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

Masayuki Inoue; Masahiro Hirama

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;

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

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References

<A NAME="RA33003ST-1">1</A> For a recent review on ciguatera see: Lewis RJ. Toxicon 2001, 39: 97

<A NAME="RA33003ST-2">2</A> Yasumoto T. Nakajima I. Bagnis R. Adachi R. Bull. Jpn. Soc. Sci. Fish. 1977, 43: 1015

For reviews on ciguatoxins and related marine natural products see:

<A NAME="RA33003ST-3A">3a</A> Yasumoto T. Murata M. Chem. Rev. 1993, 93: 1897

<A NAME="RA33003ST-3B">3b</A> Shimizu Y. Chem. Rev. 1993, 93: 1685

<A NAME="RA33003ST-3C">3c</A> Murata M. Yasumoto T. Nat. Prod. Rep. 2000, 17: 293

<A NAME="RA33003ST-3D">3d</A> Yasumoto T. Chem. Rec. 2001, 1: 228

<A NAME="RA33003ST-3E">3e</A> Daranas AH. Norte M. Fernández JJ. Toxicon 2001, 39: 1101

<A NAME="RA33003ST-4">4</A> Scheuer PJ. Tetrahedron 1994, 50: 3

<A NAME="RA33003ST-5A">5a</A> Scheuer PJ. Takahashi W. Tsutsumi J. Yoshida T. Science 1967, 155: 1267

<A NAME="RA33003ST-5B">5b</A> Tachibana K. Ph. D. Dissertation University of Hawaii; Honolulu: 1980.

<A NAME="RA33003ST-5C">5c</A> Tachibana K. Nukina M. Joh Y.-G. Scheuer PJ. Biol. Bull. 1987, 172: 122

<A NAME="RA33003ST-6A">6a</A> Murata M. Legrand AM. Ishibashi Y. Yasumoto T. J. Am. Chem. Soc. 1989, 11: 8929

<A NAME="RA33003ST-6B">6b</A> Murata M. Legrand A.-M. Ishibashi Y. Fukui M. Yasumoto T. J. Am. Chem. Soc. 1990, 112: 4380

<A NAME="RA33003ST-7">7</A> Satake M. Murata M. Yasumoto T. Tetrahedron Lett. 1993, 34: 1975

<A NAME="RA33003ST-8">8</A> Satake M. Fukui M. Legrand A.-M. Cruchet P. Yasumoto T. Tetrahedron Lett. 1998, 39: 1197

<A NAME="RA33003ST-9">9</A> Yasumoto T. Igarashi T. Legrand A.-M. Cruchet P. Chinain M. Fujita T. Naoki H. J. Am. Chem. Soc. 2000, 122: 4988

<A NAME="RA33003ST-10">10</A> Lewis RJ. Vernoux J.-P. Brereton IM. J. Am. Chem. Soc. 1998, 120: 5914

<A NAME="RA33003ST-11">11</A> Satake M. Morohashi A. Oguri H. Oishi T. Hirama M. Harada N. Yasumoto T. J. Am. Chem. Soc. 1997, 119: 11325

<A NAME="RA33003ST-12">12</A> Yasumoto T. Fukui M. Sasaki K. Sugiyama K. J. AOAC. Int. 1995, 78: 125

For attempts toward the preparation of anti-CTX antibodies see:

<A NAME="RA33003ST-13A">13a</A> Oguri H. Tanaka S.-I. Hishiyama S. Oishi T. Hirama M. Tsumuraya T. Tomioka Y. Mizugaki M. Synthesis 1999, 1431

<A NAME="RA33003ST-13B">13b</A> 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

<A NAME="RA33003ST-13C">13c</A> Hokama Y. Takenaka WE. Nishimura KL. Ebesu JSM. Bourke R. Sullivan PK. J. AOAC Int. 1998, 81: 727

<A NAME="RA33003ST-13D">13d</A> Pauillac S. Sasaki M. Inoue M. Naar J. Branaa P. Chinain M. Tachibana K. Legrand A.-M. Toxicon 2000, 38: 669

<A NAME="RA33003ST-14">14</A> 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

<A NAME="RA33003ST-15A">15a</A> Lombet A. Bidard J.-N. Lazdunski M. FEBS Lett. 1987, 219: 355

<A NAME="RA33003ST-15B">15b</A> Dechraoui M.-Y. Naar J. Pauillac S. Legrand A.-M. Toxicon 1999, 37: 125

For recent reviews on voltage-sensitive sodium channel see:

<A NAME="RA33003ST-16A">16a</A> Catterall WA. Neuron 2000, 26: 13

<A NAME="RA33003ST-16B">16b</A> Anger T. Madge DJ. Mulla M. Riddall D. J. Med. Chem. 2001, 44: 115

<A NAME="RA33003ST-17A">17a</A> 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

<A NAME="RA33003ST-17B">17b</A> Brevetoxin A: Shimizu Y. Chou H.-N. Bando H. Van Duyne G. Clardy JC. J. Am. Chem. Soc. 1986, 108: 514

<A NAME="RA33003ST-17C">17c</A> 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

<A NAME="RA33003ST-18A">18a</A> Poli MA. Mende TJ. Baden DG. Mol. Pharmacol. 1986, 30: 129

<A NAME="RA33003ST-18B">18b</A> Baden DG. FASEB J. 1989, 3: 1807

<A NAME="RA33003ST-18C">18c</A> Trainer VL. Baden DG. Catterall WA. J. Biol. Chem. 1994, 269: 19904

<A NAME="RA33003ST-18D">18d</A> Jeglitsch G. Rein K. Baden DG. Adams D. J. Pharmacol. Exp. Ther. 1998, 284: 516

For recent synthetic studies of ciguatoxins from other groups see:

<A NAME="RA33003ST-19A">19a</A> Takakura H. Noguchi K. Sasaki M. Tachibana K. Angew. Chem. Int. Ed. 2001, 40: 1090

<A NAME="RA33003ST-19B">19b</A> Sasaki M. Ishikawa M. Fuwa H. Tachibana K. Tetrahedron 2002, 58: 1889

<A NAME="RA33003ST-19C">19c</A> Takakura H. Sasaki M. Honda S. Tachibana K. Org. Lett. 2002, 4: 2771

<A NAME="RA33003ST-19D">19d</A> Fujiwara K. Koyama Y. Doi E. Shimawaki K. Ohtaniuchi Y. Takemura A. Souma S.-i. Murai A. Synlett 2002, 1496

<A NAME="RA33003ST-19E">19e</A> Fujiwara K. Koyama Y. Kawai K. Tanaka H. Murai A. Synlett 2002, 1835

<A NAME="RA33003ST-19F">19f</A> Tanaka H. Kawai K. Fujiwara K. Murai A. Tetrahedron 2002, 58: 10017

<A NAME="RA33003ST-19G">19g</A> Kira K. Hamajima A. Isobe M. Tetrahedron 2002, 58: 1875

<A NAME="RA33003ST-19H">19h</A> Baba T. Isobe M. Synlett 2003, 547

<A NAME="RA33003ST-19I">19i</A> Takai S. Sawada N. Isobe M. J. Org. Chem. 2003, 68: 3225

<A NAME="RA33003ST-19J">19j</A> Eriksson L. Guy S. Perlmutter P. Lewis R. J. Org. Chem. 1999, 64: 8396

<A NAME="RA33003ST-19K">19k</A> Bond S. Perlmutter P. Tetrahedron 2002, 58: 1779

<A NAME="RA33003ST-19L">19l</A> Leeuwenburgh MA. Kulker C. Overkleeft HS. van der Marel GA. van Boom JH. Synlett 1999, 1945

<A NAME="RA33003ST-19M">19m</A> Clark JS. Hamelin O. Angew. Chem. Int. Ed. 2000, 39: 372 ; and references cited therein

<A NAME="RA33003ST-20A">20a</A> Hirama M. Oishi T. Uehara H. Inoue M. Maruyama M. Oguri H. Satake M. Science 2001, 294: 1904

<A NAME="RA33003ST-20B">20b</A> Oishi T. J. Synth. Org. Chem. Jpn. 2003, 61: 562

<A NAME="RA33003ST-21">21</A> Inoue M. Uehara H. Maruyama M. Hirama M. Org. Lett. 2002, 4: 4551

<A NAME="RA33003ST-22">22</A> Recent example of the insight into polyether activities: Inoue M. Hirama M. Satake M. Sugiyama K. Yasumoto T. Toxicon 2003, 41: 469

For reviews of polyether synthesis see:

<A NAME="RA33003ST-23A">23a</A> Alvarez E. Candenas M.-L. Pérez R. Ravelo JL. Martín JD. Chem. Rev. 1995, 95: 1953

<A NAME="RA33003ST-23B">23b</A> Mori Y. Chem.-Eur. J. 1997, 3: 849

<A NAME="RA33003ST-23C">23c</A> Yet L. Chem. Rev. 2000, 100: 2963

<A NAME="RA33003ST-23D">23d</A> Sasaki M. Inoue M. J. Synth. Org. Chem. Jpn. 2001, 59: 193

<A NAME="RA33003ST-23E">23e</A> Marmsäter FP. West FG. Chem.-Eur. J. 2002, 8: 4347

<A NAME="RA33003ST-24A">24a</A> Nicolaou KC. Rutjes FPJT. Theodorakis EA. Tiebes J. Sato M. Untersteller E. J. Am. Chem. Soc. 1995, 117: 1173

<A NAME="RA33003ST-24B">24b</A> Nicolaou KC. Rutjes FPJT. Theodorakis EA. Tiebes J. Sato M. Untersteller E. J. Am. Chem. Soc. 1995, 117: 10252

<A NAME="RA33003ST-25A">25a</A> Nicolaou KC. Yang Z. Shi G.-Q. Gunzner JL. Agrios KA. Gärtner P. Nature (London, U. K.) 1998, 392: 264

<A NAME="RA33003ST-25B">25b</A> Nicolaou KC. Gunzner JL. Shi G.-Q. Agrios KA. Gärtner P. Yang Z. Chem.-Eur. J. 1999, 5: 646

<A NAME="RA33003ST-26A">26a</A> Fuwa H. Sasaki M. Satake M. Tachibana K. Org. Lett. 2002, 4: 2981

<A NAME="RA33003ST-26B">26b</A> Fuwa H. Kainuma N. Tachibana K. Sasaki M. J. Am. Chem. Soc. 2002, 124: 14983

<A NAME="RA33003ST-27">27</A> Kadota I. Takamura H. Sato K. Ohno A. Matsuda K. Yamamoto Y. J. Am. Chem. Soc. 2003, 125: 46

<A NAME="RA33003ST-28A">28a</A> Nicolaou KC. Reddy KR. Skokotas G. Sato F. Xiao X.-Y. J. Am. Chem. Soc. 1992, 114: 7935

<A NAME="RA33003ST-28B">28b</A> Nicolaou KC. Reddy KR. Skokotas G. Sato F. Xiao X.-Y. Hwang C.-K. J. Am. Chem. Soc. 1993, 115: 3558

<A NAME="RA33003ST-28C">28c</A> Kadota I. Jung-Youl P. Koumura N. Pollaud G. Matsukawa Y. Yamamoto Y. Tetrahedron Lett. 1995, 36: 5777

<A NAME="RA33003ST-28D">28d</A> Katoda I. Yamamoto Y. J. Org. Chem. 1998, 63: 6597

<A NAME="RA33003ST-28E">28e</A> Morimoto M. Matsukura H. Nakata T. Tetrahedron Lett. 1996, 37: 6365

<A NAME="RA33003ST-28F">28f</A> Mori Y. Yaegashi K. Furukawa H. J. Am. Chem. Soc. 1997, 119: 4557

<A NAME="RA33003ST-28G">28g</A> Mori Y. Yaegashi K. Furukawa H. J. Org. Chem. 1998, 63: 6200

<A NAME="RA33003ST-28H">28h</A> Rainier JD. Allwein SP. Cox JM. J. Org. Chem. 2001, 66: 1380

<A NAME="RA33003ST-28I">28i</A> Holland JM. Lewis M. Nelson A. Angew. Chem. Int. Ed. 2001, 40: 4082

<A NAME="RA33003ST-28J">28j</A> Holland JM. Lewis M. Nelson A. J. Org. Chem. 2003, 68: 747

<A NAME="RA33003ST-28K">28k</A> Zakarian A. Batch A. Holton RA. J. Am. Chem. Soc. 2003, 125: 7822

For recent reviews of RCM see:

<A NAME="RA33003ST-29A">29a</A> Fürstner A. Angew. Chem. Int. Ed. 2000, 39: 3013

<A NAME="RA33003ST-29B">29b</A> Trnka TM. Grubbs RH. Acc. Chem. Res. 2001, 34: 18

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

<A NAME="RA33003ST-31A">31a</A> Maruyama M. Maeda K. Oishi T. Oguri H. Hirama M. Heterocycles 2001, 54: 93

<A NAME="RA33003ST-31B">31b</A> Maruyama M. Inoue M. Oishi T. Oguri H. Ogasawara Y. Shindo Y. Hirama M. Tetrahedron 2002, 58: 1835

<A NAME="RA33003ST-32">32</A> Maeda K. Oishi T. Oguri H. Hirama M. Chem. Commun. 1999, 1063

<A NAME="RA33003ST-33">33</A> Lewis MD. Cha JK. Kishi Y. J. Am. Chem. Soc. 1982, 104: 4976

<A NAME="RA33003ST-34">34</A> Cipolla L. Lay L. Nicotra F. J. Org. Chem. 1997, 62: 6678

<A NAME="RA33003ST-35A">35a</A> Fu GC. Nguyen ST. Grubbs RH. J. Am. Chem. Soc. 1993, 115: 9856

<A NAME="RA33003ST-35B">35b</A> Schwab P. Grubbs RH. Ziller JW. J. Am. Chem. Soc. 1996, 118: 100

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

<A NAME="RA33003ST-37">37</A> Crimmins MT. Wells AJ. Kirinich SJ. Choy AL. Synth. Commun. 1998, 28: 3675

Crimmins and co-workers applied the asymmetric aldol reaction and RCM to the synthesis of the medium sized ethers, for examples see:

<A NAME="RA33003ST-38A">38a</A> Crimmins MT. Choy AL. J. Am. Chem. Soc. 1999, 121: 5653

<A NAME="RA33003ST-38B">38b</A> Crimmins MT. Tabet EA. J. Am. Chem. Soc. 2000, 122: 5473

<A NAME="RA33003ST-39A">39a</A> Oishi T. Uehara H. Nagumo Y. Shoji M. Le Brazidec J.-Y. Kosaka M. Hirama M. Chem. Commun. 2001, 381

<A NAME="RA33003ST-39B">39b</A> Uehara H. Oishi T. Inoue M. Shoji M. Nagumo Y. Kosaka M. Le Brazidec J.-Y. Hirama M. Tetrahedron 2002, 58: 6493

<A NAME="RA33003ST-40">40</A> Tatami A. Inoue M. Uehara H. Hirama M. Tetrahedron Lett. 2003, 44: 5229

<A NAME="RA33003ST-41">41</A> Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc. 1988, 110: 3560

<A NAME="RA33003ST-42A">42a</A> Mori Y. Yaegashi K. Furukawa H. J. Am. Chem. Soc. 1996, 118: 8158

<A NAME="RA33003ST-42B">42b</A> Mori Y. Furuta H. Takase T. Mitsuoka S. Furukawa H. Tetrahedron Lett. 1999, 40: 8019

<A NAME="RA33003ST-43">43</A> Tazaki M. Takagi M. Chem. Lett. 1979, 767

<A NAME="RA33003ST-44">44</A> Oishi T. Shoji M. Kumahara N. Hirama M. Chem. Lett. 1997, 845

<A NAME="RA33003ST-45">45</A> Takano S. Sekiguchi Y. Sato N. Ogasawara K. Synthesis 1987, 139

<A NAME="RA33003ST-46">46</A> Ireland RE. Mueller RH. Willard AK. J. Am. Chem. Soc. 1976, 98: 2868

<A NAME="RA33003ST-47">47</A> Bartlett PA. Myerson J. J. Am. Chem. Soc. 1978, 100: 3950

<A NAME="RA33003ST-48">48</A> Roush WR. Ando K. Powers DB. Palkowitz AD. Halterman RL. J. Am. Chem. Soc. 1990, 112: 6339

For NAP ether references see:

<A NAME="RA33003ST-49A">49a</A> Gaunt MJ. Yu J. Spencer JB. J. Org. Chem. 1998, 63: 4172

<A NAME="RA33003ST-49B">49b</A> Wright JA. Yu J. Spencer JB. Tetrahedron Lett. 2001, 42: 4033

<A NAME="RA33003ST-49C">49c</A> Xia J. Abbas SA. Locke RD. Piskorz CF. Alderfer JL. Matta KL. Tetrahedron Lett. 2000, 41: 169

<A NAME="RA33003ST-49D">49d</A> Xia J. Alderfer JL. Piskorz CF. Matta KL. Chem.-Eur. J. 2001, 7: 356

<A NAME="RA33003ST-50">50</A> Oishi T. Nagumo Y. Hirama M. Chem. Commun. 1998, 1041

<A NAME="RA33003ST-51">51</A> Hanessian S. Dube D. Hodges PJ. J. Am. Chem. Soc. 1987, 109: 7063

<A NAME="RA33003ST-52">52</A> Nicolaou KC. Hwang C.-K. Nugiel DA. J. Am. Chem. Soc. 1989, 11: 4136

<A NAME="RA33003ST-53">53</A> Tebbe FN. Parshall GW. Reddy GS. J. Am. Chem. Soc. 1978, 100: 3611

<A NAME="RA33003ST-54A">54a</A> Nicolaou KC. Postema MHD. Claiborne CF. J. Am. Chem. Soc. 1996, 118: 1565

<A NAME="RA33003ST-54B">54b</A> Nicolaou KC. Postema MHD. Yue EW. Nadin A. J. Am. Chem. Soc. 1996, 118: 10335

<A NAME="RA33003ST-55">55</A> Oishi T. Nagumo Y. Shoji M. Le Brazidec J.-Y. Uehara H. Hirama M. Chem. Commun. 1999, 2035

<A NAME="RA33003ST-56">56</A> Scholl M. Ding S. Lee CW. Grubbs RH. Org. Lett. 1999, 1: 953

<A NAME="RA33003ST-57">57</A> Schrock RR. Murdzek JS. Bazan GC. Robbins J. DiMare M. O’Regan M. J. Am. Chem. Soc. 1990, 112: 3875

For successful applications of metathesis reactions to enol ethers see:

<A NAME="RA33003ST-58A">58a</A> Postema MHD. Calimente D. Liu L. Behrmann TL. J. Org. Chem. 2000, 65: 6061

<A NAME="RA33003ST-58B">58b</A> Liu L. Postema MHD. J. Am. Chem. Soc. 2001, 123: 8602

<A NAME="RA33003ST-58C">58c</A> Clark JS. Kettle JG. Tetrahedron 1999, 55: 8231

<A NAME="RA33003ST-58D">58d</A> Rainier JD. Allwein SP. Cox JM. Org. Lett. 2000, 2: 231

<A NAME="RA33003ST-58E">58e</A> Rainier JD. Cox JM. Allwein SP. Tetrahedron Lett. 2001, 42: 179

<A NAME="RA33003ST-59A">59a</A> Horikawa Y. Watanabe M. Fujiwara T. Takeda T. J. Am. Chem. Soc. 1997, 119: 1127

<A NAME="RA33003ST-59B">59b</A> Rahim MA. Fujiwara T. Takeda T. Tetrahedron 2000, 56: 763

<A NAME="RA33003ST-59C">59c</A> Rahim MA. Sasaki H. Saito J. Fujiwara T. Takeda T. Chem. Commun. 2001, 625

<A NAME="RA33003ST-60">60</A> Inanaga J. Hirata K. Saeki H. Katsuki T. Yamaguchi M. Bull. Chem. Soc. Jpn. 1979, 52: 1989

<A NAME="RA33003ST-61">61</A> Charette AB. Mellon C. Rouillard L. Malenfant . Synlett 1993, 81

<A NAME="RA33003ST-62">62</A> Imai H. Uehara H. Inoue M. Oguri H. Oishi T. Hirama M. Tetrahedron Lett. 2001, 42: 6219

<A NAME="RA33003ST-63A">63a</A> Sasaki M. Noguchi T. Tachibana K. Tetrahedron Lett. 1999, 40: 1337

<A NAME="RA33003ST-63B">63b</A> Sasaki M. Noguchi T. Tachibana K. J. Org. Chem. 2002, 67: 3301

<A NAME="RA33003ST-64A">64a</A> Fukuzawa S.-I. Tsuchimoto T. Hotaka T. Hiyama T. Synlett 1995, 1077

<A NAME="RA33003ST-64B">64b</A> Ishihara K. Karumi Y. Kubota M. Yamamoto H. Synlett 1996, 839

<A NAME="RA33003ST-65">65</A> Inoue M. Sasaki M. Tachibana T. J. Org. Chem. 1999, 64: 9416

<A NAME="RA33003ST-66A">66a</A> Masaki Y. Serizawa Y. Kaji K. Chem. Lett. 1985, 1933

<A NAME="RA33003ST-66B">66b</A> Maruoka K. Miyazaki T. Ando M. Matsumura Y. Sakane S. Hattori K. Yamamoto H. J. Am. Chem. Soc. 1983, 105: 2831

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.

<A NAME="RA33003ST-68">68</A> Kim S. Do JY. Kim SH. Kim D. J. Chem. Soc., Perkin Trans. 1 1994, 2357

<A NAME="RA33003ST-69A">69a</A> Lee E. Tae JS. Lee C. Park CM. Tetrahedron Lett. 1993, 34: 4831

<A NAME="RA33003ST-69B">69b</A> Lee E. Song HY. Kang JW. Kim D.-S. Jung C.-K. Joo JM. J. Am. Chem. Soc. 2002, 124: 384

For related examples of radical additions to β-alkoxyacryl-ates see:

<A NAME="RA33003ST-70A">70a</A> Evans PA. Roseman JD. J. Org. Chem. 1996, 61: 2252

<A NAME="RA33003ST-70B">70b</A> Evans PA. Roseman JD. Garber LT. J. Org. Chem. 1996, 61: 4880

<A NAME="RA33003ST-70C">70c</A> Yuasa Y. Sato W. Shibuya S. Synth. Commun. 1997, 27: 573

<A NAME="RA33003ST-70D">70d</A> Berlin S. Ericsson C. Engman L. Org. Lett. 2002, 4: 3

<A NAME="RA33003ST-70E">70e</A> Pandey G. Hajra S. Ghorai MK. J. Org. Chem. 1997, 62: 5966

<A NAME="RA33003ST-70F">70f</A> Hori N. Matsukura H. Matsuo G. Nakata T. Tetrahedron Lett. 1999, 40: 2811

<A NAME="RA33003ST-70G">70g</A> Hori N. Matsukura H. Matsuo G. Nakata T. Tetrahedron 2002, 58: 1853

<A NAME="RA33003ST-71A">71a</A> Sasaki M. Inoue M. Noguchi T. Takeichi A. Tachibana K. Tetrahedron Lett. 1998, 39: 2783

<A NAME="RA33003ST-71B">71b</A> Inoue M. Wang J. Wang G.-X. Ogasawara Y. Hirama M. Tetrahedron 2003, 59: 5645

This slow conformational change appears to be the unique property of doubly trans-fused 9-membered ring. See for examples:

<A NAME="RA33003ST-72A">72a</A> Inoue M. Sasaki M. Tachibana K. Tetrahedron Lett. 1997, 38: 1611

<A NAME="RA33003ST-72B">72b</A> Inoue M. Sasaki M. Tachibana K. Tetrahedron 1999, 55: 10949

<A NAME="RA33003ST-72C">72c</A> 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

<A NAME="RA33003ST-73">73</A> Sabes SF. Urbanek RA. Forsyth CJ. J. Am. Chem. Soc. 1988, 120: 2534

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