Decarboxylative couplings as versatile tools for late‐stage peptide modifications

Abstract

While strategies for the late‐stage modification of peptides are crucial to the design and synthesis of new peptide‐based materials and therapeutics, synthetic methods have historically focused on the modification of select, nucleophilic amino acids. This review highlights decarboxylative coupling strategies as emerging tools for the targeted functionalization of native peptidic acids—α‐carboxylic acids and aspartic/glutamic acid residues—through complexity building CC and Cheteroatom bond formations. Decarboxylation strategies employing both activated carboxylic acids (redox‐active esters) and the direct application of unprotected carboxylic acids are discussed. Emphasis is placed on the scope and limitations of the methodologies as well as their compatibility with complex peptide substrates.

Ketones from Nickel‐Catalyzed Decarboxylative, Non‐Symmetric Cross‐Electrophile Coupling of Carboxylic Acid Esters

“…As afurther test of the utility of this ketone synthesis,we explored couplings with polypeptides on solid support (Figure 1). Solid-supported synthesis is the most common format for amide bond formation, but only al imited set of other reactions have been employed in this context, [17,18] and cross-electrophile coupling has never been employed in solidphase peptide synthesis.Ketones in polypeptides are useful in peptidomimetic backbones as ketomethylene isosteres, [19] and Table 2: Substrate scope for the decarboxylative coupling of NHP esters with thioesters. [a] [a] Reactionsw ere conducted on 0.5 mmol scale in 1mLofsolvent for 24 h. Yields are isolated yields after purification unless otherwise noted.…”

Photocatalytic methods for amino acid modification

“…For discussions of other amino acid modification strategies please refer to other reviews of the field. 8,[12][13][14][15][16]…”

Peptide modification and cyclization via transition-metal catalysis

“…amidation and esterification), however, acids have been generally overlooked as handles for functionalization [1]. Advances in transition-metal catalyzed decarboxylative functionalizations have recently fueled a renaissance of acidcentered diversification strategies [19]. Conceptually, such methods proceed through two distinct pathways: 1) the modification of activated carboxylic acid esters (so-called redox-active esters, RAEs, such as 9, Figure 3A); and 2) the direct modification of native acids.…”