Reversing polarity: a family of chemoselective oxidations

Organic synthesis is the art of uniting carbon atoms to form new bonds. In creating a carbon- carbon bond, one generally looks to merge two precursors where the carbon atoms to be joined together have opposing, complementary polarity. The natural polarity of most molecules tends to be utilized in this endeavor, as it typically allows the mildest of reaction conditions to be employed. Thus, for instance a carbon-halogen bond is positively polarized on carbon; whereas the carbon atom alpha to a carbonyl C=O tends to be viewed as a negatively polarized fragment. The inversion of this polarity, colloquially termed Umpolung among synthesis practitioners, is a conceptual challenge. But not only in an academic sense: reversing polarity of carbon-based building blocks should also enable entirely new combinations and open up totally novel approaches for synthesis. Surprisingly, the Umpolung at the position alpha- to a carbonyl group is scarcely documented. This is surprising, particularly given how much of an impact the chemistry of naturally polarized enolates and their equivalents have made in synthesis at large. We hereby present a general and innovative approach to this gap in synthetic methodology. Our strategy unfolds as a suite of oxidative-type transformations that will break new ground in organic synthesis. Applications to the preparation of biologically relevant substances, such as a highly potent histone deacetylase inhibitor the synthesis of which can be cut down in half with our Umpolung strategy, are also presented.

In this project, novel reactivity principles aiming at the extension of the concept of "Umpolung" to a broad family of transformations allowing access to the alpha-position to a carbonyl center were developed. This resulted in remarkable new insights into the chemistry of amides, but also ketones and other carbonyl derivatives. The results of this project range from fundamental discoveries within the field of amide activation to groundbreaking chemistry with the potential to impact e.g. radiolabelling, biology and medicine.