Solid‐Phase Peptide Modification via Deaminative Photochemical Csp³‐Csp³Bond Formation Using Katritzky Salts

Abstract

Introduction of unnatural amino acids can significantly improve the binding affinity and stability of peptides. Commercial availability of such amino acids is limited, and their synthesis is a long and tedious process. We here describe a method that allows the functionalization of peptides directly on solid-support by converting lysine residues to Katritzky salts, and subjecting them to a photochemical Giese reaction under mild reaction conditions. The method avoids the need for amino acid synthesis and instead offers a late-stage modification route for rapid peptide diversification. While numerous modification approaches at the lysine amine have been described, this work provides the first example of deaminative functionalization of peptides at lysine. The two-step protocol is compatible with various substrates, lysine analogues, resins, and all proteinogenic amino acids. Finally, by leveraging solid-phase modification, this protocol facilitates the functionalization of longer peptides as was demonstrated using biologically relevant peptides of up to 15 amino acids.

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

“…Recognizing the advantages of using the innate enantiopurity of a natural (or non-proteinogenic) amino acid to prepare enantiopure noncanonical variants, we have developed deaminative conditions that allow lysine, ornithine, 2,4-diaminobutyric acid (DAB), and 2,3-diaminopropanoic acid (DAP) to be converted to aryl alanines and homologated derivatives with varying chain lengths. , Because reductive cross-electrophile couplings occur under neutral (non-basic) conditions, − this approach would allow conservation of enantiopurity in the coupling of Katritzky pyridinium salts and aryl bromides to access diverse arylated amino acids (Scheme C). We prioritized the use of aryl bromides over aryl iodides because they are a much more available and diverse substrate class.…”

Late‐Stage Functionalisation of Peptides on the Solid Phase by an Iodination‐Substitution Approach

“…and Openy et al. performed the functionalisation of lysine residues by a Katritzky salt formation and subsequent Giese reaction [9] . Surprisingly, less complex chemical transformations like on‐resin nucleophilic substitutions are rare.…”

“…[7] Furthermore, a transitionmetal-free method, the on-resin Petasis reaction, was recently applied for LSF by Ricardo et al [8] and Openy et al performed the functionalisation of lysine residues by a Katritzky salt formation and subsequent Giese reaction. [9] Surprisingly, less complex chemical transformations like on-resin nucleophilic substitutions are rare. Very few examples describe the introduction of halogenated amino acids such as bromo-or chlorohomoalanine [10] that were only used to integrate stable cystathione as disulfide mimetics.…”

Solid-Phase Photochemical Peptide Homologation Cyclization

“…Recently, we reported the first example of solid-phase photochemical modification of peptides, in which we developed conditions for the on-resin intermolecular hydroalkylation of peptide-bound enamides . Shortly thereafter, solid-phase deaminative photochemical Giese additions using Katritzky salts were also demonstrated on peptides …”

“…14 Shortly thereafter, solid-phase deaminative photochemical Giese additions using Katritzky salts were also demonstrated on peptides. 15 The photochemical radical pathway has several advantages over RCM and nickel-catalyzed decarboxylative hydroalkylation, including being able (1) to use Asp and Glu as inexpensive chiral radical precursors, (2) to modify a common intermediate for late-stage transformations, (3) to use lightmediated transformations that are mild and often compatible with aqueous buffers and typically operate within minutes under ambient conditions, (4) to avoid organometallic catalysts by using photoinduced electron transfer activation from EDA complexes, (5) to incorporate multicomponent reactions via dual photocatalytic cycles, ideal for the synthesis of diverse peptide macrocycles, 16 and (6) to provide flexibility for the use of both RCM and radical chemistry in parallel to synthesize peptides with multiple cyclizations.…”