A cross-metathesis approach to the stereocontrolled synthesis of the AB ring segment of ciguatoxin

Article abstract of DOI:10.1016/j.tetlet.2008.03.145

Synthesis of the AB ring segments of ciguatoxin is described. The present synthesis includes a Lewis acid mediated cyclization of allylstannane with aldehyde, cross-metathesis reaction introducing the side chain, and Grieco-Nishizawa dehydration on the A ring.

Full text of DOI:10.1016/j.tetlet.2008.03.145

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3643–3647
A cross-metathesis approach to the stereocontrolled
synthesis of the AB ring segment of ciguatoxin
a,
b
a
a
b
*
Isao Kadota , Takashi Abe , Miyuki Uni , Hiroyoshi Takamura , Yoshinori Yamamoto
a Department of Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan
b Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 29 February 2008; revised 22 March 2008; accepted 31 March 2008
Available online 8 April 2008
Abstract
Synthesis of the AB ring segments of ciguatoxin is described. The present synthesis includes a Lewis acid mediated cyclization of all-
ylstannane with aldehyde, cross-metathesis reaction introducing the side chain, and Grieco–Nishizawa dehydration on the A ring.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Ciguatoxin; Polycyclic ethers; Allylstannane–aldehyde condensation; Cross-metathesis
Ciguatoxin (1), a principal causative toxin of ‘ciguatera’
seafood poisoning, was isolated from moray eel Gymnotho-
rax javanicus.1 The potent neurotoxicity and novel poly-
cyclic ether framework including five- to nine-membered
rings have attracted the attention of synthetic chemists.2,3
The first total synthesis of 1 was achieved by Inoue and
Hirama in 2006.4 As well as the construction of the huge
molecular architecture, synthesis of the labile dihydroxy-
butenyl substituent on the A ring moiety is a great
synthetic challenge.5 In this Letter, we describe a stereocon-
trolled synthesis of the AB ring segment of ciguatoxin (1)
via a cross-metathesis reaction.6
Scheme 1 illustrates our synthetic strategy. The AB ring
segment 2 is retrosynthetically broken down into the side
chain moiety 3 and bicycle 4. The 6–7 ring system 4 would
be constructed from 5 via an intramolecular reaction of all-
ylstannane with aldehyde. The vinyl group of 4, generated
by the cyclization process, can be a suitable substrate for
the subsequent cross-metathesis. The cyclization precursor
5 can be prepared from the known compound 6.
Grieco–Nishizawa protocol. Thus, the treatment of 7 with
2-nitro-phenylselenocyanate/Bu3P afforded alkyl selenide 8
via SN2 stereoinversion (Scheme 2). Oxidation of 8 with
H2O2 gave selenoxide intermediate 9, which immediately
underwent syn-elimination to furnish 10 as the sole product
in 88% overall yield.8,9 Although the desired 1,4-diene was
obtained in good yield, however, the reaction with the ole-
fin 1110 using metathesis catalyst such as the second gener-
ation Grubbs catalyst 1211 gave poor result. Only a trace
amount of the desired product 13 was detected in the reac-
tion mixture.12
After several unfruitful attempts, we found that the
cross-metathesis of 7 and 11 in the presence of catalyst
12 proceeded to give product 14 in reasonable yield
(Scheme 3). Alcohol 14 was then dehydrated to give 1,4-
diene 13 in 54% yield.13,14
Encouraged by these results, we next investigated the
synthesis of the AB ring segment 2. Protection of the known
alcohol 1515 as an ethoxyethyl ether followed byhydrobora-
tion–oxidation provided the corresponding primary alco-
hol, which was treated with CSA in MeOH giving diol 16
in 81% overall yield (Scheme 4). Selective protection of
the primary hydroxyl group with TBDPSCl/imidazole
afforded 17 in quantitative yield. Treatment of the second-
ary alcohol with the c-methoxy-allylstannane 18 gave the
As a preliminary study, we examined the synthesis of a
1,4-diene system by using the simple substrate 77 via the
*
Corresponding author. Tel./fax: +81 86 251 7836.
E-mail address: kadota-i@cc.okayama-u.ac.jp (I. Kadota).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.145

3644
I. Kadota et al. / Tetrahedron Letters 49 (2008) 3643–3647
Me
H
H
HO
Me
Me
O
H
O
I
OH
H
H
J
H
H
O
H
G
O
H
O
H
H
H
O
K
O
H
H
O
D
A
H
HO
B
H O
E
O
M
C
L
O
F
H
H
HO
H
O
O
H
Me
H
H
HO
H
Me
OH
Ciguatoxin (1)
H
H
H
H
H
H
O
O
B
H
HO
OBn
OBn
OBn
OBn
A
RO
OR
+
O
H
O
H
H
OBn
H
OBn
RO
3
OR
2
4
H
H
H
O
H
H
H
OHC
O
OBn
OBn
OBn
O
HO
OBn
H
OBn
H
OBn
Bu3Sn
6
5
Scheme 1.
NO
2
H
O
H
H
Ph
H
O
Ph
H
Se
SeCN, PBu
H O , NaHCO
2 2 3
3
HO
O
O
NO
2
O
O
THF, 40 °C
0 °C
H
H
H
8
7
BnO
11
H
H
H
O
Ph
O
Ph
-
H
H
syn elimination
88%
OBn
O
O
Ph
Se
O
O
+
O
O
O
H
H
NO
2
O
H
H
Mes N N Mes
H
Ph
Cl
BnO
10
OBn
13
Ru
Cl
9
PCy
3
12
Scheme 2.
NO
2
H
H
O
Ph
11 (8 eq)
SeCN
HO
7
13
O
O
12
(10 mol%)
benzene (0.25 M)
reflux, 2.5 h
H
PBu , THF, 40 °C
H
3
then H O , NaHCO
3
2
2
BnO
OBn
14
0 °C
54%
61%
Scheme 3.

I. Kadota et al. / Tetrahedron Letters 49 (2008) 3643–3647
3645
H
H
H
H
1) ethyl vinyl ether,
CSA, CH2Cl2,0 °C
H
H
H
TBDPSCl
imidazole
H
H
H
H
O
O
O
OBn
OBn
HO
OBn
OBn
TBDPSO
OBn
OBn
HO
HO
HO
2) (Sia)2BH, THF, 0 °C
then H2O2, NaOH
3) CSA, MeOH, rt
DMF, 0 °C
H
OBn
OBn
OBn
100%
15
16
17
81%
OMe
18
H
H
H
H
H
O
O
TBDPS
TBDPS
OBn
OBn
OBn
OBn
Bu Sn
3
TBAF
TMSI, HMDS
O
O
H
H
H
OBn
CSA, CH2Cl2, rt
98%
THF, rt
CH2Cl2, 0 °C
OBn
OMe
Bu Sn
3
Bu Sn
3
74% (2 steps)
19
20
H
H
H
H
H
H
H
H
H
O
O
OHC
O
H
BF3·OEt2
SO3·py, DMSO
HO
OBn
OBn
OBn
OBn
HO
O
H
O
OBn
OBn
H
OBn
Et3N, CH2Cl2
0 °C
CH2Cl2
-78 °C
O
H
H
OBn
OBn
Bu Sn
Bu Sn
3
3
80% (2 steps)
21
5
4
Scheme 4.
mixed acetal 19 in 98% yield. Acetal cleavage of 19 was per-
formed using TMSI/HMDS to give the allylic stannane
20,16 which was treated with TBAF furnishing 21 in 74%
overall yield. Oxidation of the primary alcohol with SO3
Ápy/DMSO/Et 3N gave aldehyde 5, which was then sub-
jected to the BF3ÁOEt2 mediated cyclization to afford the
bicyclic compound 4 as a single stereoisomer in 80% overall
yield.17–19 The cyclization product 4 having a vinyl group
can be used directly for the next cross-metathesis reaction.
Preparation of the chiral side chain segment is described
in Scheme 5. Hydrolysis of acetonide 22, prepared from
D-mannitol, 20 gave the corresponding diol 23, which was
treated with TBDPSCl/imidazole followed by TBSCl to
afford 24 in 76% overall yield. Ozonolysis of alkene 24,
followed by Wittig reaction of the resulting aldehyde
furnished 25 in 60% overall yield. The side chain segment
26 having an MPM group was prepared via selective
removal of the TBS group followed by protection of the
resulting alcohol as an MPM ether in 42% overall yield.
Both of the substrates were in hand; we next examined
the cross-metathesis (Scheme 6). Treatment of 4 with 25
(8 equiv) in the presence of catalyst 12 (20 mol %) provided
27 as a single stereoisomer in 23% yield. The yield was
slightly improved by using the less hindered substrate 26,
and product 28 was obtained in 34% yield. Finally, alco-
hol 28 was subjected to the Grieco–Nishizawa protocol to
TBDPSCl
CSA
CO2Et
CO2Et
imidazole
HO
O
O
OH
23
DMF, 0 °C
then TBSCl, rt
MeOH
rt
22
76% (2 steps)
1) O3, CH2Cl2
-78 °C
then PPh3
CO2Et
TBDPSO
TBDPSO
2) Ph3P+CH3Br-
NaHMDS, THF
OTBS
OTBS
25
24
0 °C
60%
1) CSA, MeOH, 0 °C
TBDPSO
OMPM
26
2) MPMOC(=NH)CCl3
CSA, CH2Cl2, rt
42%
Scheme 5.

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.;

I. Kadota et al. / Tetrahedron Letters 49 (2008) 3643–3647
3647
Takeyama, H.; Mihara, Y.; Takahata, H. Tetrahedron Lett. 2008, 49,
265–268.
19. The stereochemistry of product 4 was confirmed by 1H NMR analysis
as shown below.
H
H
15. Cipolla, L.; Lay, L.; Nicotra, F. J. Org. Chem. 1997, 62, 6678–
6681.
16. Kadota, I.; Sakaihara, T.; Yamamoto, Y. Tetrahedron Lett. 1996, 37,
3195–3198.
17. (a) Yamamoto, Y.; Yamada, J.; Kadota, I. Tetrahedron Lett. 1991,
32, 7069–7072; (b) Kadota, I.; Kawada, M.; Gevorgyan, V.;
Yamamoto, Y. J. Org. Chem. 1997, 62, 7439–7446.
18. Construction of the A ring moiety via the allylstannane–aldehyde
condensation has been investigated by Hirama, see Refs. 5b and 5c.
O
H
AcO
OBn
OBn
O
H
H
H
OBn
5.1 Hz
NOE
20. Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara, K. Synthesis
1986, 403–406.