Total synthesis and cytotoxic activity of stellatin

Abstract

Stellatin (3,4-dihydro-8-hydroxy-7-hydroxymethyl-6-methoxyisocoumarin) (8), an extrolite of fungal genera Emericella and Aspergillus, was synthesized. Thus, Vilsmeier–Haack formylation of methyl ester of 3,5-dimethoxy-4-methylphenylacetic acid (1) to afford the formyl ester (2) followed sulfamic acid–sodium chlorite oxidation of the aldehydic function to yield the carboxy ester (3). Chemoselective reduction of ester function in the latter using NaBH₄/THF/MeOH furnished the corresponding hydroxy acid (4) that on cyclodehydration afforded the 3,4-dihydro-6,8-dimethoxy-7-methylisocoumarin (5). Benzylic bromination of the C-7 methyl in 5 using NBS/benzoyl peroxide to give the 7-bromomethyldihydroisocoumarin (6) followed the nucleophilic substitution using aqueous acetone to provide 7-hydroxymethyl-dihydroisocoumarin (7). Finally, the regioselective demethylation of 8-methoxyl group using anhydrous magnesium iodide furnished the stellatin (8). The dihydroisocoumarins (5–8) were screened for cytotoxic activity against human keratinocyte cell line and were found to exhibit moderate to good activity.

Keywords:

• dihydroisocoumarin
• stellatin
• Aspergillus variecolor
• cytotoxic activity

Acknowledgement

The authors are grateful to the Pakistan Science Foundation for a research grant under Project No. PSF/Res/C-QU/Chem(395).