Enantioselective total synthesis of otteliones A and B

Article abstract of DOI:10.1021/ol902776d

(Figure Presented) Enantioselective total synthesis of otteliones A and B was accomplished. The key steps are radical cyclization of an alpha-lodoketone to construct the cs-hydrindanone skeleton and Suzuki-Miyaura coupling to incorporate the aromatic group. (+)-Ottelione A was converted to (-)-ottelione B on treatment with NaOH in THF.

Full text of DOI:10.1021/ol902776d

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1377-1379
Enantioselective Total Synthesis of
Otteliones A and B
Cheng-Hui Chen, Yu-Kai Chen, and Chin-Kang Sha*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu, Taiwan, ROC
cksha@mx.nthu.edu.tw
Received December 2, 2009
ABSTRACT
Enantioselective total synthesis of otteliones A and B was accomplished. The key steps are radical cyclization of an alpha-iodoketone to
construct the cis-hydrindanone skeleton and Suzuki-Miyaura coupling to incorporate the aromatic group. (+)-Ottelione A was converted to
(-)-ottelione B on treatment with NaOH in THF.
Ayyad and Hoye et al. isolated otteliones A (1) and B (2)
from the freshwater plant Ottelia alismoides collected in the
Nile Delta (Figure 1).1 These natural products exhibit
remarkable biological activities, including antitumor and
antitubercular activities.1,2 Upon screening against a panel
of 60 human tumor cell lines at the National Cancer Institute
in Bethesda, MD,1 these compounds were found to inhibit
tubulin polymerization into microtubules similarly to the
well-known alkaloids colchicine, vincristine, and vinblastine.3
Scientists from Rhone-Poulenc Rorer (now Sanofi-Aventis)
independently isolated compound RPR112378, which was
identical to ottelione A (1). They determined the relative
stereochemistry with extensive NMR experiments and also
investigated their biological activities.3 Because of the
powerful anticancer activities and scarcity of these natural
products, otteliones A (1) and B (2) have attracted much
attention from the synthetic community.
Mehta and co-workers reported the first total synthesis of
racemic otteliones A (1) and B (2) and confirmed the relative
stereochemistry of their structures.4a They subsequently
achieved an enantioselective total synthesis and determined
the absolute configurations of 1 and 2.4b Katoh et al.
Figure 1. Structures of otteliones A and B.
independently achieved an enantioselective total syntheses
of otteliones A (1) and B (2) and confirmed their absolute
configuration.5 Clive and co-workers reported an elegant
synthesis of (+)-ottelione A (1) and (-)-ottelione B (2)
utilizing a ring-closing metathesis to construct the hydrindane
skeleton.6 A formal total synthesis of ottelione A (1) was
also described using an asymmetric Diels-Alder reaction
(1) Ayyad, S.-E. N.; Judd, A. S.; Shier, W. T.; Hoye, T. R. J. Org.
Chem. 1998, 63, 8102.
(2) (a) Li, H.; Qu, X.; Shi, Y.; Guo, L.; Yuan, Z. Zhongguo Zhongyao
Zazhi (Chin. J. Chin. Mater. Med.) 1995, 20, 128. (b) Leboul, J.; Provost,
J. French Patent WO96/00205 1996. Chem. Abstr. 1996, 124, 242296
.
(3) Combeau, C.; Provost, J.; Lancelin, F.; Tournoux, Y.; Prod’homme,
F.; Herman, F.; Lavelle, F.; Leboul, J.; Vuilhorgne, M. Mol. Pharmacol.
2000, 57, 553.
(5) (a) Araki, H.; Inoue, M.; Katoh, T. Org. Lett. 2003, 5, 3903. (b)
Araki, H.; Inoue, M.; Suzuki, T.; Yamori, T.; Kohno, M.; Watanabe, K.;
Abe, H.; Katoh, T. Chem.sEur. J. 2007, 13, 9866.
(4) (a) Mehta, G.; Islam, K. Angew. Chem., Int. Ed. 2002, 41, 2396. (b)
Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44, 6733.
10.1021/ol902776d  2010 American Chemical Society
Published on Web 03/11/2010

by Ryu et al.7 We found that only two distinct approaches,
the Diels-Alder reaction and the ring-closing metathesis,
were employed in these total syntheses.
(7) prepared from commercially available (-)-quinic acid
according to Danishefsky’s procedure.9 Treatment of enone
7 with 4-(trimethylsilyl)-3-butynylmagnesium chloride in the
presence of CuI, followed by trapping the enolate with
chlorotrimethylsilane, furnished trimethylsilylenol ether 8.
Without purification, crude compound 8 was treated with a
solution of NaI/m-CPBA in THF to give R-iodoketone 6 as
a single stereoisomer.10 Stereochemistry of 6 was determi-
nated by single crystal X-ray analysis.11
Scheme 1. Retrosynthetic Analysis of (+)-Ottelione A
Scheme 2. Total Synthesis of Otteliones A and B
In our laboratory, we envisaged that a radical cyclization
of an R-iodocycloalkanone8 might serve as a key step to
construct the hydridanone skeleton with the desired stereo-
chemistry. The retrosynthetic analysis is shown in Scheme
1. Conjugated addition of a vinyl group to compound 3
followed by Wittig reaction and introduction of the enone
moiety would provide (+)-ottelione A (1). Compound 3
could be prepared from 4 via deprotection and oxidation
steps. Compound 4 would be obtained from 5 via hydrobo-
ration and Suzuki-Miyaura coupling. Key intermediate 5
could be synthesized via radical cyclization of R-iodoketone
6 followed by hydrodesilylation, reduction of the carbonyl
group, and protection of the resulting OH group. R-Iodoke-
tone 6 would be prepared according to our method from
chiral enone 7.9
Our synthesis, shown in Scheme 2, began with optically
active (-)-4-tert-butyldimethylsilyloxy-2-cyclohexen-1-one
(6) (a) Clive, D. L. J.; Liu, D. Angew. Chem., Int. Ed. 2007, 46, 3738.
(b) Clive, D. L. J.; Liu, D. J. Org. Chem. 2008, 73, 3078.
(7) Lee, M. Y.; Kim, K. H.; Jiang, S.; Jung, Y. H.; Sim, J. H.; Hwang,
G.-S.; Ryu, D. H. Tetrahedron Lett. 2008, 49, 1965.
Photolysis of R-iodoketone 6 with a sunlamp in the
presence of hexamethylditin,8 followed by reduction with
tributyltin hydride, gave compound 9. Hydrodesilylation of
compound 9 with trifluoroacetic acid followed by reduction
with sodium borohydride cleanly afforded alcohol 10 as a
single diastereomer. Alcohol 10 was treated with acetic
(8) (a) Sha, C.-K.; Chiu, R.-T.; Yang, C.-F.; Yao, N.-T.; Tseng, W.-H.;
Liao, F.-L.; Wang, S.-L. J. Am. Chem. Soc. 1997, 119, 4130. (b) Sha, C.-
K.; Santhosh, K. C.; Lih, S.-H. J. Org. Chem. 1988, 63, 2699. (c) Sha,
C.-K.; Lee, F.-K.; Chang, C.-J. J. Am. Chem. Soc. 1999, 121, 9875. (d)
Sha, C.-K.; Ho, W.-Y. Chem. Commun. 1998, 24, 2709. (e) Sha, C.-K.;
Liao, H.-W.; Cheng, P.-C.; Yen, S.-C. J. Org. Chem. 2003, 68, 8704. (f)
Jiang, C.-H.; Bhattacharyya, A.; Sha, C.-K. Org. Lett. 2007, 9, 3241. (g)
Liu, K.-M.; Chau, C.-M.; Sha, C.-K. Chem. Commun. 2008, 1, 91. (h) Kuo,
Y.-L.; Dhanasekaran, M.; Sha, C.-K. J. Org. Chem. 2009, 74, 2033.
(9) Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.; Danishefsky,
S. J. J. Org. Chem. 1989, 54, 3738.
(10) Sha, C.-K.; Young, J.-J.; Jean, T.-S. J. Org. Chem. 1987, 52, 3919.
(11) The molecular drawings and X-ray data of 6 are presented in the
Supporting Information.
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Org. Lett., Vol. 12, No. 7, 2010

Treatment of 4 with tetrabutylammonium fluoride (TBAF)
afforded alcohol 11. Oxidation of 11 with PCC gave ketone
12. Reaction of 12 with a mixture of 1,1,1,3,3,3-hexameth-
yldisilazane (HMDS), TMSCl, and LiI generated the corre-
sponding trimethylsilylenol ether. Saegusa oxidation of the
trimethylsilylenol ether intermediate with Pd(OAc)2 gave
compound 3.13
Scheme 3
Conjugate addition of vinylmagnesium bromide to com-
pound 3 afforded compound 13. Wittig reaction of 13 with
methyltriphenylphosphonium bromide and t-BuOK gave
compound 14. Deprotection of 14 followed by PCC oxidation
afforded compound 15. Treatment of 15 with LHMDS and
PhSeCl followed by oxidative elimination delivered com-
pound 16. Removal of the MOM protecting group eventually
25
gave (+)-ottelione A (1), [R]D +18.9 (c 0.60, CHCl3).
Furthermore, we found that treatment of ottelione A (1)
with NaOH in THF at 0 °C afforded (+)-ottelione A (1)
and (-)-ottelione B (2) in a 1:10 mixture with 82% yield.15
Ottelione B (2) was isolated by silica gel column chroma-
25
tography and recrystallized [R]D -327.3 (c 0.55, CHCl3).
The structure of ottelione B was confirmed by single-crystal
X-ray analysis.16 This method of epimerization of 1 to 2 is
more effective than the DBU4b or the t-BuOK5a method.
In conclusion, we achieved enantioselective total syntheses
of otteliones A and B in 3.8% and 2.8% overall yields. Using
the R-carbonyl radical cyclization and the Suzuki-Miyaura
coupling as the key steps, our total synthesis provides a new
access to this important class of anticancer natural products.
Our synthetic scheme is adaptable to prepare analogues of
otteliones. The synthesis of such analogues according to our
strategy for anticancer study is under current investigation.
anhydride in the presence of pyridine and 4-(N,N-dimethy-
lamino)pyridine (DMAP) to afford compound 5. Hydrobo-
ration of the exocyclic double bond of 5 with 9-BBN,12
followed by Suzuki-Miyaura coupling with 4-iodo-1-
methoxy-2-(methoxymethoxy)benzene,13 gave compound 4.
Acknowledgment. We thank the National Science Council
of the Republic of China (Taiwan) for financial support.
(12) (a) Suzuki, A.; Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa,
M.; Satoh, M. J. Am. Chem. Soc. 1989, 111, 314. (b) Danishefsky, S. J.;
Chemler, S. R.; Trauner, D. Angew. Chem., Int. Ed. 2001, 40, 4544.
(13) Feldman, K. S. J. Org. Chem. 1997, 62, 4983.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(15) The ratio of the mixture was determined with a HPLC column
(DAICEL CHIRALPAK AD-H); see ref 5a.
(16) The molecular drawings and X-ray data of 2 are presented in the
Supporting Information.
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