Total Synthesis of Obolactone via Regioselective Carbonyl Desaturation

Abstract

Total synthesis of the dihydro-γ-pyrone natural product (±)-obolactone is reported. The synthesis relies on the development of a strategy for regioselective carbonyl desaturation of tetrahydropyranone precursors via site-selective C–H bond oxidation. Identification of suitable oxidants for this transformation in a model system as well as implementation in a one-pot procedure that provides direct access to regiochemically defined dihydro-γ-pyrones from readily accessible tetrahydropyranols are described. Using this approach, obolactone was prepared in a single step from the originally proposed structure of cryptoconcatone H and just four steps from C₂ -symmetric (±)-1,8-nonadiene-4,6-diol in 24% overall yield.

Keywords

Obolactone - Total synthesis - Dihydro-γ-pyrone - C–H bond oxidation - Carbonyl desaturation - Regioselectivity

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• 28a Preparation of obolactone (4) From 18: To a solution of 18 (74.2 mg, 0.24 mmol) in CH₂Cl₂ (2.4 mL) at room temperature was added DDQ (64.7 mg, 0.29 mmol). The reaction mixture was stirred for 1 h, at which time TLC analysis indicated complete consumption of starting material. The reaction was quenched by addition of a 1:1 mixture of saturated NaHCO₃ and saturated Na₂S₂O₃ and diluted with EtOAc. The layers were separated and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed with brine before being dried over Na₂SO₄. The drying agent was removed by filtration and the solvents were removed in vacuo. Purification by silica gel flash column chromatography (1:2 hexanes/EtOAc) provided 65.0 mg (88%) of 4 as a pale yellow solid. From 19: To a solution of 19 (35.5 mg, 0.11 mmol) in CH₂Cl₂ (1.5 mL) at room temperature was added Dess-Martin periodinane (57.4 mg, 0.14 mmol). The reaction mixture was stirred for 2 h, at which time TLC analysis indicated complete consumption of 19. DDQ (30.0 mg, 0.14 mmol) was added and the resulting dark brown reaction mixture was stirred for an additional 1.5 h. The reaction was quenched by addition of a 1:1 mixture of saturated NaHCO₃ and saturated Na₂S₂O₃ and diluted with EtOAc. The resulting mixture was stirred vigorously for 30 minutes. The layers were separated and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed with brine before being dried over Na₂SO₄. The drying agent was removed by filtration and the solvents were removed in vacuo. Purification by silica gel flash column chromatography (1:2 hexanes/EtOAc) provided 26.3 mg (75%) of 4 as a pale yellow solid.
• 28b Analytical Data for 4; Mp = 115–117 °C. ¹H NMR (CDCl₃, 400 MHz): δ 7.53–7.51 (m, 2H), 7.40-7.34 (m, 4H), 6.93 (dt, J = 9.9, 4.3 Hz, 1H), 6.54 (d, J = 16.0 Hz, 1H), 6.08 (dt, J = 9.8, 1.8 Hz, 1H), 5.53 (s, 1H), 4.79–4.70 (m, 2H), 2.65–2.46 (m, 5H), 2.09 (dt, J = 14.7, 5.1 Hz, 1H). ¹³C NMR (CDCl₃, 100 MHz): δ 192.4, 168.1, 163.7, 144.8, 137.6, 135.2, 129.9, 129.0, 127.9, 121.6, 121.3, 106.4, 75.7, 74.6, 41.4, 39.4, 29.5. IR (thin film): 3056, 3045, 2920, 1702, 1646, 1624, 1577, 1562, 1497, 1448, 1418, 1396, 1353, 1249, 1229, 1148, 1065, 1024, 809, 693 cm⁻¹. HRMS (ESI): m/z calcd for C₁₉H₁₈O₄Na [M + Na⁺] 333.1103, found 333.1103