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.
