Total Synthesis of Ciguatoxin CTX3C, a Causative Toxin of Ciguatera Seafood Poisoning

Masayuki Inoue; Masahiro Hirama

doi:10.1055/s-2004-817767

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Synlett 2004(4): 577-595
DOI: 10.1055/s-2004-817767

ACCOUNT

Total Synthesis of Ciguatoxin CTX3C, a Causative Toxin of Ciguatera Seafood Poisoning

Masayuki Inoue*, Masahiro Hirama*
Department of Chemistry, Graduate School of Science, Tohoku University, and SORST, Japan Science and Technology Agency (JST), Sendai 980-8578, Japan
Fax: +81(22)2176566; e-Mail: inoue@ykbsc.chem.tohoku.ac.jp; e-Mail: hirama@ykbsc.chem.tohoku.ac.jp;

Further Information

Publication History

Received 1 September 2003
Publication Date:
10 February 2004 (online)

Abstract
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Abstract

More than 20,000 people suffer annually from ciguatera seafood poisoning in subtropical and tropical regions. The extremely low content of the causative neurotoxins, designated as ciguatoxins, in fish has hampered the isolation, detailed biological studies, and preparation of anti-ciguatoxin antibodies for detecting these toxins. Furthermore, the large (3 nanometer long) and complicated molecular structure of ciguatoxins has impeded chemists from completing their total synthesis. In 2001, our highly convergent strategic approach enabled the total synthesis of ciguatoxin CTX3C through assembling the four structural fragments. In this account, we describe the updated version of the total synthesis, where the yields and practicality are greatly improved. The high efficiency of the present synthesis ensures a supply of ciguatoxins for biomedical applications.

Key words

convergent synthesis - ring-closing olefin metathesis - CTX3C - polyether - ciguatera - ciguatoxin

References

1 For a recent review on ciguatera see: Lewis RJ. Toxicon 2001, 39: 97

Crossref Google Scholar
2 Yasumoto T. Nakajima I. Bagnis R. Adachi R. Bull. Jpn. Soc. Sci. Fish. 1977, 43: 1015

Google Scholar
For reviews on ciguatoxins and related marine natural products see:
3a Yasumoto T. Murata M. Chem. Rev. 1993, 93: 1897

Crossref Google Scholar
3b Shimizu Y. Chem. Rev. 1993, 93: 1685

Crossref Google Scholar
3c Murata M. Yasumoto T. Nat. Prod. Rep. 2000, 17: 293

Crossref Google Scholar
3d Yasumoto T. Chem. Rec. 2001, 1: 228

Crossref Google Scholar
3e Daranas AH. Norte M. Fernández JJ. Toxicon 2001, 39: 1101

Crossref Google Scholar
4 Scheuer PJ. Tetrahedron 1994, 50: 3

Crossref Google Scholar
5a Scheuer PJ. Takahashi W. Tsutsumi J. Yoshida T. Science 1967, 155: 1267

Google Scholar
5b Tachibana K. Ph. D. Dissertation University of Hawaii; Honolulu: 1980.

Google Scholar
5c Tachibana K. Nukina M. Joh Y.-G. Scheuer PJ. Biol. Bull. 1987, 172: 122

Google Scholar
6a Murata M. Legrand AM. Ishibashi Y. Yasumoto T. J. Am. Chem. Soc. 1989, 11: 8929

Crossref Google Scholar
6b Murata M. Legrand A.-M. Ishibashi Y. Fukui M. Yasumoto T. J. Am. Chem. Soc. 1990, 112: 4380

Crossref Google Scholar
7 Satake M. Murata M. Yasumoto T. Tetrahedron Lett. 1993, 34: 1975

Crossref Google Scholar
8 Satake M. Fukui M. Legrand A.-M. Cruchet P. Yasumoto T. Tetrahedron Lett. 1998, 39: 1197

Crossref Google Scholar
9 Yasumoto T. Igarashi T. Legrand A.-M. Cruchet P. Chinain M. Fujita T. Naoki H. J. Am. Chem. Soc. 2000, 122: 4988

Crossref Google Scholar
10 Lewis RJ. Vernoux J.-P. Brereton IM. J. Am. Chem. Soc. 1998, 120: 5914

Crossref Google Scholar
11 Satake M. Morohashi A. Oguri H. Oishi T. Hirama M. Harada N. Yasumoto T. J. Am. Chem. Soc. 1997, 119: 11325

Crossref Google Scholar
12 Yasumoto T. Fukui M. Sasaki K. Sugiyama K. J. AOAC. Int. 1995, 78: 125

Google Scholar
For attempts toward the preparation of anti-CTX antibodies see:
13a Oguri H. Tanaka S.-I. Hishiyama S. Oishi T. Hirama M. Tsumuraya T. Tomioka Y. Mizugaki M. Synthesis 1999, 1431

Crossref Google Scholar
13b 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

Crossref Google Scholar
13c Hokama Y. Takenaka WE. Nishimura KL. Ebesu JSM. Bourke R. Sullivan PK. J. AOAC Int. 1998, 81: 727

Crossref Google Scholar
13d Pauillac S. Sasaki M. Inoue M. Naar J. Branaa P. Chinain M. Tachibana K. Legrand A.-M. Toxicon 2000, 38: 669

Crossref Google Scholar
14 Very recently we developed the immuno-detection method of CTX3C: Oguri H. Hirama M. Tsumuraya T. Fujii I. Maruyama M. Uehara H. Nagumo Y. J. Am. Chem. Soc. 2003, 125: 7608

Crossref Google Scholar
15a Lombet A. Bidard J.-N. Lazdunski M. FEBS Lett. 1987, 219: 355

Crossref Google Scholar
15b Dechraoui M.-Y. Naar J. Pauillac S. Legrand A.-M. Toxicon 1999, 37: 125

Crossref Google Scholar
For recent reviews on voltage-sensitive sodium channel see:
16a Catterall WA. Neuron 2000, 26: 13

Crossref Google Scholar
16b Anger T. Madge DJ. Mulla M. Riddall D. J. Med. Chem. 2001, 44: 115

Crossref Google Scholar
17a Brevetoxin B: Lin Y.-Y. Risk M. Ray SM. Van Engen D. Clardy J. Golik J. James JC. Nakanishi K. J. Am. Chem. Soc. 1981, 103: 6773

Crossref Google Scholar
17b Brevetoxin A: Shimizu Y. Chou H.-N. Bando H. Van Duyne G. Clardy JC. J. Am. Chem. Soc. 1986, 108: 514

Crossref Google Scholar
17c Pawlak J. Tempesta MS. Golik J. Zagorski MG. Lee MS. Nakanishi K. Iwashita T. Gross ML. Tomer KB. J. Am. Chem. Soc. 1987, 109: 1144

Crossref Google Scholar
18a Poli MA. Mende TJ. Baden DG. Mol. Pharmacol. 1986, 30: 129

Google Scholar
18b Baden DG. FASEB J. 1989, 3: 1807

Google Scholar
18c Trainer VL. Baden DG. Catterall WA. J. Biol. Chem. 1994, 269: 19904

Google Scholar
18d Jeglitsch G. Rein K. Baden DG. Adams D. J. Pharmacol. Exp. Ther. 1998, 284: 516

Google Scholar
For recent synthetic studies of ciguatoxins from other groups see:
19a Takakura H. Noguchi K. Sasaki M. Tachibana K. Angew. Chem. Int. Ed. 2001, 40: 1090

Google Scholar
19b Sasaki M. Ishikawa M. Fuwa H. Tachibana K. Tetrahedron 2002, 58: 1889

Google Scholar
19c Takakura H. Sasaki M. Honda S. Tachibana K. Org. Lett. 2002, 4: 2771

Google Scholar
19d Fujiwara K. Koyama Y. Doi E. Shimawaki K. Ohtaniuchi Y. Takemura A. Souma S.-i. Murai A. Synlett 2002, 1496

Google Scholar
19e Fujiwara K. Koyama Y. Kawai K. Tanaka H. Murai A. Synlett 2002, 1835

Google Scholar
19f Tanaka H. Kawai K. Fujiwara K. Murai A. Tetrahedron 2002, 58: 10017

Google Scholar
19g Kira K. Hamajima A. Isobe M. Tetrahedron 2002, 58: 1875

Google Scholar
19h Baba T. Isobe M. Synlett 2003, 547

Google Scholar
19i Takai S. Sawada N. Isobe M. J. Org. Chem. 2003, 68: 3225

Google Scholar
19j Eriksson L. Guy S. Perlmutter P. Lewis R. J. Org. Chem. 1999, 64: 8396

Google Scholar
19k Bond S. Perlmutter P. Tetrahedron 2002, 58: 1779

Google Scholar
19l Leeuwenburgh MA. Kulker C. Overkleeft HS. van der Marel GA. van Boom JH. Synlett 1999, 1945

Google Scholar
19m Clark JS. Hamelin O. Angew. Chem. Int. Ed. 2000, 39: 372 ; and references cited therein

Google Scholar
20a Hirama M. Oishi T. Uehara H. Inoue M. Maruyama M. Oguri H. Satake M. Science 2001, 294: 1904

Google Scholar
20b Oishi T. J. Synth. Org. Chem. Jpn. 2003, 61: 562

Google Scholar
21 Inoue M. Uehara H. Maruyama M. Hirama M. Org. Lett. 2002, 4: 4551

Crossref Google Scholar
22 Recent example of the insight into polyether activities: Inoue M. Hirama M. Satake M. Sugiyama K. Yasumoto T. Toxicon 2003, 41: 469

Crossref Google Scholar
For reviews of polyether synthesis see:
23a Alvarez E. Candenas M.-L. Pérez R. Ravelo JL. Martín JD. Chem. Rev. 1995, 95: 1953

Google Scholar
23b Mori Y. Chem.-Eur. J. 1997, 3: 849

Google Scholar
23c Yet L. Chem. Rev. 2000, 100: 2963

Google Scholar
23d Sasaki M. Inoue M. J. Synth. Org. Chem. Jpn. 2001, 59: 193

Google Scholar
23e Marmsäter FP. West FG. Chem.-Eur. J. 2002, 8: 4347

Google Scholar
24a Nicolaou KC. Rutjes FPJT. Theodorakis EA. Tiebes J. Sato M. Untersteller E. J. Am. Chem. Soc. 1995, 117: 1173

Crossref Google Scholar
24b Nicolaou KC. Rutjes FPJT. Theodorakis EA. Tiebes J. Sato M. Untersteller E. J. Am. Chem. Soc. 1995, 117: 10252

Crossref Google Scholar
25a Nicolaou KC. Yang Z. Shi G.-Q. Gunzner JL. Agrios KA. Gärtner P. Nature (London, U. K.) 1998, 392: 264

Google Scholar
25b Nicolaou KC. Gunzner JL. Shi G.-Q. Agrios KA. Gärtner P. Yang Z. Chem.-Eur. J. 1999, 5: 646

Google Scholar
26a Fuwa H. Sasaki M. Satake M. Tachibana K. Org. Lett. 2002, 4: 2981

Crossref Google Scholar
26b Fuwa H. Kainuma N. Tachibana K. Sasaki M. J. Am. Chem. Soc. 2002, 124: 14983

Crossref Google Scholar
27 Kadota I. Takamura H. Sato K. Ohno A. Matsuda K. Yamamoto Y. J. Am. Chem. Soc. 2003, 125: 46

Crossref Google Scholar
28a Nicolaou KC. Reddy KR. Skokotas G. Sato F. Xiao X.-Y. J. Am. Chem. Soc. 1992, 114: 7935

Crossref Google Scholar
28b Nicolaou KC. Reddy KR. Skokotas G. Sato F. Xiao X.-Y. Hwang C.-K. J. Am. Chem. Soc. 1993, 115: 3558

Crossref Google Scholar
28c Kadota I. Jung-Youl P. Koumura N. Pollaud G. Matsukawa Y. Yamamoto Y. Tetrahedron Lett. 1995, 36: 5777

Crossref Google Scholar
28d Katoda I. Yamamoto Y. J. Org. Chem. 1998, 63: 6597

Crossref Google Scholar
28e Morimoto M. Matsukura H. Nakata T. Tetrahedron Lett. 1996, 37: 6365

Crossref Google Scholar
28f Mori Y. Yaegashi K. Furukawa H. J. Am. Chem. Soc. 1997, 119: 4557

Crossref Google Scholar
28g Mori Y. Yaegashi K. Furukawa H. J. Org. Chem. 1998, 63: 6200

Crossref Google Scholar
28h Rainier JD. Allwein SP. Cox JM. J. Org. Chem. 2001, 66: 1380

Crossref Google Scholar
28i Holland JM. Lewis M. Nelson A. Angew. Chem. Int. Ed. 2001, 40: 4082

Crossref Google Scholar
28j Holland JM. Lewis M. Nelson A. J. Org. Chem. 2003, 68: 747

Crossref Google Scholar
28k Zakarian A. Batch A. Holton RA. J. Am. Chem. Soc. 2003, 125: 7822

Crossref Google Scholar
For recent reviews of RCM see:
29a Fürstner A. Angew. Chem. Int. Ed. 2000, 39: 3013

Crossref PubMed Google Scholar
29b Trnka TM. Grubbs RH. Acc. Chem. Res. 2001, 34: 18

Crossref PubMed Google Scholar
31a Maruyama M. Maeda K. Oishi T. Oguri H. Hirama M. Heterocycles 2001, 54: 93

Crossref Google Scholar
31b Maruyama M. Inoue M. Oishi T. Oguri H. Ogasawara Y. Shindo Y. Hirama M. Tetrahedron 2002, 58: 1835

Crossref Google Scholar
32 Maeda K. Oishi T. Oguri H. Hirama M. Chem. Commun. 1999, 1063

Crossref Google Scholar
33 Lewis MD. Cha JK. Kishi Y. J. Am. Chem. Soc. 1982, 104: 4976

Crossref Google Scholar
34 Cipolla L. Lay L. Nicotra F. J. Org. Chem. 1997, 62: 6678

Crossref Google Scholar
35a Fu GC. Nguyen ST. Grubbs RH. J. Am. Chem. Soc. 1993, 115: 9856

Google Scholar
35b Schwab P. Grubbs RH. Ziller JW. J. Am. Chem. Soc. 1996, 118: 100

Google Scholar
37 Crimmins MT. Wells AJ. Kirinich SJ. Choy AL. Synth. Commun. 1998, 28: 3675

Crossref Google Scholar
Crimmins and co-workers applied the asymmetric aldol reaction and RCM to the synthesis of the medium sized ethers, for examples see:
38a Crimmins MT. Choy AL. J. Am. Chem. Soc. 1999, 121: 5653

Crossref Google Scholar
38b Crimmins MT. Tabet EA. J. Am. Chem. Soc. 2000, 122: 5473

Crossref Google Scholar
39a Oishi T. Uehara H. Nagumo Y. Shoji M. Le Brazidec J.-Y. Kosaka M. Hirama M. Chem. Commun. 2001, 381

Crossref Google Scholar
39b Uehara H. Oishi T. Inoue M. Shoji M. Nagumo Y. Kosaka M. Le Brazidec J.-Y. Hirama M. Tetrahedron 2002, 58: 6493

Crossref Google Scholar
40 Tatami A. Inoue M. Uehara H. Hirama M. Tetrahedron Lett. 2003, 44: 5229

Crossref Google Scholar
41 Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc. 1988, 110: 3560

Crossref Google Scholar
42a Mori Y. Yaegashi K. Furukawa H. J. Am. Chem. Soc. 1996, 118: 8158

Crossref Google Scholar
42b Mori Y. Furuta H. Takase T. Mitsuoka S. Furukawa H. Tetrahedron Lett. 1999, 40: 8019

Crossref Google Scholar
43 Tazaki M. Takagi M. Chem. Lett. 1979, 767

Google Scholar
44 Oishi T. Shoji M. Kumahara N. Hirama M. Chem. Lett. 1997, 845

Crossref Google Scholar
45 Takano S. Sekiguchi Y. Sato N. Ogasawara K. Synthesis 1987, 139

Article in Thieme Connect Google Scholar
46 Ireland RE. Mueller RH. Willard AK. J. Am. Chem. Soc. 1976, 98: 2868

Crossref Google Scholar
47 Bartlett PA. Myerson J. J. Am. Chem. Soc. 1978, 100: 3950

Google Scholar
48 Roush WR. Ando K. Powers DB. Palkowitz AD. Halterman RL. J. Am. Chem. Soc. 1990, 112: 6339

Crossref Google Scholar
For NAP ether references see:
49a Gaunt MJ. Yu J. Spencer JB. J. Org. Chem. 1998, 63: 4172

Google Scholar
49b Wright JA. Yu J. Spencer JB. Tetrahedron Lett. 2001, 42: 4033

Google Scholar
49c Xia J. Abbas SA. Locke RD. Piskorz CF. Alderfer JL. Matta KL. Tetrahedron Lett. 2000, 41: 169

Google Scholar
49d Xia J. Alderfer JL. Piskorz CF. Matta KL. Chem.-Eur. J. 2001, 7: 356

Google Scholar
50 Oishi T. Nagumo Y. Hirama M. Chem. Commun. 1998, 1041

Crossref Google Scholar
51 Hanessian S. Dube D. Hodges PJ. J. Am. Chem. Soc. 1987, 109: 7063

Crossref Google Scholar
52 Nicolaou KC. Hwang C.-K. Nugiel DA. J. Am. Chem. Soc. 1989, 11: 4136

Google Scholar
53 Tebbe FN. Parshall GW. Reddy GS. J. Am. Chem. Soc. 1978, 100: 3611

Crossref Google Scholar
54a Nicolaou KC. Postema MHD. Claiborne CF. J. Am. Chem. Soc. 1996, 118: 1565

Crossref Google Scholar
54b Nicolaou KC. Postema MHD. Yue EW. Nadin A. J. Am. Chem. Soc. 1996, 118: 10335

Crossref Google Scholar
55 Oishi T. Nagumo Y. Shoji M. Le Brazidec J.-Y. Uehara H. Hirama M. Chem. Commun. 1999, 2035

Crossref Google Scholar
56 Scholl M. Ding S. Lee CW. Grubbs RH. Org. Lett. 1999, 1: 953

Google Scholar
57 Schrock RR. Murdzek JS. Bazan GC. Robbins J. DiMare M. O’Regan M. J. Am. Chem. Soc. 1990, 112: 3875

Google Scholar
For successful applications of metathesis reactions to enol ethers see:
58a Postema MHD. Calimente D. Liu L. Behrmann TL. J. Org. Chem. 2000, 65: 6061

Crossref Google Scholar
58b Liu L. Postema MHD. J. Am. Chem. Soc. 2001, 123: 8602

Crossref Google Scholar
58c Clark JS. Kettle JG. Tetrahedron 1999, 55: 8231

Crossref Google Scholar
58d Rainier JD. Allwein SP. Cox JM. Org. Lett. 2000, 2: 231

Crossref Google Scholar
58e Rainier JD. Cox JM. Allwein SP. Tetrahedron Lett. 2001, 42: 179

Crossref Google Scholar
59a Horikawa Y. Watanabe M. Fujiwara T. Takeda T. J. Am. Chem. Soc. 1997, 119: 1127

Crossref Google Scholar
59b Rahim MA. Fujiwara T. Takeda T. Tetrahedron 2000, 56: 763

Crossref Google Scholar
59c Rahim MA. Sasaki H. Saito J. Fujiwara T. Takeda T. Chem. Commun. 2001, 625

Crossref Google Scholar
60 Inanaga J. Hirata K. Saeki H. Katsuki T. Yamaguchi M. Bull. Chem. Soc. Jpn. 1979, 52: 1989

Google Scholar
61 Charette AB. Mellon C. Rouillard L. Malenfant . Synlett 1993, 81

Article in Thieme Connect Google Scholar
62 Imai H. Uehara H. Inoue M. Oguri H. Oishi T. Hirama M. Tetrahedron Lett. 2001, 42: 6219

Crossref Google Scholar
63a Sasaki M. Noguchi T. Tachibana K. Tetrahedron Lett. 1999, 40: 1337

Crossref Google Scholar
63b Sasaki M. Noguchi T. Tachibana K. J. Org. Chem. 2002, 67: 3301

Crossref Google Scholar
64a Fukuzawa S.-I. Tsuchimoto T. Hotaka T. Hiyama T. Synlett 1995, 1077

Article in Thieme Connect Google Scholar
64b Ishihara K. Karumi Y. Kubota M. Yamamoto H. Synlett 1996, 839

Article in Thieme Connect Google Scholar
65 Inoue M. Sasaki M. Tachibana T. J. Org. Chem. 1999, 64: 9416

Crossref Google Scholar
66a Masaki Y. Serizawa Y. Kaji K. Chem. Lett. 1985, 1933

Crossref Google Scholar
66b Maruoka K. Miyazaki T. Ando M. Matsumura Y. Sakane S. Hattori K. Yamamoto H. J. Am. Chem. Soc. 1983, 105: 2831

Crossref Google Scholar
68 Kim S. Do JY. Kim SH. Kim D. J. Chem. Soc., Perkin Trans. 1 1994, 2357

Crossref Google Scholar
69a Lee E. Tae JS. Lee C. Park CM. Tetrahedron Lett. 1993, 34: 4831

Crossref Google Scholar
69b Lee E. Song HY. Kang JW. Kim D.-S. Jung C.-K. Joo JM. J. Am. Chem. Soc. 2002, 124: 384

Crossref Google Scholar
For related examples of radical additions to β-alkoxyacryl-ates see:
70a Evans PA. Roseman JD. J. Org. Chem. 1996, 61: 2252

Crossref Google Scholar
70b Evans PA. Roseman JD. Garber LT. J. Org. Chem. 1996, 61: 4880

Crossref Google Scholar
70c Yuasa Y. Sato W. Shibuya S. Synth. Commun. 1997, 27: 573

Crossref Google Scholar
70d Berlin S. Ericsson C. Engman L. Org. Lett. 2002, 4: 3

Crossref Google Scholar
70e Pandey G. Hajra S. Ghorai MK. J. Org. Chem. 1997, 62: 5966

Crossref Google Scholar
70f Hori N. Matsukura H. Matsuo G. Nakata T. Tetrahedron Lett. 1999, 40: 2811

Crossref Google Scholar
70g Hori N. Matsukura H. Matsuo G. Nakata T. Tetrahedron 2002, 58: 1853

Crossref Google Scholar
71a Sasaki M. Inoue M. Noguchi T. Takeichi A. Tachibana K. Tetrahedron Lett. 1998, 39: 2783

Crossref Google Scholar
71b Inoue M. Wang J. Wang G.-X. Ogasawara Y. Hirama M. Tetrahedron 2003, 59: 5645

Crossref Google Scholar
This slow conformational change appears to be the unique property of doubly trans-fused 9-membered ring. See for examples:
72a Inoue M. Sasaki M. Tachibana K. Tetrahedron Lett. 1997, 38: 1611

Crossref Google Scholar
72b Inoue M. Sasaki M. Tachibana K. Tetrahedron 1999, 55: 10949

Crossref Google Scholar
72c Nicolaou KC. Yang Z. Ouellette M. Shi G.-Q. Gärtner P. Gunzner JL. Agrios KA. Huber R. Chadha R. Huang DH. J. Am. Chem. Soc. 1997, 119: 8105 ; see also refs. 6-10,17c,19i,62,63

Crossref Google Scholar
73 Sabes SF. Urbanek RA. Forsyth CJ. J. Am. Chem. Soc. 1988, 120: 2534

Google Scholar

30

The numbering of carbon atoms in all compounds in this paper corresponds to that of CTX3C.

36

Compound 24 was independently synthesized in the same way by Perlmutter and co-workers (ref. 19j).

67

See ref. 65. The authors noted that the cleavage of a seven-membered acetal proceeded more easily than a six-membered acetal in a Lewis acid-catalyzed intramolecular condensation of a γ-alkoxyallylsilane.

74

Deprotection of Bn group under Birch conditions were applied to the AB ring system 24 to afford the desired compound 25 in much better yield (>59%, Scheme [2] ), which again support the distinct reactivity of the nano-scale molecule 140