Coupling of sterically hindered aldehyde with fluorinated synthons: Stereoselective synthesis of fluorinated analogues of salinosporamide A

Salinosporamide A is an irreversible inhibitor of the β-subunits of the 20S proteasome. Its C-5 cyclohexenyl moiety is the key to its affinity and potency as an anticancer agent. Here we describe the synthesis of C-5 difluoromethylated and trifluoromethylated analogues of salinosporamide A and their biological evaluation as proteasome inhibitors against purified yeast 20S proteasome. The synthetic strategy featured the stereoselective coupling reaction of sterically hindered aldehyde 3 with fluorinated organolithium reagents.