for preparing anti-ciguatoxin antibodies and as fragments for
the practical total synthesis. This prompted us to develop an
improved synthetic route to the pentacyclic left wing
fragment of 1 and 2.6,7
The synthesis design for the left half 8 was based on
recently developed acyl radical methodology (Scheme 1).8,9
induced elimination of the sulfide from 5 would produce enol
ether 6, the acyl radical addition to which would cyclize the
ether ring of 7.11 Then, the six-membered C-ring of 8 was
planned to be constructed through reductive etherification.
A series of these mild reactions were designed to simplify
the functional group manipulations of the highly oxygenated
intermediates and consequently to shorten the synthetic routes
in comparison to the previous schemes.
First, the requisite AB-ring moiety 3 was prepared from
known compound 96a (Scheme 2). The secondary alcohol
Scheme 1. Synthesis Plan of the Left-Wing Fragment of
Ciguatoxins
Scheme 2. Synthesis of the AB-Ring Fragment
We previously applied the intermolecular alkylation of an
ester enolate of the E-ring fragment to the AB-ring iodide
to synthesize 8.6a In contrast to these strong basic conditions,
the present coupling of the AB- and E-ring fragments (3 and
4) was based on a neutral reaction linking the C-O bond as
the O,S-acetal 5.10 After O,S-acetal formation, the Ag+-
of 9 was converted to 2-naphtylmethyl (NAP) ether 10,12
the acetal of which was removed under acidic conditions,
leading to diol 11. A reagent combination of I2, PPh3, and
imidazole13 chemoselectively transformed the primary alco-
hol of 11 into the iodide, and subsequent cyanide introduction
gave the one-carbon homologated product 12. After TBS
protection of 12, stepwise reduction of nitrile 13 using
DIBAL and NaBH4 resulted in alcohol 14. Finally, treatment
of 14 with (PhS)2 and n-Bu3P14 generated phenylsulfide 15,
and the chloride was subsequently introduced into the
R-position of the sulfide by the action of NCS to afford 3.15
To investigate the structural effect of R in 16 on the
efficiency of the acyl radical cyclization, side chains of the
E-ring fragments were varied; namely, the R groups of 4a,
4b, and 4c have two sp2-, two sp3-, and one sp3-carbons,
respectively, with the methoxycarbonyl terminus (Scheme
(4) (a) Oguri, H.; Hirama, M.; Tsumuraya, T.; Fujii, I.; Maruyama, M.;
Uehara, H.; Nagumo, Y. J. Am. Chem. Soc. 2003, 125, 7608. (b) Tsumuraya,
T.; Fujii, I.; Inoue, M.; Tatami, A.; Miyazaki, K.; Hirama, M. Toxicon 2006,
48, 287.
(5) (a) Inoue, M.; Miyazaki, K.; Uehara, H.; Maruyama, M.; Hirama,
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see: (a) Maruyama, M.; Inoue, M.; Oishi, T.; Oguri, H.; Ogasawara, Y.;
Shindo, Y.; Hirama, M. Tetrahedron 2002, 58, 1835. (b) 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.
(7) For syntheses of the BCDE, ABCD, or ABCDE ring part of
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Lett. 2001, 42, 2821. (b) Fujiwara, K.; Koyama, Y.; Kawai, K.; Tanaka,
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