Design,Synthesis And Application Of Bilateral Disulfurating Reagents

Sulfur-sulfur motif widely exists in biological transformation,pharmaceutical structure,natural product,material and food fields,which yearns for polysulfide construction in an efficient and convenient manner.In recent years,several reports about direct polysulfide synthesis via disulfurating reagents have been demonstrated.However,the reported disulfurating reagents were unilateral reagents,which means the reagents need multi-step preparation and transformation to install disulfur motif to the substrate.Thus,the substrates which have difficulty in disulfur introduction can't be applied in these reactions.Besides,for the application of unilateral disulfurating reagents,the adjustment of substrate limited to another cross-coupling component,which reduced the flexibility and efficiency of disulfuration.We envisioned that the design of bilateral disulfurating reagents could achieve the construction of polysulfides.Therefore,the bilateral disulfurating reagents would sequentially and modularly install functional molecules on both sides of disulfur motif,achieving modular cross-linkage,synthesizing diverse polysulfides.During my doctorate research,I mostly focused on design and synthesis of bilateral disulfurating regents and applying them to constructing unsymmetrical polysulfide.Part one: Design and synthesis of bilateral disulfurating reagentsThrough the modification of S2Cl2,we designed and synthesized a series of linear disulfurating reagents.Based on the calculation of molecular mechanics method(MM2),we designed and synthesized a series of cyclic alkoxyl disulfurating reagents.With these reagents,the reactivity of one side of disulfur motif could be differentiated from another side under the release of ring strain energy,which made it possible for constructing unsymmetrical polysulfides with disulfurating reagents.Then,with the calculation of DFT(B3LYP),6-membered amide and thiamine disulfurating reagents were successfully achieved.The construction of bilateral disulfurating reagent libraries established foundation for the synthesis of novel polysulfides and the development of novel polysulfuration reaction.Part two: Application of bilateral disulfurating reagentsUsing bilateral disulfurating reagents as disulfur source,modular installation and sequential assembly could be achieved to construct eight different kinds of polysulfides including SSSS,SSSN,SSSC,NSSS,NSSN,CSSN,CSSS,CSSC.Among them,there are disulfides,trisulfides,and tetrasulfides,even cyclic peptide with disulfur bridge.Significant life-related molecules,such as sulfonamides,cinacalcet,amino acids,peptides,glucosinolate,vitamin E,estrone could be linked with disulfur motif to achieve the linkage between drug and drug,drug and peptide,amino acid and amino acid,drug and other life-related molecules,which established foundation for drug conjuates and later-stage drug modification.Part three: New advance of bilateral disulfurating reagentsBased on the tautomerization between sulfinic group and sulfone group,symmetrical linear disulfurating reagents could be transformed to the linear disulfurating reagents with alkoxyl group on one side and sulfone group on the other side.We envision that with diverse catalysts,leaving groups on both sides of disulfur could be controllably reacted and substituted.Through two steps of sequential but relatively independent reaction,diverse polysulfides could be synthesized.We hope the strategy could help the direct polysulfuration of inactive drug and natural products,achieving polysulfide derivatives.