Repetitive Thiazolidine Deprotection Using a Thioester‐Compatible Aldehyde Scavenger for One‐Pot Multiple Peptide Ligation**

Abstract

Strategies for one-pot peptide ligation enable chemists to access synthetic proteins at a high yield in a short time. Herein, we report a novel one-pot multisegments ligation strategy using N-terminal thiazolidine (Thz) peptide and a newly designed formaldehyde scavenger. Among the designed 2-aminobenzamidebased aldehyde scavengers, 2-amino-5-methoxy-N',N'dimethylbenzohydrazide (AMDBH) can remarkably convert Thz into unprotected cysteine at pH 4.0. Furthermore, AMDBH degrades Thz at a considerably low rate at pH 7.5, and thioester degradation caused by this scavenger is negligible. As a result, we have developed an efficient one-pot peptide ligation strategy by simply repetitively changing the pH with AMDBH. Finally, we synthesize mono-ubiquitinated histone H2A.Z (209 amino acids) via AMDBH-mediated one-pot four-segment peptide ligation in good yield.

Bioinspired Synthesis of Allysine for Late‐Stage Functionalization of Peptides

“…We next modified allysine peptide 2 f by carrying out reductive amination with propargyl amine [13] and observed the formation of alkyne ligated‐peptide product 4 f (67 %) (Figure 4b, Figure S7). The functionalization of allysine peptides 2 f and 2 d with cysteine methyl ester in 2 % acetic acid in water generated thiazolidine‐modified peptides 4 g and 4 h in full conversion (~94 %) (Figure 4c, Figure S7) [12b] …”

Catalyst-free thiazolidine formation chemistry enables the facile construction of peptide/protein–cell conjugates (PCCs) at physiological pH

“…This reaction is highly specic to 1,2-aminothiol even in the presence of other internal competing sulydryl groups on the biomolecule. Over the years, this chemistry has been utilized to immobilize protein for biosensor analysis, 23 prepare ubiquitin dimer and antibody-drug conjugates, 24,25 as a very common N-terminal Cys protecting group for peptide/ protein chemical synthesis, 26 and on-demand control the function of caged protein probes for proling deubiquitinases. 27 Despite these intriguing studies, this chemistry remains an underutilized bioconjugation tool.…”

l-Methionine Selenoxide as an Oxidizing and Deprotection Reagent for the Synthesis of Multiple Disulfide Bonds in Peptides

“…Cysteine (Cys) side chains protected by acetamidomethyl (Acm), 1,3-thiazolidine (Thz), and t -butyl ( t Bu) were often used for chemical syntheses of proteins − and of peptide multiple disulfide bonds through stepwise deprotections followed by oxidations . Recently, one-pot regioselectively synthetic approaches of multiple disulfide bonds in peptides were developed by the Brik group by use of these protected Cys, being more efficient in the synthesis of such kind of peptides. ,,, Deprotection of the Cys protecting groups can be achieved using a variety of reagents such as Hg­(II), Ag­(I), Tl­(III), Pd­(II), Pt­(IV), Cu­(II), I 2 , 2,2 ′ -dithiobis­(5-nitropyridine) (DTNP), triisopropylsilane (TIS), triethylsilane (TES), 2,2-dipyridyl disulfide (DPDS), and 2,2′-dipyridyl diselenide, affording cysteine or cystine peptides.…”