Improvded synthesis of the A-E ring segment of ciguatoxin CTX3C

Article abstract of DOI:10.3987/COM-13-S(S)106

The improved synthesis of the A-E ring segment of ciguatoxin CTX3C was performed via a highly convergent approach based on intramolecular allylation-RCM methodology.

Full text of DOI:10.3987/COM-13-S(S)106

HETEROCYCLES, Vol. 88, No. 2, 2014
969
HETEROCYCLES, Vol. 88, No. 2, 2014, pp. 969 - 973. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 3rd August, 2013, Accepted, 28th August, 2013, Published online, 6th September, 2013
DOI: 10.3987/COM-13-S(S)106
IMPROVDED SYNTHESIS OF THE A-E RING SEGMENT OF
CIGUATOXIN CTX3C
Kengo Shiroma, Hiroki Asakura, Tokihiro Tanaka, Hiroyoshi Takamura,
and Isao Kadota*
Department of Chemistry, Graduate School of Natural Science and Technology,
Okayama University, 3-1-1 Tsushimanaka, Kitaku, Okayama 700-8530, Japan
e-mail: kadota-i@okayama-u.ac.jp
Dedicated to Professor Victor Snieckus on the occasion of his 77th birthday.
Abstract – The improved synthesis of the A-E ring segment of ciguatoxin
CTX3C was performed via a highly convergent approach based on intramolecular
allylation-RCM methodology.
Ciguatoxin CTX3C (1),1 one of the causative toxin of “ciguatera” seafood poisoning, was isolated from
cultured dinoflagellate Gambierdiscus toxicus (Figure 1).2 The unique structural features and potent
neurotoxicity of this molecule have attracted significant attention of synthetic chemists. 3,4 Herein, we
wish to describe the improved synthesis of the A-E ring segment of ciguatoxin CTX3C as a part of the
synthetic study of 1.
Figure 1. Structure of ciguatoxin CTX3C (1)
Previously, we reported the convergent synthesis of A-E ring segment of 1 as shown in Scheme 1.5,6
The ester 2, prepared from an AB ring carboxylic acid and E ring alcohol, was converted to
-chloroacetoxy ether 4 via the reaction with -methoxyallylstannane 3. The intramolecular allylation

970
HETEROCYCLES, Vol. 88, No. 2, 2014
of 4 followed by ring-closing metathesis provided the A-E ring segment 5.7 In this paper, we wish to
describe the improved synthesis of the A-E ring segment having a suitable side chain for the construction
of the F ring moiety.
Scheme 1
To improve the efficiency of the synthesis, we planed to perform the reaction of 3 with the AB ring
moiety before the segment coupling. Selective tosylation of known diol 66b with TsCl/pyridine gave
monotosylate 7 in 96% yield (Scheme 2). Reaction of the alcohol 7 with -methoxyallylstannane 3 in
the presence of CSA provided the mixed acetal 8 as a mixture of diastereoisomers in 92% yield.8
Treatment of 8 with NaCN in DMSO afforded 9 in 92% yield. DIBAL-H reduction of the nitrile 9
followed by Pinnick oxidation of the resulting aldehyde gave carboxylic acid 10, which was subjected to
the Yamaguchi esterification with the alcohol 11 to provide ester 12 in 87% overall yield.9 Treatment of
12 with TMSI/HMDS gave allylic stannane 13 in 86% yield.8 Modified Rychnovsky acetylation of the
ester 13 provided the -chloroacetoxy ether 4.10,11
Scheme 2. Reagents and conditions: (a) TsCl, pyridine, 0 ºC, 96%; (b) 7, CSA, CH2Cl2, rt,
92%; (c) NaCN, DMSO, 70 ºC, 92%; (d) (i) DIBAL-H, CH2Cl2, -78 ºC; (ii) NaClO2, NaH2PO4,
2-methyl-2-butene, t-BuOH/H2O, 0 ºC; (e) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, then
11, DMAP, toluene, rt, 87% (3 steps); (f) TMSI, HMDS, CH2Cl2, -15 to 0 ºC, 86%; (g)
DIBAL-H, toluene, -78 ºC, then (ClCH2CO)2O, DMAP, -78 to 0 ºC.

HETEROCYCLES, Vol. 88, No. 2, 2014
971
We next examined the key reaction, intramolecular allylation of 4 (Table 1). In our previous work, the
reaction was carried out with BF3·OEt2/MS4A in MeCN/CH2Cl2 to give a 4:1 mixture of the desired
products 14 and its diasteroisomer 15 in 60% yield (entry 1).5 After several experiments, we found that
the use of the conditions described in entry 2 gave better result. Thus, the reaction of 4 with
MgBr2·OEt2/MS5A in toluene provided a 92:8 mixture of 14 and 15 in 85% overall yield. Although
actual effects of the conditions used were not clear yet, it contributes to an improvement of the synthesis.
Table 1. The reaction of -acetoxy ether 4a
H
H
H
H
O
H
O
O
H
H
H
H
H
H
H
H
H
H
H
H
O
Ph
O
O
O
Ph
+
C
O
O
O
O
H H
O
OR
H
H
O
H
O
O
O
H
H
NAPO
NAPO
SnBu3
R = COCH2Cl
14
15
4
entry
Lewis acid
BF3·OEt2
additive
MS4A
MS5A
yieldb
60%
85%
solvent
temperature
-40 ºC
ratio (14:15)
80 : 20
1
2
MeCN/CH2Cl2 (10:1)
MgBr2·OEt2
toluene
0 ºC
92 : 8
b
aThe reactions were carried out with 5 equiv of Lewis acid. Isolated yields.
Further transformation was carried out as shown in Scheme 3. Ring-closing metathesis of 14 with the
Grubbs’ catalyst 16 provided the pentacyclic ether 5 in 82% yield (Scheme 3).12 Thus, the key synthetic
intermediate 5 was obtained in 39% overall yield by 10 steps from the diol 6. In our previous synthesis
of 5 from 6, the overall yield was 11% by 13 steps. Removal of the benzylidene acetal of 5 with CSA in
MeOH afforded 17 in 93% yield. Selective tosylation of the primary alcohol of 17 with TsCl/pyridine
followed by TBS protection of the remaining secondary alcohol with TBSOTf/2,6-lutidine gave tosylate
18 in 83% overall yield. Treatment of 18 with NaCN in DMSO afforded nitrile 19 in 98% yield.
Reduction of 19 with DIBAL-H followed by LiAlH4 provided alcohol 20. Removal of the TBS
protective group of 20 with TBAF followed by selective protection of the remaining primary alcohol with
TBDPSCl/Et3N/DMAP furnished the A-E ring segment 21 in 82% overall yield.
In conclusion, an improved synthesis of the A-E ring segment of ciguatoxin CTX3C (1) was performed
by using a highly convergent synthetic strategy. Moreover, the key reaction steps, preparation of the
-chloroacetoxy ether 3 and its cyclization, were considerably optimized. Further studies towards the
total synthesis of 1 are in progress in our laboratory.

972
HETEROCYCLES, Vol. 88, No. 2, 2014
Scheme 3. Reagents and conditions: (a) 16, CH2Cl2, reflux, 82%; (b) CSA, MeOH, reflux,
93%; (c) (i) TsCl, pyridine, 0 ºC; (ii) TBSOTf, 2,6-lutidine, CH2Cl2, 0 ºC, 83% (2 steps); (d)
NaCN, DMSO, 70 ºC, 98%; (e) (i) DIBAL-H, CH2Cl2, -78 ºC; (ii) LiAlH4, THF, -15 to 0 ºC;
(f) (i) TBAF, THF, rt; (ii) TBDPSCl, Et3N, DMAP, CH2Cl2, reflux, 82% (4 steps).
ACKNOWLEDGEMENTS
This work was financially supported by The Research Foundation for Pharmaceutical Sciences, The
Kurata Memorial Hitachi Science and Technology Foundation, and the Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
REFERENCES AND NOTES
1. M. Satake, M. Murata, and T. Yasumoto, Tetrahedron Lett., 1993, 34, 1975.
2. (a) T. Yasumoto and M. Murata, Chem. Rev., 1993, 93, 1897; (b) P. J. Scheuer, Tetrahedron, 1994,
50, 3; (c) R. J. Lewis, Toxicon, 2001, 39, 97; (d) T. Yasumoto, Chem. Rec., 2001, 1, 228.
3. For the total synthesis of 1, see: (a) M. Hirama, T. Oishi, H. Uehara, M. Inoue, M. Maruyama, H.
Oguri, and M. Satake, Science, 2001, 294, 1904; (b) M. Inoue, H. Uehara, M. Maruyama, and M.
Hirama, Org. Lett., 2002, 4, 4551; (c) M. Inoue, K. Miyazaki, H. Uehara, M. Maruyama, and M.
Hirama, Proc. Natl. Acad. Sci. U.S.A., 2004, 101, 12013; (d) M. Inoue and M. Hirama, Synlett, 2004,
577; (e) M. Inoue and M. Hirama, Acc. Chem. Res., 2004, 37, 961; (f) M. Hirama, Chem. Rec., 2005,
5, 240; (g) S. Yamashita, Y. Ishihara, H. Morita, J. Uchiyama, K. Takeuchi, M. Inoue, and M.
Hirama, J. Nat. Prod., 2011, 74, 357.
4. For selected reviews on syntheses of polycyclic ethers, see: (a) T. Nakata, Chem. Rev., 2005, 105,
4314; (b) M. Inoue, Chem. Rev., 2005, 105, 4379.
5. I. Kadota, T. Abe, M. Uni, H. Takamura, and Y. Yamamoto, Tetrahedron, 2009, 65, 7784.
6. For the synthesis of the A-E ring segment of 1 by other groups, see: (a) M. Maruyama, K. Maeda, T.
Oishi, H. Oguri, and M. Hirama, Heterocycles, 2001, 54, 93; (b) M. Maruyama, M. Inoue, T. Oishi,

HETEROCYCLES, Vol. 88, No. 2, 2014
973
H. Oguri, Y. Ogasawara, Y. Shindo, and M. Hirama, Tetrahedron, 2002, 58, 1835; (c) H. Fuwa, S.
Fujikawa, K. Tachibana, H. Takakura, and M. Sasaki, Tetrahedron Lett., 2004, 45, 4795; (d) S.
Kobayashi, Y. Takahashi, K. Komano, B. H. Alizadeh, Y. Kawada, T. Oishi, S. Tanaka, Y.
Ogasawara, S. Sasaki, and M. Hirama, Tetrahedron, 2004, 60, 8375; (e) K. Fujiwara, A. Goto, D.
Sato, Y. Ohtaniuchi, H. Tanaka, A. Murai, H. Kawai, and T. Suzuki, Tetrahedron Lett., 2004, 45,
7011; (f) M. Inoue, S. Yamashita, Y. Ishihara, and M. Hirama, Org. Lett., 2006, 8, 5805; (g) J. S.
Clark, J. Conroy, and A. J. Blake, Org. Lett., 2007, 9, 2091.
7. I. Kadota, A. Ohno, K. Matsuda, and Y. Yamamoto, J. Am. Chem. Soc., 2002, 124, 3562.
8. I. Kadota, T. Sakaihara, and Y. Yamamoto, Tetrahedron Lett., 1996, 37, 3195.
9. J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, and M. Yamaguchi, Bull. Chem. Soc. Jpn., 1979, 52,
1989.
10. I. Kadota, H. Takamura, K. Sato, A. Ohno, K. Matsuda, and Y. Yamamoto, J. Am. Chem. Soc., 2003,
125, 46.
11. For the original conditions, see: (a) V. H. Dahanukar and S. D. Rychnovsky, J. Org. Chem., 1996, 61,
8317; (b) D. J. Kopecky and S. D. Rychnovsky, J. Org. Chem., 2000, 65, 191; (c) D. J. Kopecky and
S. D. Rychnovsky, Org. Synth., 2003, 80, 177.
12. P. Schwab, M. B. France, J. W. Ziller, and R. H. Grubbs, Angew. Chem., Int. Ed. Engl., 1995, 34,
2039; (b) P. Schwab, R. H. Grubbs, and J. W. Ziller, J. Am. Chem. Soc., 1996, 118, 100.