Convergent Synthesis of the BCDE-Ring Part of Ciguatoxin

Kenshu  Fujiwara; Yasuhito  Koyama; Kentaro  Kawai; Hideki  Tanaka; Akio  Murai

doi:10.1055/s-2002-34904

LETTER

Convergent Synthesis of the BCDE-Ring Part of Ciguatoxin

Kenshu Fujiwara*, Yasuhito Koyama, Kentaro Kawai, Hideki Tanaka, Akio Murai*
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Fax: +81(11)7064924; e-Mail: fjwkn@sci.hokudai.ac.jp;

Abstract

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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.

Key words

heterocycles - stereoselective synthesis - natural products - polyethers - polycycles

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References

Present address: 6-14-44, Asabu-cho, Kita-ku, Sapporo
001-0045, Japan, Fax: +81(11)7476963,
E-mail: amurai@rmail.plala.or.jp

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

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.

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.

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.