Katritzky Salts for the Synthesis of Unnatural Amino Acids and Late‐Stage Functionalization of Peptides

Abstract

Peptide drug discovery often benefits from the large structural diversity permitted by unnatural amino acids (UAAs). Indeed, numerous approved peptide drugs include UAAs in their sequences. Therefore, innovative chemical approaches either to synthesize UAAs or to allow late‐stage functionalization of peptides are emerging themes in peptide drug discovery. Thanks to the recent advances in deaminative strategies using alkylpyridiniums salts, often referred to as Katritzky salts, a variety of radical alkylation methods have been developed. In recent years the use of Katritzky salts have become popular in peptide chemistry due to their ease of preparation from a primary amine, which is a predominant functional group in amino acids. This review highlights the progress that has been made by using Katritzky salts in the synthesis of UAAs, late‐stage peptide functionalization, and peptide macrocyclization.

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

“…42,43 Recently, alkyl Katritzky salts have emerged as stable and versatile radical precursors, providing an alternative way to access diverse and customizable side chain functionality in peptides. 44 Conversion of lysine, and related AAs with primary amine-containing side chains, into the corresponding pyridinium salts involves straightforward, high-yielding, and robust chemistry. In addition, the resulting Fmoc-protected building blocks are often resistant to S N 2 and epimerization reactions and can be seamlessly incorporated into peptides through standard SPPS and trifluoroacetic acid (TFA) deprotection workflows.…”

“…Recently, alkyl Katritzky salts have emerged as stable and versatile radical precursors, providing an alternative way to access diverse and customizable side chain functionality in peptides . Conversion of lysine, and related AAs with primary amine-containing side chains, into the corresponding pyridinium salts involves straightforward, high-yielding, and robust chemistry.…”

Electrochemical Synthesis of Unnatural Amino Acids Embedding 5- and 6-Membered Heteroaromatics

“…The past decade has witnessed spectacular progress in the field of unnatural amino acids (UAAs), molecular entities widely employed in proteomics, protein engineering, and peptidomimetics. − Many methodologies have been devised for the de novo synthesis of UAAs. − An alternative approach is instead based on the lateral chain modification of natural amino acids, a useful strategy to retain the α-stereocenter. This is particularly true for aspartic acid (Asp) and glutamic acid (Glu), whose side-chain carboxylic group offers a strategic handle for derivatizations, especially those based on radical decarboxylations of the corresponding redox-active esters (RAEs). − However, side-chain decarboxylation of these amino acids is usually more challenging than decarboxylation of α-CO 2 H since only the latter provides a stabilized intermediate, which is an α-amino radical (Scheme ).…”

Synthesis of Unnatural Amino Acids via Ni/Ag Electrocatalytic Cross-Coupling

“…Electron-rich (6,8,9) and electron-poor (1, 7) aryl iodides, imidazoles (25), pyridines (18, 23), pyrimidines (2,4,16,24), protected and unprotected azaindoles (5,11,12,20,21,26), unprotected pyridinones (19), chromenones (3,14,15,27), imidazopyridazines (17,22), indazoles (13), and benzothiophenes (10) were successfully coupled with at least one amino acid. Additionally, free alcohols (6,8,9,14,27) and amines (18), alkyl fluorides (7,17,22), thioethers (2,16,24), and esters (2,16,24) were tolerated. More importantly, the applied method shows high chemoselectivity for electron-poor (hetero)aryl iodides; hence, it tolerating more electron-rich bromides and chlorides (1,4,17,22,23).…”