An efficient synthesis of a 4'-phosphonodifluoromethyl-3'-formyl-phenylalanine containing SRC SH2 ligand.
A CuBr-mediated, regioselective cross-coupling between methyl 2,5-diiodobenzoate (4) and [(diethoxyphosphinyl)difluoromethyl]zinc bromide is reported. Palladium-catalyzed incorporation of an amino acid side chain, followed by subsequent modifications resulted in the rapid construction of 2. Compound 2 was designed to engage Cys188 of the Src SH2 domain, however, this was not observed spectroscopically.
The Role of 4-phosphonodifluoromethyl- and 4-phosphono-phenylalanine in the selectivity and cellular uptake of SH2 domain ligands
Incorporation of 4-phosphonodifluoromethyl-phenylalanine (F2Pmp) and 4-phosphono-phenylalanine into SH2 targeted peptides and peptidomimetic ligands was found to effect binding affinity and selectivity of these ligands toward the Src and Abl SH2 domains. Furthermore, dipeptide analogs containing these phosphonate amino acids were used to produce prodrugs with excellent cellular delivery and reconversion rates.
Synthesis of nucleoside 5′-deoxy-5′-difluoromethylphosphonates
Abstract 1- O -Acetyl-2,3-di- O -benzoyl- d -ribofuranose 5-deoxy-5-difluoromethylphosphonate was synthesized in three steps from 1- O -methyl-2,3- O -isopropylidene-β- d -ribofuranose 5-deoxy-5-difluoromethylphosphonate. Condensation of this suitably derivatized sugar with silylated pyrimidines and purines afforded novel nucleoside 5′-deoxy-5′-difluoromethylphosphonates.