Synthetic Efforts toward the Isoindolinone Core of Muironolide A

Abstract

Studies directed toward the isoindolinone core of muironolide A are described. An initial plan to implement an intramolecular Diels–Alder cycloaddition was thwarted by an undesired conjugate addition during the attempted preparation of the Diels–Alder substrate. A revised retrosynthetic analysis revealed a direct, albeit challenging, intermolecular Diels–Alder disconnection. Toward this end, a sterically hindered and electronically deactivated diene was utilized with N-phenylmaleimide to achieve a Diels–­Alder cycloaddition.

Key words

cycloaddition - Diels–Alder reaction - muironolide A - natural products - total synthesis

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• 25 Experimental Procedure for the Synthesis of Isoindolinone 21: N-Phenylmaleimide 20 (89 mg, 0.51 mmol), BHT (11 mg, 0.05 mmol), and diene 6 (56 mg, 0.25 mmol) were dissolved in toluene (1.0 mL). The solution was sealed in a Teflon-capped vial, heated to 100 °C for 6 d, cooled to 23 °C, and then concentrated under reduced pressure. Purification by flash column chromatography (hexanes–EtOAc, 60:40) delivered isoindolinone 21 (75 mg, 76%) as a white solid; mp 80–82 °C; R_f  = 0.13 (hexanes–EtOAc, 60:40). IR (neat): 1769, 1705, 1147, 727, 691 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.39 (s, 3 H), 1.54 (s, 9 H), 2.71 (ddd, J = 2.8, 9.0, 17.8 Hz, 1 H), 3.10 (ddd, J = 1.3, 7.5, 17.8 Hz, 1 H), 3.36 (d, J = 8.9 Hz, 1 H), 3.49 (ddd, J = 1.3, 8.9, 9.0 Hz, 1 H), 3.63 (d, J = 11.6 Hz, 1 H), 4.73 (d, J = 11.6 Hz, 1 H), 6.97 (dd, J = 2.8, 7.5 Hz, 1 H), 7.18–7.20 (m, 2 H), 7.38–7.48 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 24.5, 26.7, 28.1 (3), 35.8, 39.1, 47.8, 53.9, 83.3, 126.5 (2), 129.0, 129.3 (2), 131.4, 131.6, 139.9, 150.4, 163.7, 175.5, 177.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₅N₂O₅: 397.1763; found: 397.1769.