CN-122011005-A - Use of tris (trimethylsilyl) silane in disulfide hydrosilation reactions

Abstract

The invention discloses application of tri (trimethylsilyl) silane in disulfide hydrosilation reaction. The present invention has found that TTMSS can achieve rapid hydrosilation of disulfides under mild conditions. Due to the remarkable kinetic stabilization effect brought by the tri (trimethylsilyl) silicon-based substituent, the obtained S-Si (TMS) 3-type silicon-based thioether is obviously superior to the reported traditional silicon-sulfur compound in the aspect of hydrolytic stability. Meanwhile, the silicon-based protecting group can realize efficient and controllable removal under the action of fluoride ions. The method has the advantages of stable yield, wide application range and the like, and can be applied to synthesis and modification of cysteine-containing polypeptide and the later conversion of disulfide-bond-containing functional molecules. Has been successfully applied to cysteine polypeptide synthesis, polypeptide disulfide bond modification, and the later-stage regioselective thiol protection, fluorescent labeling and disulfide bond reconstruction of the drug molecule lipoic acid.

Inventors

• ZHU TINGSHUN
• ZHANG YING
• Lin Kejuan
• ZANG ZHENMING

Assignees

• 中山大学

Dates

Publication Date

20260512

Application Date

20260130

Claims (4)

1. 1. The application of tri (trimethylsilyl) silane in disulfide hydrosilation reaction, wherein the structure of the tri (trimethylsilyl) silane is shown as a formula I; 。
2. 2. The use according to claim I, in the hydrosilation of chain aromatic disulphide compounds, in the hydrosilation of chain aliphatic disulphide compounds, in the hydrosilation of symmetrical cyclic disulphide compounds, in the hydrosilation of asymmetrical cyclic disulphide compounds, as cysteine thiol protecting groups for polypeptide synthesis, in the selective hydrosilation ring opening of disulphide-containing cyclic polypeptides, in the reconstitution of disulphide bonds, in the structural expansion of disulphide compounds in combination with thiamichael addition and azido deacetylene addition, in the fluorescent labelling of disulphide compounds in combination with thiamichael addition.
3. 3. A kit for disulfide ring opening and thiol protection comprising a tris (trimethylsilyl) silane according to claim I.
4. 4. Kit for disulfide ring opening and thiol protection as claimed in claim I, characterized in that it comprises one or more of the following components: (1) Hydrosilylated ring-opening reagent, tris (trimethylsilyl) silane or deuterated tris (trimethylsilyl) silane or isotopically labeled analogues thereof; (2) Reaction medium methyl tertiary butyl ether or other organic solvents, or mixed solvent of DMF and MTBE; (3) The illumination condition is a visible light blue light source; (4) A deprotecting/desilicating agent, a fluoride ion source or an acidic substance; (5) Disulfide bond reconstruction reagents, either oxidizing reagents or disulfide reagents.

Description

Use of tris (trimethylsilyl) silane in disulfide hydrosilation reactions Technical Field The invention relates to tri (trimethylsilyl) silane, in particular to application of tri (trimethylsilyl) silane in disulfide hydrosilation reaction. Background Thiol and disulfide bonds are widely present in polypeptides, proteins and a variety of small bioactive molecules, and are important building blocks for maintaining molecular spatial conformation, bioactivity, and reversible redox processes. Thiol functional groups are highly reactive and susceptible to oxidation or undesired side reactions during organic synthesis, polypeptide synthesis and biomolecular modification, often requiring temporary protection by protecting groups and deprotection or disulfide bond reconstitution at appropriate stages. The thiol protecting group system commonly used at present is widely applied to synthesis and modification of sulfur-containing amino acids such as cysteine and the like, and forms a relatively mature technical route. Different protecting group systems have the characteristics of deprotection conditions, selectivity, application range and the like. However, when multifunctional molecules, complex structural substrates or post-modification applications are involved, there is still a need for further optimization of the partial deprotection conditions in terms of operating conditions, system compatibility or application flexibility. The silicon-based protecting group can be removed under mild conditions, so that the silicon-based protecting group is widely adopted in the field of hydroxyl protection, and a mature orthogonal protecting system is formed. However, when the silicon-based protection strategy is directly applied to the thiol functional group, the problems of insufficient stability of silicon-sulfur bonds, harsh reaction conditions, limited applicable substrate range and the like still exist. The existing silicon-sulfur bond construction method generally requires high temperature, a metal catalyst or specific activation conditions, and the obtained silicon-based thioether is easy to hydrolyze or decompose in the storage or purification process, so that the practical application of the silicon-based thioether in thiol protection and disulfide bond modification is limited. In this context, tris (trimethylsilyl) silane (TTMSS) has attracted attention as a structurally unique hydrosilylation agent. TTMSS shows good water resistance and oxygen resistance due to the highly hindered trisilicon-based substituted structure, and has higher chemical stability and lower toxicity. Compared with the common silane reagent, the TTMSS has lower Si-H bond energy (about 84 kcal mol < -1 >) and is more easily broken to generate silicon-based free radicals. At the same time, the bulky tri (trimethylsilyl) silicon-based substituent can provide significant kinetic stabilization of the generated silicon-based radicals. Because of the two characteristics of thermodynamic activity and kinetic stability, TTMSS is widely applied in the field of free radical chemistry, and covers multiple directions of organic synthesis, polymer chemistry, material chemistry and the like. Based on the above characteristics we envisage that TTMSS can provide new solutions for protection of thiol functions and selective modification of disulfide bonds. Disclosure of Invention The invention aims to overcome the defects of the prior art and find a new application of the tri (trimethylsilyl) silane. The present invention finds application in the hydrosilation of disulfides with tris (trimethylsilyl) silane. In order to achieve the above purpose, the present invention adopts the following technical scheme: the structure of the tri (trimethylsilyl) silane is shown as a formula I; Tris (trimethylsilyl) silane reagent structure (CAS: 1873-77-4), tris (trimethylsilyl) silane (TTMSS) or 1, 3-hexamethyl-2- (trimethylsilyl) TRISILANE (TTMSS). The tri (trimethylsilyl) silane can be applied to disulfide hydrosilation, and the application refers to application to hydrosilation of chain aromatic disulfide compounds, hydrosilation of chain aliphatic disulfide compounds, hydrosilation of symmetrical cyclic disulfide compounds, hydrosilation of asymmetrical cyclic disulfide compounds, application as a cysteine sulfhydryl protecting group to polypeptide synthesis, selective hydrosilation ring opening of disulfide-containing cyclic polypeptides, disulfide bond reconstruction, structure expansion of disulfide compounds by combining thiaMichael addition and azido deacetylene addition, and fluorescent labeling of disulfide compounds by combining thiaMichael addition. The tris (trimethylsilyl) silane-mediated disulfide hydrosilation reaction is shown below: A kit for disulfide bond ring opening and thiol protection comprising the above tris (trimethylsilyl) silane. Specifically comprises one or more of the following components: (1) Hydrosilylated ring-opening reagent, tris (trimeth