Synthesis of the bicyclic dienone core of the antitumor agent ottelione B

Article abstract of DOI:10.1039/b205753k

The intramolecular Diels-Alder adduct 12 was converted via dimesylate 20 into dienone 7, which represents the unusual, and apparently quite stable, core of the antitumor agent ottelione B (1).

Full text of DOI:10.1039/b205753k

Synthesis of the bicyclic dienone core of the antitumor agent ottelione B
Derrick L. J. Clive* and Stephen P. Fletcher
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
E-mail: derrick.clive@ualberta.ca
Received (in Corvallis, OR, USA) 5th June 2002, Accepted 28th June 2002
First published as an Advance Article on the web 31st July 2002
The intramolecular Diels–Alder adduct 12 was converted via
dimesylate 20 into dienone 7, which represents the unusual,
and apparently quite stable, core of the antitumor agent
ottelione B (1).
substitution pattern9 and can be changed by introduction of a
double bond,10 the situation with respect to 7 was not
predictable by appeal to experimental evidence.11 We report
here the preparation of 7 by two related approaches, as well as
some observations on its properties.
Ottelione B (1), was isolated from a sample of the freshwater
plant Ottelia alsimoides.1 The substance has conspicuously high
antitumor activity, 1 as judged by in vitro tests using a panel of
human tumor cell lines—many of the IC50 values being at the
nanomolar level. A stereoisomer, tentatively assigned structure
2,1,2 was isolated from the same extract, and was named
ottelione A. The 1a,3a,3aa,7aa relative stereochemistry shown
in 2 was judged1 more likely than the 1a,3a,3ab,7ab ster-
eochemistry, but in a more recent publication3 the assignment
made is 1a,3b,3aa,7aa. Ottelione A also has antitumor
properties;1–3 it appears to be even more potent than 1,1 and has
been shown to inhibit tubulin polymerization.2 The impressive
biological activity of 1 and 2, and their unusual structures—as
well as the need to confirm those structures—make them
worthy synthetic targets.
The known12 phosphonate 10 was made as indicated in
Scheme 1. Olefination of (5E)-5,7-octadienal13 with phospho-
nate 10 gave the expected triene 1112 (53–75%), and Diels–
Alder cycloaddition, using the chiral catalyst [Cu(S,S)-t-Bu-
box](SbF6)2,14 led to 12 (44–58%). Material prepared in this
way is reported to have an ee of 86%,12 but in this study we did
not monitor the optical purity of our compounds. Detachment of
the auxiliary (LiOH, H2O2, 90–98%) liberated acid 13, whose
structure was confirmed by X-ray analysis.† Treatment with I2–
KI–NaHCO3 produced iodohydrin 14, and the structure of this
compound was also determined by X-ray analysis.† While there
is precedent for formation of iodohydrins from olefins,15 the
normal outcome where a suitably-placed carboxy is present is
The otteliones represent a rare compound class, and a search
of the Beilstein database, using substructure 3,4 retrieved few
relevant examples,5 apart from the two otteliones and the
models mentioned below; none of the examples had trans ring
fusion. The dienone substructures 4, characteristic of the
otteliones, have not been studied extensively,5 and little
synthetic work has yet been published on the otteliones
themselves. The synthesis of (±)-56 and of optically pure 67
have been reported, as has a route8 to functionalized hydrinde-
nones structurally related to ottelione A.
Scheme 1 Reagents and conditions: (i) NaH, THF, reflux; add bromoacetyl
bromide at 0 °C, 18 h at 0 °C, 49%; (ii) (MeO)3P, 0 °C, 6 h, then 15 h at room
temperature, then reflux 2 h, 81%; (iii) (5E)-5,7-octadienal, Et3N, LiCl,
MeCN, 4 h, 53–75%; (iv) [Cu((S,S)-t-Bu-box)](SbF6)2, CH2Cl2, 1 week,
44–58%; (v) LiOH·H2O, 30% H2O2, 3+1 THF–water, 4 h, 90–98%; (vi) I2,
KI, NaHCO3, water–CH2Cl2, 13 h; (vii) CH2N2, Et2O, 20 min, 73% over
two steps; (viii) Ac2O, pyridine, DMAP, CH2Cl2, 12 h, 94%; (ix) (a)
TEMPO, Bu3SnH (added in portions), PhMe, 70 °C, ca. 1.5 h; (b) Zn,
AcOH, THF, water, 70 °C, 4 h, 67% over two steps; (x) t-BuMe2SiO-
SO2CF3, 2,6-lutidine, CH2Cl2, 0 °C, 4 h, room temperature, 15 h, 92–98%;
(xi) LiBH4, THF, 5 days, 97%; (xii) MeSO2Cl, Et3N, CH2Cl2, 0 °C, 40 min,
room temperature, 4 h, 94%.
Before embarking on a synthesis of ottelione B, we thought it
advisable to make the fundamental carbon skeleton 7 so as to
establish its properties—in particular the stability of the
stereogenic center a to the carbonyl and the tendency, if any, of
the dienone to aromatize. Although the relative stability of cis
and trans isomers of hydrindanones is influenced by the
1940
CHEM. COMMUN., 2002, 1940–1941
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iodolactonization. In the present case, however, inspection of
Dreiding models shows that generation of an iodonium ion on
the b-face of 13 and intramolecular trapping by the carboxylate
must proceed by way of a boat-like six-membered ring, and
either of the resulting lactones would be highly strained. In
contrast, these unfavorable geometrical changes are avoided by
formation of an a-iodonium ion, followed by intermolecular
trans diaxial ring opening by H2O or HO2, leading to 14. The
positive charge on such an a-iodonium ion may well be
stabilized by the negatively charged carboxylate.16
Esterification (14?15) and acetylation gave iodide 16, and
the halogen was then replaced by an hydroxy (16?17), using a
standard free radical method17 (see Scheme 1, 67%). Silylation
(17?18, 92–98%) and reduction (LiBH4) gave the crystalline
diol 19 (97%), which was subjected to X-ray analysis.† The diol
was then converted (94%) into the bis-mesylate 20, which is a
key intermediate in our synthesis.
Although dienone 7 is crystalline, we were unable to obtain
material suitable for X-ray analysis. Therefore, in order to prove
that no epimerization had occurred a to the carbonyl in 23 or 7,
the latter was reduced with NaBH4/CeCl3·7H2O, giving a new
alcohol to which we assign structure 28. Although crystalline,
adequately diffracting crystals could not be obtained for this
substance either. Fortunately, Mitsunobu inversion18 converted
28 back into 27, the structure and stereochemistry of which can
be assigned on the basis of the X-ray data obtained for its
precursor 19 (Scheme 1). These observations show that no
change in ring fusion stereochemistry occurs in any of the steps
involving generation or manipulation of ketones 23 or 7.
The trans ring-fused dienone 7 appears to be a quite robust
compound. It can be distilled unchanged (kugelrohr, oven at
170 °C), is stable to silica gel chromatography, and is largely
recovered after being heated for 1 h in THF containing
TsOH·H2O (3 equiv.). Evidently, the substituents of ottelione B
are not essential to stabilize the dienone substructure.
Desilylation of 20 (Scheme 2) led directly to epoxide 21
(79%) and, on treatment with PhSeNa, the bis-selenide 22 was
obtained (81%). In order to facilitate the subsequent selenoxide
elimination, the hydroxy group was oxidized (22?23, Dess-
Martin reagent, 69%), and then treatment with H2O2 afforded
the target ketone 7 (58%).
Acknowledgment is made to NSERC and to Wyeth-Ayerst
(Pearl River) for financial support. We thank Dr R. McDonald
for crystal structure determinations, Professor M. Klobukowski
for the calculations, and Professor K. Narasaka for advice on the
preparation of 9. S. F. holds an NSERC Postgraduate Schol-
arship..
Notes and references
† CCDC 189592, 189593 and 190875. See http://www.rsc.org/suppdata/cc/
b2/b205753k/ for crystallographic data in CIF or other electronic format.
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Scheme 2 Reagents and conditions: (i) Bu4NF, THF, 2 h, 79%; (ii)
PhSeSePh, NaBH4, MeOH, 40 h, 81%; (iii) Dess-Martin periodinane,
CH2Cl2, 70 min, 69%; (iv) 30% H2O2, CH2Cl2, 25 h, 58%.
Bis-mesylate 20 was also converted into 7 by the reactions
summarized in Scheme 3. The primary methanesulfonyloxy
group was displaced (20?24) with o-O2NC6H4Se2 (5 equiv.),
and selenoxide elimination then produced the exocyclic olefin
25 [58% from 20, after correction for recovered 20 (11%)].
Treatment with DBU in refluxing o-xylene now served to
generate the diene system (25?26), and desilylation released
alcohol 27 (79% from 25). Oxidation, again with the Dess-
Martin reagent, afforded 7 (90%).
10 H. O. House and G. H. Rasmussen, J. Org. Chem., 1963, 28, 31.
11 Ab initio DFT calculations using the 6-31G** basis set indicated that in
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mol21). The energies have not been modified for zero-point energy
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Scheme 3 Reagents and conditions: (i) o-O2NC6H4SeCN (5 equiv.),
NaBH4, MeOH, 70 °C, 7 h; (ii) 30% H2O2, THF, 14 h, 58% over two steps,
corrected for recovered dimesylate (11%); (iii) DBU, o-xylene, reflux, 10 h;
(iv) Bu4NF, THF, 24 h, 79% over two steps; (v) Dess-Martin periodinane,
CH2Cl2, 2 h, 90%; (vi) CeCl3·7H2O, NaBH4, MeOH, 278 °C, 10 min, ca.
86%; (vii) p-O2NC6H4CO2H, DEAD, Ph3P, PhH, 5 °C, 1.5 h, 79%; K2CO3,
MeOH, 30 min, 69%.
18 S. F. Martin and J. A. Dodge, Tetrahedron Lett., 1991, 32, 3017.
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