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 O-alkylation method has been developed for the synthesis of a series of O-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 N,O-acetal intermediates to afford the corresponding O-alkylated product. Moreover, N-alkylated byproducts are selectively decomposed under basic conditions and removed by extraction and crystallization, thus eliminating laborious column chromatography processes in scale-up synthesis.