Diversifying Amino Acids and Peptides via Deaminative Reductive Cross-Couplings Leveraging High-Throughput Experimentation

Abstract

A deaminative reductive coupling of amino acid pyridinium salts with aryl bromides has been developed to enable efficient synthesis of noncanonical amino acids and diversification of peptides. This method transforms natural, commercially available lysine, ornithine, diaminobutanoic acid, and diaminopropanoic acid to aryl alanines and homologated derivatives with varying chain lengths. Attractive features include ability to transverse scales, tolerance of pharma-relevant (hetero)aryls and biorthogonal functional groups, and the applicability beyond monomeric amino acids to short and macrocyclic peptide substrates. The success of this work relied on high-throughput experimentation to identify complementary reaction conditions that proved critical for achieving the coupling of a broad scope of aryl bromides with a range of amino acid and peptide substrates including macrocyclic peptides.

Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp3–sp2 Carbon–Carbon Bonds

“…Producing carbon–carbon bonds from readily available feedstocks is particularly impactful. The C­(sp 3 )–C­(sp 2 ) substructure is often synthesized from an organometallic reagent and an alkyl or aryl (pseudo)­halide via cross-coupling with palladium, − nickel, − copper, − iron, − cobalt, − or other metal catalysts. − Recently, nickel catalysis has found complementary utility in reductive C­(sp 3 )–C­(sp 2 ) couplings. − …”

Beyond 20 in the 21st Century: Prospects and Challenges of Non-canonical Amino Acids in Peptide Drug Discovery

“…Openy et al showcased the first example of utilizing a side chain Katritzky salt for on-resin peptide LSF, accessing diverse ncAAs via a photochemical Giese reaction using commercially available Michael acceptors . With line of sight to readily transform abundant canonical AA feedstocks into unique ncAAs, an academic–industrial collaboration between Merck and the Watson group at the University of Delaware recently reported a cross-electrophile coupling between lysine-derived Katritzky salts and aryl halides to access aryl alanines and homologated derivatives (Figure D) . Through this work, facile access to LSF substrates was achieved, ultimately providing diverse, boutique side chain functionality on fully elaborated peptidic structures.…”

Mary P. Watson Selected to Receive the 2023 ACS Catalysis Lectureship for the Advancement of Catalytic Science

“…The Watson method enables amines to be converted into active electrophiles and then cross-coupled with a variety of coupling partners . Rich collaborations have already developed between her group and researchers from the pharmaceutical industry to leverage this exciting new advance. − …”

“…Further, through detailed mechanistic studies, the Watson Group has shown that the transformation proceeds via a radical intermediate for Katritzky salts, which is likely generated by single electron transfer from the nickel catalyst to the pyridinium salt . In collaboration with researchers from Merck, the Watson Group has shown how the method, when applied to amino acid side chains, can be used to create structures with noncanonical amino acids …”

“…2 In collaboration with researchers from Merck, the Watson Group has shown how the method, when applied to amino acid side chains, can be used to create structures with noncanonical amino acids. 9 Professor Watson's achievements will be celebrated in an award symposium in her honor at the 266th ACS National Meeting in San Francisco, California (August 2023). Please join us in congratulating her and mark the time in your calendar to see the latest and greatest in deaminative coupling at her award symposium!…”