Oxidative Desymmetrization Enables the Concise Synthesis of a trans ‐Cyclooctene Linker for Bioorthogonal Bond Cleavage

Abstract: 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.

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch

References and Relationships

• Bibliographic citation: Oxidative Desymmetrization Enables the Concise Synthesis of a trans ‐Cyclooctene Linker for Bioorthogonal Bond Cleavage ; day:24 ; month:11 ; year:2022 ; extent:1 ; Chemistry - a European journal ; (24.11.2022) (gesamt 1)

Contributors, Places and Time

• Creator: Kuba, Walter ; Sohr, Barbara ; Keppel, Patrick ; Svatunek, Dennis ; Humhal, Viktoria ; Stöger, Berthold ; Goldeck, Marion ; Carlson, Jonathan C. T. ; Mikula, Hannes

Further information

• DOI: 10.1002/chem.202203069
• URN: urn:nbn:de:101:1-2022112514150176421506
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 15.08.2025, 7:28 AM CEST