S-to-N acyl transfer is a high-yielding chemoselective process for amide bond formation. It is widely utilized by chemists for synthetic applications, including peptide and protein synthesis, chemical modification of proteins, protein-protein ligation and the development of probes and molecular machines. Recent advances in our understanding of S-to-N acyl transfer processes in biology and innovations in methodology for thioester formation and desulfurization, together with an extension of the size of cyclic transition states, have expanded the boundaries of this process well beyond peptide ligation. As the field develops, this chemistry will play a central role in our molecular understanding of Biology.
Thiyl‐radical mediated reactions have been extensively investigated for the preparation of carbohydrate derivatives. Due to the mild reaction conditions, high yields and tolerance to a wide range of functional groups, these reactions are ideally suited to the preparation of bioconjugates including glycopeptides and glycoproteins. This microreview covers the various synthetic strategies that have been employed for the preparation of thiosugars, glycoconjugates and glycodendrimers, employing the carbohydrate unit as both the carrier of the thiyl radical and also as the acceptor. Both the inter‐ and intramolecular thiol‐ene and ‐yne processes are presented and discussed. Future perspective and directions for this methodology in glycoscience are also examined.
A novel intramolecular thiol-yne cyclisation strategy has been developed for the synthesis of thioglycals. Both ionic and radical mediated cyclisation pathways have been investigated for D-and L-sugars. The ionic cyclisation provides exclusive access to 5-exo products directly from the thioesters whereas the radical cyclisation provides access to both 5-exo and 6-endo products upon photochemical irradiation of the free thiols. These are the first examples of intramolecular thiol-yne cyclisation reactions applied to thiosugar synthesis.Intramolecular, free-radical mediated cyclisation reactions are of critical importance for the synthesis of a diverse array of heterocycles. While many free-radical cyclisation reactions involve carbon-centred radicals, the investigation of systems where the heteroatom is the reactive radical intermediate represents an area of intensive research focus in organic chemistry. 1 One such system that has received significant attention in recent times is the intramolecular thiol-ene reaction. The synthetic scope of this reaction for the efficient preparation of sulphur containing heterocycles has been extensively reviewed. 2 Sulfur containing heterocycles are becoming increasingly important in the context of pharmaceutical drug design and new methods for their preparation are highly desirable. 3 We have reported that the free-radical mediated, intramolecular thiol-ene reaction can be applied to the efficient synthesis of a range of thiosugars with a high degree of regioselectivity and stereoselectivity. 4 In contrast to the intramolecular thiol-ene process, the related intramolecular thiol-yne reaction has not been investigated for synthetic applications. Indeed, there exists only a single report of this reaction in the literature. Surzur and co-workers investigated the cyclisation of pent-4-yne-1-thiol under photochemical conditions and observed formation of both the 5-exo and the 6-endo cyclisation products, with the six-membered ring being formed preferentially. 5 We set out to investigate the intramolecular thiol-yne reaction on carbohydrate derived substrates as a novel synthetic route to both exo-and endo-thioglycals. Thioglycals are the sulphur analogues of the widely used carbohydrate building blocks, glycals and have been demonstrated to behave as competitive inhibitors of glycosidases. 6 Detailed studies of their therapeutic application have been hampered by a lack of robust synthetic methodologies to prepare these substrates. Thioglycals have previously been prepared starting from commercially available 5-thio-D-glucose 6a but this reagent is prohibitively expensive for use in multistep synthesis and offers only limited access to thioglycals. We reasoned that the intramolecular thiol-yne reaction would offer a general and efficient synthetic route to novel thioglycals and thiosugars as putative glycosidase inhibitors. The related intermolecular thiol-yne process is emerging as a widely employed conjugation reaction with applications in materials science, supramolecular che...
Dehydroalanine (ΔAla) is a highly electrophilic residue that can react efficiently with sulfur nucleophiles to furnish cysteinyl analogues. Herein, we report an efficient synthesis of N-terminal cysteinyl thioesters, suitable for S,Nacyl transfer, based on β,γ-C,S thiol-Michael addition. Both ionic and radical-based methodologies were found to be efficient for this process.
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