Functional groups, acid-labile linker

In order to investigate dendrimers of a different nature [230], Bradley described the synthesis and transfection efficiency of polyamidourea dendrimers synthesised from isocyanate-containing AB3 monomers [231-234]. The use of this kind of tris-branched building block was addressed to enhance dendrimer synthesis by replacement of the 1,4-addition step typical of PAMAM synthesis and to a rapid increase in terminal functionality. The dendritic structures were synthesised using a divergent, microwave-assisted, solid-phase approach with the dendrimers assembled on polystyrene resin via an acid labile linker (see Fig. 26). In particular, a G3.0 polyamidourea bis-dendron with the peripheral amino groups conjugated to L-lysine residues demonstrated remarkable transfection abilities [234],... 

This brief, incomplete survey should have provided a flavor of the many functional groups that can be hooked onto and released from a solid support using acid-labile linkers. Acids, alcohols, phenols, amines, hydroxylamines, and halides have been successfully attached to a variety of resins through the judicious choice of the linker... 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

Most acid-labile benzyl alcohol linkers suitable for the attachment of carboxylic acids to insoluble supports can also be used to attach aliphatic or aromatic alcohols as ethers. The attachment of alcohols as ethers is less easily accomplished than esterification, and might require the use of strong bases (Williamson ether synthesis [395,552,553]) or acids. These harsh reaction conditions limit the range of additional functional groups that may be present in the alcohol. Some suitable etherification strategies are outlined in Figure 3.31. Etherifications are treated in detail in Section 7.2. 

The conditions for the release of a peptide from a linker depends not only on the linker structure but also on the nature of the leaving group, i.e., the functional group it releases. This has been summarized for BAL-type handles in Table 1, where the acid-lability of three linkers is also compared. In summary, the leaving group capability decreases in the order sulfonamide, carbamate urea, secondary (substituted) amide > primary amide > amine. 

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