Iridium-Catalysed C–H Borylation Facilitates a Total Synthesis of the HRV 3C Protease Inhibitor (±)-Thysanone

Abstract

A new total synthesis of the HRV 3C protease inhibitor (±)-thysanone is described. The synthetic route hinges on an iridium-catalysed borylation to install the resorcinol-derived component of the natural product.

Key words

thysanone - oxa-Pictet–Spengler reaction - pyranonaphthoquinone - HRV 3C protease - CH activation

• References and Notes

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• 9 To a mixture of (±)-1-deoxythysanone (13 mg, 50 μmol) in CCl₄ (8 mL) was added bromine (50 μL, 1 M in CCl₄, 50 μmol). The mixture was heated at reflux under irradiation with a desk lamp for 30 min. The mixture was concentrated in vacuo, and THF (1 mL) and H₂O (0.5 mL) were added. The resulting mixture was stirred for 1 h at r.t. Then CH₂Cl₂ (5 mL) and H₂O (5 mL) were added. The aqueous layer was extracted with CH₂Cl₂ (3 × 100 mL/mmol_SM). The combined organic extracts were washed with brine (5 mL) and dried with MgSO₄. The solvent was removed in vacuo, and the residue was purified by preparative TLC (SiO₂, toluene–ethyl formate–formic acid = 50:49:1) to afford the title compound (6.09 mg, 22 μmol, 44%) as a yellow solid. ¹H NMR (400 MHz, acetone-d ₆): δ = 12.26 (1 H, s, OH), 9.93 (1 H, s, OH), 7.08 (1 H, d, J = 2.4 Hz, H-6), 6.62 (1 H, d, J = 2.4 Hz, H-8), 5.91 (1 H, dd, J = 18.2, 5.8 Hz, H-1), 4.39–4.29 (1 H, m, H-3), 2.70 (1 H, dd, J = 19.2, 3.4 Hz, H-4A), 2.18–2.08 (1 H, m, H-4B), 1.31 (3 H, d, J = 6.3 Hz, H-Me), lactol OH not observed. R_f = 0.74 (hexanes–EtOAc, 1:2). The spectroscopic data were in agreement with those reported^4c in the literature.