Synthesis and Physicochemical Characterization of 5‐Trifluoromethyl‐Substituted Tetrahydrofurans and Tetrahydrothiophenes

Fluorinated saturated heterocycles are valuable yet underexplored motifs in drug design. Here, we present a scalable strategy for the synthesis of fluorinated tetrahydrofuran (THF) and tetrahydrothiophene (THT) building blocks from simple and readily available starting materials. The optimized conditions enabled access to CF 3 ‐substituted ketones and the corresponding stereodefined alcohol, amine, and amino acid derivatives on a decagram scale. Physicochemical profiling established clear structure–property relationships. p K a and isoelectric point (pI) values were affected by strong inductive effects of heteroatoms and SO 2 groups, with CF 3 substitution consistently enhancing the compound's acidity and lowering isoelectric points. Lipophilicity (Log P ) measurements highlighted scaffold‐ and substituent‐dependent lipophilicity, with sulfur‐containing motifs being most lipophilic and sulfone derivatives beingleast lipophilic. Overall, this work delivers a robust platform for accessing versatile fluorinated building blocks (including noncanonical amino acids) for drug discovery.