Methodologies for the Formation of 2-Substituted Oxetanes: Synthesis of (<i>S</i>)-Oxetan-2-ylmethyl Tosylate

The compound (S)-oxetan-2-ylmethyl tosylate 1 was identified as a key synthetic fragment for the introduction of the 2-substituted oxetane functionality in potential drug candidates under development in our laboratories. The focus of this paper is to highlight methodologies evaluated in our quest for synthetic routes to 2-substituted oxetanes suitable for enabling manufacture. Of the five routes investigated, three (Route 1A, Route 2, and Route 3) were successfully demonstrated in the laboratory. Subsequently, Route 3 was executed at scale to deliver metric ton quantities of the oxetane tosylate 1 as a solution in EtOAc, which was integrated into the synthesis of 2 and aforementioned drug candidates.