Oxidative Cyclization and Enzyme-free Deiodination of Thyroid Hormones

We introduce the first non-enzymatic deiodination of thyroid hormones from a so far unknown hypervalent iodaoxinium state. After developing oxidative processes for thyroxine(T4)-derived model cyclic diaryliodonium salts, we successfully produced an iodaoxinium salt through the direct oxidation of O-and N-protected T4. DFT calculations revealed a novel halogen bonding-based deiodination mechanism, circumventing the traditional selenium-dependent pathways. Our findings open new avenues in thyroid hormone chemistry, suggesting alternative mechanisms for their involvement in metabolic processes, regulation of oxidative stress, and gene expression.