The click reaction between functionalized trans-cyclooctenes (TCOs) and tetrazines is a compelling method for bioorthogonal conjugation in combination with payload releasing capabilities. However, the synthesis of difunctionalized TCOs has remained a challenge due to the long multistep sequences that are typically required. In this contribution, a novel and scalable synthesis of a new class of bioorthogonal difunctionalized TCOs is reported involving only four steps starting from commercially available starting materials. This pathway also includes a continuous and hence scalable liquid-liquid separation, in which trans-cyclooctenes are selectively extracted from a solution containing a mixture of cis- and trans-cyclooctynes. In addition, the click kinetics and payload release of these new TCOs will be discussed along with several applications in biomedical and biological systems.

Readily accessible strained difunctionalized trans-cyclooctenes with fast click and release capabilities

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