Convergent synthesis of the ABCDE-ring part of ciguatoxin CTX3C

Article abstract of DOI:10.1016/j.tetlet.2004.07.145

The ABCDE-ring part (2) of ciguatoxin CTX3C was concisely synthesized from the AB-ring and the E-ring parts (4 and 5).

Full text of DOI:10.1016/j.tetlet.2004.07.145

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7011–7014
Convergent synthesis of the ABCDE-ring part
of ciguatoxin CTX3C
Kenshu Fujiwara,* Akiyoshi Goto, Daisuke Sato, Yuko Ohtaniuchi, Hideki Tanaka,
Akio Murai,ꢀ Hidetoshi Kawai and Takanori Suzuki
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 30 June 2004; revised 28 July 2004; accepted 30 July 2004
Abstract—Convergent synthesis of the ABCDE-ring part (2) of ciguatoxin CTX3C (1) has been achieved. A carbanion stabilized by
a dimethyldithioacetal S-oxide group in the AB-ring part (4) readily reacted with an aldehyde group in the E-ring part (5). The
resulting adduct was facilely converted to the corresponding b,c-unsaturated a,e-dihydroxy ketone (3). The subsequent reductive
hydroxy-ketone-cyclization reactions constructed the CD-ring part efficiently. Thus, the ABCDE-ring part (2) was concisely synthe-
sized in 10 steps in 11% overall yield from the AB-ring and the E-ring parts (4 and 5).
Ó 2004 Elsevier Ltd. All rights reserved.
CTX3C (1)1 was isolated as a congener of ciguatoxin
(CTX)2 from cultured dinoflagellate Gambierdiscus toxi-
cus by the Yasumoto group. It shows potent neurotox-
icity [ip LD50 (mouse): 1.3lg/kg]1 by strong binding to
voltage-sensitive sodium channels.3 Its unique ladder-
shaped trans-fused polycyclic structure possessing 13
ether rings is a synthetic challenge and has attracted
the attention of synthetic chemists.4,5 During the course
of our studies directed toward CTXs,6 we achieved the
syntheses of their individual medium ring parts6h and
developed a convergent method for the construction of
their X/6/7/X ring systems.6g Here, efficient convergent
synthesis of the ABCDE-ring part (2)7 of 1 based on
our established methodology is described.
dihydroxy ketone 3. The subsequent reductive hydr-
oxy-ketone cyclization reactions9 would construct the
CD-ring part. We designed the synthesis of 4 from D-
glucose derivative 6 through A-ring formation by ring-
closing olefin metathesis reaction (RCM). The E ring 5
was planned to be synthesized according to our previous
method.6h The medium ring part would be constructed
by RCM of the corresponding diene precursor 7 derived
from the tri-O-acetyl D-glucal via C-glycoside 8.
The synthesis of 4, started from known D-glucose
derivative 6,10 is shown in Scheme 2. The diol 6 was
converted to 1,1,3,3-tetraisopropyldisiloxan-1,3-diyl
(TIPDS) derivative 9 (95% yield). Selective deprotection
of the allyl group in 9 using Ogasawaraꢁs method11 fol-
lowed by Swern oxidation12 and addition of an allyl
Grignard reagent to the resulting lactone produced
hemiacetal 10 (87% overall yield), which was treated
with EtSH in the presence of BF3ÆOEt2 to afford diol
11 (80% yield). Conversion of 11 to diol 12 was per-
formed through a three-step process [(i) oxidation of
the ethylthio group of 11 followed by one-pot reductive
etherification; (ii) formation of a 2-naphthylmethylidene
acetal; and (iii) removal of the TIPDS group] (66% over-
all yield). Diol 12 was selectively protected by TBS and
the resultant alcohol was transformed into allyl ether 13,
which was converted to 15 through RCM using Grubbsꢁ
first-generation ruthenium catalyst13 followed by depro-
tection of the TBS group (40% overall yield from 12).
After protection of 15 as a p-bromobenzyl (PBB) ether,
We planned to synthesize the ABCDE-ring part 2 from
two parts, AB-ring 4 and E-ring 5 (Scheme 1).6i The
dimethyldithioacetal mono-S-oxide group of 4 would
be deprotonated facilely by an appropriate amide base
to give an acyl anion equivalent,8 which would be read-
ily coupled with aldehyde 5. The resulting adduct would
be converted to the corresponding b,c-unsaturated a,e-
Keywords: Polyether; Ciguatoxin CTX3C; Natural product synthesis;
Acyl anion equivalent; Convergent synthesis.
*
Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706
4924; e-mail: fjwkn@sci.hokudai.ac.jp
ꢀ Present address: 6-14-44, Asabu-cho, Kita-ku, Sapporo 001-0045,
Japan.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.145

7012
K. Fujiwara et al. / Tetrahedron Letters 45 (2004) 7011–7014
Me
H
H
OHC
O
HO
D-Glucose
H
Tri-O-acetyl
D-glucal
O
H
Me
H
O
Me
L
I
O
H
K
TBSO
O
Ph
H
H
H
G
H
J
O
OH
H
H
H
H
H
H
O
TBSO
O
H
O
B
E
H
H
O
H
H
8
F
D
H
AllO
O
C
O
A
O
O
H
TBSO
O
O
O
H
O
M
H
H
O
Me
HO
O
Ph
PBB: 4-Bromobenzyl
O
OH
H
Ciguatoxin CTX3C (1)
Me
TBSO
NAP: 2-Naphthylmethyl
Ph
HO
H
O
6
7
α,ε-Dihydroxy Ketone
Formation
Reductive Etherification
O
Me
H
H
H
HO
O
H
H
S
H
H
H
H
H
H
TBSO
OH
OBn
O
O
B
O
E
O
S
Me
OBn
OBn
E
D
C
O
A
O
A
O
B
O
O
H
H
H
O
H
OHC
O
HO
ONAP
PBBO
H
H
H
ONAP
H
H
H
H
OH
OBn
PBBO
BnO
4
5
3
2
Reductive Etherification
Scheme 1. Synthetic plan for the ABCDE-ring part (2) of CTX3C (1).
H
H
H
The E-ring part 5 was synthesized from the previously
reported aldehyde 8,6h prepared from tri-O-acetyl D-glu-
cal in six steps in 49% overall yield (Scheme 3). Allyl-
ation of 8 by chiral allylboron reagent 1814 gave
homoallyl alcohol 19 as the sole product (93% yield).
Removal of the TBS groups of 19 followed by oxidative
cleavage of the resulting 1,2-diol and the subsequent
reduction gave triol 20 (96% overall yield). The triol
20 was selectively protected with phenyl boronic acid
and acetic anhydride to afford 21, which was trans-
formed into bis-TBS ether 22 through a deprotection/
protection sequence (64% overall yield from 20). The
bis-TBS ether 22 was converted to diene 7 by a three-
step process [(i) removal of the acetyl group; (ii) Swern
oxidation;12 and (iii) Wittig reaction]. Cyclization of 7
using Grubbsꢁ second-generation ruthenium catalyst15
followed by selective partial removal of the TBS group
gave 23 (ꢀ100% overall yield). The alcohol 23 was oxi-
dized to the corresponding aldehyde, which was con-
verted to 24 through dibromoolefination followed by
removal of the benzylidene acetal group (88% overall
yield). When the diol 24 was protected with benzyl bro-
mide under the basic conditions, dehydrobromination
took place synchronously and bromoacetylene 25 was
obtained in good yield (100%). The bromoacetylene 25
was transformed into 5 through hydroxymethylation,
Lindlar hydrogenation and Dess–Martin oxidation16
reactions (88% overall yield). Thus, the E-ring part 5
was prepared from the known 8 in 20 steps in 38% over-
all yield.
AllO
HO
O
O
O
AllO
O
O
a
b, c, d
O
Ph
O
O
Ph
H
HO
TIPDS
6
9
TIPDS: -(i-Pr)2SiO(i-Pr)2Si-
SEt
O
OH
H
O
OH
O
e
f, g, h
O
OH
O
O
Ph
H
O
O
TIPDS
TIPDS
10
11
H
H
O
O
i, j
O
O
k
O
HO
O
O
Np
Np
O
O
Np
p
H
H
HO
TBSO
13
12
H
H
H
O
O
n, o
OTf
ONAP
OPBB
17
4
O
O
H
H
OR
14: R=TBS
15: R=H
16: R=PBB
H
l
m
Scheme 2. Synthesis of the AB-ring part 4. Reagents and conditions:
(a) Cl(i-Pr)2SiO(i-Pr)2SiCl, imidazole, DMF, 23°C, 95%; (b) Et3Al,
[NiCl2(dppp)] (cat.), toluene, 0 ! 24°C, 99%; (c) (COCl)2, DMSO,
CH2Cl2, ꢁ78°C, then Et3N, ꢁ78 ! 0°C; (d) allylmagnesium bromide,
Et2O, ꢁ78°C, 88% from 9; (e) EtSH, BF3ÆOEt2, CH2Cl2, ꢁ20°C, 80%;
(f) mCPBA, CH2Cl2, 0°C, then Et3SiH, BF3ÆOEt2, 0°C, 80%; (g) 2-
naphthaldehyde, PPTS, benzene, reflux, 92%; (h) TBAF, THF, 23°C,
90%; (i) TBSOTf, 2,6-lutidine, CH2Cl2, ꢁ78°C; (j) allyl bromide, NaH,
Bu4NI, THF, 0°C; (k) (Cy3P)2Cl2Ru@CHPh (cat.), CH2Cl2, reflux; (l)
TBAF, THF, 23°C, 40% from 12; (m) 4-bromobenzyl bromide, NaH,
Bu4NI, THF, 24°C; (n) LiAlH4, AlCl3, CH2Cl2–Et2O, 24°C; (o) Tf2O,
2,6-lutidine, CH2Cl2, ꢁ78°C; (p) MeSCH2S(O)Me, BuLi, THF,
ꢁ20°C, then 17, ꢁ20 ! 0°C, 59% from 15.
Convergent construction of the CD-ring part is illus-
trated in Scheme 4. Deprotonation of 4 with NaHMDS
followed by the reaction with 5 (0.32equiv) gave 28 in
54% yield based on 5 along with recovered 4 (62% recov-
ery). The adduct 28 was transformed into a,e-dihydr-
oxy-b,c-unsaturated ketone 3 through removal of the
TBS group with TBAF followed by treatment with
TFA in aqueous THF (50% overall yield). The ketone
3 was stable enough to be purified by silica gel flash
chromatography. Cyclization of 3 was performed with
an excess amount of Et3SiH in the presence of TMSOTf
in CH2Cl2 to produce two tetracyclic ethers 30 (47%
yield) and 31 (47% yield), which were separately oxi-
dized with DMPI to give 32 (ꢀ100% yield) and 33
reductive cleavage of the naphthylidene acetal 16 and
the subsequent formation of a triflate ester gave 17.
The triflate was substituted by lithiated methylthio-
methyl methyl sulfoxide to produce 4 (59% overall yield
from 15). Thus, the AB-ring part 4 was synthesized from
6 in 16 steps in 12% overall yield.

K. Fujiwara et al. / Tetrahedron Letters 45 (2004) 7011–7014
7013
H
H
H
O
OHC
O
a
b, c, d
O
HO
O
TBSO
O
Ph
TBSO
O
Ph
H
CO2i-Pr
TBSO
TBSO
O
B
8
9
CO2i-Pr
O
18
Ph
B
H
H
H
OAc
H
O
O
e, f
g, h
HO
O
O
O
O
HO
O
Ph
H
Ph
H
HO
20
O
21
OAc
H
TBSO
TBSO
TBSO
TBSO
i, j, k
l, m
H
O
O
O
O
H
7
Ph
Ph
H
O
O
22
TBSO
HO
TBSO
Br
n, o, p
H
O
q, r
OH
OH
O
O
H
Ph
Br
24
O
23
TBSO
TBSO
R
s, t
OBn
OBn
OBn
OBn
Scheme 4. Synthesis of the ABCDE-ring part 2. Reagents and
5
O
O
X
conditions: (a) NaHMDS (0.97equiv), THF, ꢁ78°C, then
(0.32equiv), 28: 54% from 5, recovered 4: 62%; (b) TBAF, THF,
23°C, 93%; (c) THF–H2O–TFA (10:10:1), 23°C, 54%; (d) TMSOTf
(2equiv), Et3SiH–CH2Cl2 (1:2), 0°C, 30: 47%, 31: 47%; (e) DMPI,
CH2Cl2, 23°C, ꢀ100%; (f) DMPI, CH2Cl2, 23°C, 81%; (g) DBU,
toluene, 90°C, 32: 33%, 33: 67%; (h) DDQ, CH2Cl2–pH 7 phosphate
buffer (10:1), 0°C, 81%; (i) TMSOTf (2equiv), Et3SiH–CH2Cl2 (1:4),
0°C, 93%; (j) LDBB (excess), THF, ꢁ78°C, 78%.
25: X=Br
26: X=CH2OH
27: R=CH2OH
5: R=CHO
Scheme 3. Synthesis of the E-ring part 5. Reagents and conditions: (a)
18, CH2Cl2, ꢁ78°C, 93%; (b) TBAF, THF, 23°C; (c) NaIO4, 1,4-
dioxane-H2O, 23°C; (d) NaBH4, MeOH, 0 ! 23°C, 96% from 19; (e)
PhB(OH)2, benzene, reduced pressure; (f) Ac2O, DMAP (cat.),
pyridine, 24°C; (g) H2O2, EtOAc, 24°C; (h) TBSOTf, 2,6-lutidine,
CH2Cl2, 24°C, 64% from 20; (i) DIBAH, CH2Cl2, ꢁ78°C; (j) (COCl)2,
DMSO, CH2Cl2, ꢁ78°C, then Et3N, ꢁ78 ! ꢁ20°C; (k) Ph3PCH3Br,
NHMDS, THF, ꢁ78 ! 23°C, 85% from 22; (l) [{CH2(Mes)N}2C]
(Cy3P)(Cl)2Ru@CHPh (cat.), CH2Cl2, reflux, ꢀ100%; (m) AcOH–
THF–H2O (3:1:1), 23°C, ꢀ100%; (n) (COCl)2, DMSO, CH2Cl2,
ꢁ78°C, then Et3N, ꢁ78 ! ꢁ20°C; (o) Ph3P, CBr4, CH2Cl2, 0°C, 98%
from 23; (p) ethanedithiol, BF3ÆOEt2, CH2Cl2, ꢁ30°C, 90%; (q) BnBr,
NaH, Bu4NI, THF, 24°C, ꢀ100%; (r) MeLi, THF, ꢁ20°C, then
(CH2O)n, 0°C, 93%; (s) H2, Lindlar cat., EtOH–quinoline (250:1),
95%; (t) DMPI, NaHCO3, CH2Cl2, 23°C, ꢀ100%.
In conclusion, convergent synthesis of the ABCDE-ring
part (2) of ciguatoxin CTX3C has been achieved from
the AB-ring 4 and the E-ring 5. A carbanion derived
from 4 readily reacted with the aldehyde group of 5.
The resulting adduct 28 was facilely converted to the
corresponding b,c-unsaturated a,e-dihydroxy ketone 3.
The subsequent reductive hydroxy-ketone-cyclization
reactions constructed the CD-ring part efficiently. Fur-
ther studies toward total synthesis of ciguatoxin CTX3C
are currently under way in our laboratory.
(81% yield), respectively. The presence of NOE between
H11 and H16 in 33 showed that 33 had the desired ste-
reochemistry. The undesired 32 was isomerized into 33 by
treatment with DBU in toluene at 90°C according to the
Hirama and co-workers procedure.17 Selective removal
of the NAP group in 33 with DDQ gave 34 (81% yield),
which was efficiently cyclized with Et3SiH–TMSOTf
reagent system into pentacyclic ether 35 (93% yield).
At this stage, the pentacyclic structure of 35 was con-
firmed by X-ray crystallographic analysis.18 Treatment
of 35 with an excess amount of lithium 4,40-di-tert-
butylbiphenylide (LDBB) induced not only benzyl
detachment from oxygenes at C20 and C22 but also con-
version of the PBBO group at C7 to a BnO group to
produce 2 successfully (78% yield).19 Thus, concise con-
vergent construction of the ABCDE-ring part 2 of
CTX3C from the AB-ring part 4 and E-ring part 5
was achieved in ten steps, including an isomerization
step, in 11% overall yield based on 5.
Crystallographic data (excluding structure factors) of 35
have been deposited with the Cambridge Crystallo-
graphic Data Center as supplementary publication num-
bers CCDC 243276. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44 (0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
We thank Mr. Kenji Watanabe and Dr. Eri Fukushi
(GC–MS and NMR Laboratory, Graduate School of
Agriculture, Hokkaido University) for the measure-
ments of mass spectra. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology
of Japanese Government.

7014
K. Fujiwara et al. / Tetrahedron Letters 45 (2004) 7011–7014
H.; Kawai, K.; Fujiwara, K.; Murai, A. Tetrahedron 2002,
58, 10017.
References and notes
7. The ABCDE ring part 2 was first reported by Hirama, see:
Ref. 4a. Alternative synthesis of the same part was
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˚
˚
´
P212121 (No. 19), a = 4.912(2)A, b = 18.371(6)A, c =
F. M.; Cintado, C. G.; Morales, E. Q.; Brouard, I.; Dıaz,
´
49.95(1)A, V = 3695(2)A , Dc (Z = 4) = 1.387g/cm3,
T = 153K, l = 11.70cmꢁ1. The final R value is 0.060 for
2596 independent reflections with I > 3rI and 470
parameters.
3
˚
˚
´
´
M. T.; Rico, M.; Rodrıguez, E.; Rodrıguez, R. M.; Perez,
´
´
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19. Under the conditions, the PBB group at C7-oxygen of 35
was not removed but effectively converted to a Bn group.
It could be explained as follows: The PBB group was first
reduced by LDBB into an electron-rich p-lithiobenzyl
group, which was not further affected by LDBB; Then,
reductive cleavage of the Bn ether parts at C20 and C22
took place; Finally, protonation of the p-lithiobenzyl
group during workup produced the benzyl group at C7-
oxygen. The details will be described elsewhere.