Total Synthesis of (±)-Phaeocaulisin D

Abstract

The tropone sesquiterpene phaeocaulisin D, isolated from the rhizomes of Curcuma phaeocaulis, has previously been shown to inhibit nitric oxide production in macrophages. A total synthesis of phaeocaulisin D was accomplished by using an intramolecular cyclization–dearomatization as a key step. The highlights of the synthesis are effective formation of the 5–7 fused tropone system, and selective methylation of a late-stage intermediate.

Key words

tropones - dearomatization - sesquiterpenes - medicinal chemistry - total synthesis - phaeocaulisin

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• 10 Phaeocaulisin D (1) A 3 M solution of MeMgBr in THF (230 μL, 0.68 mmol) was added to a solution of tropone ketone 17 (80 mg, 0.34 mmol) in anhyd THF (3 mL) at –20 °C, and the mixture was warmed to 0 °C and stirred for 2 h. The reaction was quenched by addition of sat. aq NH₄Cl (2 mL), and the mixture was diluted with EtOAc (20 mL). The organic layer washed with H₂O (5 mL) and brine (5 mL) then dried (Na₂SO₄). The solvent was evaporated under reduced pressure, and the crude product was purified by chromatography [silica gel, hexane–EtOAc (60:40 to 40:60 over 15 min)] to give a yellow oil; yield: 67.4 mg (79%). FTIR (film): 2983, 1704, 1603, 1554, 1297, 1146, 1020 cm^–1. ¹H NMR (400 MHz, CD₃OD): δ = 7.90 (s, 1 H), 6.99 (s, 1 H), 2.93 (m, 1 H), 2.81 (m, 1 H), 2.31 (s, 3 H), 2.19 (m, 1 H), 2.06 (m, 1 H), 1.58 (s, 3 H), 1.57 (s, 3 H), 1.43 (s, 3 H). ¹³C NMR (100 MHz, CD₃OD): δ = 188.6, 157.4, 151.8, 148.4, 140.8, 131.6, 84.8, 75.4, 40.1, 32.6, 29.3, 29.0, 27.5, 24.6. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₂₁O₃: 249.1485; found: 249.1463.