Reagent-Controlled Regioselective [3,3]-Sigmatropic Rearrangement of N-Trifluoroacetyl Enehydroxylamine and Its Synthetic Application

Abstract

Regioselective [3,3]-sigmatropic rearrangement provides a novel method for the construction of hexahydrodibenzofuran with a quaternary carbon in the ring juncture. Upon treatment with TFAA, oxime ethers carrying an electron-withdrawing group smoothly underwent regioselective rearrangement to give the hexahydrodibenzofuran with a quaternary carbon. On the other hand, the reaction of oxime ethers with TFAT-DMAP gave tetrahydrodibenzofurans carrying a substituent at the 4-position. The hexahydrodibenzofuran with a quaternary carbon was effectively converted into a key intermediate for lunarine synthesis.

benzofuran - enehydroxylamine - [3,3]-sigmatropic rearrangement - lunarine - galanthamine

References and Notes

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7

The stereostructure of compound 6a was established as cis-isomer by NOESY of ¹H NMR spectra while stereostructures of 6b and 6c have not been established.

8

The compounds 7a-c were obtained as a mixture of two diastereomers and found to be 4a,9b-cis-configuration, but relative configuration at 4-position is not established.

9

Reaction of 5b with TFAA.
To a solution of oxime ether 5b (47 mg, 0.18 mmol) in CH₂Cl₂ (1.8 mL) was added TFAA (0.050 mL, 0.36 mmol) under a nitrogen atmosphere at r.t. After being stirred at the same temperature for 4 h, the reaction mixture was concentrated at reduced pressure. Purification of the residue by medium-pressure column chromatography (n-hexane-EtOAc, 5:1) afforded ethyl 4a-(2,2,2-trifluoroacetamido)-1,2,3,4,4a,9b-hexahydro-9b-dibenzofurancarboxylate (6b, 50 mg, 78%) as colorless crystals, mp 39-41 °C (hexane). ¹H NMR (500 MHz, CDCl₃): δ = 8.70 (1 H, br s), 7.24 (1 H, br d, J = 8 Hz), 7.23 (1 H, br td, J = 8, 1 Hz), 6.98 (1 H, td, J = 8, 1 Hz), 6.95 (1 H, br d, J = 8 Hz), 4.37-4.27 (2 H, m), 2.87 (1 H, br dt, J = 15, 5 Hz), 2.39 (1 H, br dt, J = 15, 5 Hz), 2.30 (1 H, br ddd, J = 15, 10, 5 Hz), 1.71-1.51 (5 H, m), 1.34 (3 H, t, J = 7 Hz), ¹³C NMR (125 MHz, CDCl₃): δ = 172.7, 156.5, 156.1 (q, COCF₃), 130.8, 129.5, 123.8, 122.1, 115.4 (q, CF₃), 111.7, 97.4, 62.6, 57.9, 35.3, 30.0, 20.8, 20.7, 14.0. IR (CHCl₃): 3380, 1741 cm^-1. HRMS (EI): m/z calcd for C₁₇H₁₈F₃NO₄ [M⁺]: 357.1187; found: 357.1196.
Reaction of 5b with TFAT in the Presence of DMAP.
To a solution of oxime ether 5b (47 mg, 0.18 mmol) in CH₂Cl₂ (1.8 mL) were added DMAP (66 mg, 0.54 mmol) and TFAT (0.13 mL, 0.90 mmol) under a nitrogen atmosphere at r.t. After being stirred at the same temperature for 24 h, the reaction mixture was diluted with H₂O and extracted with CHCl₃. The organic phase was washed with H₂O, dried over MgSO₄ and concentrated at reduced pressure. Purification of the residue by medium-pressure column chromatography (n-hexane-EtOAc, 7:1) afforded ethyl 1,2,3,4-tetrahydro-4-dibenzofurancarboxylate (8b, 28 mg, 64%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 7.44 (1 H, br t, J = 8.0 Hz), 7.43 (1 H, br d, J = 8.0 Hz), 7.24 (1 H, br dd, J = 8.0, 1.0 Hz), 7.20 (1 H, br td, J = 8.0, 1.0 Hz), 4.25-4.20 (2 H, m), 3.85 (1 H, br tt, J = 6.0, 2.0 Hz), 2.72 (1 H, br dtd, J = 15.0, 6.0, 2.0 Hz), 2.63 (1 H, br dddd, J = 15.0, 7.5, 6.0, 2.0 Hz), 2.25 (1 H, br dddd, J = 13.0, 7.5, 6.0, 2.5 Hz), 2.13 (1 H, br dddd, J = 13.0, 10.0, 6.0, 3.0 Hz), 2.02-1.98 (1 H, m), 1.87 (1 H, br dddd, J = 16.0, 7.5, 6.0, 3.0 Hz), 1.29 (3 H, t, J = 7 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 172.3, 154.7, 149.5, 128.2, 123.8, 122.3, 118.9, 115.3, 111.2, 61.2, 40.6, 27.2, 20.6, 20.3, 14.2. IR (CHCl₃): 1731 cm^-1. HRMS (EI): m/z calcd for C₁₅H₁₆O [M⁺]: 244.1098; found: 244.1107.