Chemical Methods for N‐ and O‐Sulfation of Small Molecules, Amino Acids and Peptides

Abstract

Sulfation of the amino acid residues of proteins is a significant post‐translational modification, the functions of which are yet to be fully understood. Current sulfation methods are limited mainly to O‐tyrosine (sY), which requires negatively charged species around the desired amino acid residue and a specific sulfotransferase enzyme. Alternatively, for solid‐phase peptide synthesis, a de novo protected sY is required. Therefore, synthetic routes that go beyond O‐sulfation are required. We have developed a novel route to N‐sulfamation and can dial‐in/out O‐sulfation (without S‐sulfurothiolation), mimicking the initiation step of the ping‐pong sulfation mechanism identified in structural biology. This rapid, low‐temperature and non‐racemising method is applicable to a range of amines, amides, amino acids, and peptide sequences.

The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studies

“…2b and Scheme 1). The persulfation of all tetraol intermediates was carried out using the TBSAB-sulfation methodology [19][20][21] (Scheme 1), specifically, the use of this reagent afforded the heparan sulfate-glycomimetics α-4 (C1) and β-5 (C2) in 88% and 86% yield, respectively.…”

Chemical Modification of Glycosaminoglycan Polysaccharides

“…Sulphoethylation in 2-propanol solvated sodium vinylsulphonate, sodium chloroethanesulphonate monohydrate, or sodium bromoethanesulphonate monohydrate, generated variable yields, with sodium vinylsulphonate proving the most effective [ 74 , 75 ]. An interesting recent development is the application of tributylsulfoammonium betaine (TBSAB) to achieve N - and O -sulfations of smaller molecules, amino acids, and peptides [ 76 , 77 ]. It will be interesting to discover whether these can be applied to GAGs.…”

A novel exchange method to access sulfated molecules

“…Our own interest in developing sulfated molecules resulted from a medicinal chemistry challenge to reliably synthesise sulfated glycomimetics 15 – 18 . We recently reported the development of an all-in-one sulfating reagent, Bu 3 NSO 3 (TBSAB) 19 , 20 .…”

“…Recent work by Montero Bastidas et al 21 , and Mihai et al 22 have shown the importance of routes to sulfated molecules with a sterically bulky tetrabutylammonium cation for iridium catalysed para -selective C–H borylations. An alternate approach is to design an all-in-one reagent with a sulfating agent combined with a lipophilic counterion, such as our own work 19 , 20 and the work of Kowalska et al 23 .…”

“…The sp 3 hybridised Lewis base of Me 3 N donates electrons more strongly into the LUMO of SO 3 forming a hard-hard Lewis adduct with increased stability and decreased reactivity compared to sp 2 hybridised Lewis base seen in Py-SO 3 24 . Next, using the knowledge obtained from the sulfate ester optimisation and our prior work on sulfamates 20 , initial conditions of switching to Me 3 NSO 3 resulted in quantitative conversion of the benzyl sulfamate (Scheme 1). Slightly lowering the reaction temperature due to the increased nucleophilicity of the sp 3 nitrogen atom, resulted in a quantitative conversion for both the formation of the sulfamate trimethylammonium species and the cation exchanged sulfamate tributylammonium species.…”