A concise route to the right wing of ciguatoxin

Article abstract of DOI:10.1016/S0040-4039(03)01214-0

A concise route to the HIJKLM-ring fragment 10 of ciguatoxin (CTX) and 51-hydroxyCTX3C was developed in which oxiranyl anion addition and intramolecular carbonyl olefination were utilized as key transformations. The present procedure requires only 23 steps from the I-ring 5, while 35 steps were employed in a previous synthesis of the corresponding right wing 11 of CTX3C. The high efficiency of the present synthesis ensures a supply of 10 for total synthesis and biomedical applications.

Full text of DOI:10.1016/S0040-4039(03)01214-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5229–5233
A concise route to the right wing of ciguatoxin
Atsushi Tatami, Masayuki Inoue,* Hisatoshi Uehara and Masahiro Hirama*
Department of Chemistry, Graduate School of Science, Tohoku University, and SORST, Japan Science and Technology
Corporation (JST), Sendai 980-8578, Japan
Received 19 April 2003; revised 9 May 2003; accepted 16 May 2003
Abstract—A concise route to the HIJKLM-ring fragment 10 of ciguatoxin (CTX) and 51-hydroxyCTX3C was developed in which
oxiranyl anion addition and intramolecular carbonyl olefination were utilized as key transformations. The present procedure
requires only 23 steps from the I-ring 5, while 35 steps were employed in a previous synthesis of the corresponding right wing 11
of CTX3C. The high efficiency of the present synthesis ensures a supply of 10 for total synthesis and biomedical applications.
© 2003 Elsevier Science Ltd. All rights reserved.
Many tropical species of fish may cause an intoxication
known as ciguatera.1 The causative toxins, ciguatoxins,2
originate in epiphytic dinoflagellates Gambierdiscus
toxicus, and subsequently enter the food chain.3
Dinoflagellate toxins, such as CTX3C (1, Fig. 1)2d and
CTX4B 3,2a,b undergo oxidation in fish, yielding more
toxic products, for instance, 51-hydroxyCTX3C 22e and
ciguatoxin (CTX, 4).2a,b Upon ingestion, these potent
neurotoxins target voltage-sensitive sodium channels,
and cause persistent activation of these channels.4
Because the presence of these toxins in fish is unpre-
The final stage of our synthesis of 1 involved coupling
between the left and right wings with subsequent con-
struction of the central FG-ring system.6,9 This strategy
is applicable to all ciguatoxins, because they share the
FG-ring structure.2 To synthesize structural variants of
ciguatoxins for antibody-preparations and detailed
SAR, we selected oxidized ciguatoxins (2, 4) as impor-
tant targets. In this paper, we describe the concise
synthesis of the NAP-protected10 right wing 10 of 2 and
4
by applying
a significantly improved protocol
(Scheme 1).
dictable,
a sensitive immunochemical method for
detecting ciguatoxins has long been necessary.5 Very
recently, we achieved the first practical total synthesis
of CTX3C 1,6,7 and developed an immunoassay for 1
by utilizing synthetic haptens,8 which has paved the
way for biomedical research on ciguatoxins.
In the previous synthesis of the right half of CTX3C
(11, Scheme 1), while the IJKLM-ring segment 6 was
constructed from the I-(5) and LM-ring segments in a
convergent manner, the subsequent attachment of the
H-ring to 6 required 20 synthetic steps.11 To facilitate
Figure 1. Structures of ciguatoxins.
Keywords: convergent synthesis; intramolecular carbonyl olefination; low-valent titanium complex; polyether; ciguatoxin; 51hydroxy-CTX3C.
* Corresponding authors. Fax: +81-22-217-6566; e-mail: inoue@ykbsc.chem.tohoku.ac.jp; hirama@ykbsc.chem.tohoku.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01214-0

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A. Tatami et al. / Tetrahedron Letters 44 (2003) 5229–5233
The coupling partner of 9, the HI-ring fragment 8,
was prepared from the known I-ring 511 using Mori’s
oxiranyl anion strategy (Scheme 3).12 Diol 5 was con-
verted to the protected triflate 22 by stepwise addition
of Tf2O and TESOTf in the presence of base and
molecular sieves. A mixture of the resultant 22 and
epoxysulfone 712d in THF–HMPA was treated with
n-BuLi at −110°C for 30 min, leading to the forma-
tion of the desired coupling adduct 23. Then, 6-endo
cyclization to construct the H-ring was realized by
submitting 23 to p-TsOH in CH2Cl2 with p-methoxy-
benzylidene methylacetal17 to afford the bicyclic fused
ether 24 through concomitant removal of TES (46%
from 5). Thus, obtained 24 was reduced using
NaBH4, and the newly formed alcohol was protected
as its TIPS ether to give 25 as the sole product in
quantitative yield (two steps). After acid-promoted
removal of the MP acetal from 25, one-carbon exten-
Scheme 1. Synthesis plan of the right wing of ciguatoxin
and 51-hydroxyCTX3C.
H-ring construction for 10, the four-carbon unit 7
was planned to be directly introduced via the oxiranyl
anion strategy developed by Mori.12 Additionally, the
H-ring was to be built on the I-ring fragment (5“8)
instead of the IJKLM-ring system in order to maxi-
mize the synthetic convergency and minimize the pro-
tective group manipulations.
Synthesis of the LM-ring fragment 9 began with the
previously reported olefin 12 (Scheme 2).11,13,14 After
conversion of hemiacetal 12 to methylacetal 13 (94%),
the 51-OH group was installed by Sharpless asymmet-
ric dihydroxylation using (DHQ)2PYR,15 which led to
the desired diol 14 as the major diastereomer (14:15=
4:1, 97% yield). Intramolecular trans-acetalization of
the isolated 14 with CSA generated five-membered
spiroacetals favoring the requisite stereoisomer 16b
(16a:16b=1:2, 90% yield). The separated epimer 16a
was subjected to thermodynamic equilibration to yield
the same ratio of the diastereomers. The secondary
alcohol of the combined spiroacetal 16b was tempo-
rarily masked with TIPS, and the benzyl group was
then removed by hydrogenolysis to provide the pri-
mary alcohol 17 (96% for two steps). After oxidation
of 17, addition of Roush’s crotyl boronate 1916 to
aldehyde 18 set the two stereocenters (C43, C44), giv-
ing rise to 20 with complete stereochemical control
(69% for 2 steps). Removal of the TIPS group from
20 and introduction of the NAP group produced the
bis-NAP ether 21 in 99% yield. Finally, oxidative
cleavage of the terminal olefin of 21, followed by
oxidation to the carboxylic acid, led to LM-ring frag-
ment 9 in 82% yield for the two steps.
Scheme 2. Reagents and conditions: (a) (MeO)3CH, CSA,
(CH2Cl)2, rt, 94%; (b) OsO4, (DHQ)2PYR, K3Fe(CN)6,
K2CO3, t-BuOH/H2O (1:1), 0°C, 97% (14:15=4:1); (c)
CSA, (CH2Cl)2, rt, 90% (16a:16b=1:2); (d) PPTS, PhH/
(CH2Cl)2 (1:1), 60°C, 75% (16a:16b=1:2); (e) TIPSOTf, 2,6-
lutidine, CH2Cl2, −78°C, 96%; (f) Pd(OH)2/C, H2, EtOAc,
rt, 100%; (g) (COCl)2, DMSO, CH2Cl2, −78°C, then Et3N;
,
(h) 19, 4 A MS, toluene, −78°C, 69% (two steps); (i)
TBAF, THF, rt; (j) NAPBr, TBAI, NaH, THF/DMF (3:1),
0°C to rt, 99% (two steps); (k) OsO4, NMO, t-BuOH/H2O
(1:1), rt, then NaIO4; (l) NaClO2, NaPO4·H2O, 2-methyl-2-
butene, t-BuOH/H2O (4:1), 82% (two steps).

A. Tatami et al. / Tetrahedron Letters 44 (2003) 5229–5233
5231
sion of 26 at the primary alcohol via a two-step sequence,
followed by the TES protection of the secondary alcohol,
resulted in nitrile 27 in 73% yield from 25. Then, 27 was
reduced to the corresponding aldehyde, which was con-
verted to dithioacetal 28 using phenyldisulfide and PBu3
(83% yield, two steps).18 For the next coupling reaction,
the TES group of the tris-silylated 28 was selectively
removed using PPTS in MeOH–CH2Cl2 at 0°C to produce
the HI-ring alcohol 8 in 84% yield.
Having synthesized both fragments, the coupling and
subsequent construction of the JK-ring were pursued
(Scheme 4). Condensation of alcohol 8 and carboxylic
acid 9 using the Yamaguchi protocol19 gave the corre-
sponding ester 29 in 77% yield. Cyclization of the J-ring
from 29 was then achieved by intramolecular carbonyl
olefination using the low-valent titanium reagent devel-
oped by Takeda,20 which successfully closed the six-mem-
bered J-ring to afford 30 in 68% yield.11 Hydroboration
of enol ether 30 installed an alcohol at C41 to generate
a separable mixture of 31a (57%) and 31b (19%), both
of which were separately oxidized with Dess–Martin
periodinane into ketones 32a and 32b, respectively. The
undesired isomer 32a was effectively converted to 32b by
three cycles of the DBU-mediated isomerization–separa-
tion sequence in 66% yield. Combined 32b was then
exposed to trifric acid and (MeO)3CH in hexane, directly
leading to seven-membered methylacetal 33 via loss of the
MOM group (62% yield). Reductive etherification21 of
acetal 33 using Et3SiH and BF3·OEt2 in the presence of
molecular sieves constructed the last ether ring to afford
the HIJKLM-ring system 34 in 78% yield, whose NOE
experiment verified the selective attack of hydride from
,
Scheme 3. Reagents and conditions: (a) Tf2O, 2,6-lutidine, 4 A
MS, CH2Cl2, thenTESOTf, −78°C;(b)7, n-BuLi, HMPA, THF,
−110°C; (c) TsOH·H2O, CH2Cl2, (MeO)2CH(p-MeOPh), 0°C
tort, 46%(threesteps);(d)NaBH4, CH2Cl2/MeOH(1:1), −78°C,
100%; (e) TIPSOTf, 2,6-lutidine, (CH2Cl)2, 50°C, 100%; (f)
,
TFA/THF/H2O (1:10:5), rt, 87%; (g) Ph3P, I2, imidazole, 4 A
MS, THF, −30 to 0°C, 87%; (h) NaCN, DMSO, 40°C, 97%;
(i) TESOTf, 2,6-lutidine, CH2Cl2, −78°C, 100%; (j) DIBAL,
CH2Cl2, −78°C; (k) PhSSPh, n-Bu3P, 40°C, 83% (two steps);
(l) PPTS, MeOH/CH2Cl2 (5:1), 0°C, 84%.
Scheme 4. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, toluene, then DMAP, 35°C, 77%; (b)
Cp2Ti[P(OEt)3]2, THF, reflux, 68%; (c) BH3·SMe2, THF, 0°C to rt then NaOH, H2O2, 76% (31a:31b=3:1); (d) Dess–Martin
periodinane, CH2Cl2, rt, 90% for 32a, 97% for 32b; (e) DBU, CH2Cl2, rt, 66% (three cycles, 12% of 32a was recovered); (f) TfOH,
,
(MeO)3CH, hexane, rt, 62%; (g) BF3·OEt2, Et3SiH, 4 A MS, CH2Cl2, −50 to −20°C, 78%; (h) HF·Py, Py/THF (1:2), rt, 76%; (i)
,
SO3·Py, Et3N, DMSO/CH2Cl2 (1:2), 0°C to rt; (j) allylSnBu3, MgBr2·OEt2, 4 A MS, toluene, −78°C to rt, 62%, C29-epimer 21%
(two steps); (k) NAPBr, TBAI, NaH, THF/DMF (3:1), rt, 91%.

5232
A. Tatami et al. / Tetrahedron Letters 44 (2003) 5229–5233
the a-face of the molecule. In this way, the JK-ring was
assembled from the fragments (8, 9) through only seven
synthetic operations.
5. For attempts toward the preparation of anti-CTX antibod-
ies, see: (a) Oguri, H.; Tanaka, S.-I.; Hishiyama, S.; Oishi,
T.; Hirama, M.; Tsumuraya, T.; Tomioka, Y.; Mizugaki,
M. Synthesis 1999, 1431–1436; (b) Nagumo, Y.; Oguri, H.;
Shindo, Y.; Sasaki, S.-y.; Oishi, T.; Hirama, M.; Tomioka,
Y.; Mizugaki, M.; Tsumuraya, T. Bioorg. Med. Chem.
Lett. 2001, 11, 2037–2040; (c) Hokama, Y.; Takenaka, W.
E.; Nishimura, K. L.; Ebesu, J. S. M.; Bourke, R.; Sullivan,
P. K. J. AOAC Int. 1998, 81, 727–735; (d) Pauillac, S.;
Sasaki, M.; Inoue, M.; Naar, J.; Branaa, P.; Chinain, M.;
Tachibana, K.; Legrand, A.-M. Toxicon 2000, 38, 669–
685.
To complete the synthesis of the right wing of CTX, the
carbon chain corresponding to the G-ring was intro-
duced (Scheme 4). HF·pyridine effected the selective
removal of TBPS to afford 35 in 76% yield. The alcohol
of 35 was in turn oxidized with SO3·pyridine to aldehyde
36, which was subjected to MgBr2-promoted allylation
using allyltributylstannane to generate alcohol 37 (62%)
and the C29-epimer (21%). Finally, NAP protection of
37 gave rise to the targeted right wing 10 in 91% yield,
which can be readily coupled with the left wing after
modification of the terminal olefin.6,9,22
6. (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.
In conclusion, the right half of CTX and 51-hydroxy-
CTX3C was synthesized by a highly convergent strategy
using a significantly improved protocol. The present
synthesis of 10 only requires 23 steps from I-ring 5,
whereas the previous procedure for 11 involved 35
steps.11 Of note in the present synthesis is the successful
application of the oxiranyl anion strategy for the H-ring
and the intramolecular carbonylation protocol for the
J-ring, both of which substantially contributed to the
conciseness of the synthesis. The total syntheses of
ciguatoxin and 51-hydroxyCTX3C have become our
next focus, and will be reported in due course.
7. For recent synthetic studies of ciguatoxins from other
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2771–2774; (d) Sasaki, M.; Noguchi, T.; Tachibana, K. J.
Org. Chem. 2002, 67, 3301–3310; (e) Fujiwara, K.;
Takaoka, D.; Kusumi, K.; Kawai, K.; Murai, A. Synlett
2001, 691–693; (f) Fujiwara, K.; Koyama, Y.; Doi, E.;
Shimawaki, K.; Ohtaniuchi, Y.; Takemura, A.; Souma,
S.-i. Murai, A. Synlett 2002, 1496–1499; (g) Fujiwara, K.;
Koyama, Y.; Kawai, K.; Tanaka, H.; Murai, A. Synlett
2002, 1835–1838; (h) Tanaka, H.; Kawai, K.; Fujiwara, K.;
Murai, A. Tetrahedron 2002, 58, 10017–10031; (i) Kira, K.;
Isobe, M. Tetrahedron Lett. 2001, 42, 2821–2824; (j) Kira,
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Takai, S.; Sawada, N.; Isobe, M. J. Org. Chem. 2003, 68,
3225–3231; (m) Eriksson, L.; Guy, S.; Perlmutter, P.;
Lewis, R. J. Org. Chem. 1999, 64, 8396–8398; (n) Bond,
S.; Perlmutter, P. Tetrahedron 2002, 58, 1779–1787; (o)
Leeuwenburgh, M. A.; Kulker, C.; Overkleeft, H. S.; van
der Marel, G. A.; van Boom, J. H. Synlett 1999, 1945–
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8. Oguri, H.; Hirama, M.; Tsumuraya, T.; Fujii, I.;
Maruyama, M.; Uehara, H.; Nagumo, Y. J. Am. Chem.
Soc., in press.
9. (a) Imai, H.; Uehara, H.; Inoue, M.; Oguri, H.; Oishi, T.;
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10. Application of NAP (2-naphthylmethyl) group was
demonstrated in the practical total synthesis of CTX3C
(Ref. 6b). For NAP ether references, see: (a) Gaunt, M. J.;
Yu, J.; Spencer, J. B. J. Org. Chem. 1998, 63, 4172–4173;
(b) Wright, J. A.; Yu, J.; Spencer, J. B. Tetrahedron Lett.
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Acknowledgements
This work was supported in part by a grant from the
Takeda Science Foundation (M.I.).
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;
(500 MHz, CDCl3) l 1.01–1.11 (33H, m, TIPS, Me54,
Me55, Me56, Me57), 1.14 (3H, s, Me53), 1.37 (1H, q,
J=11.5 Hz, H40), 1.50–1.63 (3H, m, H35, 37, 47), 1.72
(1H, q, J=11.5 Hz, H32), 1.80–1.89 (4H, m, H35, H36,
H37, H48), 2.10 (1H, dt, J=11.5, 5.5 Hz, H40), 2.13–2.22
(4H, m, H32, H43, H50×2), 2.49–2.58 (2H, m, H28×2),
2.85 (1H, dd, J=9.5, 4.5 Hz, H42), 2.99 (1H, ddd,
J=11.5, 9.5, 2.0 Hz, H38), 3.04–3.12 (2H, m, H33, H39),
3.30 (1H, dt, J=9.5, 3.5 Hz, H34), 3.42 (1H, t, J=9.5 Hz,
H46), 3.43 (1H, d, J=3.5 Hz, H44), 3.62 (1H, d, J=9.5
Hz, H45), 3.66 (1H, dd, J=8.0, 4.5 Hz, H29), 3.82 (1H,
dd, J=9.5, 5.0 Hz, H52), 3.85 (1H, ddd, J=11.5, 9.5, 5.5
Hz, H41), 3.98 (1H, dd, J=9.5, 1.5 Hz, H52), 4.26 (1H,
dd, J=11.5, 5.0 Hz, H31), 4.27 (1H, br, H51), 4.59 (1H,
d, J=12.0 Hz, NAP), 4.62 (1H, d, J=12.0 Hz, NAP), 4.74
(1H, d, J=12.5 Hz, NAP), 4.75 (1H, d, J=12.5 Hz,
NAP), 4.81 (1H, d, J=11.0 Hz, NAP), 4.84 (1H, d,
J=11.0 Hz, NAP), 5.01 (1H, dd, J=10.5, 2.0 Hz, H26),
5.12 (1H, dd, J=17.0, 1.5 Hz, H26), 5.99 (1H, ddt,
J=17.0, 10.5, 6.5 Hz, H27), 7.41–7.83 (21H, m, NAP×3);
13C NMR (125 MHz, CDCl3) l; 13.3, 13.8, 14.2, 14.3,
16.2, 18.57, 18.59, 20.1, 27.8, 28.3, 29.6, 29.9, 31.8, 32.1,
33.5, 38.6, 38.7, 40.4, 40.8, 41.8, 42.7, 45.7, 46.2, 68.6, 71.4,
71.70, 71.77, 72.1, 72.4, 73.7, 74.4, 78.0, 78.8, 80.2, 81.1,
82.2, 83.2, 83.3, 84.8, 86.9, 109.2, 116.1, 125.6, 125.90,
125.93, 126.01, 126.03, 126.05, 126.1, 126.2, 126.32,
126.38, 126.39, 126.5, 127.8, 127.94, 127.97, 128.00,
128.07, 128.09, 128.42, 132.9, 133.1, 133.2, 133.4, 133.5,
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