Aldehyde Capture Ligation for Synthesis of Native Peptide Bonds

Abstract

Chemoselective reactions for amide bond formation have transformed the ability to access synthetic proteins and other bioconjugates through ligation of fragments. In these ligations, amide bond formation is accelerated by transient enforcement of an intramolecular reaction between the carboxyl and the amine termini of two fragments. Building on this principle, we introduce an aldehyde capture ligation that parlays the high chemoselective reactivity of aldehydes and amines to enforce amide bond formation between amino acid residues and peptides that are difficult to ligate by existing technologies.

Chemoselective and site-selective peptide and native protein modification enabled by aldehyde auto-oxidation

“…Even though a complex combination of multiple parameters is involved, operationally simple front-end protocol would also excite the non-experts. The transformation is efficient in the modification of peptides and structurally diverse proteins with a wide range of Lys residues (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Interception of formylation of protein by a distinct electrophile confirms extended application of this chemical platform.…”

“…The preferential reaction of N α -NH 2 with aldehydes has established the later as a privileged electrophile. The examples include reductive amination, 8 Wittig olefination, 9 Pictet-Spengler ligation, 10 aldehyde capture ligation, 11 imidazolidinone formation, 5a and transamination. 12 On the other hand, it also highlights the extreme challenge involved in the site-selective N ε -NH 2 modification in preference over N α -NH 2 .…”

Rhodium‐Catalyzed Synthesis of Heteroarylselenyl Esters from Diheteroaryl Diselenides and Acid Fluorides

“…Organoselenyl esters have attracted attention owing to their high reactivity as acylating reagents compared with thioesters and esters, and have been employed in the synthesis of peptides . Accordingly, diverse organoselenyl esters with different acyl moieties have been synthesized . For use as organoselenating reagents, variety at the organoselenyl groups is critical, which, however, has been limited to substituted phenyls and simple alkyls.…”

“…The treatment of diselenides with strong reducing agents, however, was reported to induce deselenation in some cases . Several modified methods have also been reported, which include selenoacid alkylation, selenol acylation, alkyne addition, and aldehyde oxidation reactions . Phenylselenation of acid chlorides with rhodium‐catalyzed reduction of diphenyldiselenide using hydrogen was also reported .…”

Rongalite®/PEG-400 as reducing system in the synthesis of new glycerol-derived selenol esters using anhydrides and bis-(2,2-dimethyl-1,3-dioxolanylmethyl)diselenide as substrates

“…They have been used as precursors of acyl radicals and anions, [1][2][3][4] intermediates in the synthesis of ketones, 5,6 as building blocks of heterocyclic compounds, 7 in Diels-Alder, 8,9 cyclocondensation 10 and various cyclization reactions. [11][12][13][14] They were also used as a precursors in the synthesis of vinyl compounds, 15 in the formation of C-peptide bonds, [16][17][18] and the synthesis of some natural occurring compounds, [19][20][21][22][23] besides having proven antioxidant properties. 24 Various methods have been described for the synthesis of selenol esters, for example, by the condensation of selenolate anions 25 or radicals 26 with carbonyl compounds, such as aldehydes, 27,28 anhydrides 26,29-34 acyl chlorides [29][30][31][32][33][34] or starting from chalcogen acetylenes 35 and aryl iodides.…”