Abstract
From life science to material science, to pharmaceutical industry, and to food chemistry, polysulfides are vital structural scaffolds. However, there are limited synthetic methods for unsymmetrical polysulfides. Conventional strategies entail two pre-sulfurated cross-coupling substrates, R–S, with higher chances of side reactions due to the characteristic of sulfur. Herein, a library of broad-spectrum polysulfurating reagents, R–S–S–OMe, are designed and scalably synthesized, to which the R–S–S source can be directly introduced for late-stage modifications of biomolecules, natural products, and pharmaceuticals. Based on the hard and soft acids and bases principle, selective activation of sulfur-oxygen bond has been accomplished via utilizing proton and boride for efficient unsymmetrical polysulfuration. These polysulfurating reagents are highlighted with their outstanding multifunctional gram-scale transformations with various nucleophiles under mild conditions. A diversity of polysulfurated biomolecules, such as SS−(+)-δ-tocopherol, SS-sulfanilamide, SS-saccharides, SS-amino acids, and SSS-oligopeptides have been established for drug discovery and development.
Highlights
From life science to material science, to pharmaceutical industry, and to food chemistry, polysulfides are vital structural scaffolds
Potent bioactive natural products and pharmaceuticals possessing sulfur–sulfur bonds have been discovered, such as the antifungal polycarpamine family[7], the anti-poliovirus epidithiodiketopiperazine (ETPs) family[8, 9], romidepsin[10], gliotoxin[11], and some new histone deacetylase/ methyltransferase inhibitors[12], which, mechanism-wise, either sequester enzyme-cofactor zinc or generate highly reactive electrophiles to induce DNA strand scission. When it comes to antibody-drug conjugates (ADC), the disulfide bond has been extensively utilized as a linker to deliver the active drug into the targeted cell after cleavage upon internalization of ADC19–22
To cite the allium-derived diallyl trisulfide (DATS) as an example, it serves as a gasotransmitter precursor and an excellent hydrogen sulfide donor, mediating and regulating the release of hydrogen sulfide upon physiological activation (Fig. 1b)[23, 24]
Summary
From life science to material science, to pharmaceutical industry, and to food chemistry, polysulfides are vital structural scaffolds. Potent bioactive natural products and pharmaceuticals possessing sulfur–sulfur bonds have been discovered, such as the antifungal polycarpamine family[7], the anti-poliovirus epidithiodiketopiperazine (ETPs) family[8, 9], romidepsin[10], gliotoxin[11], and some new histone deacetylase/ methyltransferase inhibitors[12], which, mechanism-wise, either sequester enzyme-cofactor zinc or generate highly reactive electrophiles to induce DNA strand scission When it comes to antibody-drug conjugates (ADC), the disulfide bond has been extensively utilized as a linker to deliver the active drug into the targeted cell after cleavage upon internalization of ADC19–22. Two sulfur atoms were successfully introduced in one step via oxidative cross-couplings of acetyl masked disulfurating nucleophiles and organometallic reagents (Fig. 2b)[52]
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