Saeed Aamer, Ashraf Zaman, Rafique Hummera
Department of Chemistry, Quaid-I-Azam University, Islamabad, Pakistan.
J Asian Nat Prod Res. 2011 Feb;13(2):97-104. doi: 10.1080/10286020.2010.544654.
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 NaBH(4)/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.
合成了来自真菌埃默森菌属和曲霉属的一种外毒素——星芒菌素（3,4 - 二氢 - 8 - 羟基 - 7 - 羟甲基 - 6 - 甲氧基异香豆素）（8）。因此，3,5 - 二甲氧基 - 4 - 甲基苯乙酸甲酯（1）经Vilsmeier - Haack甲酰化反应得到甲酰酯（2），随后醛基经氨基磺酸 - 亚氯酸钠氧化生成羧酸酯（3）。使用NaBH(4)/THF/MeOH对后者的酯官能团进行化学选择性还原，得到相应的羟基酸（4），该羟基酸经环脱水反应生成3,4 - 二氢 - 6,8 - 二甲氧基 - 7 - 甲基异香豆素（5）。使用NBS/过氧化苯甲酰对5中C - 7甲基进行苄基溴化反应，得到7 - 溴甲基二氢异香豆素（6），随后使用丙酮水溶液进行亲核取代反应，得到7 - 羟甲基 - 二氢异香豆素（7）。最后，使用无水碘化镁对8 - 甲氧基进行区域选择性脱甲基反应，得到星芒菌素（8）。对二氢异香豆素（5 - 8）针对人角质形成细胞系进行细胞毒性活性筛选，发现它们表现出中等至良好的活性。
