A short synthetic route to the core structures of otteliones A and B

Article abstract of DOI:10.1016/j.tetlet.2005.06.021

Conjugate addition of the cuprate derived from 2-lithio-2,3-butadiene to 1-cylopentenecarbaldehyde, reaction with vinylmagnesium bromide, ring closing metathesis, and oxidation gives the cis-ring fused core of the anticancer agent ottelione A. Epimerization of the initial conjugate addition product and application of the same reactions as used for the ottelione A core, give the trans-ring fused core of ottelione B.

Full text of DOI:10.1016/j.tetlet.2005.06.021

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5305–5307
A short synthetic route to the core structures of otteliones A and B
Derrick L. J. Clive* and Dazhan Liu
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
Received 8 May 2005; accepted 7 June 2005
Abstract—Conjugate addition of the cuprate derived from 2-lithio-2,3-butadiene to 1-cylopentenecarbaldehyde, reaction with vinyl-
magnesium bromide, ring closing metathesis, and oxidation gives the cis-ring fused core of the anticancer agent ottelione A. Epi-
merization of the initial conjugate addition product and application of the same reactions as used for the ottelione A core, give
the trans-ring fused core of ottelione B.
Ó 2005 Elsevier Ltd. All rights reserved.
Ottelione A (1)1–3 and ottelione B (2)1 are notably pow-
erful antitumor agents isolated in small amounts (each
0.0009% of dry weight)1 from a fresh water plant called
Ottelia alismoides whose native range is east Asia and
southeast Asia to Australia.4 Ottelione A shows GI50
values (50% growth inhibition) against many tumor cell
lines of <100 pm,1–3 while ottelione B was found to have
GI50 values of <1 nm.1 Total growth inhibition was ob-
served against several cell lines, again in the pm to nm
range.1 Ottelione A is an inhibitor of tubulin polymeri-
zation.3 The structures of the two compounds were de-
duced1–3 from very detailed NMR analyses but, while
the relative stereochemistry of ottelione B was fully
assigned,1 that for ottelione A1,3 had to await total synthe-
sis5 before a firm decision could be made.
it would be advisable to begin by making the core struc-
ture 3 so as to evaluate its properties, the expectations
being, of course, that the compound might be sensitive
to isomerization to the indane 4, and that an examina-
tion of the properties of 3 would be helpful in any at-
tempt at total synthesis of the actual natural product.
OH
4
Although those early experiments6 did indeed lead to
3, it so happened that immediately after submitting the
work for publication, a paper by Mehta and Islam ap-
peared5 in which the first route to ( )-ottelione B was
described. Key features of that route were formation
of ( )-ottelione A and the finding that the compound
could be isomerized efficiently to the trans isomer (ottel-
ione B). In the light of this publication, it did not seem
appropriate to continue our own studies. Several
months later, the same authors,7 and also Katoh and
co-workers,8 independently described syntheses of opti-
cally active natural otteliones A and B; both approaches
were again based on the cis!trans isomerization of ott-
elione A (Scheme 1).9 Mehta and Islam7 carried out this
crucial step by using DBU in PhH at 65 °C. Katoh and
co-workers found8 (at least in their preliminary experi-
ments) that under these conditions a 1:1 mixture of the
two otteliones is formed; they were, however, able to
effect isomerization using t-BuOK in t-BuOH, although
isolation of the desired product from the resulting 23:77
OMe
OH
OMe
OH
O
4
O
O
H
H
H
3
3a
7a
1
H
H
H
1
2
3
Several years ago, work was begun in this laboratory on
the synthesis of ottelione B. At that time it was felt that
Keywords: Ottelione A; Ottelione B; Ring closing metathesis; Synthe-
sis; Core structure; Anticancer activity.
*
Corresponding author. Tel.: +1 7804923251; fax: +1 7804928231;
e-mail: derrick.clive@ualberta.ca
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.021

5306
DerrickL. J. Clive, D. Liu / Tetrahedron Letters 46 (2005) 5305–5307
DBU, PhH, 65 ˚C
synthetic ottelione A
[α]D 19.2 (c 0.52, CHCl3)
synthetic ottelione B (83%)
[α]D -250 (c 0.24, CHCl3)
reference 7
OMe
OH
OMe
O
O
H
H
OH
H
H
t-BuOK, t-BuOH, 79%
of a 23:77 mixture of
otteliones A & B
1
2
synthetic ottelione B (23%)
[α]D -333 (c 0.18, CHCl3)
synthetic ottelione A
[α]D 17.3 (c 0.55, CHCl3)
reference 8
Scheme 1.
ottelione A/ottelione B mixture required HPLC separa-
tion. It would appear that the cis!trans isomerization is
not straightforward, and so further synthetic work on
the otteliones can be justified, especially in view of their
exceptional anticancer1–3 potency. Therefore, we have
taken up this project again and report here a simple
method for making the two core structures 3 and 5.
The cis isomer 5 was prepared first.
A cursory examination was made of the possibility of
equilibrating the cis and trans isomers. The cis isomer
appeared to be inert to the action of DBU in CH2Cl2
(room temperature, 48 h), or at reflux in DME (12 h)
or PhMe (12 h). Conversely, the trans isomer 3 was con-
verted to only a small extent (<10%), if at all, by warm-
ing with TsOHÆH2O in THF.6 Deprotonation with
LDA, and reprotonation appeared to give a 77:23 mix-
ture in favor of the trans isomer. The selectivity among
the double bonds in the two ring closing metathesis reac-
tions is precedented14 but, in the case of 12, it was not
clear what influence the trans disposition of the pen-
dants might have; fortunately, the conversion to 13 does
Our route begins with the readily available10 aldehyde 6.
The compound was subjected to conjugate addition with
the organocuprate 7, itself prepared from lithium 2-
thienylcyanocuprate (THF solution) and 2-lithio-1,3-
butadiene, which were generated by Shapiro reaction11,12
on the 2,4,6-tri-ispopropylbenzenesulfonyl hydrazone of
methyl vinyl ketone. The conjugate addition13 produced
in modest yield (68%) a mixture of isomers that was
largely (ca. 95%) the cis compound 8. When the crude
material was treated with vinylmagnesium bromide, it
was possible to isolate triene 9 (73%) as a single isomer.
The stereochemistry at C-4 (ottelione numbering) was
not established, as that center is subsequently converted
to sp2 hybridization. The triene underwent smooth ring
closing metathesis14 (78%) in the presence of 5 mol %
Grubbs I catalyst at room temperature to afford the
single alcohol 10. Finally, Dess–Martin oxidation gave
515—the core of ottelione A.
OHC
S
7
6
Cu(CN)Li2
68%
OHC
OHC
DBU, CH2Cl2, 48 h
11 (ca 85% trans)
8 (ca 95% cis)
73%
67%
OH
MgBr
MgBr
O
H
OH
4
4
H
5
9
12
Grubbs I,
CH2Cl2,
Grubbs I,
CH2Cl2,
In order to produce the isomeric trans-ring fused com-
pound 3, the adduct from the conjugate addition was
isomerized by prolonged treatment (48 h) with DBU at
room temperature (8!11). This experiment afforded a
material that was highly enriched in the trans isomer
11 (ca. 85% trans), and reaction with vinylmagnesium
bromide allowed isolation (67%) of a mixture of the
trans alcohols 12, epimeric at C-4. Without separation,
these were treated with the Grubbs I catalyst (12!13),
and the resulting alcohols,16 were converted efficiently
by Dess–Martin oxidation into 317—the core of otteli-
one B.
24 h, 78%
24 h, 83%
OH
OH
10
13
Dess-Martin,
CH2Cl2, 92%
Dess-Martin,
CH2Cl2, 92%
5
3
Scheme 2.

DerrickL. J. Clive, D. Liu / Tetrahedron Letters 46 (2005) 5305–5307
5307
2193–2194; (b) Trembleau, L.; Patiny, L.; Ghosez, L.
Tetrahedron Lett. 2000, 41, 6377–6381; (c) Mehta, G.;
Islam, K. Synlett 2000, 1473–1475; (d) Mehta, G.; Islam,
K. Org. Lett. 2002, 4, 2881–2884; (e) Araki, H.; Inoue, M.;
Katoh, T. Synlett 2003, 2401–2403.
not involve any seriously strained intermediate, and the
yield is satisfactory.
The approach of Scheme 2 is very simple and, in princi-
ple, it should be applicable to other ottelione analogs,
but we have not (yet) demonstrated this.
10. Kozikowski, A. P.; Tuckmantel, W. J. Org. Chem. 1991,
56, 2826–2837.
¨
11. (a) Brown, P. A.; Jenkins, P. R. J. Chem. Soc., Perkin
Trans. 1 1986, 1129–1131; (b) Brown, P. A.; Jenkins, P. R.
Tetrahedron Lett. 1982, 23, 3733–3734; Cf. (c) Chamber-
lin, A. R.; Stemke, J. E.; Bond, F. T. J. Org. Chem. 1978,
43, 147–154.
12. 2-Lithio-1,3-butadiene is also available from 2-chloro-1,3-
butadiene: Wada, E.; Kanemasa, S.; Fujiwara, I.; Tsuge,
O. Bull. Chem. Soc. Jpn. 1985, 58, 1942–1945.
13. Cf. Kende, A. S.; Jungheim, L. N. Tetrahedron Lett. 1980,
21, 3849–3852.
Acknowledgments
We thank the Natural Sciences and Engineering Re-
search Council of Canada for financial support. D.L.
holds a Province of Alberta Graduate Fellowship. We
thank Dr. Stephen Fletcher for the isomerization studies
with 5.
14. Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62,
7310–7318.
15. Compound 5 had: FTIR (CH2Cl2 cast) 2953, 2871, 1664,
References and notes
1. Ayyad, S.-E. N.; Judd, A. S.; Shier, W. T.; Hoye, T. R.
J. Org. Chem. 1998, 63, 8102–8106.
906 cmꢀ1 1H NMR (500 MHz, CDCl3) d 1.53–1.66 (m,
;
3H), 1.85–1.93 (m, 2H), 2.20–2.25 (m, 1H), 2.76 (dd,
J = 7.8, 11.3 Hz, 1H), 3.06 (dd, J = 7.8, 16.3 Hz, 1H), 5.37
(d, J = 5.8 Hz, 2H), 5.92 (d, J = 5.8 Hz, 1H), 6.97 (d,
J = 9.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 200.8 (s),
145.5 (d), 143.4 (s), 126.6 (d), 120.4 (t), 49.2 (d), 44.4 (d),
33.6 (t), 27.7 (t), 23.0 (t); exact mass m/z calcd for C10H12O
148.08882, found 148.08852.
2. Leboul, J.; Provost, J. WO 96/00205.
3. Combeau, C.; Provost, J.; Lancelin, F.; Tournoux, Y.;
Prudꢀhomme, F.; Herman, F.; Lavelle, F.; Leboul, J.;
Vuilhorgne, M. Mol. Pharmacol. 2000, 57, 553–563.
4. Cook, C. D. K.; Urmi-Ko¨nig, K. Aquat. Bot. 1984, 20,
131–177.
5. Mehta, G.; Islam, K. Angew. Chem., Int. Ed. 2002, 41,
2396–2398.
6. Clive, D. L. J.; Fletcher, S. P. J. Chem. Soc., Chem.
Commun. 2002, 1940–1941.
16. The material was a mixture of a and b isomers in a 73:27
ratio, the a-alcohol being identified by spectral compar-
ison with the sample described in Ref. 6.
1
17. Compound 3 had: H NMR (500 MHz, CDCl3) d 1.66–
7. Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44, 6733–
6736.
8. Araki, H.; Inoue, M.; Katoh, T. Org. Lett. 2003, 5, 3903–
3906.
9. For other synthetic work related to otteliones, see: (a)
Mehta, G.; Srinivasa Reddy, D. Chem. Commun. 1999,
1.71 (m, 1H), 1.75–1.82 (m, 3H), 1.93–1.98 (m, 1H), 2.03–
2.07 (m, 1H), 2.38–2.43 (m, 1H), 2.53–2.58 (m, 1H), 5.24
(s, 1H), 5.33 (s, 1H), 5.96 (d, 1H, J = 9.6 Hz), 7.05 (d, 1H,
J = 9.6 Hz); 13C NMR (125 MHz, CDCl3) d 201.3 (s),
147.1 (d), 145.5 (s), 128.8 (d), 116.4 (t), 54.1 (d), 47.6 (d),
27.6 (t), 23.3 (t), 21.6 (t).