Total Synthesis of 1-Oxomiltirone and Arucadiol

Abstract

A practical and efficient approach for the total synthesis of arucadiol and 1-oxomiltirone is reported. The key step which involves an intramolecular [4+2] cycloaddition catalyzed by gold(III) bromide or copper(II) triflate leads to the formation of 6-6-6-fused aromatic abietane core.

Key words

arucadiol - 1-oxomiltirone - [4+2]-benzannulation - gold(III) bromide - copper(II) trifluoromethanesulfonate

• References and Notes

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• 21 Procedure for the AuBr₃-Catalyzed CyclizationA 5 mL seal tube was charged with 6a (58.5 mg, 0.20 mmol) and dry 1,2-dichloroethane (0.4 mL). To this solution was added AuBr₃ (3 mol%) under argon atmosphere at 0 °C. The resultant mixture was stirred at 120 °C for 30 min and cooled down to room temperature. The solvent was removed under reduced pressure to give crude products which were purified by flash silica gel chromatography using a mixture of ethyl acetate/hexane (1:6) to furnish 7a in 90% yield (52.7mg).Procedure for the Cu(OTf)₂-Catalyzed CyclizationA 5 mL seal tube was charged with 6a (22.4 mg, 0.08 mmol) and dry 1,2-dichloroethane (0.4 mL). To the solution was added Cu(OTf)₂ (10 mol%) under argon atmosphere at 0 °C. The resultant mixture was stirred at 120 °C for 30 min and cooled down to room temperature. The solvent was removed under reduced pressure to give crude products which were purified by flash silica gel chromatography using a mixture of ethyl acetate/hexane (1:6) to furnish 7a in 80% yield (17.9 mg). Compound 7a: ¹H NMR (400 MHz, CDCl₃): δ = 8.88 (s, 1 H), 7.89 (d, J = 8.6 Hz, 1 H), 7.55 (s, 1 H), 7.38 (d, J = 8.6 Hz, 1 H), 4.00 (s, 3 H), 3.44–3.35 (m, 1 H), 2.84 (t, J = 7.4, 6.4 Hz, 2 H), 2.08 (t, J = 7.4, 6.4 Hz, 2 H), 1.45 (s, 6 H), 1.29 (d, J = 6.8 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 201.3, 158.9, 153.7, 138.6, 134.2, 131.1, 128.2, 124.8, 124.8, 121.3, 104.8, 55.5, 43.6, 37.5, 37.1, 35.3, 30.2, 27.2, 22.7.Procedure for the Cyclization of 6bThe virtually same procedure for 6b was applied, and then the product 7b was isolated in 95% when employing Cu(OTf)₂ (10 mol%) as a catalyst. However, AuBr₃ catalyzed this reaction to give a 1:1 mixture of products 7.1b and 7b in combined 90% yield. Compound 7.1b: ¹H NMR (400 MHz, CDCl₃): δ = 7.63 (d, J = 8.3 Hz, 1 H), 7.45 (s, 1 H), 7.24 (d, J = 8.3 Hz, 1 H), 3.98 (s, 3 H), 3.96 (s, 3 H), 3.53 (t, J = 7.2 Hz, 2 H), 3.41 (sept, J = 6.9 Hz, 1 H), 2.06 (t, J = 7.3 Hz, 2 H), 1.34 (s, 3 H), 1.32 (d, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 149.7, 149.1, 148.2, 141.5, 135.4, 131.4, 127.0, 125.5, 120.9, 120.3, 60.8, 60.8, 43.6, 41.4, 31.4, 29.9, 29.0, 27.5, 23.7.Compound 7b: ¹H NMR (400 MHz, CDCl₃): δ = 7.78 (d, J = 8.6 Hz, 1 H), 7.38 (s, 1 H), 7.33 (d, J = 8.6 Hz, 1 H), 3.91 (s,3 H), 3.88 (s, 3 H), 3.43–3.35 (m, 1 H), 2.93 (t, J = 7.2 Hz, 2 H), 2.11 (t, J = 7.2 Hz, 2 H), 1.37 (s, 6 H), 1.30 (d, J = 6.9 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 200.1, 151.4, 150.4, 148.0, 143.3, 132.0, 131.0, 130.0, 124.4, 121.6, 120.1, 60.7, 59.7, 36.80, 36.78, 35.3, 28.8, 27.5, 23.6.