Direct synthesis of N-terminal thiazolidine-containing peptide thioesters from peptide hydrazides

Abstract

We report a simple and promising synthetic method to oxidize peptide hydrazides containing N-terminal thiazolidine as a protected cysteine. This yields the corresponding thioester via a peptide azide without decomposition of the thiazolidine ring. The newly developed protocol was validated by the synthesis of the bioactive peptide LacZα.

A Modular Ligation Strategy for Asymmetric Bivalent Nucleosomes Trimethylated at K36 and K27

“…By performing the oxidation step with equimolar amounts of NaNO 2 , followed by the addition of the thiol additive methyl thioglycolate (MTG), peptide 1 was cleanly converted into thioester 1 SR . It is worth noting, an alternative approach employing the addition of TFA to the conversion mixture was recently described …”

Optimizing the Semisynthesis towards glycosylated interferon-β-polypeptide by utilizing bacterial protein expression and chemical modification

“…To circumvent this problem, Mase and co-workers developed a protocol with the NaNO 2mediated activation step in a TFA-based cocktail. 35 Using this strategy, the azide formation and subsequent transthioesterification were successfully performed to yield Thz-segment B-thioester 14. Finally, in order to ligate segment B with segment C through the thioester method, ε-amine lysine on Thz-segment B-thioester was protected with tert-butyl N-succinimidyl carbonate (Boc-OSu) to yield Thz-segment B-thioester 15 in 73% yield (isolated yield, 7.3 mg).…”

“…The triphenylmethyl (Trt) group, the phenacyl (Pac) group and thiazolidine (Thz) are candidates for Cys thiol protecting groups for peptides prepared in E. coli; however, the Trt and Thz protecting groups are labile to the acidic reaction conditions during the conversion of a peptide-hydrazide to a thioester. 35 Therefore peptide-hydrazinolysis and subsequent acidic thioesterification with NaNO 2 could generate a side product due to the reaction of the resultant thioester and free Cys-thiol caused by acidic deprotection. 35 To retain the repertoires of thiol protecting groups on chemical protein synthesis, we studied peptidehydrazinolysis and thioesterification in the presence of Thz at the N-terminus.…”

“…35 Therefore peptide-hydrazinolysis and subsequent acidic thioesterification with NaNO 2 could generate a side product due to the reaction of the resultant thioester and free Cys-thiol caused by acidic deprotection. 35 To retain the repertoires of thiol protecting groups on chemical protein synthesis, we studied peptidehydrazinolysis and thioesterification in the presence of Thz at the N-terminus.…”

Fmoc-Compatible and External-Thiol-Free Peptide C-Terminus Alkyl Thioester Formation Using Cysteinylprolyl Imide

“…In chemical protein synthesis, [1][2][3][4][5][6][7] native chemical ligation (NCL) is a promising strategy to ligate two unprotected peptide fragments between an N-terminal cysteine peptide and a C-terminal peptide thioester. 8 To prepare peptide thioesters through Fmoc SPPS, 9 most previous procedures utilized an excess amount of external thiol against the various thioester surrogates [10][11][12][13][14][15][16][17][18][19][20][21] , to accelerate the thioesterification and suppress competing hydrolysis. However, this procedure is sometime problematic because the particular amino-acid (aa) next to the thioester such as Thr, Val, Ile, or Pro, partially block the nucleophilic attack of external thiols due to its bulky side chain or stereoelectronic effects.…”