The relationship between carrier functionalization and linker
Linker is a structural fragment between the carrier and the target compound (polypeptide).
Its chemical activity, i.e. sensitivity, is closely related to the type of reaction followed by the assembly of the target compound, the protective group form of the component and the cracking reaction type after Zui.
The matrix material of the carrier is a relatively stable polymer structure, which requires the introduction of chemically active functional groups through functionalization reaction to carry out the related reactions of organic synthetic peptides.
The relationship between function base and linker structure can be divided into the following two cases.
(1) The functional group structure itself is linker structure, such as mbha resin, Wang resin and trityl resin
The functional groups of the three resins have no structural change except one proton lost in the bonding reaction with the component.
(2) The local structure changes of functional group structure after Di one-step assembly reaction (attachment or loading), forming cleavable linker.
For example, the functional group of merifeld resin is benzyl chloride structure, and the benzyl alcohol ester formed by reaction with components containing – COOH is the linker structure that can be cleaved
For example, the functional acrylic acid of REM resin does not have the cleavable function of linker, but after assembly reaction, it becomes a linker structure which can undergo Hofmann elimination of Chu reaction
A kind of functional group named DHP (dihydropyran) resin is also transformed into a cleavable acetal linker after assembly reaction. Therefore, this kind of functional group should be regarded as the precursor of linker.
Linker performance
One
The components to be assembled in one step should have ideal chemical activity.
For example, amino group in mbha resin and ampicil in Merrifield resin can be condensed with carboxylic acid active ester and carboxylic acid cesium salt respectively.
Two
For Di, the assembly reactions after the second step did not participate in the activity, but tolerated these assembly reactions.
Except for the cleavage reaction after Zui, the integrity of linker structure is not affected.
Three
It has high activity and specificity for the cleavage reaction, that is, the product structure is inert to the pyrolysis reaction.
In designing the reaction route of solid phase synthesis, the relationship between the conditions of assembly reaction and the reverse condition of pyrolysis is orthogonal to each other.
Four
Linker structure directly affects the matching of protective groups and reaction conditions in subsequent synthesis.
For example, trityl linker and DHP linker are sensitive to acidic conditions.
Therefore, in the subsequent synthesis, if the functional groups on some components need temporary protection, only the temporary protection bases sensitive to alkaline conditions can be used to protect the integrity of linker.
For example, in the following synthesis of dihydropteridone, since the linker of Wang resin is sensitive to acid, the acid reaction conditions should be avoided in the whole Bu reaction.
However, Fmoc is needed to protect the amino acid of DI in order to remove it with Hexahydropyridine.
If BOC was used as the protective group, the subsequent acidic conditions of de BOC would lead to the premature cleavage of wanglinker.
From the above linker properties and functions, Zui’s important strategy design is to select a reasonable linker structure.
This is the key to determine the whole Bu reaction mode and protection strategy, and also the key to the success of the whole synthesis. At the same time, it is one of the important basis to show whether the solid-state organic synthesis technology is mature.
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