A Catalytic, Oxidative Synthesis of Olivetol, Methyl Olivetolate and Orthogonally Protected Methyl Ether Derivatives

Abstract

Olivetol, methyl olivetolate and a series of orthogonally protected methyl ether derivatives were synthesized from commonly available precursors using an atom-economical, catalytic oxidative aromatization process.

Key words

olivetol - olivetolic acid - aromatization - catalysis - oxidation - polyketide - meroterpenoid

• References and Notes

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• 10 Synthesis of Diketo Ester 8: To a solution of dimethyl malonate (12 mL, 100 mmol) in methanol (20 mL) was added a 25 wt% solution of sodium methoxide in methanol (20 mL, 89 mmol). To the resulting solution was added (E)-3-nonen-2-one (12 mL, 70 mmol) over 0.5 h with vigorous stirring. The pale-yellow slurry was heated at reflux over 3 h under a nitrogen atmosphere. Upon cooling, the resulting yellow solution was cooled to room temperature then methanol was removed using a rotary evaporator with heating not exceeding 40 °C. To the pale-yellow solid was added water (70 mL) and diethyl ether (10 mL) and the mixture was stirred until no visible solid remained. The biphasic mixture was extracted with diethyl ether (2 × 50 mL). The clear orange aqueous solution was carefully adjusted to pH 4 with HCl conc. and allowed to stand at room temperature for 12 h. The desired product 8 was obtained as a mixture of isomers by vacuum filtration as a white crystalline solid (12.54 g, 74%). ¹H NMR (600 MHz, CDCl₃): δ = 5.48 (s, 1 H), 3.82 (s, 3 H), 3.80 (s, 3 H), 3.76 (s, 3 H), 3.68 (dd, J = 17.2, 0.8 Hz, 1 H), 3.45 (d, J = 6.7 Hz, 1 H), 3.39 (d, J = 17.2 Hz, 1 H), 3.17 (d, J = 10.0 Hz, 1 H), 2.84 (dd, J = 15.4, 4.5 Hz, 1 H), 2.61 (dd, J = 17.5, 4.8 Hz, 1 H), 2.54–2.46 (m, 1 H), 2.43 (dd, J = 15.4, 7.5 Hz, 1 H), 2.19 (dd, J = 17.5, 9.9 Hz, 1 H), 1.46–1.17 (m, 8 H), 0.87 (m, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 206.69, 202.36, 198.93, 191.19, 185.55, 171.94, 171.32, 169.34, 167.94, 103.98, 102.84, 60.78, 57.53, 56.86, 52.78, 52.38, 51.80, 44.03, 43.12, 42.62, 36.24, 35.71, 34.73, 33.77, 33.48, 33.41, 31.75, 31.62, 31.57, 31.34, 26.57, 25.95, 25.85, 22.47, 22.38, 13.96, 13.91.
• 11 Synthesis of Cyclic Diketone 9: To a solution of dimethyl malonate (11.5 mL, 100.4 mmol) in methanol (20 mL) was added a 25 wt% solution of sodium methoxide in methanol (20 mL, 89 mmol). To the resulting slurry was added (E)-3-nonen-2-one (11.6 mL, 70.2 mmol) over 0.5 h with vigorous stirring. The pale-yellow slurry was heated at reflux over 3 h under a nitrogen atmosphere. The resulting yellow solution was cooled to room temperature whereupon the methanol was removed using a rotary evaporator with heating not exceeding 40 °C. The resulting yellow solid was dissolved in 20 wt% sodium hydroxide solution (70 mL) then heated at reflux over 2.5 h. The solution was cooled to room temperature, then extracted with diethyl ether (2 × 50 mL). To the aqueous solution was added HCl until rapid gas evolution was observed (30 mL), the effervescent, clear yellow solution was heated at reflux over 1 h, then the aqueous solution was slowly acidified with HCl conc. to the first appearance of a precipitate (pH 5) and left to stand over 12 h. The desired product 9 was obtained by vacuum filtration, then drying under high vacuum (ca. 0.1 mmHg) to afford a pale-pink solid as a mixture of tautomers (10.88 g, 84 %). ¹H NMR (600 MHz, CDCl₃): δ = 5.49 (s, 1 H), 3.66 (s, 1 H), 3.37 (s, 2 H), 2.73 (dd, J = 15.5, 3.8 Hz, 1 H), 2.45 (d, J = 12.5 Hz, 1 H), 2.36 (dd, J = 15.4, 10.3 Hz, 1 H), 2.20–1.98 (m, 2 H), 1.45–1.19 (m, 8 H), 0.88 (t, J = 6.9 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 203.84, 191.74, 104.24, 57.99, 46.39, 38.82, 35.44, 35.21, 33.75, 31.76, 31.57, 30.66, 26.26, 26.21, 22.56, 22.48, 14.01, 13.96.
• 12 Synthesis of Olivetolic Acid Methyl Ester 3: To a solution of 8 (6.9391 g, 28.87 mmol) in DMSO (7 mL) was added iodine (1.0236 g, 4.03 mmol) and the brown solution was stirred at 80 °C for 24 h. The reaction mixture was diluted with ethyl acetate (70 mL), then extracted with 0.1 M sodium thiosulfate (3 × 10 mL), then water (10 mL). The organic solution was concentrated in vacuo to afford a viscous dark-red liquid. The crude material was passed through a plug of silica, using hexanes–ethyl acetate (4:1) to elute. The eluent was concentrated and dried under reduced pressure (ca. 0.1 mmHg) to afford the desired product 3 as a pale-yellow crystalline solid (6.050 g, 88%). ¹H NMR (600 MHz, CDCl₃): δ = 11.78 (s, 1 H), 6.29 (d, J = 2.5 Hz, 1 H), 6.24 (d, J = 2.5 Hz, 1 H), 3.92 (s, 3 H), 2.81 (dd, J = 8.9, 6.8 Hz, 2 H), 1.58–1.47 (m, 2 H), 1.39–1.28 (m, 4 H), 0.90 (t, J = 6.8 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 172.03, 165.08, 160.59, 149.00, 110.96, 104.91, 101.39, 51.95, 36.81, 32.07, 31.47, 22.51, 14.07.
• 13 Synthesis of Olivetol 1: To solution of 9 (10.88 g, 59.7 mmol) in DMSO (10 mL) was added iodine (0.4837 g, 1.9 mmol) and the brown solution was stirred in an 80 °C bath over 27 h. The reaction mixture was diluted with ethyl acetate (100 mL) then extracted with 0.1 M sodium thiosulfate (50 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL), and the organic fractions were pooled, and concentrated in vacuo to afford a viscous dark-red liquid. The crude material was distilled under reduced pressure (ca. 0.1 mmHg, 80 °C) to afford olivetol 1 as a colourless crystalline solid (5.051 g, 48%). ¹H NMR (600 MHz, CDCl₃): δ = 6.26 (d, J = 2.1 Hz, 2 H), 6.18 (t, J = 2.2 Hz, 1 H), 5.01 (s, 2 H), 2.51–2.44 (m, 2 H), 1.61–1.53 (m, 2 H), 1.40–1.21 (m, 4 H), 0.88 (t, J = 7.0 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 156.46, 146.26, 108.16, 100.20, 35.79, 31.46, 30.72, 22.53, 14.02.
• 14 Synthesis of Methyl Olivetolate Monomethyl Ether 4: To a round-bottom flask charged with methanol (4 mL) was added 8 (480.6 mg, 2.00 mmol), iodine (100.0 mg, 0.394 mmol) and DMSO (234.0 mg, 3.00 mmol) and the mixture was heated at reflux over 72 h until the disappearance of 8 was observed. The reaction mixture was quenched with dropwise addition of Na₂S₂O₃ (0.1 M, 10 mL), then extracted with hexanes (3 × 5 mL). The combined organic fractions were washed with water (5 mL), dried over Na₂SO₄, filtered, and concentrated to give a pale-yellow oil. The crude mixture was purified by flash chromatography using hexane–ethyl acetate (4:1) as eluent to give 4 as a colourless oil (138.2 mg, 27%). ¹H NMR (600 MHz, CDCl₃): δ = 11.73 (s, 1 H), 6.32 (d, J = 2.6 Hz, 1 H), 6.28 (d, J = 2.6 Hz, 1 H), 3.91 (s, 3 H), 3.78 (s, 3 H), 2.85–2.81 (m, 2 H), 1.56–1.48 (m, 2 H), 1.35–1.31 (m, 4 H), 0.90 (t, J = 6.9 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 171.98, 165.59, 163.97, 148.04, 110.60, 104.59, 98.75, 55.20, 51.78, 36.89, 32.08, 31.55, 22.52, 14.06.
• 15 Synthesis of Methyl Olivetolate Monomethyl Ether 4 and Methyl Olivetolate Dimethyl Ether 5: To a round-bottom flask charged with methanol (4 mL) was added 8 (481.0 mg, 2.00 mmol), iodine (101.2 mg, 0.399 mmol) and trimethyl orthoformate (0.8 mL, 8.0 mmol). The solution was stirred under nitrogen, at room temperature, over 1 h, until consumption of 8 was observed. DMSO (234.1 mg, 3.00 mmol) was added and the mixture was heated at reflux over 72 h. The reaction mixture was quenched by dropwise addition of Na₂S₂O₃ (0.1 M, 10 mL), then extracted with hexanes (3 × 5 mL). The combined organic fractions were washed with water (5 mL), dried over Na₂SO₄, filtered and concentrated to give a pale-yellow oil. The crude mixture was purified by flash chromatography using hexane–ethyl acetate (4:1) as eluent to give 4 as a colourless oil (108.3 mg, 21%) and 5 as a colourless oil (210.9 mg, 49%). ¹H NMR (600 MHz, CDCl₃): δ = 6.33 (d, J = 2.1 Hz, 1 H), 6.31 (d, J = 2.2 Hz, 1 H), 3.88 (s, 1 H), 3.81 (s, 1 H), 3.79 (s, 1 H), 2.56–2.51 (m, 1 H), 1.61–1.54 (m, 1 H), 1.33–1.29 (m, 1 H), 0.88 (t, J = 7.0 Hz, 1 H). ¹³C NMR (151 MHz, CDCl₃): δ = 168.98, 161.40, 157.99, 143.10, 116.20, 105.83, 96.09, 55.84, 55.31, 52.03, 33.90, 31.68, 30.86, 22.43, 13.96.