New Access to a Tricyclo[3.2.1.0^2,7]oct-3-ene Structure

Abstract

A thermally induced reaction cascade including an electrocyclic rearrangement, two Diels-Alder reactions and a 1,4-elimination from a simple cyclobutene carbonate can explain the synthesis of a complex tricyclo[3.2.1.0^2,7]oct-3-ene core structure.

Key words

1,4-elimination - Diels-Alder - electrocyclic reaction - polycycles - stereoselective synthesis

References and Notes

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• 1b Bohlmann F. Jakupovic J. Ahmed M. Grenz M. Suding H. Robinson H. King RM. Phytochemistry  1981,  20:  113 
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• 3a Hodgson DM. Marriott RE. Tetrahedron Lett.  1997,  38:  887 
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• 5 Kiattansakul R. Snyder JK. Tetrahedron Lett.  1999,  40:  1079 
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• 7a Abad A. Agullo C. Cunat AC. De Alfonso I. Navarro I. Vera N. Molecules  2004,  9:  287 
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• 7c Ng SM. Beaudry CM. Trauner D. Org. Lett.  2003,  5:  1701 
• 8 Danheiser RL. Savariar S. Cha DD. Org. Synth.  1990,  68:  32 
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Methyl 3-Phenylcyclobut-2-enyl Carbonate ( 5). To a solution of 3-phenylcyclobutenone (3, 2.1 g, 14.5 mmol) and CeCl₃·7H₂O (5.6 g, 22.7 mmol) in MeOH (50 mL) at r.t. was slowly added NaBH₄ (580 mg, 15 mmol) over 15 min. The reaction mixture was stirred at that temperature for 5 min, hydrolyzed with brine (50 mL) and extracted with Et₂O (3 × 50 mL). The organic layer was dried over MgSO₄ and evaporated to give a residue (2.1 g) which was dissolved in CH₂Cl₂ (150 mL) in the presence of Et₃N (8 mL, 57 mmol) and 4-dimethylamino pyridine (1 g, 8 mmol). Then, ClCO₂Me (4.7 mL, 60 mmol) was slowly added and the reaction mixture was stirred for 75 min at r.t. After dilution in CH₂Cl₂ (50 mL), it was hydrolyzed with brine (100 mL) and extracted with Et₂O (3 × 100 mL). The organic layer was dried over MgSO₄, evaporated and the residue was purified by flash chromatography (pentane-CH₂Cl₂ = 70:30) to give the carbonate 5 as a yellow oil (1.83 g, 62%). ¹H NMR (400 MHz, CDCl₃): δ = 7.50-7.30 (m, 5 H), 6.34 (br s, 1 H), 5.40 (dt, J = 3.9, 1.0 Hz, 1 H), 3.81 (s, 3 H), 3.23 (ddd, J = 13.1, 3.9, 1.0 Hz, 1 H), 2.83 (dt, J = 13.1, 1.0 Hz, 1H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 155.4, 148.6, 133.0, 129.1, 128.4, 125.6, 125.0, 71.1, 54.6, 36.9 ppm. IR (CHCl₃): ν = 3062-2850, 1743, 1444, 1259 cm^-1. MS (EI): m/z = 146 [MNH₄ ⁺ - MeOCO₂H].

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Compounds 6:
The carbonate 5 (300 mg, 1.5 mmol) in DMSO (1 mL) was heated at DMSO reflux for 1.5 h under argon. The crude reaction mixture was diluted with brine (15 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was dried over MgSO₄, evaporated and the residue was purified by flash chromatography (CH₂Cl₂-pentane = 1:2) to give the compound 6 as a white solid (84 mg, 33%). ¹H NMR (300 MHz, CDCl₃): δ = 7.50-7.20 (m, 10 H, arom.), 6.59 (dd, J = 6.2, 2.3 Hz, H³), 5.26 (dd, J = 4.7, 2.3 Hz, 1 H, H⁶), 3.71 (t, J = 3.9 Hz, 1 H, H⁵), 3.69 (s, 3 H, H¹⁰), 2.35 (dd, J = 6.8, 2.4 Hz, 1 H, H⁷), 2.23 (dd, J = 8.0, 6.2 Hz, 1 H, H²), 2.18 (dd, J = 11.7, 5.1 Hz, 1 H, H^{8 ′}), 1.57 (d, J = 11.7 Hz, 1 H, H⁸) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 155.5 (C=O), 141.2 (Ph), 139.2 (C⁴), 135.9, 127.5, 126.7, 126.2, 126.0, 124.9 (Ph), 120.4 (C³), 75.5 (C⁶), 54.5 (methoxy), 38.3 (C⁵), 31.9 (C¹), 31.2 (C⁸), 28.2 (C²), 27.2 (C⁷) ppm. Mp 117 °C. IR (KBr): 3031, 2922, 2856, 1742, 1440, 1292, 1265, 968, 755, 697 cm^-1. Anal. Calcd for C₂₂H₂₀O₃: C, 79.50; H, 6.06. Found: C, 79.50; H, 6.31.

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The carbonate 5 (368 mg, 1.8 mmol) was heated at 140 °C (neat) for 30 min. The residue was purified by flash chromatography (pentane-Et₂O = 95:5, followed by pentane-Et₂O = 80:20) to afford successively the tricyclic compound 6 as a white solid (62 mg, 21%), a mixture of the diastereomers 8 (69 mg, 19%) and diene 7 (10 mg, 5%).
Diastereomers 8: ¹H NMR (300 MHz, CDCl₃): δ = 7.50-7.20 (m, 20 H, Ph), 6.95 (d, J = 12.6 Hz, 1 H, CH_trans), 6.91 (d, J = 12.7 Hz, 1 H, CH_trans), 6.32 (br d, J = 5.1 Hz, 1 H, CH), 6.29 (dt, J = 4.3, 1.6 Hz, 1 H, CH), 5.73 (d, J = 12.6 Hz, 1 H, CH_trans), 5.65 (d, J = 4.3 Hz, 1 H, CHO), 5.63 (d, J = 12.7 Hz, 1 H, CH_trans), 5.51 (d, J = 5.1 Hz, 1 H, CHO), 3.82 (s, 3 H, OMe), 3.81 (s, 3 H, OMe), 3.77 (s, 3 H, OMe), 3.55 (s, 3 H, OMe), 2.70-2.40 (m, 4 H, CH₂), 2.40-2.10 (m, 4 H, CH₂) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 155.4, 155.0, 153.4, 153.3 (CO), 142.9, 142.2, 142.1, 142.0 (C_ipso), 140.1, 140.0 (C_Q), 138.9, 138.4 (CH), 128.4, 128.3, 128.2, 128.1, 127.9, 127.3, 126.9, 126.8, 126.7, 125.6, 125.5, 120.6, 119.5, 118.9, 118.7 (CH), 77.2, 75.7 (CH), 55.2, 55.1, 54.8, 54.6 (CH₃), 44.4, 44.1 (C_Q), 29.7, 27.7, 25.5, 25.1 (CH₂) ppm. HRMS: m/z calcd for C₂₄H₂₈O₆N [M + NH₄]: 426.1917; found: 426.1915.
Diene 7: ¹H NMR (300 MHz, CDCl₃): δ = 7.09 (d, J = 12.4 Hz, 1 H), 6.32 (dd, J = 12.4, 0.8 Hz, 1 H), 5.27 (dd, J = 1.5, 0.6 Hz, 1 H), 5.15 (d, J = 1.5 Hz, 1 H), 3.84 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 153.3, 143.6, 140.3, 139.5, 128.4, 127.8, 117.2, 116.5, 55.3 ppm. MS (EI): m/z = 178 [MNH₄ ⁺ - CO₂].