The versatility of 2-pyrones as starting materials for ring-forming processes en route to bioactive compounds such as pharmaceuticals has been explored for almost a century. Direct pericyclic annulations of 2-pyrones, such as [4+2]-cycloadditions and 4π electrocyclizations, have proven to be effective tactics for accessing synthetically versatile bicycles that have been applied, for example, in natural product total synthesis. Our lab has applied the [4+2]-cycloaddition chemistry of 2-pyrones to the total synthesis of the ceforalides and cephanolides. Alternatively, novel annulation strategies, enabled by the nucleophilic 1,6- and 1,2-ring opening of 2-pyrones, have been developed to access myriad ring systems. Continuing efforts to expand the scope of this versatile pyrone remodeling strategy to increase the diversity of scaffolds that can be obtained from 2-pyrone are ongoing. Our recent work has focused on the novel syntheses of substituted benzoates using rhodium-mediated Hopf cyclizations, as well as syntheses of substituted aromatic rings. These transformations commence with cross-couplings of alkynes to 2-pyrone, followed by treatment with either NaCN or morpholine to effect a 1,6-ring opening of the resulting adducts, which cyclize under either metal-catalyzed or no-metal added conditions. Future work on this project will focus on exploring the scope of this methodology as well as underlying mechanism.  Overall, these complementary transformations set the stage to further diversify 2-pyrones into various carbo- and heterocyclic ring systems and should find widespread application in the preparation of bioactive compounds of pharmaceutical relevance.

Progress toward the diversification of 2-pyrones

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