Stereoselective Synthesis of the Fully Functionalized HIJ-ring Framework of Ciguatoxin

Abstract

An efficient convergent synthetic route to construct the HIJ-ring system of ciguatoxin was achieved via stereo controlled eight-membered ring formation by using acetylene cobalt complex and subsequent six-membered ring formation through intramolecular 1,4-addition reaction.

alkyne cobalt complexes - reductive decomplexation - medium sized ring closure reaction - intramolecular 1,4-addition reaction - ciguatoxin.

References

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11

Physical data for 7a. ¹H NMR (400 MHz, CDCl₃): δ = 1.39 (1 H, q, J = 11.0 Hz, H-43a), 1.84 (1 H, br, -OH), 2.58 (1 H, dd, J = 15.5, 9.0 Hz, H-40a), 2.61 (1 H, dt, J = 11.0, 4.0 Hz, H-43b), 2.92 (1 H, dd, J = 15.5, 2.0 Hz, H-40b), 3.25-3.45 (4 H, m, H-41, H-42, H-44, H-45), 3.38 (3 H, s, -OCH ₃ ), 3.39 (3 H, s, -OCH ₃ ), 3.56 (1 H, dd, J = 10.5, 4.0 Hz, H-46a), 3.64 (1 H, dd, J = 10.5, 1.5 Hz, H-46b). HRMS (FAB) calcd for C₁₂H₂₀F₃O₇S⁺ [M + H]⁺: 365.0882. Found: 365.0872.

12

Physical data for 6. ¹H NMR (300 MHz, CDCl₃): δ = 1.10, 1.11 (3 H, s, -CH₃), 1.37, 1.38 [3 H, s, -C(CH ₃ )₂], 1.46 [3 H, s, -C(CH ₃ )₂], 1.78-1.90 (total 1 H, m, H-35a), 1.95, 2.07 (total 1 H, ddd, J = 14.5, 5.0, 2.5 Hz and J = 14.5, 4.0, 2.0 Hz, H-35b), 2.50-2.61 (total 2 H, m, H-36, acetylene), 2.78, 2.84 (total 1 H, dd, J = 17.0, 3.5 Hz and J = 17.5, 3.0 Hz, H-31), 3.03, 3.22 (total 1 H, br-s, -OH), 3.82, 4.10 (total 1 H, dd, J = 10.0, 2.0 Hz and J = 10.0, 2.5 Hz, H-34), 4.22, 4.29 (total 1 H, dd, J = 9.5, 3.0 Hz and J = 9.0, 3.5 Hz, H-32), 4.64, 4.75 (total 1 H, m, H-36). Anal. Calcd for C₁₃H₁₉NO₄: C, 61.64; H, 7.56; N, 5.53. Found: C, 61.65; H, 7.51; N, 5.43.

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15b

Absence of BTMSA leads to further reduction of unsaturated ketone product to corresponding saturated carbonyl compound.

16

Physical data for 20. ¹H NMR (400 MHz, CDCl₃) δ = 1.34 (3 H, s, H-56), 1.40 (1 H, q, J = 11.5 Hz, H-43a), 1.93 (1 H, q, J = 11.5 Hz, H-35a), 2.50 (1 H, dt, J = 11.5, 5.0 Hz, H-35b), 2.53 (1 H, ddd, J = 11.5, 4.5, 4.0 Hz, H43b), 2.60 (1 H, dd, J = 17.0, 4.0 Hz, H-31a), 2.62 (1 H, dd, J = 17.0, 8.0 Hz, H-31b), 2.69 (1 H, ddd, J = 11.0, 4.0, 2.0 Hz, H-38a), 2.79-2.89 (3 H, m, H-38b, H-40a, H-40b), 3.21 (1 H, d, J = 8.0 Hz, -OH), 3.20-3.26 (2 H, m, H-44, H-45), 3.32 (1 H, ddd, J = 11.5, 9.5, 4.5 Hz, H-42), 3.34 (3 H, s, -OCH ₃), 3.38 (3 H, s, -OCH ₃), 3.43 (1 H, ddd, J = 11.5, 9.5, 5.0 Hz, H-36), 3.48 (1 H, ddd, J = 10.5, 9.5, 4.5 Hz, H-41), 3.53 (1 H, dd, J = 10.5, 4.0 Hz, H-46b), 3.61 (1 H, dd, J = 10.5, 1.5 Hz, H-46b), 3.74 (1 H, td, J = 8.0, 4.0 Hz, H-32), 3.75 (1 H, ddd, J = 10.5, 9.5, 4.0 Hz, H-37), 5.40 (1 H, dd, J = 12.0, 5.0 Hz, H-34), 7.45-7.52 (2 H, m, aromatic), 7.60-7.64 (1 H, m, aromatic), 7.96-8.00 (2 H, m, aromatic). HRMS (FAB) calcd for C₂₇H₃₅NNaO₉ ⁺ [M + Na]⁺: 540.2210. Found: 540.2180.

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19

Physical data for 29. ¹H NMR (400 MHz, CDCl₃) δ = 0.89-1.06 {21 H, m, -Si[CH(CH ₃)₂]₃}, 1.07 (3 H, d, J = 7.0 Hz, CH₃-57), 1.33 (1 H, m, H-43a), 1.45-1.71 (2 H, m, H-38a, H-40a), 1.47 (3/2 H, s, H-56), 1.49 (3/2 H, s, H-56*), 1.72-1.80 (1 H, m, H-35a), 1.82-2.09 (3 H, m, H-38b, H-39, H-40b), 2.48-2.57 (3 H, m, H-31a, H-35b, H-43b), 2.82 (1/2 H, dd, J = 16.5, 5.5 Hz, H-31b), 2.89 (1/2 H, dd, J = 16.5, 5.5 Hz, H-31b*), 3.10-3.66 (6 H, m, H-36, H-37, H-41, H-42, H-44, H-45), 3.35 (3 H, s, -OCH ₃) 3.40 (3 H, s, -OCH ₃), 3.49 (1 H, dd, J = 10.5, 5.5 Hz, H-46a), 3.63 (1 H, dd, J = 10.5, 2.0 Hz, H-46b), 3.97 (1/2 H, t, J = 5.5 Hz, H-32), 4.05 (1/2 H, dd, J = 5.5, 4.5 Hz, H-32*), 5.15 (1 H, dd, J = 11.5, 4.5 Hz, H-34), 7.44-7.49 (2 H, m, aromatic), 7.58-7.62 (1 H, m, aromatic), 7.99-7.02 (2 H, m, aromatic). The fractional integral values result from the existence of a rotational isomer at C32-C33 bond. HRMS (FAB) calcd for C₃₇H₅₉O₈NNaSi⁺ [M + Na]⁺: 696.3907. Found: 696.3917.

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