A scalable synthesis of trans −1,2‐fluoroalkyl‐substituted cyclopentane building blocks was developed. The approach relies on orthogonal late‐stage functionalization of a common precursor – monoester of trans −1,2‐cyclopentanecarboxylic acid. Fluoromethyl‐substituted derivatives were accessed via exhaustive reduction of the COOH group, activation of the resulting primary alcohol as a triflate, and nucleophilic substitution with fluoride. Meanwhile, difluoro‐ and trifluoromethyl groups were introduced through deoxofluorination of the corresponding aldehyde or carboxylic acid. The resulting fluorinated esters were efficiently diversified into a broad range of building blocks relevant to medicinal chemistry, including carboxylic acids, primary amines, azides, alcohols, and sulfonyl chlorides. In addition to the synthetic developments, the effect of the fluoroalkyl substituent (CH 2 F, CHF 2 , CF 3 ) on physicochemical properties of the cyclopentane derivatives was established by measuring p K a and Log P values of model derivatives.
Bobovskyi et al. (Wed,) studied this question.