The diversification of natural products (NPs) constitutes a significant source of inspiration for generating novel molecular scaffolds possessing previously inaccessible biological properties. Due to the prevalent embodiment of hydroxy motifs in natural products, deoxy-functionalization has emerged as one of the most attractive methods for diversifying natural product scaffolds into novel compound libraries with remarkable properties relevant to drug design. However, existing strategies for the functional transformation of hydroxy groups operate under forcing conditions that ultimately give rise to competing pathways (such as elimination), non-stereospecificity, low efficiencies, and limited substrate compatibility. To address these challenges, we sought to develop a robust, unified protocol for the chemical diversification of alcohol-bearing molecular scaffolds. Our approach showcases a one-step deoxy-functionalization of alcohols that proceeds via a domino sulfur(VI)-Fluoride Exchange (SuFEx) and fluoride activation of a silicon bound-nucleophile. Using this approach, a diverse range of hydroxy-embedded biomolecules and natural products were transformed into new derivatives with highly sought bond connections such as C-C, C-N, and C-X (X = Cl, Br). Gratifyingly, the reaction proceeds under mild conditions that efficiently facilitate broad substrate compatibility and diverse functional group tolerance.

Deoxy-diversification of alcohols via a tandem sulfur(VI)-fluoride exchange (SuFEx) and desilylative nucleophilic addition

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