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Oxidative Desymmetrization Enables the Concise Synthesis of a trans ‐Cyclooctene Linker for Bioorthogonal Bond Cleavage
Author(s) -
Kuba Walter,
Sohr Barbara,
Keppel Patrick,
Svatunek Dennis,
Humhal Viktoria,
Stöger Berthold,
Goldeck Marion,
Carlson Jonathan C. T.,
Mikula Hannes
Publication year - 2023
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202203069
Subject(s) - desymmetrization , bioorthogonal chemistry , linker , chemistry , oxidative cleavage , oxidative phosphorylation , cleavage (geology) , bond cleavage , cyclooctene , combinatorial chemistry , stereochemistry , organic chemistry , computer science , biochemistry , catalysis , materials science , click chemistry , enantioselective synthesis , operating system , composite material , fracture (geology)
Modified trans ‐cyclooctenes (TCO) are capable of highly efficient molecular manipulations in biological environments, driven by the bioorthogonal reaction with tetrazines (Tz). The development of click‐cleavable TCO has fueled the field of in vivo chemistry and enabled the design of therapeutic strategies that have already started to enter the clinic. A key element for most of these approaches is the implementation of a cleavable TCO linker. So far, only one member of this class has been developed, a compound that requires a high synthetic effort, mainly to fulfill the multilayered demands on its chemical structure. To tackle this limitation, we developed a dioxolane‐fused cleavable TCO linker (dcTCO) that can be prepared in only five steps by applying an oxidative desymmetrization to achieve diastereoselective introduction of the required functionalities. Based on investigation of the structure, reaction kinetics, stability, and hydrophilicity of dcTCO, we demonstrate its bioorthogonal application in the design of a caged prodrug that can be activated by in‐situ Tz‐triggered cleavage to achieve a remarkable >1000‐fold increase in cytotoxicity.