Two-Component Redox Organocatalyst for Peptide Bond Formation

Abstract

Peptides are fundamental therapeutic modalities whose sequence-specific synthesis can be automated. Yet, modern peptide synthesis remains atom uneconomical and requires an excess of coupling agents and protected amino acids for efficient amide bond formation. We recently described the rational design of an organocatalyst that can operate on Fmoc amino acidsthe standard monomers in automated peptide synthesis (J. Am. Chem. Soc. 2019, 141, 15977). The catalytic cycle centered on the conversion of the carboxylic acid to selenoester, which was activated by a hydrogen bonding scaffold for amine coupling. The selenoester was generated in situ from a diselenide catalyst and stoichiometric amounts of phosphine. Although the prior system catalyzed oligopeptide synthesis on solid phase, it had two significant requirements that limited its utility as an alternative to coupling agentsit depended on stoichiometric amounts of phosphine and required molecular sieves as dehydrating agent. Here, we address these limitations with an optimized method that requires only catalytic amounts of phosphine and no dehydrating agent. The new method utilizes a two-component organoreductant/organooxidantrecycling strategy to catalyze amide bond formation.

Cellulase Immobilization on Nanostructured Supports for Biomass Waste Processing

“…Despite the length of glutaraldehyde is only 0.75 nm [ 66 ], it apparently provides a sufficient distance to prevent non-specific adsorption of the enzyme. Longer linkers, such as tetradecanedioic and docosanedioic dicarboxylic acids with approximate extended chain lengths of 1.4 and 2.2 nm, respectively, were also explored [ 67 ], however, the interaction of carboxyl group terminal linkers with amino functionalized supports (formation of a peptide bond) is less than favorable, requiring elevated temperatures or/and a catalyst [ 68 , 69 ].…”

Recent Advances in Carbon‐Nitrogen/Carbon‐Oxygen Bond Formation Under Transition‐Metal‐Free Conditions

“…[39b] In 2021, our group reported the synthesis of secondary and tertiary amines between heteroaryl halides (54) and amines under metal-, external-base-and solvent-free conditions (Scheme 11a). [39c] Using this protocol, various heteroaromatic amines and their HCl forms (55) were obtained in up to 97 % yields. Mechanistic studies via precision prediction of pK aH (amines) and selectivity experiments revealed that the acidity of both amine substrates and products played a crucial role in promoting this amination process, while the excess amounts of the amine substrates were beneficial for this transformation.…”

“…In 2022, Arora and co-workers reported a two-component organocatalyst for peptide bond formation (Scheme 17a). [55] A combination of a seleno-containing urea catalyst (64) and 34 * [O] was used as the catalytic system, while molecular oxygen (O 2 ) was utilized as a terminal oxidant and PhSiH 3 as a terminal reductant (Scheme 17b). With regard to the proposed catalytic cycle, the carboxylic acid ( 91) was firstly converted into the corresponding selenoester (Int-11) in situ from a diselenide catalyst (Catalyst-Se) 2 (64), which was then attacked by the amine substrate (92).…”

Design and Evaluation of Ambiphilic Aryl Thiol–Iminium-Based Molecules for Organocatalyzed Thioacyl Aminolysis

“…To streamline protein retrosynthesis and develop tools to improve CPS user access, we hypothesized that a rationally designed ambiphilic organocatalyst combining nucleophilic (e.g., thiol) ,, and electrophilic (e.g., aldehyde, iminium) − ,− functionalities could catalyze an aqueous thioester aminolysis reaction between solid-phase peptide synthesis accessible peptide partners (Figure a) . Inspired by the mechanisms of NCL and auxiliary-based ligation reactions, ,, we envisioned an organocatalytic process to achieve Cys-independent thioacyl aminolysis between any C -terminal thioester peptide-1 and N -terminal peptide-2.…”