Sythetic flexibility of a bromopyrrole ester intermediate : toward novel biologically active compounds

Compounds containing the pyrrole ring as a core structural motif continue to show significant biological activity, and both natural product derivatives and novel chemical scaffolds show potential for use as pharmaceuticals in treating a variety of cancers, infections, and inflammation. Given the widespread and important applications of compounds containing this motif, novel, rapid, and selective methods for the synthesis of multifunctional pyrroles is of some importance. Previous work in our group has utilized palladium-mediated Suzuki cross-coupling as a powerful tool for functionalizing activated bromopyrrole esters, generating structural analogues of bioactive natural products. We have also used a similar approach to synthesize a novel class of microtubule polymerization inhibitors that have potential as future antitumor agents. Herein we describe methods for the selective modification of the C3 and C5 positions on the pyrrole ring, which have modified and expanded upon the previous work using crosscoupling and other common methods, to improve synthetic flexibility and broaden the scope of these reactions. I also show application to the synthesis of new derivatives of Lycogarubin C natural product, as well as preparation of novel microtubule-inhibiting agents as part of a structure-activity relationship study (SAR) for development of new cancer chemotherapeutics.