Convergent Synthesis of the BCDE-Ring Part of Ciguatoxin

Abstract

The BCDE-ring part of ciguatoxin has been convergently synthesized by a sequence of reactions involving coupling of the E-ring part having a Z-enal group with the B-ring part as an acyl anion equivalent, selective removal of a p-bromobenzyl protective group using Miyaura’s conditions, and reductive cyclization.

heterocycles - stereoselective synthesis - natural products - polyethers - polycycles

References

1

Present address: 6-14-44, Asabu-cho, Kita-ku, Sapporo
001-0045, Japan, Fax: [phone],
E-mail: [e-mail]

For the isolation and structure determination of ciguatoxin, see:

2a Scheuer PJ. Takahashi W. Tsutsumi J. Yoshida T. Science  1967,  155:  1267 

2b Tachibana K. Ph.D. Thesis   University of Hawaii; Hawaii: 1980. 

2c Nukina M. Koyanagi LM. Scheuer PJ. Toxicon  1984,  22:  169 

2d Murata M. Legrand A.-M. Ishibashi Y. Fukui M. Yasumoto T. J. Am. Chem. Soc.  1989,  111:  8929 

2e Murata M. Legrand A.-M. Ishibashi Y. Fukui M. Yasumoto T. J. Am. Chem. Soc.  1990,  112:  4380 

2f Satake M. Morohashi A. Oguri H. Oishi T. Hirama M. Harada N. Yasumoto T. J. Am. Chem. Soc.  1997,  119:  11325 

2g For reviews of ciguatoxin and related marine toxins, see: Yasumoto T. Murata M. Chem. Rev.  1993,  93:  1897 

2h See also: Scheuer PJ. Tetrahedron  1994,  50:  3 

2i For a review of ciguatera, see: Lewis RL. Toxicon  2001,  39:  97 

For the bioactivities of ciguatoxin and related compounds, see:

3a Bidard J.-N. Vijverberg HPM. Frelin C. Chungue E. Legrand A.-M. Bagnis R. Lazdanski M. J. Biol. Chem.  1984,  259:  8353 

3b Lombet A. Bidard JN. Lazdanski M. FEBS Lett.  1987,  219:  355 

3c For a review, see: Dechraoui M.-Y. Naar J. Pauillac S. Legrand A.-M. Toxicon  1999,  37:  125 ; see also the references cited in ref. 11

4 For the total synthesis of CTX3C, a congener of ciguatoxin, see: Hirama M. Oishi T. Uehara H. Inoue M. Maruyama M. Oguri H. Satake M. Science  2001,  294:  1904 

For the recent synthetic studies of ciguatoxins, see:

5a Takakura H. Sasaki M. Honda S. Tachibana K. Org. Lett.  2002,  4:  2771 

5b Uehara H. Oishi T. Inoue M. Shoji M. Nagumo Y. Kosaka M. Brazidec J.-YL. Hirama M. Tetrahedron  2002,  58:  6493 

5c Sasaki M. Noguchi T. Tachibana K. J. Org. Chem.  2002,  67:  3301 

5d Takai S. Isobe M. Org. Lett.  2002,  4:  1183 

5e Bond S. Perlmutter P. Tetrahedron  2002,  58:  1779 

5f Maruyama M. Inoue M. Oishi T. Oguri H. Ogasawara Y. Shindo Y. Hirama M. Tetrahedron  2002,  58:  1835 

5g Kira K. Hamajima A. Isobe M. Tetrahedron  2002,  58:  1875 

5h Sasaki M. Ishikawa M. Fuwa H. Tachibana K. Tetrahedron  2002,  58:  1889 

5i Candenas ML. Pinto FM. Cintado CG. Morales EQ. Brouard I. Díaz MT. Rico M. Rodríguez E. Rodríguez RM. Pérez R. Pérez RL. Martín JD. Tetrahedron  2002,  58:  1921 

5j Takakura H. Noguchi K. Sasaki M. Tachibana K. Angew. Chem. Int. Ed.  2001,  40:  1090 

5k Oishi T. Tanaka S.-i. Ogasawara Y. Maeda K. Oguri H. Hirama M. Synlett  2001,  952 

5l Imai H. Uehara H. Inoue M. Oguri H. Oishi T. Hirama M. Tetrahedron Lett.  2001,  42:  6219 

5m Kira K. Isobe M. Tetrahedron Lett.  2001,  42:  2821 

5n Saeeng R. Isobe M. Heterocycles  2001,  54:  789 

5o Oguri H. Tanaka S. Oishi T. Hirama M. Tetrahedron Lett.  2000,  41:  975 

5p Sasaki M. Noguchi K. Fuwa H. Tachibana K. Tetrahedron Lett.  2000,  41:  1425 

5q Kira K. Isobe M. Tetrahedron Lett.  2000,  41:  5951 

5r Liu T.-Z. Isobe M. Tetrahedron  2000,  56:  5391 

5s Liu T.-Z. Isobe M. Tetrahedron  2000,  56:  10209 

For the convergent approaches, see:

6a Nicolaou KC. Angew. Chem., Int. Ed. Engl.  1996,  35:  589 ; and the references cited therein

6b Alvarez E. Díaz MT. Hanxing L. Martín JD. J. Am. Chem. Soc.  1995,  117:  1437 

6c Alvarez E. Pérez R. Rico M. Rodríguez RM. Martín JD. J. Org. Chem.  1996,  61:  3003 

6d Ravelo JL. Regueiro A. Rodríguez E. de Vera J. Martín JD. Tetrahedron Lett.  1996,  37:  2869 

6e Oishi T. Nagumo Y. Hirama M. Synlett  1997,  980 

6f Oishi T. Nagumo Y. Hirama M. Chem. Commun.  1998,  1041 

6g Sasaki M. Fuwa H. Inoue M. Tachibana K. Tetrahedron Lett.  1998,  39:  9027 

6h Sasaki M. Fuwa H. Ishikawa M. Tachibana K. Org. Lett.  1999,  1:  1075 

6i Inoue M. Sasaki M. Tachibana K. Tetrahedron  1999,  55:  10949 

6j Fujiwara K. Morishita H. Saka K. Murai A. Tetrahedron Lett.  2000,  41:  507 

6k Matsuo G. Hinou H. Koshino H. Suenaga T. Nakata T. Tetrahedron Lett.  2000,  41:  903 

6l Mori Y. Mitsuoka S. Furukawa H. Tetrahedron Lett.  2000,  41:  4161 

6m Díaz MT. Pérez RL. Rodríguez L. Ravelo JL. Martín JD. Synlett  2001,  345 

6n Kadota I. Ohno A. Matsuda K. Yamamoto Y. J. Am. Chem. Soc.  2002,  124:  3562 

For the synthetic studies of ciguatoxin in this laboratory, see:

7a Oka T. Murai A. Chem. Lett.  1994,  1611 

7b Oka T. Fujiwara K. Murai A. Tetrahedron  1996,  52:  12091 

7c Atsuta H. Fujiwara K. Murai A. Synlett  1997,  307 

7d Oka T. Fujiwara K. Murai A. Tetrahedron Lett.  1997,  38:  8053 

7e Oka T. Murai A. Tetrahedron  1998,  54:  1 

7f Oka T. Fujiwara K. Murai A. Tetrahedron  1998,  54:  21 

7g Fujiwara K. Saka K. Takaoka D. Murai A. Synlett  1999,  1037 

7h Fujiwara K. Tanaka H. Murai A. Chem. Lett.  2000,  610 

7i Fujiwara K. Takaoka D. Kusumi K. Kawai K. Murai A. Synlett  2001,  691 

7j Fujiwara K. Koyama Y. Doi E. Shimawaki K. Ohtaniuchi Y. Takemura A. Souma S. Murai A. Synlett  2002,  1496 

8a Ogura K. Tsuchihashi G. Tetrahedron Lett.  1972,  2681 

8b Herrmann JL. Richman JE. Wepplo PJ. Schlessinger RH. Tetrahedron Lett.  1973,  4707 

9 Ishiyama T. Murata M. Miyaura N. J. Org. Chem.  1995,  60:  7508 

10 Corey EJ. Fuchs PL. Tetrahedron Lett.  1972,  3769 

11 Nicolaou KC. Hwang C.-K. Nugiel DA. J. Am. Chem. Soc.  1989,  111:  4136 

12

When CH₂Cl₂ was used as the solvent for the cyclization, the yield of 29 was reduced (35%) and many unidentified byproducts were formed.

13

Stereochemistries at C9 and C10 of 29 were confirmed by the presence of NOE (H9/H14) and the absence of NOE (H9/H10) as well as the large value of ³ J _H9-H10 (7.5 Hz). The stereochemistries at C9 and C10 of 30 were determined by the absence of NOEs (H9/H14 and H9/H10) and the large value of ³ J _H9-H10 (8.0 Hz). So far, the isomerization at C9 in the ketone resulting from oxidation of 30 into the desired stereochemistry has not been successful. The isomerization at C9 and improvement of the selectivity during the reductive cyclization of 4 are under investigation.

14

Compound 31 would be produced by the addition of CH₃CN to the intermediate cyclic oxonium ion generated from 4 with TMSOTf during the course of the reaction.

15

Representative data for 2: Colorless needles; mp 118-119 °C; [α]_D ²⁴ -13.6 (c 0.02, CHCl₃); ¹H NMR (600 MHz, CD₃CN, CHD₂CN as 1.93 ppm): δ = 7.39-7.25 (30 H, m, Ph), 5.81 (1 H, dt, J = 13.2, 2.5 Hz, H15), 5.67 (1 H, brd, J = 13.2 Hz, H12), 5.64 (1 H, br d, J = 13.2 Hz, H11), 5.60 (1 H, dt, J = 13.2, 2.5 Hz, H16), 4.91 (1 H, d, J = 11.0 Hz, Bn), 4.85 (1 H, d, J = 11.0 Hz, Bn), 4.75 (1 H, d, J = 11.0 Hz, Bn), 4.61 (1 H, d, J = 11.4 Hz, Bn), 4.59 (1 H, d, J = 11.0 Hz, Bn), 4.53 (1 H, d, J = 12.1 Hz, Bn), 4.49 (1 H, d, J = 12.1 Hz, Bn), 4.47 (1 H, d, J = 12.1 Hz, Bn), 4.43 (1 H, d, J = 11.4 Hz, Bn), 4.40 (1 H, d, J = 12.1 Hz, Bn), 4.18 (1 H, br d, J = 9.2 Hz, H13), 4.06 (1 H, dq, J = 8.2, 2.1 Hz, H17), 4.03 (1 H, dq, J = 9.2, 2.1 Hz, H14), 3.81 (1 H, br d, J = 9.2 Hz, H10), 3.70 (1 H, ddd, J = 8.2, 5.9, 2.8 Hz, H18), 3.64 (1 H, dd, J = 11.0, 2.8 Hz, H19a), 3.56-3.51 (4 H, m, H1, H5, H19b), 3.39 (1 H, td, J = 9.2, 6.6 Hz, H3), 3.35 (1 H, ddd, J = 11.4, 9.2, 4.8 Hz, H9), 3.21 (1 H, t, J = 9.2 Hz, H4), 3.05-3.15 (2 H, m, H6, H7), 2.20 (1 H, m, H8a), 2.02 (1 H, m, H2a), 1.56 (1 H, m, H2b), 1.41 (1 H, q, J = 11.4 Hz, H8b); ¹³C NMR (100 MHz, CD₃CN, CD₃ ¹³CN as 118.2 ppm): δ = 140.1 (C in Ph), 139.8 (C in Ph), 139.60 (C in Ph), 139.56 (C in Ph), 139.2 (C in Ph), 134.3 (C12), 133.4 (C16), 131.6 (C11), 130.8 (C15), 128.2-129.2 (CH in Ph × 25), 84.49 (C5), 84.46 (C18), 83.8 (C14), 83.7 (C13), 82.7 (C6), 82.5 (C4), 80.8 (C10), 79.8 (C9), 77.4 (C17), 76.8 (C3), 75.6 (Bn), 75.1 (Bn), 73.9 (C7), 73.6 (Bn), 73.0 (Bn), 71.9 (Bn), 71.7 (C19), 66.7 (C1), 37.4 (C8), 32.9 (C2); IR(film): ν_max = 3091, 3062, 3030, 2954, 2925, 2854, 1453, 1092, 738, 695 cm^-1; HR-FDMS: calcd for C₅₄H₅₉O₉ [M + H]⁺: 851.4159. Found: 851.4182.