Selective and Scalable <i>O</i>‑Alkylation of Serine and Threonine Enabled by Chelation-Controlled Reductive C–N Cleavage of <i>N</i>,<i>O</i>‑Acetals

A selective and scalable <i>O</i>-alkylation method has been developed for the synthesis of a series of <i>O</i>-alkyl serine and threonine derivatives as useful unnatural amino acids. The use of Ti(IV) species capable of bis-ligation enables chelation-controlled reductive C–N cleavage of <i>N</i>,<i>O</i>-acetal intermediates to afford the corresponding <i>O</i>-alkylated product. Moreover, <i>N</i>-alkylated byproducts are selectively decomposed under basic conditions and removed by extraction and crystallization, thus eliminating laborious column chromatography processes in scale-up synthesis.