6,6-Difluorobicyclo[3.1.0]hexane as a Rigidified 4,4-Difluorocyclohexane Mimetic: Multigram Synthesis, Physicochemical Characterization, and Incorporation into Maraviroc Analogs

Multigram synthesis of diastereomerically pure cis- and trans-6,6-difluorobicyclo[3.1.0]hexane building blocks starting from commercially available compounds is described. The diastereomeric mixture obtained by reaction of TMSCF₃ – NaI system with non-activated cyclopentene fragment using the slow addition protocol was effectively separated by flash column chromatography. Further simple chemical transformations produced diastereopure amines and carboxylic acids – promising building blocks for drug discovery. Physicochemical properties (i.e., pK_a and LogP) were measured for the title scaffold derivatives and compared with those with monocyclic and non-fluorinated counterparts. Two rigidified analogues of marketed anti-HIV drug Maraviroc were synthesized and evaluated by docking and molecular dynamics studies.