α-Fluoroalkyl-Substituted Cyclopentane Building Blocks for Drug Discovery

A scalable synthesis of α-fluoroalkyl-substituted cyclopentane building blocks was developed. An entry into these chemotypes relied on α-fluoromethylation of cyclopentane carboxylate (for CH₂F-substituted substrates) and the deoxofluorination of the corresponding aldehyde or carboxylic acid (for CHF₂- and CF₃-substituted substrates) to access fluorine-containing esters, which were further diversified into various building blocks containing functional groups relevant to medicinal chemistry applications. The impact of fluoroalkyl substituent (CH₂F/CHF₂/CF₃) on the physicochemical properties of the synthesized derivatives was evaluated by experimental determination of their pKₐ and LogP values.