Concise Synthesis of the Click-to-Release Linker iTCO Enabled by Telescoped Flow Photohydrolysis and Iodolactonization

Abstract

The tetrazine-trans-cyclooctene (Tz-TCO) click-to-release reaction is widely used for bioorthogonal payload release in chemical biology and drug delivery. The recently developed intramolecularly controlled click-cleavable trans-cyclooctene linker iTCO enables fast, near-quantitative release across diverse tetrazine classes, but its broader use has been limited by a lengthy, low-yielding synthesis (eleven steps, ∼1% overall yield). We report a seven-step route centered on a telescoped flow photohydrolysis-iodolactonization sequence, providing gram-scale access to iTCO in 8% overall yield.