Advances in Synthetic Methods for Chiral Trifluoromethylthiolated Compounds

Driven by its strong electron-withdrawing properties and high lipophilicity, the trifluoromethylthio (–SCF3) group has emerged as a privileged motif in bioactive small molecules, particularly in pharmaceutical and agrochemical development. However, the asymmetric synthesis of chiral –SCF3-containing compounds remains a significant challenge. This review provides a comprehensive overview of recent advances in the synthesis of chiral SCF3-containing compounds, highlighting a strategic paradigm shift from traditional “direct trifluoromethylthiolation” to the “building block approach”. Although atom-economical, direct methods are largely constrained by substrate-inherent reactivity, typically restricted to activated sites like α-carbonyls and alkenes. Conversely, the rapidly evolving building block approach circumvents the functional group compatibility risks of late-stage SCF3 installation. This review summarizes the progress of both synthetic strategies and discusses current challenges and future opportunities, aiming to provide a reference for the discovery of innovative chiral fluorinated pharmaceuticals.