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Synlett 2002(11): 1835-1838
DOI: 10.1055/s-2002-34904
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
Further Information

Publication History

Received 14 August 2002
Publication Date:
21 October 2002 (online)

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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

1

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

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): νmax = 3091, 3062, 3030, 2954, 2925, 2854, 1453, 1092, 738, 695 cm-1; HR-FDMS: calcd for C54H59O9 [M + H]+: 851.4159. Found: 851.4182.