Gram-Scale Syntheses of a Series of Fluorinated Oxetane-Based Building Blocks

Keywords

fluorine - oxetanes - lipophilicity - metabolic stability - pK _a

Significance

The use of oxetanes in drug discovery programs is becoming more prevalent owing to their ability to effectively mimic ketones, esters and carboxylic acids, while their rigid geometry potentially leads to improved binding to a biological target. In a similar vein, fluorine substitution has long been established within medicinal chemistry as a strategy to improve the overall physicochemical properties of a lead molecule specifically through improving metabolic stability and modulating lipophilicity and solubility. The current report describes the gram-scale syntheses of a wide range of bifunctional 3,3-disubstituted oxetane building blocks, and benchmarks several of their physicochemical properties not only against the non-fluorinated parent oxetanes but also with other fluorinated cyclic systems (cyclopropyl, cyclobutyl).

Comment

The robust synthetic approaches reported herein originate from the bulk, inexpensive starting material oxetan-3-one with an initial Strecker reaction employed to provide 3,3-difunctionalization. Typically, fluorine atoms were introduced through classical deoxyfluorination reactions utilizing Morph-DAST as the workhorse reagent. One key exception to this overarching strategy was for the trifluoromethyl-functionalized amine, which was obtained through a modified-Strecker type reaction (Eur. J. Org. Chem. 2024, 27, e202300935). Analysis of the physicochemical properties highlighted the combined impact of the oxetane and fluorine substitutions, most notably on the pK _a of the building blocks.

Publication History

Article published online:
16 December 2025