Peptide synthesis: ball-milling, in solution, or on solid support, what is the best strategy?

Abstract

While presenting particularly interesting advantages, peptide synthesis by ball-milling was never compared to the two traditional strategies, namely peptide syntheses in solution and on solid support (solid-phase peptide synthesis, SPPS). In this study, the challenging VVIA tetrapeptide was synthesized by ball-milling, in solution, and on solid support. The three strategies were then compared in terms of yield, purity, reaction time and environmental impact. The results obtained enabled to draw some strengths and weaknesses of each strategy, and to foresee what will have to be implemented to build more efficient and sustainable peptide syntheses in the near future.2087

Mechanoenzymatic Transformations in the Absence of Bulk Water: A More Natural Way of Using Enzymes

“…Much more akin to low η conditions of liquid‐assisted mechanochemistry, enzymes secreted by microorganisms thrive on moist surfaces, and intracellular enzymes function in highly concentrated, organized environments. This observation is consistent with the ongoing change in our understanding of chemical transformations, with the growing realization that many reactions readily proceed in solvent‐less mechanochemical environments . Indeed, mechanochemistry, which was recently proposed to be involved in the emergence of small organic molecules on the early Earth, has successfully provided routes to chemical selectivity, as well as reactions or molecules that have otherwise been considered difficult or even impractical to access.…”

“…[108] Mechanochemical reactions, which proceed either in the absence or with very small quantities of al iquid additive, present an ovel approacht oc ontrol the reactivity of proteases.M echanochemicaln onenzymatic solid-state approaches ford ipeptide and oligopeptide synthesis [109][110][111][112][113] have been shown to surpasss olution synthesis and even SPPS in terms of shorterr eaction times, improved product purity and reduced environmental impact. [114,115]…”

From Synthesis of Amino Acids and Peptides to Enzymatic Catalysis: A Bottom‐Up Approach in Mechanochemistry

“…[42] Addressing the preparation of 39 a by ball-milling and solution-based peptide methods revealed the superiority of the mechanochemicala pproachi nt erms of reactiont ime, yield, and purity of the product (Scheme 10). Very recently,t he previously described mechanochemical Oxyma/EDC peptide coupling (Scheme 5, bottom) was appliedi nt he synthesis of the tetrapeptide 39 a (Boc-NH-Val-Val-Ile-Ala-OBn;S cheme 10).…”

Mechanochemie gasförmiger Reaktanten

“…Automatisiertes Kugelmahlen ist unter den verschiedenen Arten der Anwendung von mechanischer Energie zu einer Standardtechnik geworden, um mechanochemische Reaktionen in verschieden Gebieten, wie der organischen [6] und der anorganischen Chemie, [7] der Metallorganik, [8] der Biokatalyse oder Polymerchemie, [9,10] um nur einige zu nennen, durchzuführen. [11] Abgesehen davon, dass sie als nachhaltigere Alternative zur Einleitung chemischer Umwandlungen anerkannt wurde, [12] hat Mechanochemie durch Kugelmahlen die Synthese von Substanzen ermçglicht, die schwer oder gar nicht durch klassische Synthese zugänglich sind. [11] Abgesehen davon, dass sie als nachhaltigere Alternative zur Einleitung chemischer Umwandlungen anerkannt wurde, [12] hat Mechanochemie durch Kugelmahlen die Synthese von Substanzen ermçglicht, die schwer oder gar nicht durch klassische Synthese zugänglich sind.…”