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.

Key words

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

References and Notes

• 1a Hoshino O. The Alkaloids   Vol. 51:  Cordell GA. Academic Press; New York: 1998.  p.323-424  
• 1b Marco-Contelles J. Carreiras MDC. Rodríguez C. Villarroya M. García AG. Chem. Rev.  2006,  106:  116 
• 2a Santavy F. The Alkaloids   Vol. 17:  Manske RHF. Rodorico RGA. Academic Press; New York: 1979.  p.385-519  
• 2b Trost BM. Tang W. Toste D. J. Am. Chem. Soc.  2005,  127:  14785 
• 3a Poupat C. Husson H.-P. Das BC. Bladon P. Potier P. Tetrahedron  1972,  28:  3103 
• 3b Husson H.-P. Poupat C. Rodriguez B. Potier P. Tetrahedron  1973,  29:  1405 
• 3c Nagao Y. Takao S. Miyasaka T. Fujita E. J. Chem. Soc., Chem. Commun.  1981,  286 
• 3d Hamilton CJ. Fairlamb AH. Eggleston IM. J. Chem. Soc., Perkin Trans. 1  2002,  1115 
• 3e Hamilton CJ. Saravanamuthu A. Fairlamb AH. Eggleston IM. Bioorg. Med. Chem.  2003,  11:  3683 
• 3f Hamilton CJ. Saravanamuthu A. Poupat C. Fairlamb AH. Eggleston IM. Bioorg. Med. Chem.  2006,  14:  2266 
• 4 Laronze J.-Y. Boukili RE. Royer D. Lévy J. Tetrahedron  1991,  47:  10003 
• 5 Kaminsky D. Shavel J. Meltzer RI. Tetrahedron Lett.  1967,  859 
• 6a Miyata O. Takeda N. Morikami Y. Naito T. Org. Biomol. Chem.  2003,  1:  254 
• 6b Miyata O. Takeda N. Naito T. Org. Lett.  2004,  6:  1761 

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.