Stereoselective Construction of a Contiguous Tetraol System in Tetrodotoxin by Means of Repetitive Operations Involving Epoxidation and Ring-opening Reactions of Allyl Sulfone

Abstract

Stereoselective construction of a tetraol system corresponding to C-5, 6, 7, and 11 in tetrodotoxin was achieved. Epoxidation of allyl sulfide 3 followed by base-induced ring-opening reaction gave hydroxyallyl sulfone 6. Repetition of the above reactions gave 1,3-dihydroxyvinyl sulfone 8, which was transformed to protected tetraols 18 and 20 by a series of sequential reactions: 1) reductive removal of the phenylsulfonyl group, 2) inversion of the α-axial TBSoxy group to an β-equatorial position, and 3) dihydroxylation with OsO₄.

Key words

tetrodotoxin - allyl sulfone - quinic acid - epoxidation - ring-opening reaction

References

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29

A mixture of 18 and 19 was difficult to separate. The major isomer 18 was partially purified by repeating silica gel chromatography. 18: colorless oil. [α]_D ²¹ +131.3 (c 0.60, CHCl₃). FT-IR (neat): 3445, 2992, 2952, 2857, 2836, 1734, 1472, 1464, 1377, 1252, 1171, 1139, 1038, 940, 866, 851, 837, 777, 758, 667 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 5.27 (1 H, d, J = 5.9 Hz), 4.89 (1 H, d, J = 5.9 Hz), 4.48 (1 H, dd, J = 10.2, 9.6 Hz), 4.40 (1 H, dd, J = 10.2, 2.9 Hz), 4.29 (1 H, dd, J = 9.6, 3.6 Hz), 4.06 (1 H, d, J = 10.9 Hz), 3.98 (1 H, d, J = 10.9 Hz), 3.93 (1 H, dd, J = 2.9, 1.6 Hz), 3.81 (1 H, brs), 3.28 (3 H, s), 3.24 (3 H, s), 1.34 (3 H, s), 1.30 (3 H, s), 0.90 (9 H, s), 0.12 (3 H, s), 0.10 (3 H, s). ¹³ C NMR (100 MHz, CDCl₃): δ = 101.3, 100.6, 89.2, 76.6, 73.3, 72.9, 70.5, 69.8, 69.0, 64.6, 47.8, 47.6, 25.7, 18.1, 17.8, 17.7, -4.5, -4.9. Mass (FAB^-): m/z calcd for (M - H) ^- [C₂₀H₃₇O₉Si]^- 449.2206. Found: 449.2202.

30

Colorless oil. [α]_D ²¹ +170.0 (c 0.96, CHCl₃). FT-IR (neat): 3462, 2951, 2853, 2836, 2359, 2341, 1737, 1457, 1374, 1242, 1170, 1137, 1087, 1032, 930, 878, 757, 668, 448
cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 5.38 (1 H, dd, J = 10.0, 3.3 Hz), 5.26 (1 H, d, J = 5.9 Hz), 4.91 (1 H, d, J = 5.9 Hz), 4.70 (1 H, t, J = 10.0 Hz), 4.49 (1 H, dd, J = 10.0, 2.9 Hz), 4.24 (1 H, dd, J = 3.3, 1.4 Hz), 4.08 (1 H, d, J = 11.2 Hz), 3.97 (1 H, dd, J = 2.9, 1.4 Hz), 3.88 (1 H, d, J = 11.2 Hz), 3.77 (1 H, br s), 3.26 (3 H, s), 3.24 (3 H, s), 2.12 (3 H, s), 1.33 (3 H, s), 1.29 (3 H, s). ¹³ C NMR (150 MHz, CDCl₃): δ = 171.2, 101.5, 100.9, 88.8, 72.8, 72.6, 72.5, 69.6, 69.5, 68.8, 64.5, 47.8, 47.4, 20.9, 17.6, 17.5. HRMS (FAB^-): m/z calcd for (M - H) ^- [C₁₆H₂₅O₁₀]^- 377.1447. Found: 377.1452.

31

Colorless oil. [α]_D ¹⁹ +26.7 (c 0.36, CDCl₃). FT-IR (neat): 3470, 2925, 2853, 1736, 1372, 1246, 1168, 1139, 1117, 1033, 878, 757, 666 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 5.48 (1 H, d, J = 4.6 Hz), 5.05 (1 H, d, J = 4.6 Hz), 4.96 (1 H, dd, J = 10.1, 2.5 Hz), 4.64 (1 H, t, J = 10.1 Hz), 4.18 (1 H, s), 4.06 (1 H, brs), 3.78 (1 H, dd, J = 10.1, 3.4 Hz), 3.77 (1 H, d, J = 11.6 Hz), 3.61 (1 H, d, J = 11.6 Hz), 3.27 (3 H, s), 3.24 (3 H, s), 2.14 (3 H, s), 1.36 (3 H, s), 1.29 ( 3H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 170.9, 101.1, 100.5, 86.8, 73.6, 73.2, 71.8, 71.5, 68.2, 68.1, 64.1, 47.9, 47.6, 21.1, 17.7, 17.6. HRMS (FAB^-): m/z calcd for (M - H) ^- [C₁₆H₂₅O₁₀]^- 377.1447. Found: 377.1449.