Abstract
Sulfur-sulfur motifs widely occur in vital function and drug design, which yearns for polysulfide construction in an efficient manner. However, it is a great challenge to install desired functional groups on both sides of sulfur-sulfur bonds at liberty. Herein, we designed a mesocyclic bilateral disulfurating reagent for sequential assembly and modular installation of polysulfides. Based on S-O bond dissociation energy imparity (mesocyclic compared to linear imparity is at least 5.34 kcal mol−1 higher), diverse types of functional molecules can be bridged via sulfur-sulfur bonds distinctly. With these stable reagents, excellent reactivities with nucleophiles including C, N and S are comprehensively demonstrated, sequentially installing on both sides of sulfur-sulfur motif with various substituents to afford six species of unsymmetrical polysulfides including di-, tri- and even tetra-sulfides. Life-related molecules, natural products and pharmaceuticals can be successively cross-linked with sulfur-sulfur bond. Remarkably, the cyclization of tri- and tetra-peptides affords 15- and 18-membered cyclic disulfide peptides with this reagent, respectively.
Highlights
Sulfur-sulfur motifs widely occur in vital function and drug design, which yearns for polysulfide construction in an efficient manner
Given the excellent metabolism of sulfur–sulfur bond in organism, cutting-edge drug design strategies of antibody–drug conjugates (ADCs)[7,8,9] and small molecule-drug conjugates (SMDCs)[10,11,12,13] involved disulfur extensively, such as Mylotarg[14] and Vintafolide[15], in which sulfur–sulfur bond serves as a reversible cross-linker
A series of bilateral disulfurating reagents were synthesized (Fig. 3a), whose structures were further confirmed through X-ray analysis of 1f
Summary
Sulfur-sulfur motifs widely occur in vital function and drug design, which yearns for polysulfide construction in an efficient manner. Based on S-O bond dissociation energy imparity (mesocyclic compared to linear imparity is at least 5.34 kcal mol−1 higher), diverse types of functional molecules can be bridged via sulfur-sulfur bonds distinctly. With these stable reagents, excellent reactivities with nucleophiles including C, N and S are comprehensively demonstrated, sequentially installing on both sides of sulfur-sulfur motif with various substituents to afford six species of unsymmetrical polysulfides including di-, tri- and even tetra-sulfides. Based on our concept of mask effect[27], we envision that disulfurating reagents with bilateral masks will cross-link two designated functional molecules with sulfur–sulfur bond sequentially and modularly (Fig. 2a). We show a mesocyclic bilateral disulfurating reagent for sequential assembly and modular installation of unsymmetric polysulfides
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