Biomimetic Synthesis of Isoindolinones Related to the Marilines

Abstract

The non-enzymatic formation of the racemic isoindolinone core structure during the biosynthesis of the marine natural products mariline A and B was mimicked by employing structurally closely related model substrates. Thus, condensation of 2-formyl-3,5-dimethoxy-4-methyl-acetophenone with different primary amines in the presence of AcOH afforded the isoindolinone products in up to 73% yield.

Key words

natural products - biomimetic synthesis - heterocycles - isoindolinones - aromatic compounds.

• References

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• 6 Synthesis of Isoindolinones; General Procedure (Scheme 4): To a stirred solution of o-formyl-acetophenone 10 (111 mg, 1 mmol) in 1,4-dioxane (2 mL) were added aq AcOH (H₂O–AcOH = 9:1; 1.59 M, 0.8 mL, 2.3 mmol) and the respective amine (1 mmol). After 10 min, the reaction mixture was diluted with sat. aq NH₄Cl and extracted three times with MTBE. The organic layers were dried with MgSO₄. After removal of all volatiles under reduced pressure, the residue was purified by flash column chromatography to give the pure isoindolinones. Characteristic Data for rac-14: R_f = 0.18 (SiO₂; cyclohexane–EtOAc, 2:1). ¹H NMR (500 MHz, CDCl₃): δ = 6.79 (s, 2 H), 6.66 (s, 1 H), 5.02 (q, J = 6.6 Hz, 1 H,), 4.02 (s, 3 H), 3.92 (s, 3 H), 3.88 (s, 6 H), 3.84 (s, 3 H), 2.17 (s, 3 H), 1.44 (d, J = 6.6 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 165.6 (s), 162.6 (s), 157.0 (s), 153.5 (s, 2C), 147.5 (s), 135.8 (s), 133.4 (s), 120.4 (s), 115.9 (s), 101.7 (d, 2C), 99.2 (d), 62.4 (q), 61.06 (q), 56.9 (d), 56.4 (q, 2C), 56.1 (q), 19.4 (q), 8.6 (q). FTIR (ATR): 1682 (s), 1590 (s), 1506 (s) cm^–1. HRMS (ESI): m/z [M+H]⁺ calcd: 388.1755; found: 388.1753. Characteristic Data for rac-15: R_f = 0.07 (SiO₂; cyclohexane–EtOAc, 1:3). ¹H NMR (600 MHz, CDCl₃): δ = 7.35 (1 H), 6.58 (s, 1 H), 4.48 (q, J = 6.7 Hz, 1 H), 3.98 (s, 3 H), 3.88 (s, 3 H), 3.84 (t, J = 5.0 Hz, 2 H), 3.80–3.76 (m, 1 H), 3.53–3.50 (m, 1 H), 2.13 (s, 3), 1.44 (d, J = 6.7 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 168.7 (s), 162.2 (s), 156.4 (s), 148.5 (s), 119.9 (s), 115.5 (s), 99.3 (d), 62.7 (t), 62.3 (q), 57.1 (d), 56.0 (q), 44.6 (t), 18.9 (q), 8.6 (q). FTIR (ATR): 3405 (br), 1659 (s), 1605 (s), 1130 (s) cm^–1. HRMS (ESI): m/z [M+H]⁺ calcd: 266.1387; found: 266.1387. Characteristic Data for rac-16: R_f = 0.32 (SiO₂; cyclohexane–EtOAc, 2:1). ¹H NMR (500 MHz, CDCl₃): δ = 7.24 (d, J = 8.2 Hz, 1 H), 6.65 (s, 1 H), 6.55–6.53 (m, 2 H), 5.34 (t, J = 6.5 Hz, 1 H), 5.02 (q, J = 6.7 Hz, 1 H), 4.53–4.45 (m, 2 H), 4.06 (s, 3 H), 3.92 (s, 3 H), 3.82 (s, 3 H), 2.18 (s, 3 H), 1.71 (s, 3 H), 1.66 (s, 3 H), 1.30 (d, J = 6.8 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 166.3 (s), 161.9 (s), 159.8 (s), 156.7 (s), 155.7 (s), 148.9 (s), 137.3 (s), 130.9 (d), 119.8 (d), 119.4 (s), 118.9 (s), 115.9 (s), 104.7 (d), 101.0 (d), 99.2 (d), 65.8 (t), 62.4 (q), 57.1 (d), 56.0 (q), 55.7 (q), 25.8 (q), 19.2 (q), 18.4 (q), 8.6 (q). FTIR (ATR): 1686 (s), 1605 (s), 1510 (s), 1233 (s) cm^–1. HRMS (ESI): m/z [M+H]⁺ calcd: 412.2118; found: 412.2117.
• 7 For a recent review on the chemistry of isoindole natural products, see: Speck K, Magauer T. Beilstein J. Org. Chem. 2013; 9: 2048