While palladium-catalyzed Buchwald-Hartwig cross coupling reactions between amines and aryl halides/triflates have been demonstrated using a variety of substrates, efficient and mild methods for the N-arylation of amino acids without racemization have only recently emerged. We previously demonstrated the utility of electron-rich N-aryl peptides in oxime ligation reactions and found that they readily oxidize into reactive alpha-imino amide intermediates under mild aqueous conditions depending on the electronics of the aryl ring. However, the synthesis of N-aryl peptides was limited by the need to use of commercially available bromoacetic acid derivatives, which significantly limited the extent of side-chain diversity at the site of ligation. Here, we describe the N-arylation of amino acid esters using 4-bromo-N,N-dimethylaniline as a coupling partner and Buchwald’s t-BuBrettPhos Pd G3 precatalyst to expand the scope of N-aryl peptide substrates. The resulting N-aryl amino acid building blocks possessing a range of natural and unnatural side chains were installed on the N-terminus of a series of peptides to explore their reactivity in oxime ligation reactions. In order to gain access to all natural amino acids at the site of ligation and simplify the synthesis of N-aryl peptides, we have begun to explore the N-arylation of resin-bound peptides. Preliminary data on the optimization and scope of this Pd-catalyzed on-resin peptide N-arylation reaction will be reported.

Synthesis of N-aryl peptides for expansion of side-chain diversity in ketoxime ligations

ACS Spring Meeting 2021

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