A Total Synthesis of Yellowish Aphid Pigment Furanaphin through Fries Rearrangement Assisted by Boron Trifluoride-Acetic Acid Complex

Abstract

The yellowish aphid pigment furanaphin, isolated from Aphis spiraecola and possessing cytotoxicity against HL-60 (human promyelocytic leukemia-60) cells, was synthesized by utilizing the Fries rearrangement assisted with a BF₃·2AcOH complex as a key step. It was confirmed that the complex effectively mediated the reaction even though the compounds had an electron-withdrawing substituent.

Key words

dyes - pigments - Fries rearrangement - total synthesis - natural products

• References and Notes

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• 20 Fries Rearrangement of 4: To a solution of acetate 4 (104.1 mg, 0.327 mmol) in CH₂Cl₂ (0.5 mL) was added BF₃·2AcOH (440 μL, 3.16 mmol) under an Ar atmosphere, and the resulting mixture was heated at reflux for 30 min. After addition of H₂O (3 mL) at 0 °C, the resulting mixture was extracted with CH₂Cl₂ (3 × 5 mL), and the combined organic extracts were washed with brine (10 mL), dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane–EtOAc, 8:1) to give ethyl 3-acetyl-4-hydroxy-5,7-dimethoxy-2-naphthoate (3) in 91% yield as colorless crystals; mp 100–101 °C (EtOAc). ¹H NMR (400 MHz, CDCl₃): δ = 9.64 (s, 1 H), 7.75 (d, J = 0.4 Hz, 1 H), 6.77 (d, J = 2.0 Hz, 1 H), 6.57 (d, J = 2.0 Hz, 1 H), 4.35 (q, J = 7.2 Hz, 2 H), 4.04 (s, 3 H), 3.90 (s, 3 H), 2.65 (s, 3 H), 1.38 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 203.7, 166.7, 159.0, 157.7, 152.2, 136.5, 128.4, 122.0, 120.7, 111.9, 100.5, 100.2, 61.5, 56.4, 55.5, 31.8, 14.0. IR (ATR): 3329, 1708, 1624, 1578, 1364, 1250, 1198, 1153, 1111, 1045 cm^–1. MS (EI): m/z (%)= 318 [M]⁺, 303, 275 (100). HRMS (EI): m/z calcd for C₁₇H₁₈O₆: 318.1103; found: 318.1128
• 21 Furanaphin (1): Orange-yellow needles (MeOH); mp 218–219 °C (MeOH) {Lit¹¹ 211–214 °C (dec)}. ¹H NMR (400 MHz, acetone-d ₆): δ = 14.28 (s, 1 H), 9.17 (s, 1 H), 6.40 (dd, J = 2.4, 2.4 Hz, 1 H), 6.35 (d, J = 2.4 Hz, 1 H), 6.17 (d, J = 2.4 Hz, 1 H), 5.51 (d, J = 2.4 Hz, 2 H), 2.67 (s, 3 H). ¹³C NMR (100 MHz, acetone-d ₆): δ = 184.8, 184.3, 167.4, 164.7, 143.9, 143.5, 115.2, 111.7, 107.4, 104.7, 100.5, 77.6, 16.1. IR (ATR): 3333, 1650, 1569, 1382, 1170, 1153, 1130, 1085, 985, 887, 823 cm^–1. MS (EI): m/z (%) = 231 [M+H]⁺, 230 (100) [M]⁺. HRMS (EI): m/z calcd for C₁₃H₁₀O₄: 230.0579; found: 230.0575