trans-Cyclooctenes (TCOs) are high strain energy compounds utilized in the realm of bioorthogonal chemistry. TCOs undergo inverse electron-demand Diels-Alder reactions with tetrazine molecules in the fastest bioorthogonal reaction to date, the tetrazine-trans-cyclooctene ligation. TCOs have been used for live-cell imaging, 18F labeling, biomaterials, and probing sulfenic acids formed on proteins experiencing high redox poise. With these applications, TCOs of diverse functionality that are also hydrophilic and synthetically accessible are desired. While the TCOs currently in the ever-growing “toolbox” have fast reaction kinetics, they are limited in scope, involve difficult separations, produce low yields of the desired isomers, and exhibit lower hydrophilicities. This work focuses on the synthesis of derivatized hydroxy-TCOs that are made from the diastereoselective functionalization of keto-TCO. Nucleophilic addition to keto-TCO results in the exclusive formation of the axial orientation of the hydroxyl group. This is pertinent for sulfenic acid tagging, affords higher yields of the ‘faster’ diastereomer, and makes purification more facile. Photoisomerization of keto-TCO is scalable and moderate yielding. The synthesized derivatives of keto-TCO include alcohol, propargyl, oxime, activated ester, amine, and etc. Several of these hydrophilic TCOs have been used as sulfenic acid probes as well as conjugated to a fluorophore for intracellular probing.

Diverse derivatization of trans-cyclooctenes using diastereoselective functionalization of a scalable ketone-trans-cyclooctene precursor

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.