Enantioselective total synthesis of eurylene, 14-deacetyl eurylene, and their 11-epimers: The relation between lonophoric nature and cytotoxicity

Article abstract of DOI:10.1021/ol036471i

(Equation presented) Enantioselective synthesis of eurylene, 14-deacetyl eurylene, and their 11-epimers was achieved. The characteristic structural feature of these compounds is two tetrahydrofuran (THF) rings substituted in different stereochemistry. The

Full text of DOI:10.1021/ol036471i

ORGANIC
LETTERS
2004
Vol. 6, No. 6
961-964
Enantioselective Total Synthesis of
Eurylene, 14-Deacetyl Eurylene, and
Their 11-Epimers: The Relation between
Ionophoric Nature and Cytotoxicity
Hideaki Hioki,† Suzuyo Yoshio,† Masatoshi Motosue,† Yuka Oshita,†
,†
Yukari Nakamura,† Daisaku Mishima,† Yoshiyasu Fukuyama,† Mitsuaki Kodama,*
Keisuke Ueda,‡ and Takashi Katsu‡
Faculty of Pharmaceutical Sciences, Tokushima Bunri UniVersity, Yamashiro-cho,
Tokushima 770-8514, Japan, and Faculty of Pharmaceutical Sciences,
Okayama UniVersity, Tsushima, Okayama 700-8530, Japan
kodama@ph.bunri-u.ac.jp
Received December 19, 2003
ABSTRACT
Enantioselective synthesis of eurylene, 14-deacetyl eurylene, and their 11-epimers was achieved. The characteristic structural feature of these
compounds is two tetrahydrofuran (THF) rings substituted in different stereochemistry. The synthetic approach involves nonstereoselective
THF ring formation to afford both segments from a common precursor. We also investigated their ionophoric nature and cytotoxicity. The
complexation of these compounds with K+ might be related to their cytotoxic activity.
Eurylene (1) and 14-deacetyl eurylene (2), shown in Figure
1, are triterpene polyethers isolated by Itokawa et al. from
2, and modified Mosher’s method. Because of the unique
squalenoid polyether structures and biological activity (vide
infra), synthetic studies were performed by various groups2
and total syntheses of 1 by Ujihara et al.2c and of 2 by
Morimoto et al.2d have been accomplished. In addition to
the structure of 1 and 2, Itokawa et al. discussed the relation
between the cytotoxic activity and conformation of these
triterpene polyethers on the basis of the findings that 1 has
an extended conformation with essentially no cytotoxic
activity (IC50 for KB cell: >100 µg/mL), whereas 2, as well
as longilene peroxide and teurilene, has a folded conforma-
Figure 1. The structures of eurylene derivatives.
(1) (a) Itokawa, H.; Kishi, E.; Morita, H.; Takeya, K.; Iitaka, Y.
Tetrahedron Lett. 1991, 32, 1803-1804. (b) Itokawa, H.; Kishi, E.; Morita,
H.; Takeya, K.; Iitaka, Y. Chem. Lett. 1991, 2221-2222. (c) Morita, H.;
Kishi, E.; Takeya, K.; Itokawa, H.; Iitaka, Y. Phytochemistry 1993, 34,
765-771.
(2) For previous synthetic studies of eurylene, see: (a) Gurjar, M. K.;
Saha, U. K. Tetrahedron Lett. 1993, 34, 1833-1836. (b) Molander, G. A.;
Swallow, S. J. Org. Chem. 1994, 59, 7148-7151. (c) Ujihara, K.;
Shirahama, H. Tetrahedron Lett. 1996, 37, 2039-2042. (d) Morimoto, Y.;
Muragaki, K.; Iwai, T.; Morishita, Y.; Kinoshita, T. Angew. Chem., Int.
Ed. 2000, 39, 4082-4084.
the wood of Eurycoma longifolia together with longilene
peroxide and teurilene.1 The structures of 1 and 2 were
determined on the basis of spectroscopic analysis, X-ray
crystallographic analysis of 1, which was directly related to
† Tokushima Bunri University.
‡ Okayama University.
10.1021/ol036471i CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/24/2004

tion and possesses potent cytotoxicity (IC50 of 2 for KB
cell: 0.52 µg/mL).1c Morimoto et al. suggested that the
cytotoxic activities of 2, longilenperoxide, and teurilene are
caused by their ionophoric nature, that is, their ability to bind
physiologically important divalent metal cations such as
Mg2+ and Ca2+.3 There has been no experimental evidence,
however, for this assumption.
Scheme 2 Nonstereoselective THF Ring Formationa
In the course of our synthetic studies of natural products
using bakers’ yeast reduction as the chirality induction
method,4 we achieved enantioselective synthesis of 2, which
was transformed into 1 by Morimoto’s group.2d In addition
to 1 and 2, their epimers at C-11 (3 and 4) were also
simultaneously available from our synthesis. Therefore, we
attempted to clarify the relation of the ionophoric complexing
nature with cytotoxic activity. Our retrosynthetic analysis is
illustrated in Scheme 1. Disconnection of the target molecules
a Reagents and conditions: (a) VO(acac)2, t-BuOOH, benzene;
(b) mCPBA, rt, CH2Cl2.
Scheme 1. Retrosynthetic Analysis of Eurylene
and 8 in almost equal amounts. The stereochemistry of these
products was determined by NOE experiments (shown by
the arrows in the structures). After the more polar product 7
was converted to 9 by sequential deprotection and protection
of the resulting diol, the acetonide 9 was treated with
prenylmagnesium chloride in the presence of cuprous iodide
to yield the alcohol 10 in high yield. The acetonide protecting
group in 10 was hydrolyzed and the resulting diol was
cleaved to give the aldehyde 11, which was further oxidized
and esterified to give 12, the left-half segment (Scheme 3).
Scheme 3. Synthesis of the Left-Half Segmenta
at the central part leads to two C-15 segments A and B. These
diastereomeric segments are readily accessible from a
common precursor, such as C, by the nonstereoselective THF
ring formation followed by addition of a prenyl group.
7 and 8 were prepared from common precursor 6 (Scheme
2). The (R)-allylic alcohol 5, obtained in more than 99% ee
by using bakers’ yeast reduction,4a was first converted into
the epoxide 6 in 86% diastereomeric excess. Treatment of 6
with mCPBA afforded, as desired, two THF derivatives 7
a Reagents and conditions: (a) n-Bu4NF, THF; (b) DMP, PPTS,
CH2Cl2; (c) Me2CdCHCH2MgCl, CuI, THF, -15 to 0 °C; (d)
PPTS, EtOH; (e) NaIO4, aq THF; (f) NaClO2, 2-methyl-2-butene,
NaH2PO4, aq t-BuOH; (g) MeI, K2CO3, DMF; (h) TMSCl, Imid,
DMF.
(3) Morimoto, Y.; Iwai, T.; Yoshimura, T.; Kinoshita, T. Bioorg. Med.
Chem. Lett. 1998, 8, 2005-2010.
(4) (a) Kodama, M.; Minami, H.; Mima, Y.; Fukuyama, Y. Tetrahedron
Lett. 1990, 31, 4025-4026. (b) Kodama, M.; Yoshio, S.; Yamaguchi, S.;
Fukuyama, Y.; Takayanagi, H.; Morinaka, Y.; Usui, S.; Fukazawa, Y.
Tetrahedron Lett. 1993, 34, 8453-8456. (c) Kodama, M.; Matsushita, M.;
Terada, Y.; Takeuchi, A.; Yoshio, S.; Fukuyama, Y. Chem. Lett. 1997, 117-
118. (d) Kodama, M.; Yoshio, S.; Tabata, T.; Deguchi, Y.; Sekiya, Y.;
Fukuyama, Y. Tetrahedron Lett. 1997, 38, 4627-4630. (e) Hioki, H.; Ooi,
H.; Hamano, M.; Mimura, Y.; Yoshio, S.; Kodama, M.; Ohta, S.; Yanai,
M.; Ikegami, S. Tetrahedron 2001, 57, 1235-1246. (f) Hioki, H.; Kanehara,
C.; Ohnishi, Y.; Umemori, Y.; Sakai, H.; Yoshio, S.; Matsushita, M.;
Kodama, M. Angew. Chem., Int. Ed. 2000, 39, 2552-2554. (g) Hioki, H.;
Hamano, M.; Kubo, M.; Uno, T.; Kodama, M. Chem. Lett. 2001, 898-
899.
In a similar way, the less polar product 8 was transformed
into the diol 14 through the acetonide 13 in 56% overall
yield. The diol 14 was selectively converted into mono-
mesylate, which was treated with base to yield the epoxide
15. The lithio-anion of methylphenyl sulfone (2.5 mol equiv)
was then reacted with 15 and two hydroxy groups were
962
Org. Lett., Vol. 6, No. 6, 2004

1
protected by the p-methoxyphenylmethyl (MPM) group and
trimethylsilyl (TMS) groups to complete the synthesis of the
right-half segment 16 (Scheme 4).
respectively. The H and 13C NMR spectra of synthetic 1
and 2 were in excellent agreement with those of the natural
products.
Following the synthesis of the four eurylene derivatives
1-4, we studied the relationship between their ion transport
abilities and cytotoxic activity. The ionophoric nature was
evaluated in combination with ion-selective electrodes and
liposomes.5,6 In the present study, K+,7 Na+,8 and Ca2+
electrodes9 were used to simultaneously monitor the move-
ment of ions across the liposomal membrane composed of
egg phosphatidylcholine. The results are shown in Table 1
Scheme 4. Synthesis of the Right-Half Segmenta
Table 1. Relation between Ion Transport Ability and Cytotoxic
Activity of Eurylene Derivatives
ion transport
abilitya (%)
b
IC50
compd
K+ Na+ Ca2+
(µg/mL)
nonactin
valinomycin
eurylene (1)
14-deacetyl eurylene (2)
11-epi-eurylene (3)
11-epi-14-deacetyl eurylene (4) 23
40
38
1
14
7
24
7
0
2
1
8
4
0
1
0
2
>100
a Reagents and conditions: (a) n-Bu4NF, THF; (b) DMP, PPTS,
CH2Cl2; (c) Me2CdCHCH2MgCl, CuI, THF, -15 to 0 °C; (d)
PPTS, EtOH; (e) MsCl, Py; (f) K2CO3, MeOH; (g) MeSO2Ph,
n-BuLi, DMPU, THF, -78 to 0 °C; (h) MPMCl, NaH, DMF; (i)
TMSCl, Imid, DMF.
13.6 ( 1.7
8.9 ( 2.3
14.1 ( 2.1
2
a Expressed as percentage transported for 3 min. See Supporting
Information for detailed experimental conditions. b IC50 (inhibitory con-
centration 50): values represent the drug concentration ((SD) required to
reduce cell growth by 50% with respect to untreated controls.
A coupling reaction of the lithio-anion of 16 and 12
proceeded smoothly as shown in Scheme 5. After reductive
desulfonylation and deprotection of the TMS group, ketone
17 was obtained in high yield. Reduction of 17 with NaBH4
(95%) or DIBAH (91%) afforded an ca. 1:1 mixture of
epimeric alcohols. Because these alcohols were difficult to
separate, the mixture was acetylated and then separated to
provide pure 18 and 19. On deprotection of the MPM group,
18 and 19 afforded 14-deacetyl eurylene (2), mp 63.5-65
°C (lit.1c mp 63-65 °C), [R]19.3 +6.4 (lit. [R]19.3 +6;1c
together with those for nonactin and valinomycin, well-
known ionophores.10 Eurylene (1) had essentially no ability
to transport any ions, while the other derivatives 2-4 acted
as K+-selective ionophores. In particular, 2 and 4 had strong
K+ transport ability, though the effects were weaker than
that of valinomycin, a typical K+-selective ionophore. The
cytotoxic activities of compounds 1-4 on KB cells are
shown in Table 1. Although 14-deacetyl eurylene (2) had
over 20 times less activity than the reported value, the
structure and activity relation between 1 and 2 are compa-
rable to the reported data.1c 11-epi-Eurylene (3) exhibited
higher cytotoxicity in contrast to 1. The results show that
D
D
+6.022d), and its epimer 4, oil, [R]19.3D +26.0, respectively.
Acetylation of 2 and 4 afforded eurylene (1), mp 149.5-
150.0 °C (lit.1a mp 146-148 °C), [R]17.9D +8.1 (lit. [R]17.9
D
+4;1a,2c +4.862d), and its epimer 3, oil, [R]17.2 +31.2,
D
Scheme 5. Synthesis of Eurylene, 14-Deacetyl Eurylene, and Their 11-Epimersa
a Reagents and conditions: (a) LHMDS, DMPU, THF, -78 to -30 °C; (b) SmI2, THF-MeOH (5:1), -78 °C; (c) 1 M HCl, MeOH; (d)
NaBH4, MeOH; (e) Ac2O, Py, 50 °C; (f) DDQ, CH2Cl2-NaHCO3 (10:1).
Org. Lett., Vol. 6, No. 6, 2004
963

the stereochemistry at C-11 has an important role in the
cytotoxicity.11 On the other hand, the activity of 11-epi-14-
deacetyl eurylene (4) was comparable to that of its 11-epimer
(2). Some cytotoxic natural products involving the THF ring
selectively form strong complexes with Ca2+.12 The bio-
activity is postulated to be responsible for the metal ion
complexation, which supports the idea that the cytotoxic
activity of 2 might be due to its ionophoric nature.3 Our
results, however, demonstrated that cytotoxic compounds
2-4 are not Ca2+ ionophores but rather K+ ionophores. The
complexation with K+ might be related to the cytotoxic
activity.13 The 11-epi-eurylene (3), however, had the most
potent activity despite less ability to transport K+ compared
to 14-deacetyl derivatives 2 and 4.
In conclusion, we completed the total asymmetric synthesis
of four eurylene derivatives, 1-4. Investigation of their
ionophoric nature and cytotoxicity revealed K+ ionophoric
activity in the cytotoxic compounds 2-4.
(5) Barsukov, L. I.; Shkrob, A. M.; Bergel’son, L. D. Biophysics 1972,
17, 1032-1036.
(6) Katsu, T.; Nakashima, K. Analyst 1999, 124, 883-886.
(7) Katsu, T.; Kobayashi, H.; Fujita, Y. Biochim. Biophys. Acta 1986,
860, 608-619.
(8) Suzuki, K.; Sato, K.; Hisamoto, H.; Siswanta, D.; Hayashi, K.;
Kasahara, N.; Watanabe, K.; Yamamoto, N.; Sasakura, H. Anal. Chem. 1996,
68, 208-215.
(9) Katsu, T.; Nakagawa, H.; Yasuda, K. Antimicrob. Agents Chemother.
2002, 46, 1073-1079.
(10) Pressman, B. C. Annu. ReV. Biochem. 1976, 45, 501-530.
(11) To investigate the conformational difference between 1 and 3, a
Monte Carlo conformational search was performed employing the MM2
force field that is included with MacroModel software (v. 6.0). There was
no significant conformational difference. The low-energy conformations
of 1 and 3 are mainly folded conformations.
(12) (a) Sasaki, S.; Naito, H.; Maruta, K.; Kawahara, E.; Maeda, M.
Tetrahedron Lett. 1994, 35, 3337-3340. (b) Peyrat, J.-F.; Figadere, B.;
Cave, A.; Mahuteau, J. Tetrahedron Lett. 1995, 36, 7653-7656. (c) Peyrat,
J.-F.; Mahuteau, J.; Figadere, B.; Cave, A. J. Org. Chem. 1997, 62, 4811-
4815. (d) Sasaki, S.; Maruta, K.; Naito, H.; Maemura, R.; Kawahara, E.;
Maeda, M. Tetrahedron 1998, 54, 2401-2410.
Acknowledgment. We thank Dr. Toshihiro Noguchi
(Sumitomo Pharmaceuticals Co., Ltd., Japan) for the cyto-
toxicity testing and Prof. Koich Takeya (Tokyo University
of Pharmacy and Life Science, Japan) for the NMR spectra
of natural 14-deacetyl eurylene.
Supporting Information Available: Experimental condi-
tions and spectral data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL036471I
(13) Nonactin and valinomycin exhibited cytotoxicity against KB cells,
see: Otake, N.; Sasaki, T. Agric. Biol. Chem. 1977, 41, 1039-1047.
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