Concise Asymmetric Synthesis of (+)-Conocarpan and Obtusafuran

 

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Abstract

The asymmetric synthesis of three natural products: (+)-conocarpan, both (+)- and (–)- obtusafuran is disclosed. The highlights of the synthesis are the enantioselective hydrogenation of prochiral ketones via dynamic kinetic resolution to afford chiral alcohols. Intramolecular ring closure via either S_NAr reaction or metal-catalyzed C–O bond formation led to the construction of the trans-dihydrobenzofuran core.

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• 16 Procedure for the preparation of (+)-obtusafuran: Obtusafuran OTIP ether (22, 0.40 g, 0.969 mmol) and tetrabutylammonium fluoride trihydrate (0.459 g, 1.454 mmol) in THF (4.00 ml) were stirred at ambient temperature for 12 h to complete the desilylation reaction. Methyl tert-butylether (5 mL) was added. The organic layer was washed with water (2 × 5 mL), dried (Na₂SO₄) and concentrated in vacuum to an oil. The oil was chromatographed over silica gel, eluted with methyl tert-butylether–hexanes (1:3), to afford (+)-obtusafuran (0.234 g, 0.931 mmol, 94% yield) as a solid. mp 111–113 °C. [α]_D ²⁵ +50 (c 0.33, MeOH) [lit. 4 [α]_D ²⁵+47 (c 0.86, MeOH). ¹H NMR (500 MHz, CDCl₃) δ = 1.41 (d, J = 6.7 Hz, 3 H), 3.40 (m, 1 H), 3.90 (s, 3 H), 5.14 (d, J = 8.5 Hz, 1 H), 5.29 (s, 1 H), 6.54 (s, 1 H), 6.76 (s, 1 H), 7.40 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃) δ = 18.5, 45.7, 56.3, 92.8, 94.2, 109.5, 122.9, 126.0, 128.2, 128.6, 140.0, 141.0, 146.3, 152.4. The enantiopurity of (+)-conocarpan was determined to be 99.1% using Chiralcel OZ column (250 × 4.6 mm), gradient method: 4% MeOH/25 mM IBA/CO₂ for 4 min, then ramp at 6%/min to 40% MeOH, hold 5 min, 15 min runtime, 200 bar, 35 °C, 3 mL/min, 215 nm, retention time: 9.56 min.
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