Toward a Total Synthesis of Divergolide A; Synthesis of the Amido Hydro- quinone Core and the C10–C15 Fragment

Abstract

A ring-closing metathesis (RCM) approach was envisioned for installing the E double bond at the C9 and C10 positions of divergolide A, isolated from a mangrove endophyte. Accordingly, the C10–C15 diene diol fragment and the amido hydroquinone core with the requisite functionalities and stereochemistry have been synthesized by using the norephedrine-based syn-selective glycolate aldol and the anti-selective aldol reactions, respectively. CuI-catalyzed amidation was employed to access the anilide intermediate, which was further transformed into the amido hydroquinone core.

Key words - aldol reactions - selectivity - natural products - hydroquinone - total synthesis

• References and Notes

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• 14 Synthesis of Diene 13 from Ester 12: To a solution of 12 (285.4 mg, 0.75 mmol) in anhydrous CH₂Cl₂ (8 mL) cooled in a dry ice–acetone bath (–78 °C) under an N₂ atmosphere was added slowly a solution of DIBAL-H (1 M in toluene, 1.1 mL, 1.1 mmol). The resultant mixture was stirred for 1.5 h at the same temperature, then MeOH (2 mL) was added to quench the reaction. The reaction mixture was allowed to warm to –40 °C, then a saturated aqueous solution of potassium sodium tartrate was added followed by stirring at r.t. until the mixture became clear. The mixture was extracted with CH₂Cl₂ (5 × 3 mL) and the combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude aldehyde. The latter was dissolved in anhydrous THF (2 mL) for use in the next step without further purification. To a solution of Ph₃P⁺CH(Me)₂I^– (486.3 mg, 1.13 mmol) in anhydrous THF (10 mL) cooled in an ice–water bath (0 °C) under an N₂ atmosphere was added n-BuLi (1.5 M in hexane, 0.74 mL, 1.1 mmol) followed by stirring at the same temperature for 30 min. After cooling the resultant solution of the ylide to –78 °C, the above THF solution of the aldehyde was added and the resultant mixture was stirred for 2 h at –78 °C. The reaction was quenched by the addition of saturated aqueous NH₄Cl at –78 °C and the reaction mixture was allowed to warm to r.t. and extracted with EtOAc (8 × 3 mL). The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂; EtOAc–petroleum ether, 1:120) to give diene 13 (248.6 mg, 88% yield for 2 steps from 12). Compound 13: Colorless oil; [α]_D ²⁰ +3.78 (c 1.20, CHCl₃); R_f = 0.40 (EtOAc–petroleum ether, 1%); IR (film): 2954, 2925, 2854, 1614, 1514, 1249, 1064, 1039 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.25 (d, J = 8.8 Hz, 2 H), 6.85 (d, J = 8.8 Hz, 2 H), 5.87 (ddd, J = 16.8, 10.4, 5.2 Hz, 1 H), 5.24 (d, J = 17.2 Hz, 1 H), 5.09 (d, J = 10.0 Hz, 1 H), 5.07 (d, J = 7.6 Hz, 1 H), 4.52 and 4.31 (ABq, J = 11.6 Hz, 2 H), 4.17 (dd, J = 5.6, 5.2 Hz, 1 H), 3.95 (dd, J = 9.6, 6.4 Hz, 1 H), 3.80 (s, 3 H), 1.76 (s, 3 H), 1.59 (s, 3 H), 0.88 (s, 9 H), 0.03 (s, 3 H), 0.02 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 158.8, 137.9, 137.4, 131.2, 129.2 (2×), 122.5, 114.9, 113.5 (2×), 78.4, 75.8, 69.4, 55.2, 26.0, 25.9 (3×), 18.7, 18.3, –4.7, –4.8. HRMS (EI+): m/z [M⁺] calcd for C₂₂H₃₆O₃Si: 376.2434; found: 376.2433.
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Fremy’s salt (potassium nitrosodisulfonate) was not available to us and it was not tested in the oxidation of 23. For recent examples, see:
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• 18 Synthesis of Quinone 24 via Oxidation of Phenol 23: To a solution of phenol 23 (257.0 mg, 0.55 mmol) in MeCN (4 mL) at r.t. was quickly added an aqueous solution of 2,6-DCPFC (334 mg in 1.1 mL H₂O, 1.1 mmol), prepared according to the literature procedure.^17a After stirring for 1 min, the reaction was quenched by addition of saturated aqueous NaHCO₃. The reaction mixture was extracted with EtOAc (10 × 3 mL) and the combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂; EtOAc–petroleum ether, 1:40) to give quinone 24 (209.3 mg, 79% yield) as a yellow solid. Mp 80–81 °C (CH₂Cl₂–pentane); [α]_D ²⁰ +53.60 (c 1.10, CHCl₃); R_f = 0.40 (EtOAc–petroleum ether, 2.4%). IR (film): 3380, 3296, 2957, 2925, 2854, 1714, 1650, 1606, 1502, 1255, 1099 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.06 (br s, 1 H, NH), 7.50 (d, J = 2.8 Hz, 1 H), 6.70 (dd, J = 2.0, 1.2 Hz, 1 H), 4.73 (d, J = 4.8 Hz, 1 H), 3.57 (dd, J = 10.0, 5.6 Hz, 1 H), 3.44 (dd, J = 10.0, 5.2 Hz, 1 H), 2.22 (s, 3 H), 1.94–1.91 (m, 1 H), 0.90 (s, 9 H), 0.89 (d, J = 6.0 Hz, 3 H), 0.81 (s, 9 H), 0.06 (s, 3 H), –0.05 (s, 3 H), –0.07 (s, 3 H), –0.09 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 188.2, 182.6, 169.1, 148.2, 138.1, 133.3, 114.5, 69.1, 63.5, 42.4, 25.8 (3×), 25.8 (3×), 24.8, 18.3, 18.0, 14.2, –4.6, –5.2, –5.5, –5.6. HRMS (EI+): m/z [M⁺] calcd for C₂₄H₄₃NO₅Si₂: 481.2680; found: 481.2682.
• 19 Synthesis of Hydroquinone 25 via Reduction of 24: To a yellow solution of quinone 24 (144.5 mg, 0.30 mmol) in a mixed solvent of THF–Et₂O–H₂O (6 mL; v/v/v = 1:1:1) at r.t., was added Na₂S₂O₄ (525 mg, 3 mmol) in portions with vigorous stirring until the yellow color of the mixture disappeared. The reaction mixture was diluted with H₂O (5 mL) and extracted with EtOAc (5 × 3 mL). The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂; EtOAc–petroleum ether, 1:3) to give hydroquinone 25 (145.2 mg, 99% yield) as a colorless oil. R_f = 0.50 (EtOAc–PE, 33%). [Note: Hydroquinone 25 was oxidized to quinone in air during acquisition of ¹³C NMR data. No optical rotation data was taken for this sample]. ¹H NMR (400 MHz, CDCl₃): δ = 8.19 (s, 1 H, NH), 8.10 (s, 1 H, OH), 7.91 (s, 1 H, OH), 7.55 (s, 1 H), 6.32 (s, 1 H), 4.84 (d, J = 6.0 Hz, 1 H), 3.61 (dd, J = 9.6, 4.4 Hz, 1 H), 3.43 (dd, J = 9.2, 7.2 Hz), 2.34 (s, 3 H), 2.15–2.07 (m, 1 H), 0.94 (s, 9 H), 0.89 (s, 9 H), 0.74 (d, J = 6.8 Hz, 3 H), 0.11 (s, 3 H), 0.9 (s, 6 H), –0.05 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.3, 149.7, 137.0, 126.9, 126.0, 109.8, 106.2, 64.7, 60.4, 42.4, 25.9 (4×), 25.7 (3×), 24.8, 18.3, 18.1, –5.1, –5.3 (2×), –5.5. HRMS (EI+): m/z [M⁺] calcd for C₂₄H₄₅NO₅Si₂: 483.2836; found: 483.2834.