Readily Accessible Strained Difunctionalized trans-Cyclooctenes with Fast Click and Release Capabilities

18 October 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The click reaction between a functionalized trans-cyclooctene (TCO) and a tetrazine is a compelling method for bioorthogonal conjugation in combination with payload releasing capabilities. However, the synthesis of difunctionalized TCOs remains challenging. As a result, these compounds are poorly accessible, which impedes the development of novel applications. In this work, the scalable and accessible synthesis of a new bioorthogonal difunctionalized TCO is reported in only four single selective steps starting from commercially available compounds. The click kinetics and payload release were assessed with various functionalized derivatives and local drug release was shown in a cellular toxicity study.


Bioorthgogonal conjugation
click chemistry
click and release

Supplementary materials

Supporting Information
Experimental procedures and characterization data, including NMR spectra


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