Synthesis of a Series of Promising Isobenzofuranones for the Treatment of Acute Mucositis Caused by Chemo- and Radiotherapy

Abstract

A small series of 3,5-dihydroxy-7-methoxy-3,6-dimethyl­isobenzofuran-1(3H)-one analogues of the immunosuppressant, mycophenolate mofelite (MMF), has been identified during a screening campaign as possible mediators to prevent mucositis. Herein, we present a general seven-step approach for the preparation of small molecule mycophenolate mofelite analogues, which are readily available for further biological evaluation in our mucositis model.

Key words

isobenzofuranones - mycophenolic acid - Alder–Rickert reaction - acute mucositis

• References and Notes


Recombinant human KGF (Palifermin, Amgen) has been approved for the prevention of oral mucositis in patients undergoing hematology stem cell transplantation. For example, see:
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• 17 3-Hydroxy-5-{[(2E,5E)-7-hydroxy-3,7-dimethylocta-2,5-dien-1-yl]oxy}-7-methoxy-3,6-dimethylisobenzofuran-1(3H)-one (4) To a stirring suspension of KSCN (84 mg, 0.866 mmol) in MeCN (1 mL), (PhSe)₂ (108 mg, 0.346 mmol) followed by BAIB (139 mg, 0.433 mmol) were added. The cloudy yellow mixture was stirred at r.t. for 10 min before the addition of a solution of compound 2 (104 mg, 0.289 mmol) in MeCN (1 mL). The resulting mixture was stirred at r.t. for 16 h. After completion of the reaction, the mixture was washed with sat. NaHCO₃–10% Na₂S₂O₃ solution (5 mL) and extracted with EtOAc (2 × 50 mL). The organic layer was washed with brine (2 × 50 mL), dried over Na₂SO₄, filtered and the volatiles evaporated under reduced pressure to afford the expected intermediate, (E)-3-hydroxy-5-{[7-isothiocyanato-3,7-dimethyl-6-(phenylselanyl)oct-2-en-1-yl]oxy}-7-methoxy-3,6-dimethylisobenzofuran-1(3H)-one as a yellow oil. Next, to a stirring mixture of NaHCO₃ (10.97 mg, 0.131 mmol) and NaIO₄ (55.8 mg, 0.261 mmol) in H₂O (4 mL) was added a solution of the phenylselenyl intermediate (50 mg, 0.087 mmol) in 1,4-dioxane (8 mL). The cloudy mixture was stirred overnight at r.t. Upon completion, the mixture was washed with sat. NH₄Cl solution (2 mL) and extracted with EtOAc (2 × 25 mL). The organic layer was washed with brine (2 × 50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude residue was purified on silica gel (FC ISCO, gradient elution: 0–70% EtOAc in heptane) to afford compound 4 as a colorless oil (18 mg, 0.048 mmol, 55% yield). ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.57 (s, 1 H, exchangeable with D₂O), 7.02 (s, 1 H), 5.59 (d, J = 14.95 Hz, 1 H), 5.51–5.49 (m, 2 H), 4.73–4.70 (m, 2 H), 4.48 (s, 1 H, exchangeable with D₂O), 3.90 (s, 3 H), 2.72 (d, J = 6.35 Hz, 2 H), 2.05 (s, 3 H), 1.71 (s, 3 H), 1.70 (s, 3 H), 1.16 (s, 6 H, 2 × CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 166.4, 163.9, 157.7, 151.7, 141.1, 140.0, 124.6, 122.6, 120.4, 109.7, 104.2, 100.6, 71.4, 66.1, 62.5, 42.2, 30.4, 30.0, 26.6, 17.4, 9.3. LC–MS: m/z = 377 [ M + H]⁺; t _R = 1.03 min (>99% by LC–MS, UV). ROESY correlation data are reported in the Supporting Information.