Synlett 2013; 24(18): 2397-2400
DOI: 10.1055/s-0033-1340060
letter
© Georg Thieme Verlag Stuttgart · New York

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

Maude Patoor
Novartis Institutes for BioMedical Research, Fabrikstrasse 22-1.051.17, 4054 Basel, Switzerland   Fax: +41(61)3248001   Email: [email protected]
,
Philippe Neuner
Novartis Institutes for BioMedical Research, Fabrikstrasse 22-1.051.17, 4054 Basel, Switzerland   Fax: +41(61)3248001   Email: [email protected]
,
Heinz Ruffner
Novartis Institutes for BioMedical Research, Fabrikstrasse 22-1.051.17, 4054 Basel, Switzerland   Fax: +41(61)3248001   Email: [email protected]
,
Carsten Spanka
Novartis Institutes for BioMedical Research, Fabrikstrasse 22-1.051.17, 4054 Basel, Switzerland   Fax: +41(61)3248001   Email: [email protected]
,
Laure C. Bouchez*
Novartis Institutes for BioMedical Research, Fabrikstrasse 22-1.051.17, 4054 Basel, Switzerland   Fax: +41(61)3248001   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 27 August 2013

Accepted after revision: 08 October 2013

Publication Date:
23 October 2013 (online)


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.

Supporting Information

 
  • References and Notes


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  • 13 Reactions carried out without cadmium led to a mixture of compounds presenting the double addition of the methyl moiety and the expected mono-alkylated product 11.
  • 14 The structures of the final compounds were fully characterized by NMR spectroscopy. They presented NOEs between H-3 and the methyl and between the methyl and the hydroxy function as depicted in the isobenzofuran-(3H)-one model (see Scheme 2).
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  • 16 See the Supporting Information for the preparation of compound 3.
  • 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.