Aerobic iron-based cross-dehydrogenative coupling enables efficient diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators

Umesh A. Kshirsagar, Regev Parnes, Hagit Goldshtein, Rivka Ofir, Raz Zarivach, Doron Pappo

Research output: Contribution to journalArticlepeer-review

Abstract

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 9 nM, respectively. Green medicinal chemistry: 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 (see scheme; DCE=dichloroethane).

Original languageAmerican English
Pages (from-to)13575-13583
Number of pages9
JournalChemistry - A European Journal
Volume19
Issue number40
DOIs
StatePublished - 27 Sep 2013

Keywords

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

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Organic Chemistry

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