Nature-Inspired Bioorthogonal Reaction: Development of β-Caryophyllene as a Chemical Reporter in Tetrazine Ligation

A nature-inspired bioorthogonal reaction has been developed, hinging on an inverse-electron-demand Diels–Alder reaction of tetrazine with β-caryophyllene. Readily accessible from the cheap starting material through a scalable synthesis, the newly developed β-caryophyllene chemical reporter displays appealing reaction kinetics and excellent biocompatibility, which renders it applicable to both in vitro protein labeling and live cell imaging. Moreover, it can be used orthogonally to the strain-promoted alkyne–azide cycloaddition for dual protein labeling. This work not only provides an alternative to the existing bioorthogonal reaction toolbox, but also opens a new avenue to utilize naturally occurring scaffolds as bioorthogonal chemical reporters.