From protein total synthesis to peptide transamidation and metathesis: playing with the reversibility of N,S-acyl or N,Se-acyl migration reactions

Exploring chemoselective S-to-N acyl transfer reactions in synthesis and chemical biology

“…Not only do these biological processes highlight the synthetic potential of the S -to- N acyl transfer, they also serve as inspiration for synthetic molecular processes utilizing S -to- N acyl transfer as a key step. A key requirement for efficient S -to- N acyl transfer is access to a suitable thioester and a number of elegant methods for their synthesis via synthetic and biological approaches have been reported, including pushing the S -to- N acyl transfer process into reverse ( Box 1 ) 13 41 42 43 . A common synthetic method employed for the preparation of thioesters involves coupling of the C-terminus of a protected peptide/glycopeptide with benzylthiol using PyBOP/DIPEA as coupling reagents (to avoid racemization) 44 .…”

“…The equilibrium of the S -to- N / N -to- S acyl transfer is thermodynamically favoured towards the amide product and is the principle driving force for amide bond formation 131 . However, the S -to- N acyl transfer can be pushed into reverse and this process offers a useful methodology for accessing thioesters without relying on the traditional synthetic approaches 41 . In the protein splicing mechanism of inteins, an N -to- S acyl shift occurs in the first step, and involves transfer of the C -terminal amino acid residue of the target protein onto the N -terminal side chain -SH of the cysteine residue of the intein 19 .…”

Accelerating chemoselective peptide bond formation using bis(2-selenylethyl)amido peptide selenoester surrogates

“…This property is also shared by the peptide bond to cysteine 31. In contrast, the capacity of some N -(2-sulfanylethyl)amides32–35 such as the bis(2-sulfanylethyl)amido (SEA) group32,36 to rearrange into thioesters in water at neutral32 or mildly acidic37–39 pH is a recent observation (Scheme 1). The reaction of a SEA peptide with an N-terminal cysteinyl peptide yields a native peptide bond to cysteine and proceeds efficiently in the presence of 4-mercaptophenylacetic acid (MPAA40).…”

“…We reasoned that the latter might participate to a selenol–thioester exchange reaction with an excess of the bis(2-selenylethyl)amine 3 to produce, after an Se , N -acyl shift, the target SeEA peptide 5 . Overall, the exchange process shown in Scheme 2 corresponds to a chemoselective transamidation reaction36 which is applied to unprotected SEA peptide segments.…”

A Cysteine Selenosulfide Redox Switch for Protein Chemical Synthesis

“…In contrast, the loss of the N-alkyl substituent was not observed when the sulfur analog of SetCys, featuring a 2-mercaptoethyl group on the -nitrogen, was treated similarly, even after extended reaction times (Figure 2b). 23,24 The reactivity observed for SetCys depends specifically on the presence of selenium in its structure and, in that respect, SetCys is a novel illustration of the high difference in reactivity than can exist between thiol and selenol compounds. 25…”