Synthesis of the common FGHI-ring part of ciguatoxins

Article abstract of DOI:10.1016/j.tetlet.2005.11.085

The common FGHI-ring part (2) of ciguatoxins has been synthesized from the F- and I-ring parts (6 and 5, respectively). The Nozaki-Hiyama-Kishi coupling of 6 with 5 followed by regio- and stereoselective epoxidation at C29 and C30 afforded an epoxide (4),

Full text of DOI:10.1016/j.tetlet.2005.11.085

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 747–751
Synthesis of the common FGHI-ring part of ciguatoxins
Ayumi Takizawa, Kenshu Fujiwara,* Eriko Doi, Akio Murai,
Hidetoshi Kawai and Takanori Suzuki
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 24 October 2005; revised 16 November 2005; accepted 18 November 2005
Available online 5 December 2005
Abstract—The common FGHI-ring part (2) of ciguatoxins has been synthesized from the F- and I-ring parts (6 and 5, respectively).
The Nozaki–Hiyama–Kishi coupling of 6 with 5 followed by regio- and stereoselective epoxidation at C29 and C30 afforded an
epoxide (4), which was transformed into a tricyclic compound (3) corresponding to the F-HI-ring part by 6-exo-epoxide opening
and the subsequent inversion of the C29 stereocenter. Reductive cyclization of 3 forming the C31–O26 bond of the G-ring success-
fully produced 2.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Ciguatoxins,1 characterized by potent neurotoxicity due
to strong activation of the voltage-sensitive sodium
channels (VSSC),2 were isolated as causative toxins of
ciguatera fish poisoning.3 They have a ladder-shaped
trans-fused polyether structure including 13 medium
rings, such as ciguatoxin CTX3C (1)1a shown in Scheme
1. Since the structural complexity and the strong bioac-
tivity have attracted the attention of chemists, ciguatox-
ins have been studied extensively in the synthetic view
point.4,5 So far, in the course of our program toward
total synthesis of ciguatoxins,6 we reported the syntheses
of the ABCDE and IJKLM-ring parts of 16k,o as well
as a method for the addition of the F-ring to the E-ring
part of CTX1B,1b,c which would also be available for the
CTX3C synthesis.6m Therefore, our recent efforts have
been focused on the construction of the middle part of
1 from the left (ABCDEF-ring) and the right (IJKLM-
ring) segments. Here, the convergent synthesis of the
common FGHI-ring part (2) of ciguatoxins is described.
center, closely related to the construction of the H-ring
part, was an issue. Therefore, we planned to employ
the 6-exo-epoxide-opening reaction of 49 for the H-ring
formation followed by inversion of the C29 stereocenter
and oxidation at C31. The epoxide 4 was intended to be
synthesized from E-iodoalkene 6 and aldehyde 5 via the
Nozaki–Hiyama–Kishi reaction10 followed by regio-
and stereoselective epoxidation. Both 5 and 6 would
be prepared from the previously reported medium-ring
ethers.6h,o
Preparation of the I-ring part 5 from known 76h,o is
illustrated in Scheme 2. Although direct PMB protection
of the hydroxy group at C34 of 7 was possible, the
resulting compound resisted the removal of the benzyl-
idene acetal without detachment of the PMB group.
Therefore, alcohol 7 was first transformed into pivaloate
8 (100%), which was converted to PMB ether 13 (overall
73%) by a five-step process [(i) removal of the benzyl-
idene acetal with Zn(OTf)2/ethanedithiol,6m,11 (ii) pro-
tection of the resulting diol with 4-bromobenzyl (PBB)
bromide, (iii) detachment of the pivaloyl (Piv) group,
(iv) PMB-protection of the resulting alcohol, (v)
removal of the TBDPS group]. Oxidation of 13 with
Dess–Martin periodinane (DMPI)12 followed by Wittig
reaction afforded 14 (79%), which was hydrolyzed in
the presence of Hg(OAc)2 to produce 5 in good yield
(95%).13
Our plan for the synthesis of 2 from the F- and I-ring
parts (6 and 5, respectively) is outlined in Scheme 1.
The G-ring of 2 was envisioned to be constructed from
hydroxy ketone 3 by reductive cyclization forming the
O26–C31 bond and the C31 stereocenter.7,8 In the syn-
thesis of 3, establishment of the C30 quaternary stereo-
Keywords: Ciguatoxin; Natural product synthesis; trans-Fused poly-
cyclic ether; Convergent synthesis.
The F-ring part 6 was synthesized from known 156h
(Scheme 3). Removal of the TBS groups of 15 (91%)
followed by protection with BnBr (90%) provided 17,
*
Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706
4924; e-mail: fjwkn@sci.hokudai.ac.jp
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.085

748
A. Takizawa et al. / Tetrahedron Letters 47 (2006) 747–751
Me
HO
BnO
H
Me
Me
19
H
Me
H
H
O
H
BnO
BnO
O
H
H
Me
H
I
O
29
19
H
H
O
F
30
H
G
I
H
G
J
31
O
OH
H
H
H
H
H
H
O
O
OPBB
OPBB
Reductive Cyclization
6-exo-Epoxide
26
H
O
B
E
O
H
H
O
O
H
K
O
40
40
H
H
F
D
H
O
H
C
O
A
O
O
O
M
L
H
H
1
52
2
Me
OH
Me
Ciguatoxin CTX3C (1)
Opening
Inversion
BnOBnO
Me 30
BnO
Me
Me
Me
Me
19
I
HO
H
19
BnO
BnO
BnO19
BnO
PMBO
I
O
H
TESO
O
29
30
O
O
O
34
34
29
31
31
+
OHC
26
OTBS
OPBB
OPBB
OPBB
OPBB
OPBB
OPBB
O
26
F
31
30
Me
O
O
O
H
OH
OTBS
40
40
40
6
5
4
3
Nozaki-Hiyama-Kishi Reaction
& Epoxidation
PBB: 4-bromobenzyl
Scheme 1. Synthetic plan for the common FGHI-ring part (2) of ciguatoxins.
Me
Me
which was hydrolyzed to give 18 (98%). The primary
alcohol of 18 was selectively protected with PivCl
(80%), and the resulting 19 was transformed into 21
(overall 96%) by a two-step TBS-protection/Piv-detach-
ment process. Conversion of 21 to triflate 22 (96%) and
the subsequent reaction with 1-propynyllithium (97%)
afforded 23,14 which was treated first with a zirconium
reagent, prepared from Cp2ZrCl2 and DIBALH,15 and
then with I2 to produce 6 regioselectively (86%).
O
OR2
OR2
RO
a
R1O
34
b
e
Ph
O
O
O
OTBDPS
OTBDPS
7: R=H
8: R=Piv
9: R1=Piv, R2=H
c
d
10: R1=Piv, R2=PBB
11: R1=H, R2=PBB
Me
Me
R1O
PMBO
MeO
OPBB
OPBB
g, h
i
Connection of 5 and 6 as well as construction of the H-
ring is depicted in Scheme 4. According to the Nozaki–
Hiyama–Kishi procedure,10 the segments 5 and 6 were
treated with CrCl2 in the presence of NiCl2 (0.5 wt.%
of CrCl2) in DMSO, and the reaction smoothly pro-
ceeded to give 24 (45% from 5) and its C31-epimer 25
(40% from 5) in good yield.16 The epimer 25 could be
transformed into 24 in good yield and selectivity (overall
100%, 24:25 = 13:1) through oxidation with Dess–Mar-
tin periodinane (DMPI) followed by reduction with
L-Selectrideꢁ.17 The VO(acac)2-catalyzed epoxidation
of 24 with TBHP exclusively afforded 26 (91%),18 which
was subjected to a protection/deprotection sequence to
produce 4 (overall 95%). The hydroxy epoxide 4 was
smoothly cyclized with catalytic CSA into 28 (80%).
The stereochemistry at C30 of 28 was confirmed by
the presence of NOE between H34 and the protons of
the methyl group at C30. Thus, the I-ring 5 and the
F-ring 6 were efficiently assembled into the F-HI-ring
part 28 in overall 57% yield for total seven steps from 5.
5
O
O
OR2
OPBB
OPBB
12: R1=PMB, R2=TBDPS
14
f
13: R1=PMB, R2=H
Scheme 2. Reagents and conditions: (a) PivCl, pyridine, 26 ꢂC, 14 h,
100%; (b) Zn(OTf)2, HS(CH2)2SH, NaHCO3, CH2Cl2, 0 to 25 ꢂC, 2 h,
88%; (c) PBBBr, NaH, Bu4NI, THF, 25 ꢂC, 14 h, 100%; (d) DIBALH,
CH2Cl2, ꢀ78 ꢂC, 1.5 h, 88%; (e) PMBBr, NaH, Bu4NI, THF, 26 ꢂC,
21 h; (f) Bu4NF, THF, 0 ꢂC, 1.5 h, 94% from 11; (g) DMPI, CH2Cl2,
0 to 23 ꢂC, 50 min; (h) Ph3P+CH2OMeClꢀ, NHMDS, 0 ꢂC, 30 min,
then aldehyde, ꢀ78 to 25 ꢂC, 17 h, 79%; (i) Hg(OAc)2, THF–H2O
(10:1), 23 ꢂC, 1 h, then Bu4NI, 1.5 h, 95%.
RO
RO
O
O
BnO
BnO
OR1
OR2
O
O
Ph
c
f
15: R=TBS
16: R=H
17: R=Bn
18: R1=H, R2=H
a
b
d
e
19: R1=Piv, R2=H
20: R1=Piv, R2=TBS
Me
BnO
BnO
OR
O
BnO
BnO
The synthesis of 2 from 28 is shown in Scheme 5. First,
inversion of the stereochemistry at C29 of 28 was per-
formed by an oxidation/reduction process. Although
alcohol 28 resisted several oxidation reactions due to
steric hindrance around the hydroxy group at C29,
Swern oxidation19 of 28 at higher temperature (ꢀ45 ꢂC)
for prolonged reaction time (1 h) was able to produce
an inseparable ꢁ5:1 mixture of ketone 29 and unreacted
28 in a good material balance (100%). The reduction of
29 to C29-epi-28 was not achieved in spite of several
attempts. Therefore, the reduction after detachment of
the TES group at O31 was then investigated. Treatment
of the mixture of 29 and 28 with HFÆPy slowly afforded
O
h
i
6
OTBS
OTBS
21: R=H
22: R=Tf
23
g
Scheme 3. Reagents and conditions: (a) Bu4NF, THF, 25 ꢂC, 11 h,
91%; (b) BnBr, NaH, Bu4NI, THF, 26 ꢂC, 5 h, 90%; (c) 3 M HCl aq–
THF (1:1), 23 ꢂC, 21 h, 98%; (d) PivCl, pyridine, 25 ꢂC, 33 h, 80%; (e)
TBSOTf, 2,6-lutidine, CH2Cl2, 0 ꢂC, 15 min, 97%; (f) DIBALH,
CH2Cl2, ꢀ78 ꢂC, 2 h, 99%; (g) Tf2O, 2,6-lutidine, CH2Cl2, 0 ꢂC,
15 min, 96%; (h) propyne, BuLi, THF, ꢀ78 ꢂC, 15 min, then 22, ꢀ78 to
25 ꢂC, 3 h, 97%; (i) Cp2ZrCl2, DIBALH, THF, 55 ꢂC, 30 min, then I2,
0 ꢂC, 15 min, 86%.

A. Takizawa et al. / Tetrahedron Letters 47 (2006) 747–751
749
BnOBnO
O
HO
Me
Me
H
H
Me
O
PMBO
HO
29
BnO
BnO
O
31
OPBB
OPBB
RO
OTBS
O
OPBB
OPBB
31
O
Me
OTBS
28: R=TES
31: R=H
a
d
25
+
a
O
Me
5
b, c
Me
H
H
6
O
BnOBnO
O
BnO
29
Me
O
31
PMBO
HO
OPBB
OPBB
BnO
RO
OTBS
O
OPBB
OPBB
31
O
29: R=TES
30: R=H
b
Me
OTBS
d
c
24
HO
Me
BnOBnO
O
Me
H
H
Me
O
R2O
29
BnO
BnO
R1O
31
O
OPBB
HO
OTBS
32
O
O
OPBB
OPBB
O
OPBB
Me
OTBS
e
26: R1=H, R2=PMB
27: R1=TES, R2=PMB
4: R1=TES, R2=H
Np
O
g
Me
Me
e
f
NOEs
Me
H
H
H 29
O
BnO
BnO
29
O
NOE
H
O
31
HO
31
Me
O
OPBB
OPBB
O
Me
H
34
O
H
O
O
BnO
BnO
OTBS
33
Np: 2-naphthyl
NAP: (2-naphthyl)methyl
30
O
Np
33
OPBB
TESO
OTBS
f
O
H
R2O
Me
OPBB
Me
H
H
28
O
29
BnO
BnO
O
31
R1O
OTBS
OPBB
OPBB
Scheme 4. Reagents and conditions: (a) 6 (3.7 equiv), CrCl2 (10 equiv),
NiCl2 (0.5 wt.% of CrCl2), DMSO, 25 ꢂC, 30 h, 24: 45% from 5, 25:
40% from 5; (b) DMPI, NaHCO3, CH2Cl2, 25 ꢂC, 2.5 h, 100%; (c) L-
Selectrideꢁ, THF, ꢀ78 ꢂC, 2 h, 100% (24:25 = 13:1); (d) VO(acac)2
(0.09 equiv), TBHP, toluene, 0 ꢂC, 2 h, 91%; (e) TESOTf, 2,6-lutidine,
CH2Cl2, 23 ꢂC, 10 min, 100%; (f) DDQ, CH2Cl2–pH 7 buffer (10:1),
0 ꢂC, 1 h, 95%; (g) CSA (0.1 equiv), CH2Cl2, 0 ꢂC, 25 min, 80%.
O
34: R1=NAP, R2=H
35: R1=NAP, R2=Bn
36: R1=H, R2=Bn
g
h
i
BnO
Me
Me
H
H
O
BnO
BnO
O
31
OPBB
OPBB
O
OR
26
O
an inseparable ꢁ5:1 mixture of hydroxy ketone 30 and
diol 31 (75%) along with a mixture of recovered 29
and 28 (ꢁ5:1, 25%). The reduction of the mixture of
30 and 31 with NaBH4 gave the desired diol 32 in 39%
yield along with 31 in 35% yield.20 The diol 31 was selec-
tively protected with TESOTf to provide 28 in quantita-
tive yield, thereby establishing the route for recycling
undesired 31. Next, selective but stepwise Bn protection
at O29 of 32 was executed. The diol 32 was exclusively
transformed into (2-naphthyl)methylene acetal 33. The
configurations at C29 and the acetal carbon of 33 were
confirmed by the presence of NOEs between the acetal
proton and H31 and between the acetal proton and
H29. Reduction of 33 with DIBALH exclusively affor-
ded (2-naphthyl)methyl (NAP)21 ether 34, which was
quantitatively converted to the requisite 36 through a
sequence of Bn protection at O29 and NAP deprotection
at O31. Alcohol 36 was oxidized with DMPI12 and the
resulting 37 was desilylated to give 3 quantitatively.
The reductive cyclization of 3 with excess Et3SiH in
the presence of TMSOTf at 0 ꢂC produced 2 stereoselec-
tively (64%).7 The stereochemistry of 2 was confirmed
by the presence of ROE between H26 and H31 as well
as the large JH31–H32ax (12.1 Hz). Thus, the FGHI-ring
part 222 was successfully constructed from the F-ring 6
and the I-ring 5 in 9.5% overall yield over 17 steps
including the transformation steps from 25 to 24.
37: R=TBS
3: R=H
j
k
BnO
Me
Me
H
H
BnO
BnO
O
H
O
F
G
31H
I
OPBB
OPBB
26
O
O
H
ROE
H
2
Scheme 5. Reagents and conditions: (a) (COCl)2, DMSO, CH2Cl2,
ꢀ45 ꢂC, 1 h, then Et3N, 0 ꢂC, 15 min, 28+29: ꢁ100% (28:29 = 1:ꢁ5);
(b) HFÆPy, THF–Py (3:1), 23 ꢂC, 7 d, 28+29: 25% (28:29 = 1:ꢁ5),
30+31: 75% (30:31 = ꢁ5:1); (c) NaBH4, MeOH, 0 ꢂC, 20 min, 32: 39%,
31: 35%; (d) TESOTf, 2,6-lutidine, CH2Cl2, ꢀ40 ꢂC, 15 min, ꢁ100%;
(e) 2-naphthaldehyde dimethylacetal, PPTS, PhH, reflux, 2 h, 89%; (f)
DIBALH, CH2Cl2, 0 ꢂC, 4 h, ꢁ100%; (g) BnBr, NaH, Bu4NI, THF,
23 ꢂC, 20 h, ꢁ100%; (h) DDQ, CH2Cl2–pH 7 buffer (10:1), 0 ꢂC,
20 min, ꢁ100%; (i) DMPI, NaHCO3, CH2Cl2, 23 ꢂC, 25 min, ꢁ100%;
(j) HFÆPy, THF, 23 ꢂC, 2 d, ꢁ100%; (k) TMSOTf, Et3SiH–CH2Cl2
(1:10), 0 ꢂC, 35 min, 64%.
Nozaki–Hiyama–Kishi reaction connecting the F-ring
with the I-ring, regio- and stereoselective epoxidation,
the 6-exo-epoxide opening reaction forming the H-ring,
inversion of the C29 stereocenter, and reductive cycliza-
tion constructing the G-ring was successfully developed.
Further studies toward the total synthesis of ciguatoxins
are now in progress in this laboratory.
In conclusion, for the synthesis of the common FGHI-
ring part (2) of ciguatoxins, a method based on the

750
A. Takizawa et al. / Tetrahedron Letters 47 (2006) 747–751
Cintada, C. G.; Morales, E. Q.; Brouard, I.; Dıaz, M. T.;
´
Acknowledgements
´
´
´
Rico, M.; Rodrıguez, E.; Rodrıguez, R. M.; Perez, R.;
´
´
Perez, R. L.; Martın, J. D. Tetrahedron 2002, 58, 1921.
6. Our synthetic studies on ciguatoxins: (a) Oka, T.; Fuji-
wara, K.; Murai, A. Tetrahedron 1996, 52, 12091; (b)
Atsuta, H.; Fujiwara, K.; Murai, A. Synlett 1997, 307; (c)
Oka, T.; Murai, A. Tetrahedron 1998, 54, 1; (d) Oka, T.;
Fujiwara, K.; Murai, A. Tetrahedron 1998, 54, 21; (e)
Fujiwara, K.; Saka, K.; Takaoka, D.; Murai, A. Synlett
1999, 1037; (f) Fujiwara, K.; Tanaka, H.; Murai, A. Chem.
Lett. 2000, 610; (g) Fujiwara, K.; Takaoka, D.; Kusumi,
K.; Kawai, K.; Murai, A. Synlett 2001, 691; (h) Fujiwara,
K.; Koyama, Y.; Doi, E.; Shimawaki, K.; Ohtaniuchi, Y.;
Takemura, A.; Souma, S.; Murai, A. Synlett 2002, 1496;
(i) Fujiwara, K.; Koyama, Y.; Kawai, K.; Tanaka, H.;
Murai, A. Synlett 2002, 1835; (j) Tanaka, H.; Kawai, K.;
Fujiwara, K.; Murai, A. Tetrahedron 2002, 58, 10017; (k)
Fujiwara, K.; Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka,
H.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett.
2004, 45, 7011; (l) Takemura, A.; Fujiwara, K.; Murai, A.;
Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004, 45, 7567;
(m) Takemura, A.; Fujiwara, K.; Shimawaki, K.; Murai,
A.; Kawai, H.; Suzuki, T. Tetrahedron 2005, 61, 7392; (n)
Domon, D.; Fujiwara, K.; Ohtaniuchi, Y.; Takezawa, A.;
Takeda, S.; Kawasaki, H.; Murai, A.; Kawai, H.; Suzuki,
T. Tetrahedron Lett. 2005, 46, 8279; (o) Domon, D.;
Fujiwara, K.; Murai, A.; Kawai, H.; Suzuki, T. Tetra-
hedron Lett. 2005, 46, 8285.
We are grateful to Mr. Kenji Watanabe and Dr. Eri
Fukushi (GC–MS and NMR Laboratory, Graduate
School of Agriculture, Hokkaido University) for the
measurements of mass spectra. We also thank Mr.
Yasuhiro Kumaki (High Resolution NMR Laboratory,
Graduate School of Science, Hokkaido University) for
the measurements of NMR spectra. This work was sup-
ported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science,
and Technology of Japanese Government.
References and notes
1. Ciguatoxin CTX3C: (a) Satake, M.; Murata, M.; Yasu-
moto, T. Tetrahedron Lett. 1993, 34, 1975; Ciguatoxin
CTX1B: (b) Murata, M.; Legrand, A.-M.; Ishibashi, Y.;
Fukui, M.; Yasumoto, T. J. Am. Chem. Soc. 1989, 111,
8929; (c) Murata, M.; Legrand, A.-M.; Ishibashi, Y.;
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Y. Chem. Rev. 1993, 93, 1685; (f) Yasumoto, T.; Murata,
M. Chem. Rev. 1993, 93, 1897; (g) Scheuer, P. J.
Tetrahedron 1994, 50, 3; (h) Yasumoto, T.; Murata, M.
Nat. Prod. Rep. 2000, 17, 293; (i) Yasumoto, T. Chem.
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2. (a) Bidard, J.-N.; Vijverberg, H. P. M.; Frelin, C.;
Chungue, E.; Legrand, A.-M.; Bagnis, R.; Lazdanski,
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Toxicon 1999, 37, 125.
7. Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am.
Chem. Soc. 1989, 111, 4136.
8. A similar ring closure of the G-ring part by reductive
etherification was reported by the Isobe group, where the
cyclization of a tricyclic compound corresponding to the
EF-H-ring part having 26-keto and 31-hydroxy groups
was successfully performed: Takai, S.; Sawada, N.; Isobe,
M. J. Org. Chem. 2003, 68, 3225.
9. Although the use of the cis-epoxide (C29-epi-4) corre-
sponding to 4 might be straightforward and exclude the
C29-inversion step, the cis-epoxide could not be prepared
so far because of the difficulty in the synthesis of the Z-
iodoalkene corresponding to 6. For successful synthesis of
a Z-iodoalkene, see: Smith, A. B., III; Beauchamp, T. J.;
LaMarche, M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto, H.;
Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 2000, 122,
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10. (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am.
Chem. Soc. 1977, 99, 3179; (b) Jin, H.; Uenishi, J.; Christ,
W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644.
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Hutchinson, J.; Prasad, C. V. C.; Ogilvie, W. W. Angew.
Chem., Int. Ed. Engl. 1991, 30, 299.
12. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155;
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277.
3. For reviews of ciguatera, see: (a) Lehane, L.; Lewis, R. J.
Int. J. Food Microbiol. 2000, 61, 91; (b) Lewis, R. J.
Toxicon 2001, 39, 97.
4. Total synthesis of CTX3C: (a) Hirama, M.; Oishi, T.;
Uehara, H.; Inoue, M.; Maruyama, M.; Oguri, H.; Satake,
M. Science 2001, 294, 1904; (b) Inoue, M.; Uehara, H.;
Maruyama, M.; Hirama, M. Org. Lett. 2002, 4, 4551; (c)
Maruyama, M.; Inoue, M.; Oishi, T.; Oguri, H.; Ogasa-
wara, Y.; Shindo, Y.; Hirama, M. Tetrahedron 2002, 58,
1835; (d) Uehara, H.; Oishi, T.; Inoue, M.; Shoji, M.;
Nagumo, Y.; Kosaka, M.; Le Brazidec, J.-Y.; Hirama, M.
Tetrahedron 2002, 58, 6493; (e) Kobayashi, S.; Takahashi,
Y.; Komano, K.; Alizadeh, B. H.; Kawada, Y.; Oishi, T.;
Tanaka, S.; Ogasawara, Y.; Sasaki, S.; Hirama, M.
Tetrahedron 2004, 60, 8375; (f) Inoue, M.; Yamashita,
S.; Tatami, A.; Miyazaki, K.; Hirama, M. J. Org. Chem.
2004, 69, 2797; Reviews: (g) Inoue, M.; Hirama, M.
Synlett 2004, 577; (h) Inoue, M.; Miyazaki, K.; Uehara,
H.; Maruyama, M.; Hirama, M. Proc. Natl. Sci. Acad.
U.S.A. 2004, 101, 12013; (i) Inoue, M.; Hirama, M. Acc.
Chem. Res. 2004, 37, 961.
13. Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2000, 122, 10521.
14. (a) Carling, R. W.; Holmes, A. B. Tetrahedron Lett. 1986,
27, 6133; (b) Kotsuki, H.; Kadota, I.; Ochi, M. Tetrahe-
dron Lett. 1990, 31, 4609.
5. Recent synthetic studies on ciguatoxins by other groups:
(a) Kobayashi, S.; Alizadeh, B. H.; Sasaki, S.-y.; Oguri,
H.; Hirama, M. Org. Lett. 2004, 6, 751; (b) Baba, T.;
Takai, S.; Sawada, N.; Isobe, M. Synlett 2004, 603; (c)
Baba, T.; Huang, G.; Isobe, M. Tetrahedron 2003, 59,
6851; (d) Fuwa, H.; Fujikawa, S.; Tachibana, K.; Taka-
kura, H.; Sasaki, M. Tetrahedron Lett. 2004, 45, 4795; (e)
Takakura, H.; Sasaki, M.; Honda, S.; Tachibana, K. Org.
Lett. 2002, 4, 2771; (f) Bond, S.; Perlmutter, P. Tetrahe-
dron 2002, 58, 1779; (g) Candenas, M. L.; Pinto, F. J.;
15. (a) Kiyotsuka, Y.; Igarashi, J.; Kobayashi, Y. Tetrahedron
Lett. 2002, 43, 2725; (b) Negishi, E.; Yoshida, T. Tetra-
hedron Lett. 1980, 21, 1501; For the hydrozirconation
reaction with the Schwartz reagent (Cp2ZrHCl), see: (c)
Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96,
8115; (d) Schwartz, J.; Labinger, J. A. Angew. Chem., Int.
Ed. Engl. 1976, 15, 333.
16. Since the R-configuration at C31 of 25 was proved by
modified Mosherꢀs method, the C31-configuration of the
other diastereomer 24 was determined as S. For modified

A. Takizawa et al. / Tetrahedron Letters 47 (2006) 747–751
751
Mosherꢀs method, see: Ohtani, I.; Kusumi, T.; Kashman,
Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
17. The reduction of the ketone prepared from 25 was
examined with several reductants, where L-Selectrideꢁ
gave the best yield and selectivity of 24. The results also
suggested that the selectivity of 24 increased with increas-
ing bulkiness of the reductant. However, the reasons for
the high stereoselectivity and the stereochemical prefer-
ence in the reduction with bulky reductants were unclear.
18. Tanaka, S.; Yamamoto, H.; Nozaki, H.; Sharpless, K. B.;
Michaelson, R. C.; Cutting, J. D. J. Am. Chem. Soc. 1974,
96, 5254.
19. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
1978, 43, 2480.
20. The net product ratio of 32 to 31 from 30 was determined
as 2:1 by the reduction of pure 30, prepared alternatively,
under the same conditions.
J = 8.1 Hz), 6.83 (2H, d, J = 8.1 Hz), 5.93 (1H, dt,
J = 6.4, 10.0 Hz), 5.82 (1H, dt, J = 5.4, 10.0 Hz), 4.85
(1H, d, J = 12.1 Hz), 4.71 (1H, d, J = 12.1 Hz), 4.39 (1H,
d, J = 12.3 Hz), 4.37 (2H, s), 4.25 (1H, d, J = 12.9 Hz),
4.22 (1H, d, J = 12.9 Hz), 4.21 (1H, d, J = 11.7 Hz), 4.11
(1H, d, J = 12.3 Hz), 3.87 (1H, d, J = 11.7 Hz), 3.70 (1H,
t, J = 6.0 Hz), 3.66–3.53 (6H, m), 3.52–3.50 (1H, m), 3.49–
3.47 (1H, m), 3.39 (1H, dd, J = 7.1, 9.9 Hz), 3.26–3.20
(2H, m), 3.07 (1H, dd, J = 4.6, 12.1 Hz), 2.94 (1H, ddd,
J = 5.0, 10.0, 13.9 Hz), 2.69–2.63 (2H, m), 2.40 (1H, dt,
J = 12.5, 4.6 Hz), 2.31–2.26 (3H, m), 2.00–1.84 (4H, m),
1.68–1.57 (2H, m), 1.44 (3H, s), 1.00 (3H, d, J = 7.3 Hz);
13C NMR (125 MHz, C6D6, 13CC5D6 as 128.0 ppm) d
11.9 (CH3), 26.9 (CH3) 27.9 (CH2), 28.6 (CH), 33.1 (CH2),
36.2 (CH2), 38.8 (CH2), 39.8 (CH2), 45.5 (CH2), 70.3
(CH2), 71.0 (CH2), 72.5 (CH+CH2 · 3), 73.3 (CH2 · 2),
79.0 (CH), 79.6 (CH · 2), 80.8 (C), 82.3 (CH), 83.1 (CH),
83.6 (CH), 85.0 (CH · 2), 86.0 (CH), 121.4 (C · 2), 127.8
(CH · 6), 128.2 (CH · 2), 129.3 (CH · 4), 131.5 (CH · 4),
137.8 (C · 2), 138.9 (C · 2), 140.2 (C) (The signals of nine
carbons of Bn groups were undetected due to overlapping
with solvent signal); IR (film) mmax 2954, 2923, 2853, 1594,
1487, 1462, 1376, 1287, 1260, 1204, 1096, 1070, 1027, 1012,
840, 803, 729, 697 cmꢀ1; HR-FDMS, calcd for C59H68-
79Br2O9 [M+]: 1078.3230, found: 1078.3217.
21. (a) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998,
63, 4172; (b) Xia, J.; Abbas, S. A.; Locke, R. D.; Piskorz,
C. F.; Alderfer, J. L.; Matta, K. L. Tetrahedron Lett. 2000,
41, 169; (c) Wright, J. A.; Yu, J.; Spencer, J. B.
Tetrahedron Lett. 2001, 42, 4033.
23
22. Selected spectral data of 2: ½aꢂD ꢀ5.0 (c 0.025, CHCl3); 1H
NMR (600 MHz, C6D6, C6HD5 as 7.15 ppm), d 7.45 (2H,
d, J = 7.3 Hz), 7.21–7.02 (17H, m), 6.94 (2H, d,