A tandem enyne/ring closing metathesis approach to 4-methylene-2- cyclohexenols: An efficient entry to otteliones and loloanolides

Article abstract of DOI:10.1021/ol2029838

A short and efficient approach to a 4-methylene-2-cyclohexenone substructure present in otteliones and loloanolides is described. This strategy involves a tandem enyne/ring closing metathesis as the key reaction to construct this labile core unit.

Full text of DOI:10.1021/ol2029838

ORGANIC
LETTERS
2012
Vol. 14, No. 1
198–201
A Tandem Enyne/Ring Closing Metathesis
Approach to 4-Methylene-2-
cyclohexenols: An Efficient Entry to
Otteliones and Loloanolides
Vipul V. Betkekar, Samaresh Panda, and Krishna P. Kaliappan*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai
400076, India
kpk@chem.iitb.ac.in
Received November 5, 2011
ABSTRACT
A short and efficient approach to a 4-methylene-2-cyclohexenone substructure present in otteliones and loloanolides is described. This strategy
involves a tandem enyne/ring closing metathesis as the key reaction to construct this labile core unit.
4-Methylene-2-cyclohexenone 1a and 4-methylene-2-
cyclohexenol 1b are unique substructures present in a few
biologically important natural products such as otteliones
A (2) and B (3), loloanolides B (4), and 1-O-acetylloloa-
nolide B (5) (Figure 1). Otteliones isolated from the fresh-
water plant Ottelia alismoides collected in the Nile Delta1,2
show an impressive biological activity profile, such as
antitubercular activity and cytotoxicity at nMÀpM levels
against a panel of 60 human cancer cell lines. Loloanolides
have been isolated3 from the extract of aerial parts of
Camchaya loloana, and they exhibit cytotoxicity against
the HepG2 cell line, with GI50 values at a nanomolar level.
It is believed that the biological activity of these molecules
is attributed to the presence of a unique 4-methylene-2-
cyclohexenone moiety.4 This moiety engages the sulfhy-
dral group of the cysteine residue on the tubulin and
microtubule dynamics. Thus, the mechanism of action of
these molecules resembles that of the cytotoxic molecule
T13067, which reacts specifically with cysteine residue 239
in β-tubulin and bindsinthe closevicinity ofthe colchicine-
binding site.5,6
Such a promising biological activity profile and the
presence of an unusual bicyclic/tricyclic framework with
the sensitive 4-methylene-2-cyclohexenone moiety have
made these molecules a new leads for the development of
chemotherapeutic agents and also attractive targets for
synthetic chemists. While considerable efforts have been
addressed to synthesize otteliones A and B, loloanolides
remain unexplored to date.
(1) Ayyad, S. E. N.; Judd, A. S.; Shier, W. T.; Hoye, T. R. J. Org.
Chem. 1998, 63, 8102–8106.
(2) Incidentally, ottelione A (2) was identical to the compound named
Mehta et al. reported the first total synthesis of racemic
otteliones A and B and, thus, confirmed the relative
RPR112378 previously reported in the patent literature by a research
^
group at Rhone-Poulenc Rorer (now Sanofi-Aventis); see: Leboul, J.;
Provost, J. French patent WO96/00205, 1996 [Chem. Abstr. 1996, 124,
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G. L. Helv. Chim. Acta 2011, 94, 105–110.
(4) Interaction of this electrophilic 4-methylene-2-cyclohexenone
chromophore with biological systems remains unexplored as this moiety
is rarely reported. (a) Murray, D. F.; Baum, M. W.; Jones, M. J. Org.
Chem. 1986, 51, 1–7. (b) Jung, M. E.; Rayle, H. L. Synth. Commun. 1994,
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651–654. (b) Luduena, R. F.; Roach, M. C. Biochemistry 1981, 20, 4444–
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r
10.1021/ol2029838
Published on Web 12/06/2011
2011 American Chemical Society

Scheme 1. Retrosynthesis
enyne/ring closing metathesis (RCM)12 and synthesis of
an AB ring of taxol13 and a taxa-oxa-sugar hybrid,14 using
a tandem enyne/IMDA reaction, we realized that it was
logical to use a tandem enyne/RCM15 to synthesize the
4-methylene-2-cyclohexenone moiety present in otteliones
and loloanolides. This strategy, if successful, could pave
the way to synthesize several simpler analogues of these
interesting natural products, in addition to their total
synthesis. It is also worth mentioning that the RCM
approach involving the triene intermediate of type 79 has
been utilized for the synthesis of otteliones and the present
approach will be using acetylene as a 2-butadienyl equiva-
lent. To check the feasibility of this approach, we initially
designed a few sugar-derived 4-methylene-2-cyclohexe-
nones 6, where a broad diversity could be introduced at
the sugar moiety. As per the retrosynthesis delineated in
Scheme 1, the proposed target scaffold 6 could be derived
from enyne 8 through a domino cross enyne metathesis
with ethylene followed by RCM and oxidation. Further,
enyne 8 could, in turn, be derived from D-glucose in a few
steps.
Figure 1. Otteliones A 2 and B 3, loloanolide B 4, and 1-O-
acetylloloanolide B 5.
stereochemistry of these molecules.7a Later, the same
group reported an enantioselective total synthesis and,
thus, determined the absolute configurations as well.7b
Since then, three more total syntheses8,9 and a few formal10
as well as partial syntheses11 for otteliones have been
reported.
Inspired by the biological and structural importance of
these molecules from the preliminary reports, we became
interested in the synthesis of these natural products.
Though our main goal has been to accomplish total
syntheses of these interesting natural products, our initial
goal was to develop an efficient approach to the construc-
tion of the more sensitive 4-methylene-2-cyclohexenone
framework. From our earlier reports on the synthesis
of angularly fused dioxatriquinanes involving tandem
Thus, our synthesis began with the stereoselective addi-
tion of lithium acetylide to the ketone 916 to afford tertiary
alcohol 10 (Scheme 2).17 Methylation of this tertiary
alcohol 10 with methyl iodide under basic conditions
afforded ether 11a in 96% yield. Selective removal of the
more exposed acetonide was carried out smoothly under
mild acidic conditions at room temperature to afford
(7) (a) Mehta, G.; Islam, K. Angew. Chem., Int. Ed. 2002, 41, 2396–
2398. (b) Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44, 6733–6736.
(8) (a) Mehta, G.; Islam, K. Org. Lett. 2002, 4, 2881–2884. (b) Araki,
H.; Inoue, M.; Katoh, T. Org. Lett. 2003, 5, 3903–3906. (c) Araki, H.;
Inoue, M.; Suzuki, T.; Yamori, T.; Kohno, M.; Watanabe, K.; Abe, H.;
Katoh, T. Chem.;Eur. J. 2007, 13, 9866–9881. (d) Chen, C. H.; Chen,
Y. K.; Sha, C. K. Org. Lett. 2010, 12, 1377–1379.
(12) Kaliappan, K. P.; Nandurdikar, R. S. Chem. Commun. 2004,
2506–2507.
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2006, 47, 981–984.
(14) Nandurdikar, R. S.; Subrahmanyam, A. V.; Kaliappan, K. P.
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3740. (b) Clive, D. L. J.; Liu, D. J. Org. Chem. 2008, 73, 3078–3087.
(10) For formal synthesis of otteliones, see: (a) Suzuki, T.; Ghozati,
K.; Katoh, T.; Sasai, H. Org. Lett. 2009, 11, 4286–4288. (b) Suzuki, T.;
Ghozati, K.; Zhou, D. Y.; Katoh, T.; Sasai, H. Tetrahedron 2010, 66,
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Hwang, G. S.; Ryu, D. H. Tetrahedron Lett. 2008, 49, 1965–1967.
(11) For partial synthesis of otteliones, see: (a) Mehta, G.; Reddy,
D. S. Chem. Commun. 1999, 2193–2194. (b) Trembleau, L.; Patiny, L.;
Ghosez, L. Tetrahedron Lett. 2000, 41, 6377–6381. (c) Mehta, G.; Islam,
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126, 15074–15080. For recent reviews on an enyne metathesis based
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Org. Lett., Vol. 14, No. 1, 2012
199

(generated in situ from Me3SI by treatment with n-BuLi in
THF at À10 °C) to furnish enyne 8a.
Scheme 2. Synthesis of Enyne 8
With a sufficient quantity of enyne 8a in hand, the stage
was now set for the execution of the key tandem enyne/
RCM sequence. Accordingly, when enyne 8a was sub-
jected to cross enyne metathesis with ethylene gas (1 atm)
in the presence of Grubbs’ second generation catalyst 15
(8 mol%), inrefluxingCH2Cl2, pleasingly the desired enyne/
RCM product was obtained in excellent yield through the
triene intermediate 7, which could not be isolated. Finally,
oxidation of alcohol 14a with DessÀMartin periodinane
delivered the targeted 4-methylene-2-cyclohexenone deriv-
ative 6a (Scheme 3). To show the diversity, alcohol 10 was
protected with different alkylating agents under similar
conditions to afford ethers 11bÀd in good yields. Further,
Scheme 4. Synthesis of Diol 19
Scheme 3. Tandem Enyne/RCM
Scheme 5. Tandem Enyne/RCM
diol 12a. Monotosylation of the primary alcohol using
tosyl chloride, followed by treatment with NaOMe,
provided the epoxide 13a in good yield. The epoxide 13a was
then readily opened with trimethylsulfonium ylide18
(18) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Gall,
T. L.; Shin, D. S.; Falck, J. R. Tetrahedron Lett. 1994, 35, 5449–5452.
200
Org. Lett., Vol. 14, No. 1, 2012

the same sequence described for 6a was extended to synthe-
size other scaffolds 6bÀd, starting from 11bÀd in good
yields.
dienol 22 was obtained in very good yield. Subsequent
oxidation of allylic alcohol with DMP afforded the key
4-methylene-2-cyclohexenone 23.
Having completed the construction of cis-fused
4-methylene-2-cyclohexenone frameworks 6aÀd, we then
planned to extend this strategy to the synthesis of trans-
fused scaffold23. To this end, the ketone 9 was subjected to
Wittig olefination and hydroboration/oxidation to afford
alcohol 16 (Scheme 4). Swern oxidation of 16 followed by
homologation using the CoreyÀFuchs protocol and sub-
sequent treatment with n-BuLi afforded the alkyne 18.
Selective removal of the acetonide afforded the diol 19.
Selective tosylation of the primary alcohol of 19 and
subsequent base mediated intramolecular nucleophilic dis-
placement afforded the epoxide 20 (Scheme 5). The ep-
oxide opening with concurrent formation of a double bond
furnished the key metathesis precursor 21.
In conclusion, we have outlined a simple and efficient
strategy for the construction of the 4-methylene-2-cyclo-
hexenone framework using a tandem enyne/RCM se-
quence. It is worth mentioning that the importance of this
work lies in the fact that this strategy can be employed for
the synthesis of a large number of analogues starting from
diverse sugar units.
Acknowledgment. K.P.K. thanks DST for the award of
the Swarnajayanti fellowship. V.V.B and S.P. thank CSIR,
New Delhi for the fellowship.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Following the same sequence of reactions involving
a tandem cross enyne metathesis/RCM, the trans-fused
Org. Lett., Vol. 14, No. 1, 2012
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