knçlker, G. Wanzl, Synlett 1995, 378–382.
[15] J. Einhorn, C. Einhorn, F. Ratajczak, J.-L. Pierre, J. Org. Chem.
1996, 61, 7452–7454.
[16] T. M. Hansen, G. J. Florence, P. Lugo-Mas, J. Chen, J. N. Abrams,
C. J. Forsyth, Tetrahedron Lett. 2003, 44, 57–59.
[17] B. Noya, M. D. Paredes, L. Ozores, R. Alonso, J. Org. Chem. 2000,
65, 5960–5968.
[18] Synthetic 1a: [a]2D5 =+86.0 (c=0.57 in CHCl3); natural 1a (see
Ref. [1a]): [a]2D5 =+91.3 (c=0.092 in CHCl3).
[19] Inula britannica flowers were purchased from Ancient Way Acu-
puncture & Herbs, Inc., 219 Pine St, Klamath Falls, Oregon 97601,
USA. Britannilactone (1a) was isolated from these flowers as de-
scribed in Ref. [1a].
[20] Synthetic 1c: [a]2D5 =ꢀ38.4 (c=0.50 in CHCl3); natural 1c (see
Ref. [21]): [a]D25 =ꢀ36.9 (c=0.64 in CHCl3).
[21] Measured with an authentic sample of natural 1c kindly provided
by Prof. Dr. M. M. Rafi, Rutgers University, New Brunswick, USA.
The positive specific optical rotation reported in Ref. [1a] is evident-
ly due to a typing error.
Received: October 11, 2010
Published online: February 14, 2011
3334
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 3332 – 3334