Ligation-desulfurization

In 2001, Yan and Dawson reported an elegant approach for the discrmnection of peptide and protein targets at alanine (Ala) residues [54], The concept combined a typical native chemical Ugation reaction between a peptide bearing an N-terminal 

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Since its inception, the concept of ligation-desulfurization chemistiy [76,77] at Cys residues has been widely adopted for the synthesis of an enormous variety of peptides and proteins, including targets bearing complex PTMs [20, 21, 28, 78]. The following discussion outlines a number of recent, illustrative examples of the technique for the ligation-based assembly of protein targets. 

Scheme 18 Construction of homogeneous antifreeze glycoproteins (AFGPs) using ligation-desulfurization chemistry...

Scheme 22 Ligation-desulfurization chemistry at p- (n = 0) or y-thiol ( = 1) amino acids...

Ligation-Desulfurization at Thiol-Derived Amino Acids... 

Scheme 26 Synthesis of a 304-amino acid tetraubiquitin protein using ligation-desulfurization at 6-thiol Lys...

Scheme 28 Total synthesis of the HIV-1 Tat protein using ligation-desulfurization at p-thiol Leu...

Scheme 29 Synthesis of a MUCl glycopeptide oligomer using a kinetically-controlled ligation-desulfurization strategy at p-thiol Arg...

Scheme 30 One-pot total synthesis of madanin-1123 using kinetically-controlled ligation-desulfurization chemistry with trifluoroethanethiol (TFET) 124...

Using a similar synthetic approach to the one employed for the synthesis of p-thiol Asp building block 97, Cergol et al. reported the preparation of y-thiol Glu derivatives 99 and 100 (Scheme 23) and their application in ligation-desulfurization chemistry [128]. Initial attempts to incorporate building block 99 into model... 

Rohde H, Seitz O (2010) Ligation-desulfurization a powerful combinatirai in the synthesis of peptides and glycopeptides. Biopolymers 94 551-559... 

Malins LR, Cergol KM, Payne RJ (2013) Peptide ligation-desulfurization chemistry at arginine. ChemBioChem 14 559-563... 

Thompson RE, Chan B, Radom L, Jolliffe KA, Payne RJ (2013) Chemoselective peptide ligation-desulfurization at aspartate. Angew Chem Int Ed 52 9723-9727... 

Thompson RE, Liu X, Alonso-Garcia N, Pereira PJB, Jolliffe KA, Payne RJ (2014) Trilluor-oethanethiol an additive for efficient one-pot peptide ligation — desulfurization chemistry. J Am Chem Soc 136 8161-8164... 

Cergol KM, Thompson RE, Malins LR, Turner P, Payne RJ (2014) One-pot peptide ligation-desulfurization at glutamate. Org Lett 16 290-293... 

The direct attachment of a thiol to a side-chain requires a post-ligation desulfurization step for its removal. This approach was first reported by Yan and Dawson, who extended hydrogenolytic desulfurization of cysteine to the chemical synthesis of proteins by NCL, utilizing Ala as a new ligation junction (Scheme 7) [134]. In the same study, they also noted that not only Raney nickel but also palladium could be used as the catalyst. In addition, the application was expanded to other residues such as Leu, Val, and Be. A subsequent refinement of this method... 

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