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Heteroaromatics are the basis for many pharmaceuticals. The ability to modify these structures through selective core-atom transformations, or “skeletal edits”, can dramatically expand the landscape for drug discovery and development. However, despite the importance of core-atom modifications, the quantitative impact of such transformations on accessible chemical space remains undefined. Here, we report a cheminformatic platform to analyze which skeletal edits would most increase access to novel chemical space. This study underscores the significance of emerging single and multiple core-atom transformations of heteroaromatics in enhancing chemical diversity, for example, at a late-stage of a drug discovery campaign. Our findings provide a quantitative framework for prioritizing core-atom modifications in heteroaromatic structural motifs, calling for the development of new methods to achieve these types of transformations. 

Abstract Skeletal modifications enable elegant and rapid access to various derivatives of a compound that would otherwise be difficult to prepare. They are therefore a powerful tool, especially in the synthesis of natural products or drug discovery, to explore different natural products or to improve the properties of a drug candidate starting from a common intermediate. Inspired by the biosynthesis of the cephalotane natural products, we report here a single-atom insertion into the framework of the benzenoid subfamily, providing access to the troponoid congeners — representing the reverse of the proposed biosynthesis (i.e., a contra-biosynthesis approach). Computational evaluation of our designed transformation prompted us to investigate a Büchner–Curtius–Schlotterbeck reaction of ap-quinol methylether, which ultimately results in the synthesis of harringtonolide in two steps from cephanolide A, which we had previously prepared. Additional computational studies reveal that unconventional selectivity outcomes are driven by the choice of a Lewis acid and the nucleophile, which should inform further developments of these types of reactions. 

The synthesis of aryl amines from 3-alkynyl-2-pyrones and various amines is described. 

A transformation of spiro[4.4]nonatrienes to aryl-substituted, enantioenriched annulated fulvenes is reported. DFT calculations and empirical results support a novel mechanism of reaction involving a 1,5-vinyl shift from a vinyl–palladium species.