Aerobic Iron-Based Cross-Dehydrogenative Coupling Enables Efficient Diversity-Oriented Synthesis of Coumestrol-Based Selective Estrogen Receptor Modulators

作者：Kshirsagar Umesh A; Parnes Regev; Goldshtein Hagit; Ofir Rivka; Zarivach Raz; Pappo Doron^*

来源：Chemistry - A European Journal, 2013, 19(40): 13575-13583.

DOI：10.1002/chem.201300389

• cross-coupling
• iron
• natural products
• structure-activity relationships
• total synthesis

An iron-based cross-dehydrogenative coupling (CDC) approach was applied for the diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators (SERMs), representing the first application of CDC chemistry in natural product synthesis. The first stage of the two-step synthesis of coumestrol involved a modified aerobic oxidative cross-coupling between ethyl 2-(2,4-dimethoxybenzoyl)acetate and 3-methoxyphenol, with FeCl3 (10 mol %) as the catalyst. The benzofuran coupling product was then subjected to sequential deprotection and lactonization steps, affording the natural product in 59 % overall yield. Based on this new methodology other coumestrol analogues were prepared, and their effects on the proliferation of the estrogen receptor (ER)-dependent MCF-7 and of the ER-independent MDA-MB-231 breast cancer cells were tested. As a result, new types of estrogen receptor ligands having an acetamide group instead of the 9-hydroxyl group of coumestrol were discovered. Both 9-acetamido-coumestrol and 8-acetamidocoumestrol were found more active than the natural product against estrogen-dependent MCF-7 breast cancer cells, with IC50 values of 30 and 9nM, respectively.

• 出版日期2013-9-27