3646
I. Kadota et al. / Tetrahedron Letters 49 (2008) 3643–3647
2. For the first total synthesis of ciguatoxin CTX3C: (a) Hirama, M.;
Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.; Oguri, H.; Satake,
M. Science 2001, 294, 1904–1907; (b) Inoue, M.; Uehara, H.;
Maruyama, M.; Hirama, M. Org. Lett. 2002, 4, 4551–4554; (c)
Inoue, M.; Miyazaki, K.; Uehara, H.; Maruyama, M.; Hirama, M.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12013–12018.
3. For recent reviews on syntheses of polycyclic ethers, see: (a) Nakata,
T. Chem. Rev. 2005, 105, 4314–4347; (b) Inoue, M. Chem. Rev. 2005,
105, 4379–4405.
H
H
H
O
H
HO
OBn
OBn
TBDPSO
+
O
H
H
OBn
OR
25: R = TBS (8 eq)
26: R = MPM (8 eq)
4
12 (20 mol%)
benzene (0.1 M)
reflux, 6.5 h
4. Inoue, M.; Miyazaki, K.; Ishihara, Y.; Tatami, A.; Ohnuma, Y.;
Kawada, Y.; Komano, K.; Yamashita, S.; Lee, N.; Hirama, M. J.
Am. Chem. Soc. 2006, 128, 9352–9354.
H
H
O
H
OBn
OBn
5. For the previous examples, see: (a) Sato, O.; Hirama, M. Synlett 1992,
705–707; (b) Oguri, H.; Hishiyama, S.; Oishi, T.; Hirama, M. Synlett
1995, 1252–1254; (c) Oguri, H.; Hishiyama, S.; Sato, O.; Oishi, T.;
Hirama, M.; Murata, M.; Yasumoto, T.; Harada, N. Tetrahedron
1997, 3057–3072; (d) Oka, T.; Fujiwara, K.; Murai, A. Tetrahedron
1998, 54, 21–44; (e) Hosokawa, S.; Isobe, M. J. Org. Chem. 1999, 64,
37–48; (f) Oguri, H.; Sasaki, S.; Oishi, T.; Hirama, M. Tetrahedron
Lett. 1999, 40, 5405–5408; (g) Oguri, H.; Tanaka, S.; Oishi, T.;
Hirama, M. Tetrahedron Lett. 2000, 41, 975–978; (h) Saeeng, R.;
Isobe, M. Heterocycles 2001, 54, 789–798; (i) Kobayashi, S.; Alizadeh,
B. H.; Sasaki, S.; Oguri, H.; Hirama, M. Org. Lett. 2004, 6, 751–754.
6. For a previous study on the synthesis of the AB ring moiety of 1 by
cross-metathesis reaction, see Ref. 5f.
7. Kadota, I.; Ohno, A.; Matsukawa, Y.; Yamamoto, Y. Tetrahedron
Lett. 1998, 39, 6373–6376.
8. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485–1486.
9. Treatment of the mesylate, prepared from 7, with KHMDS afforded
the undesired 1,3-diene derivative as the sole product.
HO
O
H
H
H
OBn
27: R = TBS (23%)
28: R = MPM (34%)
TBDPSO
OR
NO2
then H2O2, NaHCO3
30 °C
SeCN
PBu3, THF, 40 °C
47%
H
H
H
H
O
B
OBn
OBn
A
a
H
15.6 Hz
TBDPSO
O
H
OBn
Hb
OMPM
29
Scheme 6.
H
H
H
H
O
Ph
O
Ph
KHMDS
MsO
O
O
furnish the AB ring segment 29 in 47% yield. The coupling
constants, JHaÀHb = 15.6 Hz, clearly indicated the
E-geometry of the side chain olefin.
O
O
THF, 0 °C
H
H
80%
10. Olefin 11 was prepared as follows:
In conclusion, the stereocontrolled synthesis of the AB
ring segment of ciguatoxin was achieved. The Lewis acid
mediated allylstannane–aldehyde condensation was suc-
cessfully applied to the synthesis of the seven-membered
cyclic ether skeleton. Cross-metathesis and subsequent
Grieco–Nishizawa dehydration protocol were effective for
the construction of the 1,4-diene system. Further studies
towards the total synthesis of ciguatoxin are in progress
in our laboratories.
1) BnBr, NaH
THF-DMF, 60 °C
OH OBn
OH
O
OBn
OH
BnO
HO
2) CSA
MeOH, rt
OBn OH
OH
O
85%
1) NaIO4
MeOH-H2O, rt
11
2) Ph3PCH3+Br-
NaHMDS
THF, 0 °C
79%
Acknowledgments
11. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956.
This work was financially supported by the Nagase
Science and Technology Foundation, and the Grant-
in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan.
12. A similar problem of the cross-metathesis with a 1,4-diene derivative
was reported by Hirama, see Ref. 5f.
13. Protection of the hydroxy group of 7 as a TBS ether inhibited the
cross-metathesis. The reaction was very slow even in the presence of 1
equiv of 12, and the product was obtained in 35% yield after 16 h as
shown below. One of the referees suggested carrying out this reaction
to clarify the effect of the free hydroxy group on the cross-metathesis.
References and notes
H
H
11 (4 eq)
12 (100 mol%)
H
O
Ph
H
O
Ph
TBSO
TBSO
1. (a) Scheuer, P. J.; Takahashi, W.; Tsutsumi, J.; Yoshida, T. Science
1967, 155, 1267–1268; (b) Murata, M.; Legrand, A. M.; Ishibashi, Y.;
Yasumoto, T. J. Am. Chem. Soc. 1989, 111, 8929–8931; (c) Murata,
M.; Legrand, A.-M.; Ishibashi, Y.; Fukui, M.; Yasumoto, T. J. Am.
Chem. Soc. 1990, 112, 4380–4386; (d) Satake, M.; Morohashi, A.;
Oguri, H.; Oishi, T.; Hirama, M.; Harada, N.; Yasumoto, T. J. Am.
Chem. Soc. 1997, 119, 11325–11326.
O
O
benzene (0.25M)
reflux, 16 h
O
H
O
H
H
H
BnO
OBn
35%
14. Recently, the acceleration effect of allylic hydroxy group on ring-
closing enyne metathesis was reported, see: Imahori, T.; Ojima, H.;