Convergent syntheses of the enantiomeric CD- and JK-ring parts of ciguatoxin

Article abstract of DOI:10.1055/s-2001-13387

Convergent syntheses of the enantiomeric CD- and JK-ring parts of ciguatoxin, based on a coupling reaction between dithioacetal mono-S-oxide and aldehyde derivatives and reductive cyclization of the respective hydroxy ketones, have been achieved.

Full text of DOI:10.1055/s-2001-13387

LETTER
691
Convergent Syntheses of the Enantiomeric CD- and JK-Ring Parts of
Ciguatoxin
Kenshu Fujiwara,* Daisuke Takaoka, Kensuke Kusumi, Kentaro Kawai, Akio Murai*
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
E-mail: fjwkn@sci.hokudai.ac.jp
Received 14 March 2001
Scheme 1
Abstract: Convergent syntheses of the enantiomeric CD- and JK-
Our general plan for construction of the tetracyclic ether
system including 6- and 7-membered rings in the central
part is shown in Scheme 1. The success of this plan relies
ring parts of ciguatoxin, based on a coupling reaction between
dithioacetal mono-S-oxide and aldehyde derivatives and reductive
cyclization of the respective hydroxy ketones, have been achieved.
Key words: ciguatoxin, acyl anion equivalent, dithioacetal mono- on a coupling reaction of dithioacetal mono-S-oxide seg-
S-oxide, convergent synthesis, reductive etherification
ment 7 with functionalized aldehyde segment 8, formation
of dihydroxyketone 6, and stepwise reductive cycliza-
tions. Here, symmetric tricyclic and tetracyclic com-
pounds (2 and 3) corresponding to the antipodes of the
CDE and IJKL parts of 1, respectively, were selected as
the actual targets.
Ciguatoxin (1), which was isolated from the moray eel
Gymnothorax javanics as a causative toxin of ciguatera
seafood poisoning, has a particular trans-fused polycyclic
ether system including irregular-sized rings and several
functional groups.1 Aiming at the total synthesis of 1,
some efficient methods for the construction of such a
polycyclic system have been required and explored by
many research groups.2,3 Previously, we demonstrated
convergent syntheses of the simple tetracyclic ethers hav-
ing two trans-fused 6-membered ethers in the middle part
of each molecule based on the C-C bond formation using
the anion of a dithioacetal mono-S-oxide derivative.4,5
This methodology has also been applicable to the con-
struction of bicyclic systems involving both 6- and 7-
membered rings and functional groups toward the total
synthesis of 1. Here, we report convergent syntheses of
the CD- and JK-ring parts of 1.
TBSO
Br
TBSO
TBSO
OHC
a, b
c, d
O
O
O
HO
9
10 (89%)
11 (93%)
Br
O
SMe
O
SMe
HO
O
MeS
OR
e
g
O
H
SMe
12
BnO
BnO HO
BnO
O
HO
H
13: R=TBS (85% from 12)
14: R=H (100%)
15
f
HO
O
NOE
H
O
H
H
O
4
1
BnO
O
k
9
16
5
O
H
BnO
O
O
H
H
j
O
18 (47%)
h
i
Me
+
18:19=
>10:1
(85%)
O
H
Me
H
H
H
H
BnO HO
17 (74% from 14)
OH
O
H
Me
HO
H
O
4
I
O
1
J
H
O
L
K
9
H
O
5
O
H
O
M
H
H
O
H
G
H
H
BnO
H
H
O
O
H
H
H
H
H
H
H
H
19 (23%)
O
O
B
Me
E
F
OH
Me
A
O
C
O
D
H
O
H
H
H
O
9
8
4
O
H
1
Ciguatoxin (1)
n
m
HO
2
H
5
O
H
O
H
OH
OH
Me
RO HO
HO
O
OH
H
(97%)
H
H
H
H
H
O
O
20: R=Bn (84%)
21: R=H (67%)
22 (85%)
7
4 E 1
O
H
l
K 6
12
8
O
11J 9
I
O
15
D
5
5
C
1
6
4
L
O
O
H
H
3
H
H
H
Scheme 2 Reagents and conditions: (a) BuLi (2 eq), THF, 78 C,
1 h; (b) BuLi (1.4 eq), 78 C, 1 h, then (CH2O)n (2 eq), 0 C, 3 h; (c)
H2, Lindlar cat., EtOH-quinoline (250:1), 20 C, 28 h; (d) (COCl)2
(2.0 eq), DMSO (4 eq), CH2Cl2, 78 C, 15 min, then Et3N (8 eq),
20 C, 30 min; (e) 12 (2 eq), LDA (2.2 eq), THF, 78 C, 30 min, then
11, 78 C, 1.5 h; (f) TBAF (2 eq), THF, 20 C, 5 h; (g) TFA-THF-
H2O (1:10:10), 20 C, 2 h; (h) Et3SiH (10 eq), TMSOTf (1 eq),
CH2Cl2, 0 C, 1 h; (i) Dess–Martin periodinane (1 eq), CH2Cl2, 20 C,
3 h; (j) DBU (5 eq), benzene-d6, 25 C, 79 h; (k) NaBH4 (1.2 eq),
CeCl3 7H2O (2 eq), MeOH, 25 C, 30 min; (l) Na, NH3, 78 C, 30
min; (m) MnO2 (excess), Et2O, 25 C, 1 h; (n) Et3SiH (10 eq), TM-
SOTf (2 eq), CH2Cl2, 0 C, 10 min.
2
H
H
H
H
H
H
O
O
O
O
O
H
O
H
O
O
H
H
HO
H
4
5
O
HO
O
RO
O
O
SMe
+
O
H
O
H
SMe OHC
HO
RO
RO
6
7
8
Synlett 2001 No. 5, 691–693 ISSN 0936-5214 © Thieme Stuttgart · New York

692
K. Fujiwara et al.
LETTER
Tricyclic compound 2 was synthesized from aldehyde 11,
which was prepared from known 96 through a 4-step se-
quence [acetylene formation, hydroxymethylation, partial
hydrogenation, and Swern oxidation],7 and simple dithio-
acetal mono-S-oxide 125 (Scheme 2). Deprotonation of 12
with LDA followed by addition reaction with 11 afforded
13 as a mixture of diastereomers in 85% yield. Removal
of the TBS group with TBAF gave 14, which was trans-
formed into , -unsaturated dihydroxy ketone 15 on treat-
ment with TFA in aqueous THF. Because the ketone 15
was so labile to silica gel that it was decomposed into -
diketone 16 during silica gel chromatography, it was used
without further purification. The ketone 15 was cyclized
under Nicolaou’s conditions8 to produce 17 as a mixture of
four diastereomers in 74% yield from 14. The mixture was
oxidized with Dess–Martin periodinane9 to give ketones
18 and 19 in 47% and 23% yields, respectively. After de-
tailed NOE experiments on the ketones, the existence of
NOE (H4/H9) in 18 confirmed the desired stereochemis-
try. When 19 was treated with DBU in benzene-d6 at am-
bient temperature, the reaction attained equilibrium
(18:19 = >10:1) to give 18 mainly in 85% yield. After
several fruitless attempts to remove the benzyl group of
18, alcohol 22 was synthesized via a 3-step process
(Luche reduction of 18,10,11 removal of the benzyl group
by Birch reduction, and selective oxidation of the allylic
alcohol). Cyclization of 22 with Et3SiH and TMSOTf pro-
duced 212 stereoselectively in 97% yield.8 Thus, conver-
gent synthesis of 2 was achieved in 19% total yield from
11 over 10 steps.
O
O
HO
H
O
OHC
O
7
O
HO
a
b
O
O
N
6
5
1
4
Me
O
O
TBSO
TBSO
iPr
TBSO
23
24
O
N
26 (43% from 23)
iPr
25
R2O
7
6
O BnO
H
H
O
R1O
c
g
H
h
5
1
4
Me
Me
OBn
TBSO
31 (~100%)
TBSO
27: R1=H, R2=H (~100%)
O
SEt
O
d
e
f
28: R1=MMTr, R2=H (~100%)
29: R1=MMTr, R2=Bn (75%)
30: R1=H, R2=Bn (93%)
EtS
32
Ph
C
Ph
Me
MMTr:
OMe
OBn
H
O
H
O
BnO
8
l
9
5
1
Me
4
O
H
O
OBn
H
O
BnO
RO
H
34: R=TBS (10%)
35: R=H (29%)
j (~100%)
k (91%)
O
i
O
H
SEt
EtS
+
Me
OBn
O
OTBS
H
O
BnO
H
33 (96% from 31)
8
O
1
5
4
O
H
9
SEt
HO
36 (26%)
Me
Me
OBn
H
OR
H
H
O
BnO
RO
O
8
9
O
o
m
O
O
9
3
4
4
O
H
O
O
H
H
H
H
H
(86%)
37 (97%)
38: R=Bn (98%)
n
39: R=H (91%)
Scheme 3 Reagents and conditions: (a) (COCl)2 (1.5 eq), DMSO
(2.4 eq), CH2Cl2, 78 C, 20 min, then Et3N (5 eq), 78 18 C,
The synthesis of tetracyclic compound 3 is shown in
Scheme 3. The aldehyde segment 31 was prepared start-
ing from 23.13 Oxidation of 23 gave unstable aldehyde 24,
which was immediately subjected to Evans aldol reaction
with 2514 to produce 26 with the desired stereochemistry15
in 43% yield from 23. Reduction of 26 followed by se-
quential protection, deprotection, and oxidation afforded
aldehyde 31 in 70% total yield over 5 steps. Coupling re-
action of dithioacetal mono-S-oxide segment 325 with 31
led to formation of 33 as a mixture of diastereomers in
96% yield. After several attempts hydrolysis of the dithio-
acetal mono-S-oxide and TBS groups of 33 was achieved.
When 33 was treated with CuCl2 in wet methanol at am-
bient temperature until the substrate was completely con-
sumed, dihydroxy ketone 35 was given predominantly.
Although partially hydrolyzed 34 and vinylsulfide 36
were also afforded under these conditions, each product
could be converted to 35 by treatment with TsOH.16 Even-
tually, 35 was obtained in 65% total yield from 33. Reduc-
tive cyclization of 35 gave selectively tricyclic 37 in 97%
yield, which was oxidized to ketone 38 in 98% yield. Af-
ter removal of two benzyl groups of 38, dihydroxy ketone
39 was cyclized to give tetracyclic 3,17 stereoselectively in
86% yield. Accordingly, the model compound 3 corre-
sponding to the JK-rings in 1, was convergently synthe-
sized in 43% total yield from 31 over 7 steps.
13 min; (b) 25 (1.2 eq), Bu2BOTf (1.2 eq), Et3N (1.3 eq), CH3Cl2, 0
C, 50 min, then 78 C, 75 min, then 24, 78 C, 40 min, then 20
C, 100 min; (c) NaBH4 (6 eq), THF-H2O (3:1), 25 C, 2.8 h; (d)
MMTrCl (1.2 eq), DMAP (0.5 eq), CH2Cl2-pyridine (10:1), 23 C,
2.7 h; (e) NaH (excess), BnBr (14 eq), TBAI (0.5 eq), THF, 24 C, 20
h; (f) PPTS (0.05 eq), MeOH-CH2Cl2 (5:1), 23 C, 5 h; (g) (COCl)2
(3.0 eq), DMSO (4.6 eq), CH2Cl2, 78 C, 20 min, then Et3N (10 eq),
78 0 C, 15 min; (h) 33 (1.6 eq), LDA (1.6 eq), THF, 78 C, 30
min, then 32, 78 C, 25 min; (i) CuCl2 (20 eq), MeOH, 22 C, 20 h;
(j) p-TsOH H2O (cat.), TFA-THF (1:3), 21 C, 21 h; (k) p-
TsOH H2O (0.8 eq), MeOH, 22 C, 12 h; (l) Et3SiH (8.7 eq), TM-
SOTf (2 eq), CH2Cl2, 0 C, 30 min; (m) Des–Martin periodinane
(1 eq), CH2Cl2, 23 C, 2 h; (n) H2, 10% Pd/C, MeOH, 22 C, 4 h; (o)
Et3SiH (10 eq), TMSOTf (2 eq), CH2Cl2, 0 C, 30 min.
Thus, we have achieved convergent syntheses of the CD-
and JK-ring parts of 1 based on the coupling reaction
between dithioacetal mono-S-oxide and aldehyde deriva-
tives and reductive cyclization of the respective hydroxy
ketones. Further studies directed toward the total synthe-
sis of ciguatoxin (1) are currently in progress in our labo-
ratory.
Acknowledgement
This study was financially supported by Grants-in-Aid from the Mi-
nistry of Education, Culture, Sports, Science, and Technology Ja-
pan (No. 11780409, K.F. and No. 10308027, A.M.).
Synlett 2001, No. 5, 691–693 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Convergent Syntheses of the Enantiomeric CD- and JK-Ring Parts of Ciguatoxin
693
1095, 1028, 955, 683, 665 cm−1; HR-FDMS, calcd. for
C12H18O3 [M]: 210.1256, found: 210.1264.
(13) Nicolaou, K. C.; Hwang, C.-K.; Marron, B. E.; DeFrees, S. A.;
Couladouros, E. A.; Abe, Y.; Carroll, P. J.; Snyder, J. P. J. Am.
Chem. Soc. 1990, 112, 3040.
(14) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127.
(15) The stereochemistry at C6 and C7 was confirmed by the
detailed NMR analyses of 40 and 41, derived from 27, as
shown in Figure 1.
References and Notes
(1) For reviews on 1 and related compounds, see: a) Yasumoto,
T.; Murata, M. Chem. Rev. 1993, 93, 1897. b) Scheuer, P. J.
Tetrahedron 1994, 50, 3. For absolute configuration of 1, see:
c) Satake, M.; Morohashi, A.; Oguri, H.; Oishi, T.; Hirama,
M.; Harada, N.; Yasumoto, T. J. Am. Chem. Soc. 1997, 119,
11325.
(2) For our synthetic studies on 1, see: (a) Oka, T.; Fujiwara, K.;
Murai, A. Tetrahedron 1996, 52, 12091. (b) Atsuta, H.;
Fujiwara, K.; Murai, A. Synlett 1997, 307. (c) Oka, T.; Murai,
A. Tetrahedron 1998, 54, 1. (d) Oka, T.; Fujiwara, K.; Murai,
A. Tetrahedron 1998, 54, 21. (e) Fujiwara, K.; Tanaka, H.;
Murai, A. Chem. Lett. 2000, 610.
(3) For recent synthetic studies on ciguatoxin, see: (a) Oishi, T.;
Shoji, M.; Kumahara, N.; Hirama, M. Chem. Lett. 1997, 845.
(b) Oishi, T.; Maeda, K.; Hirama, M. Chem. Commun. 1997,
1289. (c) Hosokawa, S.; Isobe, M. J. Org. Chem. 1999, 64, 37.
(d) Sasaki, M.; Noguchi, T.; Tachibana, K. Tetrahedron Lett.
1999, 40, 1337. (e) Saeeng, R.; Isobe, M. Tetrahedron Lett.
1999, 40, 1911. (f) Sasaki, M.; Fuwa, H.; Ishikawa, M.;
Tachibana, K. Org. Lett. 1999, 1, 1075. (g) Oguri, H.; Sasaki,
S.; Oishi, T.; Hirama, M. Tetrahedron Lett. 1999, 40, 5405.
(h) Inoue, M.; Sasaki, M.; Tachibana, K. J. Org. Chem. 1999,
64, 9416. (i) Maeda, K.; Oishi, T.; Oguri, H.; Hirama, M.
Chem. Commun. 1999, 1063. (j) Oishi, T.; Maruyama, M.;
Shoji, M.; Maeda, K.; Kumahara, N.; Tanaka, S.; Hirama, M.
Tetrahedron 1999, 55, 7471. (k) Oishi, T.; Nagumo, Y.; Shoji,
M.; Brazidec, J.-Y. L.; Uehara, H.; Hirama, M. Chem.
Commun. 1999, 2035. (l) Sasaki, M.; Inoue, M.; Takamatsu,
K.; Tachibana, K. J. Org. Chem. 1999, 64, 9399. (m) Oguri,
H.; Tanaka, S.; Oishi, T.; Hirama, M. Tetrahedron Lett. 2000,
41, 975. (n) Sasaki, M.; Noguchi, K.; Fuwa, H.; Tachibana, K.
Tetrahedron Lett. 2000, 41, 1425. (o) Liu, T.-Z.; Isobe, M.
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Isobe, M. Tetrahedron 2000, 56, 10209.
NOE
NOE
OPiv
7
1.5 Hz
Me
H8e
O
8
O
Me
H4
H6
H
O
O
H7
R
H
7
O
O
6
Me
5
4
Me
R'
O
1
O
6
5
H8a
O
1
Me
TBSO
40
O
4
2.7 Hz
H6
Me
NOE
O
H
H5
7.7 Hz
9.2 Hz
2.4 Hz
41
Figure 1
(16) Fujiwara, K.; Murai, A; Yotsu-Yamashita, M; Yasumoto, T. J.
Am. Chem. Soc. 1998, 120, 10770.
(17) Representative data for 3: colorless crystals, mp. 141-145 C;
[ ]D25+10.8 (c 0.24, CHCl3); 1H NMR (400 MHz, C6D6,
C6HD5 as 7.15 ppm), 1.15 (3H, d, J = 7.5 Hz, H16), 1.10-
1.20 (2H, m, H2a, H14a), 1.24-1.47 (4H, m, H2b, H3ax,
H13ax, H14b), 1.73 (1H, q, J = 11.2 Hz, H10ax), 1.86-1.93
(1H, m, H13eq), 1.93-2.01 (2H, m, H3eq, 6-OH), 2.36 (1H,
ddq, J = 2.9, 5.9, 7.5 Hz, H7), 2.53 (1H, ddd, J = 3.7, 5.2, 11.2
Hz, H10eq), 2.79-2.84 (1H, m, H12), 2.84-2.90 (1H, m, H1),
2.92-3.06 (4H, m, H1ax, H5, H8, H15ax), 3.58-3.66 (3H, m,
H1eq, H4, H15eq), 3.81 (1H, br s, H6), 4.08 (1H, ddd, J = 5.2,
9.3, 11.2 Hz, H9); 13C NMR (100 MHz, C6D6, 13CC5D6 as
128.0 ppm), 20.1 (C16), 25.8 (C2, C14), 29.7 (C13), 31.1
(C3), 38.7 (C10), 42.6 (C7), 67.4 (C15), 67.6 (C1), 72.7 (C4),
75.2 (C9), 76.9 (C11), 77.7 (C6, C12), 81.3 (C5), 87.5 (C8);
IR (film), 3428, 2954, 2937, 2897, 2853, 1461, 1449, 1441,
1368, 1350, 1307, 1285, 1272, 1260, 1250, 1221, 1124, 1104,
1095, 1063, 1040, 1029, 1022, 996, 973, 965, 945, 928 cm−1;
HR-EIMS, calcd. for C16H26O5 [M]: 298.1780, found:
298.1805. HMBC spectra measured in C6D6 clarified the
linkages of C4-O-C9 and C8-O-C12 by giving cross peaks due
to 3JCH between C4/H9, C9/H4, and C8/H12. The trans-fused
structure of 3 was confirmed by NOEs between H4/H9 and
H8/H12 [measured in C6D6-CDCl3 (1:1)] as well as a large
3JH8-H9 value (9.3 Hz). Existence of NOE between H7/H9
proved that the stereochemistry at C7 was unchanged under
the final reductive cyclization conditions (Figure 2).
(4) (a) Ogura, K.; Tsuchihashi, G. Tetrahedron Lett. 1972, 2681.
(b) Herrmann, J. L.; Richman, J. E.; Wepplo, P. J.;
Schlessinger, R. H. Tetrahedron Lett. 1973, 4707.
(5) Fujiwara, K.; Saka, K.; Takaoka, D.; Murai, A. Synlett 1999,
1037.
(6) Alvarez. E.; Pérez, R.; Rico, M.; Rodríguez, R. M.; Martín, J.
D. J. Org. Chem. 1996, 61, 3003.
(7) (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. (b)
Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978,
43, 2480. (c) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(d) Tidwell; T. T. Org. React. 1990, 39, 297.
(8) Nicolaou, K. C.; Hwang, C.-K., Nugiel, D. A. J. Am. Chem.
Soc. 1989, 111, 4136.
Me
H
(9) (a) Dess, D.B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D.B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
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(10) (a) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226. (b)
Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
(11) Alcohol 20 was obtained as the only stereoisomer. See, ref 3j.
(12) Representative data for 2: colorless needles, mp. 33-35 C; 1H
NMR (300 MHz, CDCl3), 1.38-1.53 (2H, m, H3ax), 1.60-
1.75 (4H, m, H2), 2.00-2.10 (2H, m, H3eq) 3.18-3.36 (4H, m,
H1ax and H4), 3.73 (2H, br d, J = 8.6 Hz, H5), 3.85-3.92 (2H,
m, H1eq), 5.57 (2H, br s, H6); 13C NMR (75 MHz, CDCl3),
25.4 (C2), 31.2 (C3), 67.4 (C1), 79.2 (C4), 81.2 (C5), 132.1
(C6); IR (film), 2940, 2850, 1463, 1442, 1258, 1218, 1124,
OH
H
H
H
O
3
7
6
12
8
O
15
O
9
11
5
1
4
O
NOE:
3JH8-H9 = 9.3 Hz
H
H
H
Figure 2
Article Identifier:
1437-2096,E;2001,0,05,0691,0693,ftx,en;Y05901ST.pdf
Synlett 2001, No. 5, 691–693 ISSN 0936-5214 © Thieme Stuttgart · New York