Asymmetric Total Syntheses of (+)-Penostatins A and C

Abstract

Penostatins A and C are cytotoxic natural products that show promising selective inhibitory activity against PTP1B. Here the first asymmetric total syntheses of (+)-penostatins A and C are reported. Our strategy features (i) a new method for the synthesis of 6-alkyl-3-hydroxy-2-pyrones, (ii) a cascade involving the intramolecular Diels-Alder reaction of 2-pyrone and a retro-hetero-Diels-Alder (decarboxylation) reaction, (iii) Ando-Horner-Wadsworth-Emmons olefination/lactonization, and (iv) selenoxide elimination. Our study confirmed the absolute configurations of penostatins A and C and laid the groundwork for further bioactivity studies.