Convergent synthesis of the right-hand segment of ciguatoxin

Article abstract of DOI:10.1021/ol0600741

A convergent synthesis of the right-hand half of ciguatoxin (the HIJKLM ring system) has been achieved with complete stereocontrol in the introduction of the stereocenters on the eight-membered I ring. Key steps are Sonogashira coupling, dicobalt complexation, intramolecular conjugate addition, and hydrogenation of an endo-olefin to provide the 39-α-methyl group.

Full text of DOI:10.1021/ol0600741

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1205-1208
Convergent Synthesis of the Right-Hand
Segment of Ciguatoxin
Akinari Hamajima and Minoru Isobe*
Laboratory of Organic Chemistry, School of Bioagricultural Sciences,
Nagoya UniVersity, Chikusa, Nagoya 464-8601, Japan
isobem@agr.nagoya-u.ac.jp
Received January 11, 2006
ABSTRACT
A convergent synthesis of the right-hand half of ciguatoxin (the HIJKLM ring system) has been achieved with complete stereocontrol in the
introduction of the stereocenters on the eight-membered I ring. Key steps are Sonogashira coupling, dicobalt complexation, intramolecular
conjugate addition, and hydrogenation of an endo-olefin to provide the 39-r-methyl group.
Ciguatoxin (CTX1B, 1)1 is a principal toxin of ciguatera
poisoning, which is known as the most widespread seafood
problem. Several synthetic groups2 have been involved in
the total synthesis of CTX because of its remarkable
structural complexity, biological activity, and limited avail-
ability from natural sources. In 2001, the Hirama group
reported the first total synthesis of CTX3C, one of the CTX
families.3 We too have been actively pursuing a total
synthesis of CTX and have developed several methodologies
for constructing its medium-sized ether rings based on cobalt-
mediated cyclization.4
In our plan for the synthesis of CTX 1, coupling between
an acetylene from the BCDE ring 2 and an aldehyde from
the HIJKLM ring 3 is proposed followed by construction of
the central FG ring and, finally, A-ring cyclization with the
C4 side chain. We have already reported a synthesis of the
BCDE ring system 25 and the effective methodologies for
construction of the A ring6 with the side chain. In addition,
(1) (a) Scheuer, P. J.; Takahashi, W.; Tsutsumi, J.; Yoshida, T. Science
1967, 155, 1267. (b) Murata, M.; Legurand, A. M.; Ishibashi, Y.; Fukui,
M.; Yasumoto, T. J. Am. Chem. Soc. 1990, 112, 4380-4386. (c) Satake,
M.; Morohashi, A.; Oguri, H.; Oishi, T.; Hirama, M.; Harada, N.; Yasumoto,
T.; J. Am. Chem. Soc. 1997, 119, 11325-11326. (d) Yasumoto, T. Chem.
Rec. 2001, 1, 228-242.
(3) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.; Oguri,
H.; Satake, M. Science 2001, 294, 1904-1907.
(2) (a) Kobayashi, S.; Takahashi, Y.; Komano, K.; Alizadeh, B. H.;
Kawada, Y.; Oishi, T.; Tanaka, S.; Ogasawara, Y.; Sasaki, S.; Hirama, M.
Tetrahedron 2004, 60, 8375-8396. (b) Sasaki, M.; Noguchi, K.; Fuwa,
H.; Tachibana, K. Tetrahedron Lett. 2000, 41, 1425-1428. (c) Takizawa,
A.; Fujiwara, K.; Doi, E.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron
Lett. 2006, 47, 747-751. (d) Candenas, M. L.; Pinto, F. M.; Cintado, C.
G.; Morales, E. Q.; Brouard, I.; D´ıaz, M. T.; Rico, M.; Rodr´ıguez, E.;
Rodr´ıguez, R. M.; Pe´rez, R.; Pe´rez, R. L.; Mart´ın, J. D. Tetrahedron 2002,
58, 1921-1942. (e) Bond, S.; Perlmutter, P. Tetrahedron 2002, 58, 1779-
1787. and references therein.
(4) (a) Isobe, M.; Yenjai, C.; Tanaka, S. Synlett 1994, 11, 916-918. (b)
Yenjai, C.; Isobe, M. Tetrahedron 1998, 54, 916-918. (c) Isobe, M.;
Hosokawa, S.; Kira, K. Chem. Lett. 1996, 473-474. (d) Hosokawa, S.;
Isobe, M. J. Org. Chem. 1999, 64, 37-48. (e) Saeeng, R.; Isobe, M.
Tetrahedron Lett. 1999, 40, 1911-1914. (f) For a review, see: Isobe, M.;
Nishizawa, R.; Hosokawa, S.; Nishikawa, T. Chem. Commun. 1998, 2665-
2676.
(5) Kira, K.; Isobe, M. Tetrahedron Lett. 2001, 42, 2821-2824.
(6) Hosokawa, S.; Isobe, M. J. Org. Chem. 1999, 64, 37-48. Saeeng,
R.; Isobe, M. Heterocycles 2001, 54, 789.
10.1021/ol0600741 CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/25/2006

Scheme 1. Retrosynthetic Analysis
the EFGH7 rings were prepared as model studies for the final
The vinyltriflate 9 was prepared from 108 in five steps by
a series of protecting group manipulations and enolization
of methyl ketone 11 with KHMDS and PhNTf2 (Scheme 2).
Construction of the other requisite subsegment 8 required
five steps from the diol 12.9 The hydroxyl group of 12 was
then protected as an acetonide, and the nitrile was reduced
in two steps to the alcohol 13 which was protected as a
benzoate ester. The acetonide was then selectively depro-
tected to give subsegment 8.
Sonogashira coupling between acetylene 8 and vinyltriflate
9 proceeded with high efficiency to furnish the corresponding
enyne, from which the TBS groups were removed by
treatment with TBAF (Scheme 3). The resulting tetraol 14
could readily be converted into the corresponding acetylene
stages of the synthesis. On the right-hand part, the syntheses
of JKLM8 and HIJ ring9 models have already been ac-
complished. In those model studies, H-ring cyclization was
accomplished under strongly acidic conditions, which might
ultimately cause problems in our plan because of the fact
that the H-ring cyclization step should be achieved in the
presence of the acid-labile spiroketal LM ring. Furthermore,
introduction of the C(57)-methyl group required six steps.
Herein, we report the synthesis of a fully functionalized
HIJKLM ring system for ciguatoxin in a shorter number of
steps as well as under milder conditions.
Our retrosynthetic analysis of CTX1B 1 is illustrated in
Scheme 1. Crucial for introducing the C(57)-methyl group
of compound 3 would be the hydrogenation of an endo-olefin
with the 6-8-6 ether ring system. The endo-olefin in 4 has
its own stable conformer with its double bond pointing
downward as illustrated in Figure 1. Hydrogenation of the
double bond would therefore most likely proceed from the
â-face to give an R-C(57)-methyl group. The six-membered
H ring of 4 would probably be best formed by the
intramolecular 1,4-addition of the hydroxyl group in 5. Its
eight-membered ring would be prepared via the acetylene
cobalt complex 6. Opening of the eight-membered ring leads
to compound 7, in which enyne disconnection on the basis
of a Sonogashira coupling10 affords the acetylene 8 and the
vinyltriflate 9.
(7) Takai, S.; Sawada, N.; Isobe, M. J. Org. Chem. 2003, 68, 3225-
3231.
(8) Baba, T.; Huang, G.; Isobe, M. Tetrahedron 2003, 59, 6851-6872.
(9) Baba, T.; Takai, S.; Sawada, N.; Isobe, M. Synlett 2004, 603-608.
(10) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467-4470.
Figure 1. Energy-minimized conformaion of the 6-8-6 ether ring
system.
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Org. Lett., Vol. 8, No. 6, 2006

Scheme 2. Synthesis of Subsegments
Scheme 3. Synthesis of the HIJKLM Ring Fragment
dicobalt complex, which formed by simple mixing with
Co2(CO)8 in CH2Cl2. Treatment of this cobalt complex with
highly diluted BF3‚OEt2 at 0 °C under high dilution condi-
tions resulted in its total consumption within 10 min to afford
the pentacyclic system 15 having syn stereochemistry
between H(36) and H(42) in 75% isolated yield. At this point,
the stereochemistry was exclusively controlled by the
thermodynamic stability of the product.
With the requisite IJKLM ring fragment compound 15 in
hand, we turned our attention to transforming the cobalt
complex of the enyne system to an endocyclic Michael
acceptor to form the adjacent six-membered H ring. The
exocyclic olefin of 15 was cleaved by Lemieux-Johnson
oxidation to afford the corresponding ketone and a mixture
of intermediate diols, which was further exposed to NaIO4
to give only the ketone in 61% yield. In this oxidation, the
addition of acetic acid did accelerate the oxidative cleavage
of the diol and made the reaction reproducible. Hydro-
silylation of the acetylene cobalt complex in the presence
of bis(trimethylsilyl)acetylene11 proceeded regioselectively
to provide a corresponding vinylsilane. Its two hydroxyl
groups were subsequently protected as benzoates, and further
treatment with TBAF afforded enone 16.
Upon treatment of the endocyclic enone 16 with p-
toluenesulfonic acid in nitromethane, the H-ring cyclization
took place with attendant loss of the acetonide group to afford
the target hexacyclic compound 17 having syn stereochem-
istry between the C(56)-methyl and H(37) as a major product.
Through inspection of the stability of the spiroketal under
acidic conditions, it was found that the benzoyl-protected
spiroketal was more stable under acidic conditions than when
it was protected as a benzyl ether or left unprotected. In this
regard, when the spiroketal protected with O-benzyl groups
was exposed to the same acidic conditions, it decomposed
rapidly.
The only issue that remained was stereoselective introduc-
tion of the methyl group at the C(39) position (Scheme 4).
After the benzoyl group of 17 was removed, the 1,3-diol
containing primary alcohol was protected as an O-ben-
zylidene acetal. The remaining hydroxyl groups were pro-
tected as TBS ether. The ketone present in the I ring was
converted into a vinyl triflate; the C(39)-(40) double-bond
isomer was the major product. The vinyl triflate was cross-
coupled with methylmagnesium bromide in the presence of
(11) (a) Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609-
2612. (b) Kira, K.; Tanda, H.; Hamajima, A.; Baba, T.; Takai, S.; Isobe,
M. Tetrahedron 2002, 58, 6485-6492.
Org. Lett., Vol. 8, No. 6, 2006
1207

this step. Fortunately, we found that the 600 MHz 1H NMR
spectrum of deprotected diol 20 in pyridine-d5 showed good
resolution in the upfield region. NOE correlation and the 1H
NMR coupling constant determined the stereochemistry of
the C(39) position to be R.
Scheme 4. Introduction of the 57-Methyl Group
In conclusion, we have accomplished a synthesis of a fully
functionalized HIJKLM ring fragment. The key transforma-
tions in our synthesis are I-ring cyclization using the
acetylene cobalt complex, the intramolecular 1,4-hydroxy
addition under mild acidic conditions, and stereoselective
hydrogenation of the I ring endo-olefin. Further studies
toward the total synthesis of ciguatoxin are now in progress.
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Specially Promoted Research (16002007)
and a Grant of the 21st Century COE program from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy (MEXT), Japan. Dr. Takai, Mr. Sawada, and Mr. Ikemori
contributed to this study in an earlier stage. We are grateful
to Mr. Kitamura (analytical laboratory in this school) for
elemental analysis, to Mr. Koga for NMR experiments, and
to Dr. Tsujimoto for HRMS.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Fe(acac)3, affording the endo-olefin 19 in good yield.12 The
endo-olefin was hydrogenated stereoselectively using Crab-
tree’s catalyst to give a single diastereoisomer.13 We could
not determine the stereochemistry of the C(39) position in
OL0600741
(13) (a) Crabtree, R. H.; Morris, G. E. J. Chem. Soc., Chem. Commun.
1976, 716. (b) Domon, D.; Fujiwara, K.; Murai, A.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2005, 46, 8285-8288.
(12) Scheiper, B.; Bonnekessel, M.; Krause, H.; Fu¨rstner, A. J. Org.
Chem. 2004, 69, 3943-3949.
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Org. Lett., Vol. 8, No. 6, 2006