Total Synthesis and Structural Revision of Incargutines A and B

Abstract

We achieved the first total synthesis of (±)-incargutines A and B, which were isolated from the roots of Incarvillea arguta, utilizing In(OTf)₃-catalyzed enolization of cyclohexenone derivatives subsequent to an intramolecular Alder–Rickert reaction. At first, we synthesized the proposed structures of incargutines A and B. The spectral data of the synthetic proposed compounds did not correspond to those of the natural products. Then, we synthesized the methyl regioisomers of the proposed structures. Spectral data of these synthetic compounds were identical to those of natural incargutines A and B. Therefore, the structures of incargutines A and B were clearly established to be the methyl regioisomers.

Key words

total synthesis - incargutine - enols - Alder–Rickert reaction - indium

• References and Notes

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• 14 Experimental Procedure and Analytical Data of (±)-Incargutine A (25)To a solution of alcohol 39 (85.5 mg, 0.305 mmol) in CH₂Cl₂ (5.0 mL) were added MCPBA (65%, 306 mg, 2.75 mmol) and Sc(OTf)₃ (75.1 mg, 0.153 mmol) at 0 °C under Ar atmosphere, and the mixture was stirred at r.t. for 96 h. The reaction mixture was extracted with CH₂Cl₂, and the organic layer was washed with sat. aq NaHCO₃ solution (3×) and 10% Na₂S₂O₃ aq solution. The organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (hexane–EtOAc, 4:1) to give a mixture of the product and unidentified contaminants, which was used for the next reaction without further purification. To a suspension of the above mixture and NaHCO₃ (156 mg, 1.86 mmol) in CH₂Cl₂ (5.0 mL) was added Dess–Martin periodinane (157 mg, 0.371 mmol) at 0 °C, and the mixture was stirred at r.t. for 1 h. The reaction was quenched by addition of a mixture of sat. aq Na₂S₂O₃ solution and sat. aq NaHCO₃ solution (1:1), and the mixture was extracted with EtOAc. The organic layer was washed with H₂O and brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was used for the next reaction without further purification. To a solution of the above crude product in THF (3.0 mL) was added 10% HCl aq solution (3.0 mL) at 0 °C, and the mixture was stirred at r.t. for 12 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with sat. aq NaHCO₃ solution, H₂O and brine, and then dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by a preparative TLC (hexane–EtOAc, 8:1) to give (±)-incar-gutine A (25, 30.8 mg, 40% yield, 3 steps) as a white solid; mp 166–167 °C. IR (neat): 3259, 1663, 1610, 1585, 1515, 1438 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 10.18 (1 H, s), 7.69 (1 H, d, J = 7.8 Hz), 7.31 (2 H, d, J = 8.5 Hz), 7.24 (1 H, m), 6.91 (2 H, d, J = 8.5 Hz), 4.91 (1 H, m), 3.59 (1 H, m), 3.26–3.40 (2 H, m), 2.36 (1 H, m), 1.79 (1 H, m), 0.82 (3 H, d, J = 6.9 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 192.7, 155.3, 148.4, 146.5, 144.3, 133.0, 130.9, 129.9, 129.7, 129.7, 128.4, 115.4, 115.4, 37.7, 33.3, 29.9, 19.7. MS–FAB: m/z = 253 [M + H]⁺. HRMS–FAB: m/z [M + H]⁺ calcd for C₁₇H₁₇O₂: 253.1229; found: 253.1218.
• 15 Experimental Procedure and Analytical Data of (±)-Incargutine B (26)To a solution of (±)-incargutine A (25, 10.5 mg, 0.0416 mmol) and CH(OMe)₃ (0.050 mL, 0.440 mmol) in MeCN (2.0 mL) was added Amberlyst-15 (7.3 mg) at 0 °C, and the mixture was stirred at r.t. for 1 h. The reaction was quenched by addition of a sat. aq NaHCO₃ solution. The mixture was filtered and then extracted with EtOAc. The organic layer was washed with H₂O and brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by a preparative TLC (hexane–EtOAc, 5:1) to give (±)-incargutine B (26, 11.5 mg, 93% yield) as a colorless oil. IR (neat): 3375, 1612, 1592, 1519, 1214, 1108 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.36 (1 H, d, J = 7.8 Hz), 7.27 (2 H, m), 7.08 (1 H, d, J = 7.8 Hz), 6.86 (2 H, d, J = 8.4 Hz), 5.41 (1 H, s), 4.81 (1 H, m), 3.55 (1 H, m), 3.37 (6 H, s), 2.92–3.04 (2 H, m), 2.30 (1 H, m), 1.71 (1 H, m), 0.80 (3 H, d, J = 6.9 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 154.6, 146.9, 142.0, 138.7, 134.1, 132.2, 129.8, 129.8, 127.6, 124.6, 115.1, 115.1, 102.7, 53.2, 53.2, 38.2, 33.3, 29.3, 19.9. MS–FAB: m/z = 267, 298 [M]⁺. HRMS–FAB: m/z [M]⁺ calcd for C₁₉H₂₂O₃: 298.1569; found: 298.1579.