Synthesis of a C20-Deoxygenated Spirangien Derivative for Target Identification

Abstract

The synthesis of a C20-deoxygenated spirangien derivative is described that allows the incorporation of various affinity labels for target identification of this potent natural product. The synthesis takes advantage of two major building blocks that can be accessed in 8 and 14 steps, respectively. The endgame joins both fragments through a selective aldol reaction and final protecting group manipulations furnish the target molecule.

Key words

natural product synthesis - spirangien - aldol reaction - target identification

• References and Notes

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• 15 Spiroketal 4: The methylated linear precursor 18 (12.0 mg, 10.6 μmol) was dissolved in MeOH (1 mL) and CH₂Cl₂ (0.2 mL) at 0 °C and PPTS (27.0 mg, 106.1 μmol) was added. The reaction mixture was stirred for 16 h and was quenched by the addition of distilled H₂O (2 mL). The layers were separated, the aqueous layer was extracted with EtOAc (5 × 3 mL), the combined organic layers were dried over MgSO₄, filtered and the solvent was removed in vacuo. The reddish crude product was purified via column chromatography (MeOH–CH₂Cl₂, 1:50) and additional HPLC (conditions: column: Nucleodur C 18 ISIS, 5 μm; eluent: MeCN–H₂O; program: 5 min 50% MeCN, from 50% MeCN to 70% MeCN in 40 min, 15 min with 70% MeCN, from 70% MeCN to 80% MeCN in 5 min, from 80% MeCN to 100% MeCN in 5 min with a flow rate of 3 mL/min; t _R = 66.5 min) and the spiroketal 4 (1.3 mg, 1.9 μmol, 18%) was obtained; R_f 0.24 (MeOH–CH₂Cl₂, 1:75); [α]²⁰ ₅₈₉ +2.0 (c = 0.20, CHCl₃). ¹H NMR (500 MHz, CD₃OD): δ = 7.34 (d, J = 4.4 Hz, 4 H), 7.26–7.30 (m, 1 H), 7.24 (d, J = 8.6 Hz, 2 H), 6.85–6.89 (m, 2 H), 4.49–4.55 (m, 2 H), 4.36–4.46 (m, 2 H), 4.18 (dd, J = 10.3, 2.1 Hz, 1 H), 3.77 (s, 3 H), 3.74 (dd, J = 9.4, 3.7 Hz, 1 H), 3.62 (dd, J = 9.0, 4.5 Hz, 1 H), 3.48–3.54 (m, 3 H), 3.39 (dd, J = 9.3, 7.7 Hz, 1 H), 3.34–3.36 (m, 1 H), 3.32–3.33 (m, 1 H), 3.31–3.32 (m, 3 H), 2.28–2.35 (m, 1 H), 2.21–2.26 (m, 1 H), 2.14–2.19 (m, 1 H), 1.92–1.99 (m, 1 H), 1.86–1.91 (m, 1 H), 1.81–1.86 (m, 1 H), 1.78 (dd, J = 12.3, 4.5 Hz, 1 H), 1.60–1.64 (m, 1 H), 1.52–1.57 (m, 1 H), 1.38–1.46 (m, 2 H), 1.31–1.33 (m, 1 H), 1.02 (d, J = 6.7 Hz, 3 H), 0.96–1.00 (m, 6 H), 0.83 (d, J = 6.8 Hz, 3 H), 0.80 (d, J = 6.5 Hz, 3 H), 0.78 (d, J = 6.8 Hz, 3 H). ¹³C NMR (125 MHz, CD₃OD): δ = 160.7, 139.9, 132.0 (2 × C), 130.4 (2 × C), 129.4 (2 × C), 128.8 (2 × C), 128.7, 114.7, 99.4, 78.9, 78.7, 77.5, 76.4, 74.9, 74.3, 73.6, 73.5, 73.0, 55.6, 55.6, 39.0, 38.2, 37.7, 37.5, 35.0, 32.5, 32.5, 30.6, 28.7, 17.4, 15.3, 14.3, 10.9, 9.9, 4.9. HRMS (ESI): m/z [M + H⁺] calcd for C₂₉H₆₁O₈: 657.4366; found: 657.4360.