Concise Asymmetric Synthesis of (+)-Conocarpan and Obtusafuran

Cheng-yi Chen; Mark Weisel

doi:10.1055/s-0032-1317704

Synlett, Inhaltsverzeichnis

Synlett 2013; 24(2): 189-192
DOI: 10.1055/s-0032-1317704

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Concise Asymmetric Synthesis of (+)-Conocarpan and Obtusafuran

Cheng-yi Chen*

Process Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA Fax: +1(732)5945170 eMail: Cheng_chen@merck.com

,

Mark Weisel

Process Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA Fax: +1(732)5945170 eMail: Cheng_chen@merck.com

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Abstract

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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.

Key words

(+)-conocarpan - (+)- and (–)-obtusafuran - dynamic kinetic resolution - S_NAr reaction - metal-catalyzed C–O bond formation - trans-dihydrobenzofuran - 8,5′-neolignans - 8-aryl-2,3-dihydro-benzofuran

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Referenzen

References and Notes

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8b Procedure for the preparation of (+)-conocarpan from bromophenol 16: To bromophenol 16 (0.60 g, 1.966 mmol) in toluene (7.20 mL) was added potassium carbonate (0.815 g, 5.90 mmol), water (3.00 mL), trans-1-propen-1-ylboronic acid (0.338 g, 3.93 mmol) and [1,1′-bis(diphenylphospino)ferrocene]dichloropalladium(II) (0.072 g, 0.098 mmol). The mixture was degassed via nitrogen/vacuum followed by heating to 95 °C and kept at this temperature for 3 h to complete the coupling reaction. The reaction mixture was cooled to ambient temperature and the aqueous layer was removed. The organic layer was dried over MgSO_₄, concentrated and the residue was subjected to biotage separation to afford (+)-conocarpan (0.482 g, 1.809 mmol, 92% yield) as a white solid: mp 136–138 °C. ^¹H NMR (500 MHz, CDCl_₃): δ = 1.41 (d, J = 6.8 Hz, 3 H), 1.89 (d, J = 1.6, 6.7 Hz, 3 H), 3.42 (m, 1 H), 5.0 (br s, 1 H), 5.10 (d, J = 8.6 Hz, 1 H), 6.10 (dq, J = 6.7, 15.5 Hz, 1 H), 6.40 (dd, J = 1.6, 15.5 Hz, 1 H), 6.78 (d, J = 8.1 Hz, 1 H), 6.83 (m, 2 H), 7.16 (m, 2 H), 7.31 (m, 2 H). ^¹³C NMR (125 MHz, CDCl_₃) δ = 17.8, 18.4, 45.2, 92.6, 109.3, 115.5, 120.7, 123.0, 126.3, 127.9, 130.8, 131.3, 132.4, 132.9, 155.7, 158.3. The enantiopurity of (+)-conocarpan was determined to be 99.6% using the reported method cited in reference 7a.

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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.