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 Lewis RJ.
Toxicon
2001,
39:
97
2 Yasumoto T.
Nakajima I.
Bagnis R.
Adachi R.
Bull. Jpn. Soc. Sci. Fish.
1977,
43:
1015
3a Yasumoto T.
Murata M.
Chem. Rev.
1993,
93:
1897
3b Shimizu Y.
Chem. Rev.
1993,
93:
1685
3c Murata M.
Yasumoto T.
Nat. Prod. Rep.
2000,
17:
293
3d Yasumoto T.
Chem. Rec.
2001,
1:
228
3e Daranas AH.
Norte M.
Fernández JJ.
Toxicon
2001,
39:
1101
4 Scheuer PJ.
Tetrahedron
1994,
50:
3
5a Scheuer PJ.
Takahashi W.
Tsutsumi J.
Yoshida T.
Science
1967,
155:
1267
5b Tachibana K.
Ph. D. Dissertation
University of Hawaii;
Honolulu:
1980.
5c Tachibana K.
Nukina M.
Joh Y.-G.
Scheuer PJ.
Biol. Bull.
1987,
172:
122
6a Murata M.
Legrand AM.
Ishibashi Y.
Yasumoto T.
J. Am. Chem. Soc.
1989,
11:
8929
6b Murata M.
Legrand A.-M.
Ishibashi Y.
Fukui M.
Yasumoto T.
J. Am. Chem. Soc.
1990,
112:
4380
7 Satake M.
Murata M.
Yasumoto T.
Tetrahedron Lett.
1993,
34:
1975
8 Satake M.
Fukui M.
Legrand A.-M.
Cruchet P.
Yasumoto T.
Tetrahedron Lett.
1998,
39:
1197
9 Yasumoto T.
Igarashi T.
Legrand A.-M.
Cruchet P.
Chinain M.
Fujita T.
Naoki H.
J. Am. Chem. Soc.
2000,
122:
4988
10 Lewis RJ.
Vernoux J.-P.
Brereton IM.
J. Am. Chem. Soc.
1998,
120:
5914
11 Satake M.
Morohashi A.
Oguri H.
Oishi T.
Hirama M.
Harada N.
Yasumoto T.
J. Am. Chem. Soc.
1997,
119:
11325
12 Yasumoto T.
Fukui M.
Sasaki K.
Sugiyama K.
J. AOAC. Int.
1995,
78:
125
13a Oguri H.
Tanaka S.-I.
Hishiyama S.
Oishi T.
Hirama M.
Tsumuraya T.
Tomioka Y.
Mizugaki M.
Synthesis
1999,
1431
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
13c Hokama Y.
Takenaka WE.
Nishimura KL.
Ebesu JSM.
Bourke R.
Sullivan PK.
J. AOAC Int.
1998,
81:
727
13d Pauillac S.
Sasaki M.
Inoue M.
Naar J.
Branaa P.
Chinain M.
Tachibana K.
Legrand A.-M.
Toxicon
2000,
38:
669
14 Oguri H.
Hirama M.
Tsumuraya T.
Fujii I.
Maruyama M.
Uehara H.
Nagumo Y.
J. Am. Chem. Soc.
2003,
125:
7608
15a Lombet A.
Bidard J.-N.
Lazdunski M.
FEBS Lett.
1987,
219:
355
15b Dechraoui M.-Y.
Naar J.
Pauillac S.
Legrand A.-M.
Toxicon
1999,
37:
125
16a Catterall WA.
Neuron
2000,
26:
13
16b Anger T.
Madge DJ.
Mulla M.
Riddall D.
J. Med. Chem.
2001,
44:
115
17a 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
17b Shimizu Y.
Chou H.-N.
Bando H.
Van Duyne G.
Clardy JC.
J. Am. Chem. Soc.
1986,
108:
514
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
18a Poli MA.
Mende TJ.
Baden DG.
Mol. Pharmacol.
1986,
30:
129
18b Baden DG.
FASEB J.
1989,
3:
1807
18c Trainer VL.
Baden DG.
Catterall WA.
J. Biol. Chem.
1994,
269:
19904
18d Jeglitsch G.
Rein K.
Baden DG.
Adams D.
J. Pharmacol. Exp. Ther.
1998,
284:
516
19a Takakura H.
Noguchi K.
Sasaki M.
Tachibana K.
Angew. Chem. Int. Ed.
2001,
40:
1090
19b Sasaki M.
Ishikawa M.
Fuwa H.
Tachibana K.
Tetrahedron
2002,
58:
1889
19c Takakura H.
Sasaki M.
Honda S.
Tachibana K.
Org. Lett.
2002,
4:
2771
19d Fujiwara K.
Koyama Y.
Doi E.
Shimawaki K.
Ohtaniuchi Y.
Takemura A.
Souma S.-i.
Murai A.
Synlett
2002,
1496
19e Fujiwara K.
Koyama Y.
Kawai K.
Tanaka H.
Murai A.
Synlett
2002,
1835
19f Tanaka H.
Kawai K.
Fujiwara K.
Murai A.
Tetrahedron
2002,
58:
10017
19g Kira K.
Hamajima A.
Isobe M.
Tetrahedron
2002,
58:
1875
19h Baba T.
Isobe M.
Synlett
2003,
547
19i Takai S.
Sawada N.
Isobe M.
J. Org. Chem.
2003,
68:
3225
19j Eriksson L.
Guy S.
Perlmutter P.
Lewis R.
J. Org. Chem.
1999,
64:
8396
19k Bond S.
Perlmutter P.
Tetrahedron
2002,
58:
1779
19l Leeuwenburgh MA.
Kulker C.
Overkleeft HS.
van der Marel GA.
van Boom JH.
Synlett
1999,
1945
19m Clark JS.
Hamelin O.
Angew. Chem. Int. Ed.
2000,
39:
372 ; and references cited therein
20a Hirama M.
Oishi T.
Uehara H.
Inoue M.
Maruyama M.
Oguri H.
Satake M.
Science
2001,
294:
1904
20b Oishi T.
J. Synth. Org. Chem. Jpn.
2003,
61:
562
21 Inoue M.
Uehara H.
Maruyama M.
Hirama M.
Org. Lett.
2002,
4:
4551
22 Inoue M.
Hirama M.
Satake M.
Sugiyama K.
Yasumoto T.
Toxicon
2003,
41:
469
23a Alvarez E.
Candenas M.-L.
Pérez R.
Ravelo JL.
Martín JD.
Chem. Rev.
1995,
95:
1953
23b Mori Y.
Chem.-Eur. J.
1997,
3:
849
23c Yet L.
Chem. Rev.
2000,
100:
2963
23d Sasaki M.
Inoue M.
J. Synth. Org. Chem. Jpn.
2001,
59:
193
23e Marmsäter FP.
West FG.
Chem.-Eur. J.
2002,
8:
4347
24a Nicolaou KC.
Rutjes FPJT.
Theodorakis EA.
Tiebes J.
Sato M.
Untersteller E.
J. Am. Chem. Soc.
1995,
117:
1173
24b Nicolaou KC.
Rutjes FPJT.
Theodorakis EA.
Tiebes J.
Sato M.
Untersteller E.
J. Am. Chem. Soc.
1995,
117:
10252
25a Nicolaou KC.
Yang Z.
Shi G.-Q.
Gunzner JL.
Agrios KA.
Gärtner P.
Nature (London, U. K.)
1998,
392:
264
25b Nicolaou KC.
Gunzner JL.
Shi G.-Q.
Agrios KA.
Gärtner P.
Yang Z.
Chem.-Eur. J.
1999,
5:
646
26a Fuwa H.
Sasaki M.
Satake M.
Tachibana K.
Org. Lett.
2002,
4:
2981
26b Fuwa H.
Kainuma N.
Tachibana K.
Sasaki M.
J. Am. Chem. Soc.
2002,
124:
14983
27 Kadota I.
Takamura H.
Sato K.
Ohno A.
Matsuda K.
Yamamoto Y.
J. Am. Chem. Soc.
2003,
125:
46
28a Nicolaou KC.
Reddy KR.
Skokotas G.
Sato F.
Xiao X.-Y.
J. Am. Chem. Soc.
1992,
114:
7935
28b Nicolaou KC.
Reddy KR.
Skokotas G.
Sato F.
Xiao X.-Y.
Hwang C.-K.
J. Am. Chem. Soc.
1993,
115:
3558
28c Kadota I.
Jung-Youl P.
Koumura N.
Pollaud G.
Matsukawa Y.
Yamamoto Y.
Tetrahedron Lett.
1995,
36:
5777
28d Katoda I.
Yamamoto Y.
J. Org. Chem.
1998,
63:
6597
28e Morimoto M.
Matsukura H.
Nakata T.
Tetrahedron Lett.
1996,
37:
6365
28f Mori Y.
Yaegashi K.
Furukawa H.
J. Am. Chem. Soc.
1997,
119:
4557
28g Mori Y.
Yaegashi K.
Furukawa H.
J. Org. Chem.
1998,
63:
6200
28h Rainier JD.
Allwein SP.
Cox JM.
J. Org. Chem.
2001,
66:
1380
28i Holland JM.
Lewis M.
Nelson A.
Angew. Chem. Int. Ed.
2001,
40:
4082
28j Holland JM.
Lewis M.
Nelson A.
J. Org. Chem.
2003,
68:
747
28k Zakarian A.
Batch A.
Holton RA.
J. Am. Chem. Soc.
2003,
125:
7822
29a Fürstner A.
Angew. Chem. Int. Ed.
2000,
39:
3013
29b Trnka TM.
Grubbs RH.
Acc. Chem. Res.
2001,
34:
18
30 The numbering of carbon atoms in all compounds in this paper corresponds to that of CTX3C.
31a Maruyama M.
Maeda K.
Oishi T.
Oguri H.
Hirama M.
Heterocycles
2001,
54:
93
31b Maruyama M.
Inoue M.
Oishi T.
Oguri H.
Ogasawara Y.
Shindo Y.
Hirama M.
Tetrahedron
2002,
58:
1835
32 Maeda K.
Oishi T.
Oguri H.
Hirama M.
Chem. Commun.
1999,
1063
33 Lewis MD.
Cha JK.
Kishi Y.
J. Am. Chem. Soc.
1982,
104:
4976
34 Cipolla L.
Lay L.
Nicotra F.
J. Org. Chem.
1997,
62:
6678
35a Fu GC.
Nguyen ST.
Grubbs RH.
J. Am. Chem. Soc.
1993,
115:
9856
35b Schwab P.
Grubbs RH.
Ziller JW.
J. Am. Chem. Soc.
1996,
118:
100
36 Compound 24 was independently synthesized in the same way by Perlmutter and co-workers (ref. 19j).
37 Crimmins MT.
Wells AJ.
Kirinich SJ.
Choy AL.
Synth. Commun.
1998,
28:
3675
38a Crimmins MT.
Choy AL.
J. Am. Chem. Soc.
1999,
121:
5653
38b Crimmins MT.
Tabet EA.
J. Am. Chem. Soc.
2000,
122:
5473
39a Oishi T.
Uehara H.
Nagumo Y.
Shoji M.
Le Brazidec J.-Y.
Kosaka M.
Hirama M.
Chem. Commun.
2001,
381
39b Uehara H.
Oishi T.
Inoue M.
Shoji M.
Nagumo Y.
Kosaka M.
Le Brazidec J.-Y.
Hirama M.
Tetrahedron
2002,
58:
6493
40 Tatami A.
Inoue M.
Uehara H.
Hirama M.
Tetrahedron Lett.
2003,
44:
5229
41 Evans DA.
Chapman KT.
Carreira EM.
J. Am. Chem. Soc.
1988,
110:
3560
42a Mori Y.
Yaegashi K.
Furukawa H.
J. Am. Chem. Soc.
1996,
118:
8158
42b Mori Y.
Furuta H.
Takase T.
Mitsuoka S.
Furukawa H.
Tetrahedron Lett.
1999,
40:
8019
43 Tazaki M.
Takagi M.
Chem. Lett.
1979,
767
44 Oishi T.
Shoji M.
Kumahara N.
Hirama M.
Chem. Lett.
1997,
845
45 Takano S.
Sekiguchi Y.
Sato N.
Ogasawara K.
Synthesis
1987,
139
46 Ireland RE.
Mueller RH.
Willard AK.
J. Am. Chem. Soc.
1976,
98:
2868
47 Bartlett PA.
Myerson J.
J. Am. Chem. Soc.
1978,
100:
3950
48 Roush WR.
Ando K.
Powers DB.
Palkowitz AD.
Halterman RL.
J. Am. Chem. Soc.
1990,
112:
6339
49a Gaunt MJ.
Yu J.
Spencer JB.
J. Org. Chem.
1998,
63:
4172
49b Wright JA.
Yu J.
Spencer JB.
Tetrahedron Lett.
2001,
42:
4033
49c Xia J.
Abbas SA.
Locke RD.
Piskorz CF.
Alderfer JL.
Matta KL.
Tetrahedron Lett.
2000,
41:
169
49d Xia J.
Alderfer JL.
Piskorz CF.
Matta KL.
Chem.-Eur. J.
2001,
7:
356
50 Oishi T.
Nagumo Y.
Hirama M.
Chem. Commun.
1998,
1041
51 Hanessian S.
Dube D.
Hodges PJ.
J. Am. Chem. Soc.
1987,
109:
7063
52 Nicolaou KC.
Hwang C.-K.
Nugiel DA.
J. Am. Chem. Soc.
1989,
11:
4136
53 Tebbe FN.
Parshall GW.
Reddy GS.
J. Am. Chem. Soc.
1978,
100:
3611
54a Nicolaou KC.
Postema MHD.
Claiborne CF.
J. Am. Chem. Soc.
1996,
118:
1565
54b Nicolaou KC.
Postema MHD.
Yue EW.
Nadin A.
J. Am. Chem. Soc.
1996,
118:
10335
55 Oishi T.
Nagumo Y.
Shoji M.
Le Brazidec J.-Y.
Uehara H.
Hirama M.
Chem. Commun.
1999,
2035
56 Scholl M.
Ding S.
Lee CW.
Grubbs RH.
Org. Lett.
1999,
1:
953
57 Schrock RR.
Murdzek JS.
Bazan GC.
Robbins J.
DiMare M.
O’Regan M.
J. Am. Chem. Soc.
1990,
112:
3875
58a Postema MHD.
Calimente D.
Liu L.
Behrmann TL.
J. Org. Chem.
2000,
65:
6061
58b Liu L.
Postema MHD.
J. Am. Chem. Soc.
2001,
123:
8602
58c Clark JS.
Kettle JG.
Tetrahedron
1999,
55:
8231
58d Rainier JD.
Allwein SP.
Cox JM.
Org. Lett.
2000,
2:
231
58e Rainier JD.
Cox JM.
Allwein SP.
Tetrahedron Lett.
2001,
42:
179
59a Horikawa Y.
Watanabe M.
Fujiwara T.
Takeda T.
J. Am. Chem. Soc.
1997,
119:
1127
59b Rahim MA.
Fujiwara T.
Takeda T.
Tetrahedron
2000,
56:
763
59c Rahim MA.
Sasaki H.
Saito J.
Fujiwara T.
Takeda T.
Chem. Commun.
2001,
625
60 Inanaga J.
Hirata K.
Saeki H.
Katsuki T.
Yamaguchi M.
Bull. Chem. Soc. Jpn.
1979,
52:
1989
61 Charette AB.
Mellon C.
Rouillard L.
Malenfant .
Synlett
1993,
81
62 Imai H.
Uehara H.
Inoue M.
Oguri H.
Oishi T.
Hirama M.
Tetrahedron Lett.
2001,
42:
6219
63a Sasaki M.
Noguchi T.
Tachibana K.
Tetrahedron Lett.
1999,
40:
1337
63b Sasaki M.
Noguchi T.
Tachibana K.
J. Org. Chem.
2002,
67:
3301
64a Fukuzawa S.-I.
Tsuchimoto T.
Hotaka T.
Hiyama T.
Synlett
1995,
1077
64b Ishihara K.
Karumi Y.
Kubota M.
Yamamoto H.
Synlett
1996,
839
65 Inoue M.
Sasaki M.
Tachibana T.
J. Org. Chem.
1999,
64:
9416
66a Masaki Y.
Serizawa Y.
Kaji K.
Chem. Lett.
1985,
1933
66b Maruoka K.
Miyazaki T.
Ando M.
Matsumura Y.
Sakane S.
Hattori K.
Yamamoto H.
J. Am. Chem. Soc.
1983,
105:
2831
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.
68 Kim S.
Do JY.
Kim SH.
Kim D.
J. Chem. Soc., Perkin Trans. 1
1994,
2357
69a Lee E.
Tae JS.
Lee C.
Park CM.
Tetrahedron Lett.
1993,
34:
4831
69b Lee E.
Song HY.
Kang JW.
Kim D.-S.
Jung C.-K.
Joo JM.
J. Am. Chem. Soc.
2002,
124:
384
70a Evans PA.
Roseman JD.
J. Org. Chem.
1996,
61:
2252
70b Evans PA.
Roseman JD.
Garber LT.
J. Org. Chem.
1996,
61:
4880
70c Yuasa Y.
Sato W.
Shibuya S.
Synth. Commun.
1997,
27:
573
70d Berlin S.
Ericsson C.
Engman L.
Org. Lett.
2002,
4:
3
70e Pandey G.
Hajra S.
Ghorai MK.
J. Org. Chem.
1997,
62:
5966
70f Hori N.
Matsukura H.
Matsuo G.
Nakata T.
Tetrahedron Lett.
1999,
40:
2811
70g Hori N.
Matsukura H.
Matsuo G.
Nakata T.
Tetrahedron
2002,
58:
1853
71a Sasaki M.
Inoue M.
Noguchi T.
Takeichi A.
Tachibana K.
Tetrahedron Lett.
1998,
39:
2783
71b Inoue M.
Wang J.
Wang G.-X.
Ogasawara Y.
Hirama M.
Tetrahedron
2003,
59:
5645
trans -fused 9-membered ring. See for examples:
72a Inoue M.
Sasaki M.
Tachibana K.
Tetrahedron Lett.
1997,
38:
1611
72b Inoue M.
Sasaki M.
Tachibana K.
Tetrahedron
1999,
55:
10949
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
73 Sabes SF.
Urbanek RA.
Forsyth CJ.
J. Am. Chem. Soc.
1988,
120:
2534
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
[2 140
