Cyclization reactions of coumarin derivatives: Chemo- and regioselectivity effects of oxygen/sulfur isosteric replacementTROVA@unito

We synthesized several sulfur isosters of ferulenol and related prenylcoumarins from Ferula communis preliminary to finding whether the antitubercular activity of these natural compounds might be dissociated from their antithrombin activity. Direct thionation of ferprenine, an instance of "diversity-oriented" synthesis, yielded a mixture of three thiocoumarin derivatives. When 4-hydroxy-2-deoxy-2-thiocoumarin was reacted with farnesal and other alpha,beta-unsaturated aldehydes, the isosteric oxygen-sulfur substitution at position 2 surprisingly caused a regiochemical inversion in the tandem Knoevenagel-electrocyclic reaction, prevalently affording the linear adduct. An extensive investigation with variously substituted enals highlighted a competition between Knoevenagel and Michael addition. This result was rationalized by energy calculations that took into consideration steric and electronic factors as well as complex formation with the catalyst.