Rational Design of an Organocatalyst for Peptide Bond Formation

Abstract

Amide bonds are ubiquitous in peptides, proteins, pharmaceuticals, and polymers. The formation of amide bonds is a straightforward process: amide bonds can be synthesized with relative ease because of the availability of efficient coupling agents. However, there is a substantive need for methods that do not require excess reagents. A catalyst that condenses amino acids could have an important impact by reducing the significant waste generated during peptide synthesis. We describe the rational design of a biomimetic catalyst that can efficiently couple amino acids featuring standard protecting groups. The catalyst design combines lessons learned from enzymes, peptide biosynthesis, and organocatalysts. Under optimized conditions, 5 mol % catalyst efficiently couples Fmoc amino acids without notable racemization. Importantly, we demonstrate that the catalyst is functional for the synthesis of oligopeptides on solid phase. This result is significant because it illustrates the potential of the catalyst to function on a substrate with a multitude of amide bonds, which may be expected to inhibit a hydrogen-bonding catalyst.

Recent developments in catalytic amide bond formation

“…[107] This method has advantages that might be more immediately applicable to peptide chemistry, including low catalyst loadings By contrast, catalytic diselenide activation with the specific aim of achieving a practical catalytic Fmoc peptide synthesis strategy was recently reported by Arora and coworkers. [108] They rationally designed an organocatalyst (Figure 12 Figure 13, 46). [109] The corresponding carbocation is the active catalytic species and can generated in-situ from catalytic amounts of tropone and a slight excess of (COCl) 2 .…”

Urea Derivatives as Functional Molecules: Supramolecular Capsules, Supramolecular Polymers, Supramolecular Gels, Artificial Hosts, and Catalysts

“…Arora et al developed the catalyst structure further,a nd realized direct condensation reactions between carboxylic acids and amines (Scheme 4). [158] The diselenidem oiety is ac haracteristics tructure of catalyst 37,a nd reduction and oxidation of the diselenide moiety is the key to the catalytic re- action. The diselenide is reduced by tributylphosphine and the carboxyg roup is converted to as elenoester.A na mide bond is formed by nucleophilic attack of the amine on the selenoester, then the catalyst is regenerated by oxidation of the bis-selenolate.…”

“… Urea derivative 37 ‐catalyzed peptide bond formation. Reproduced with permission from reference [158], copyright 2019, American Chemical Society.…”

Flow‐based SPPS for protein synthesis: A perspective

“…Can these methods be used in AFPS and can we develop even more reactive active esters? Can catalytical methods for amide bond formation [ 130–134,135 ] be translated into flow chemistry? And can these methods be used for the synthesis of long peptides or even proteins?…”