A short and efficient total synthesis of (±)-ascofuranone

Article abstract of DOI:10.1246/cl.2010.622

Ascofuranone is a potent inhibitor of trypanosome alternative oxidase. A short and efficient total synthesis of (±)-ascofuranone was accomplished in only seven steps starting with geranyl acetate. The synthetic concept and methodology described in detail

Full text of DOI:10.1246/cl.2010.622

doi:10.1246/cl.2010.622
622
Published on the web May 15, 2010
A Short and Efficient Total Synthesis of («)-Ascofuranone
Yasushi Haga,1 Takayuki Tonoi,2 Yoshihide Anbiru,1 Yuki Takahashi,1 Sayuri Tamura,1 Masaichi Yamamoto,3
Shinsuke Ifuku,1 Minoru Morimoto,2 and Hiroyuki Saimoto*1
1Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Koyama, Tottori 680-8552
2Research Center for Bioscience and Technology, Tottori University, Koyama, Tottori 680-8552
3aRigen Pharmaceuticals, Inc., Akasaka, Minato-ku, Tokyo 107-0052
(Received March 16, 2010; CL-100249; E-mail: saimoto@chem.tottori-u.ac.jp)
Ascofuranone is a potent inhibitor of trypanosome alter-
native oxidase. A short and efficient total synthesis of
(«)-ascofuranone was accomplished in only seven steps starting
with geranyl acetate. The synthetic concept and methodology
described in detail here provide a short and simple synthesis for
ascofuranone and its derivatives.
O
OH
O
X
+
1
3
X= leaving group
OH
O
Cl
2
3
OH
AcO
O
O
4
Ascofuranone (1), one of many natural phenolic com-
pounds1 in the fungus Ascochyta viciae, was first isolated in
1972 (Figure 1).2 It has received considerable attention because
of its biological activity as an antitumor protective,3 hypolipi-
demic,4 and differentiation-inducing agent.5 In addition, Kita
et al. recently found that ascofuranone is potentially a strong
inhibitor of trypanosome alternative oxidase (TAO).6 TAO is a
terminal oxidase in the unique respiratory system of African
trypanosomes. These protozoan parasites cause African trypan-
osomiasis in human and animals, and are transmitted by tsetse
flies. Since TAO is specific to the African trypanosomes and
does not exist in mammalian hosts, it is a potent target for
chemotherapy of trypanosomiasis by ascofuranones. This
necessitates the development of a shorter and simpler synthesis
of ascofuranone than our previous synthesis.
To date, several synthetic methods have been reported for
ascofuranone. However, these methods are somewhat compli-
cated and involve multiple steps.7 We have previously reported a
12-step synthesis for («)-ascofuranone and related compounds.8
For convergent synthesis of («)-ascofuranone, it is rational to
split the compound into the aromatic ring and prenyl side chains.
Consequently, to achieve total synthesis of ascofuranone, the
aromatic moiety needs to be connected to the prenyl side chain,
with or without phenolic protection. In our previous synthesis,
for the aromatic moiety we employed a resorcinol derivative
with an ester group, and hydroxy groups protected by 2-
(trimethylsilyl)ethoxymethyl (SEM).8b Protection-deprotection
of the phenolic hydroxys and transformation of the ester group
into the formyl group hampered the synthetic efficiency. In this
study, we have reduced the protection and deprotection protocols
in our synthetic strategy in view of improving the synthetic
efficiency. Herein, we report the details of a short and simple
total synthesis of («)-ascofuranone.
O
AcO
AcO
5
geranyl acetate
Scheme 1. Retrosynthetic analysis of («)-ascofuranone (1).
Table 1. Direct coupling of phenol derivatives 2 with allyl
bromidesa
O
OH
O
OH
H
n
Br
H
n
KOH (1.4 equiv)
MeOH, –40 °C
OH
OH
Cl
Cl
2
Entry
n
Additives
Yield/%b
1
2
2
1
1
®
CaCl2 (0.7 equiv)
®
28
44
25
35
2
3c
4
CaCl2 (0.7 equiv)
aReaction conditions: 2 (0.54 mmol), allyl bromide (0.64
mmol), KOH (0.76 mmol), CaCl2 (0.38 mmol), and MeOH
(1.0 mL). Isolated yields. 10% KOH(aq), 0 °C (Ref. 7b).
b
c
Our rationalized synthesis of («)-ascofuranone primarily
involves preparation of the prenyl side chain precursor bearing a
furanone ring, and coupling of this with the aromatic moiety.
The retrosynthetic analysis is depicted in Scheme 1. Direct
coupling of the aromatic 2, without phenolic protection, and
prenyl side chain 3 affords 1. In this step, the phenolate
presumably reacts via an SN2 reaction with prenyl side chain 3,
which has good leaving groups such as halides and sulfo-
nates.7b,9 Prenyl side chain precursor 3 is accessible from
pivaloyl ester 4 via Ag(I)-catalyzed rearrangement and cycliza-
tion10 followed by displacement of a leaving group. Pivaloyl
ester 4 is easily obtained from commercially available geranyl
acetate by allylic oxidation and carbon chain extension reaction.
First, we investigated the effect of a calcium reagent
(CaCl2/KOH) on the direct coupling of pentasubstituted
benzene 2 with allyl bromides in methanol (Table 1). With
addition of CaCl2 the reaction yields of hexasubstituted
benzenes were improved, and only the desired products were
O
OH
O
*
OH
O
Cl
Figure 1. Structure of («)-ascofuranone (1).
Chem. Lett. 2010, 39, 622-623
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

623
OH
a
b
c
5
4
AcO
AcO
54%
68%
97%
OH
geranyl acetate
AcO
6
g
O
O
d
e
O
f
Br
HO
1
34%
63%
92%
96%
7
8
9
O
O
O
O
Scheme 2. Total synthesis of («)-ascofuranone (1). Reagents and conditions: a) SeO2, EtOH, reflux; b) 2-methyl-3-butyn-2-ol (0.9
equiv), n-BuLi (2.0 equiv), THF, ¹50 °C; c) t-BuCOCl (2.2 equiv), DMAP, pyridine, CHCl3, 0 °C; d) AgBF4 (8 mol %), toluene, 80 °C;
e) NaOMe, MeOH, rt; f) CBr4 (2.5 equiv), (n-C8H17)3P, Et2O, 0 °C; g) 2 (0.8 equiv), CaCl2, KOH, MeOH, 0 °C.
1973, 26, 676.
synthesized without other by-products in both cases (Entries 2
and 4).11 In the reaction of phenolate with allyl bromide, CaCl2
acts as a Lewis acid to coordinate both molecules enough to
react.
3
4
a) J. Magae, T. Hosokawa, K. Ando, K. Nagai, G. Tamura,
J. Antibiot. 1982, 35, 1547. b) J. Magae, J. Hayasaki, Y.
Matsuda, M. Hotta, T. Hosokawa, S. Suzuki, K. Nagai, K.
Ando, G. Tamura, J. Antibiot. 1988, 41, 959.
a) M. Sawada, T. Hosokawa, T. Okutomi, K. Ando, J.
Antibiot. 1973, 26, 681. b) T. Hosokawa, K. Suzuki, T.
Okutomi, M. Sawada, K. Ando, Jpn. J. Pharmacol. 1975,
25, 35.
J. Magae, K. Nagai, K. Ando, G. Tamura, Agric. Biol. Chem.
1988, 52, 3143.
a) N. Minagawa, Y. Yabu, K. Kita, K. Nagai, N. Ohta, K.
Meguro, S. Sakajo, A. Yoshimoto, Mol. Biochem. Parasitol.
1997, 84, 271. b) C. Nihei, Y. Fukai, K. Kita, Biochim.
Biophys. Acta 2002, 1587, 234.
Synthesis of racemic form of ascofuranone: a) K. Mori, T.
Fujioka, Tetrahedron 1984, 40, 2711. b) K.-M. Chen, J. E.
Semple, M. M. Joullie, J. Org. Chem. 1985, 50, 3997.
Synthesis of (S)-form of ascofuranone: c) K. Mori, S.
Takechi, Tetrahedron 1985, 41, 3049. d) H. Saimoto, M.
Yasui, S. Ohrai, H. Oikawa, K. Yokoyama, Y. Shigemasa,
Bull. Chem. Soc. Jpn. 1999, 72, 279.
a) H. Saimoto, J. Ueda, H. Sashiwa, Y. Shigemasa, T.
Hiyama, Bull. Chem. Soc. Jpn. 1994, 67, 1178. b) H.
Saimoto, S. Ohrai, H. Sashiwa, Y. Shigemasa, T. Hiyama,
Bull. Chem. Soc. Jpn. 1995, 68, 2727.
Thus, the synthesis of ascofuranone is described in
Scheme 2. Geranyl acetate was treated with SeO2 in EtOH
under reflux to afford aldehyde 512 with the desired E geometry
in 54% yield. Aldehyde selective addition of a lithium salt of 2-
methyl-3-butyn-2-ol was accomplished at ¹50 °C to give 6 in
68% yield. This was then further transformed into pivaloyl ester
4 in 97% yield. Treatment of ester 4 with a catalytic amount
(8 mol %) of AgBF4 in toluene afforded compound 7 (63%
yield) via pivaloyloxy migration and cyclization. Simultaneous
deprotection of the acetyl and pivaloyl groups of 7 with sodium
methoxide gave allyl alcohol 8 in 92% yield. Treatment of allyl
alcohol 8 with carbon tetrabromide and trioctylphosphine at
¹78 °C afforded the prenylated bromide 9 in 96% yield.
Coupling of prenylated bromide 9 with 5-chloroorsellinaldehyde
27b using CaCl2 as a Lewis acid and KOH in MeOH at 0 °C gave
(«)-ascofuranone in 34% yield. The final product exhibited
physical and spectroscopic data in agreement with the litera-
ture.7c Thus, the total synthesis of («)-ascofuranone was
accomplished in seven steps (6.7% overall yield) from geranyl
acetate.13
5
6
7
8
9
In conclusion, we have achieved a more facile and efficient
synthesis of ascofuranone using only seven steps, starting from
commercially available geranyl acetate. This methodology could
be practically applied to the preparation of various ascofuranone
derivatives. Further rationalization of the synthetic process and
investigation of the biological activities of these derivatives will
be reported in due course.
a) H. Saimoto, K. Yoshida, T. Murakami, M. Morimoto, H.
Sashiwa, Y. Shigemasa, J. Org. Chem. 1996, 61, 6768. b) Y.
Omura, Y. Taruno, Y. Irisa, M. Morimoto, H. Saimoto, Y.
Shigemasa, Tetrahedron Lett. 2001, 42, 7273.
10 a) H. Saimoto, T. Hiyama, H. Nozaki, J. Am. Chem. Soc.
1981, 103, 4975. b) H. Saimoto, T. Hiyama, H. Nozaki, Bull.
Chem. Soc. Jpn. 1983, 56, 3078. c) Y. Shigemasa, M. Yasui,
S. Ohrai, M. Sasaki, H. Sashiwa, H. Saimoto, J. Org. Chem.
1991, 56, 910.
We would like to express our gratitude to Professor Kiyoshi
Kita (the University of Tokyo) for his valuable discussions and
suggestions.
11 By-products such as corresponding chromenes8a and O-
allylated ethers were not isolated, and phenol 2 (29-47%)
was recovered. However, in the case of 2¤,4¤-dihydroxyace-
tophenone, 1H NMR analysis of crude products indicated
that both C- and O-allylated products were formed.
12 a) J. Meinwald, K. Opheim, T. Eisner, Tetrahedron Lett.
1973, 14, 281. b) J. L. Paz, J. A. R. Rodrigues, J. Braz.
Chem. Soc. 2003, 14, 975.
References and Notes
1
a) Natural Products Chemistry, ed. by K. Nakanishi, T.
Goto, S. Ito, S. Natori, S. Nozoe, Kodansha, Tokyo, 1975,
Vol. 2, p. 131. b) D. C. Aldridge, A. Borrow, R. G. Foster,
M. S. Large, H. Spencer, W. B. Turner, J. Chem. Soc., Perkin
Trans. 1 1972, 2136.
2
a) H. Sasaki, T. Okutomi, T. Hosokawa, Y. Nawata, K.
Ando, Tetrahedron Lett. 1972, 13, 2541. b) H. Sasaki, T.
Hosokawa, M. Sawada, K. Ando, G. Tamura, J. Antibiot.
13 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2010, 39, 622-623
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/