Click to Translate: Synthesis of <i>Trans</i> ‐Cyclooctene Modified 5′ mRNA Caps for Bioorthogonal Activation

mRNA translation can be controlled through chemical modification of the 5′‐Cap, yet systematic insights into structure–reactivity relationships of bioorthogonally activatable Cap analogues remain limited. Here, we report the synthesis of trans ‐cyclooctene (TCO)‐modified 5′ mRNA caps (ZipCaps) and a comparative analysis of distinct TCO isomers. A controlled synthetic strategy enabled access to axial and equatorial derivatives, revealing stereochemical effects on click‐to‐release reactivity and stability. ZipCap‐modified mRNA exhibits reduced translation that can be restored upon tetrazine addition, enabling reversible chemical control of protein expression in cells. In contrast to a recent report describing complete translational suppression, residual translation is observed, highlighting the sensitivity of Cap‐dependent translation to structural variations.