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Alkenes are indispensable feedstocks in chemistry. Functionalization at both carbons of the alkene-1,2-difunctionalization-is part of chemistry curricula worldwide 1 . Although difunctionalization at distal positions has been reported 2-4 , it typically relies on designer substrates featuring directing groups and/or stabilizing features, all of which determine the ultimate site of bond formation 5-7 . Here we introduce a method for the direct 1,3-difunctionalization of alkenes, based on a concept termed 'charge relocation', which enables stereodivergent access to 1,3-difunctionalized products of either syn- or anti-configuration from unactivated alkenes, without the need for directing groups or stabilizing features. The usefulness of the approach is demonstrated in the synthesis of the pulmonary toxin 4-ipomeanol and its derivatives., (© 2024. The Author(s).)

Controlled protein functionalization holds great promise for a wide variety of applications. However, despite intensive research, the stoichiometry of the functionalization reaction remains difficult to control due to the inherent stochasticity of the conjugation process. Classical approaches that exploit peculiar structural features of specific protein substrates, or introduce reactive handles via mutagenesis, are by essence limited in scope or require substantial protein reengineering. We herein present equimolar native chemical tagging (ENACT), which precisely controls the stoichiometry of inherently random conjugation reactions by combining iterative low-conversion chemical modification, process automation, and bioorthogonal trans -tagging. We discuss the broad applicability of this conjugation process to a variety of protein substrates and payloads., Competing Interests: O. K., A. E., S. D. and S. K. are employees of Syndivia SAS., (This journal is © The Royal Society of Chemistry.)