Peptide macrocycles have received much recent attention in the area of drug design. The macrocycle extends the peptide backbone, which enhances hydrogen bonding to target biomolecules, in particular proteolytic enzymes. In addition, the fixed conformation of these macrocycles compared to their linear peptide analogs reduces the entropic penalty when binding to the active site of proteases. The preparation of macrocycles, however, has proven to be challenging. In this study, the formation of biphenyl ether macrocyclic peptides was compared to the formation of other biaryl ether peptide macrocycles in an effort to prepare macrocyclic proteasome inhibitors that contain an oxindole. The general mechanism, a nucleophilic aromatic substitution between a hydroxylated aryl and a fluorinated nitrophenylalanine, is not always straightforward, but produces various side products depending on the amino acid composition of the peptide and the type of hydroxylated aryl. Side products determined include N-terminal peptide deprotection and acyl shifts, in addition to large variations in reaction times.<br/>

Challenges in the synthesis of peptidic macrocyclic biaryl ethers

2019 Fall National Meeting

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