Base-labile ester linkers

The oc-mercaptobenzhydryl linker 27 [71] was developed for the synthesis of thioacids by Boc synthesis. Acylation of the thiol group with Boc-amino acids leads to a resin-bound thioester. Subsequent peptide chain extension and then treatment with HF cleaves the ester-linker bond, releasing the C-terminal peptide thioacid. Unfortunately, owing to the nucleophile lability of thioesters, this approach cannot be applied to Fmoc-based methods. 

The linkage between the oligonucleotide-peptide conjugate and the solid support is usually a base-labile linker inspired by the oligonucleotide synthesis field (Fig. 5). Linkers from the peptide field are acid labile and not compatible with the oligonucleotide moiety. Most the linkers used to anchor the peptide moiety have an ester function that is cleaved with concentrated ammonia [13-17,46], ethylenediamine [34], ethanolamine [26], sodium hydroxide [27], or tetrabutylammonium fluoride (TBAF)... 

Acid-labile linkers are the oldest and still the most commonly used linkers for carboxylic acids. Most are based on the acidolysis of benzylic C-O bonds. Benzyl esters cleavable under acidic conditions were the first type of linker to be investigated in detail. The reason for this was probably the initial choice of polystyrene as an insoluble support for solid-phase synthesis [13]. Polystyrene-derived benzyl esters were initially prepared by the treatment of partially chloromethylated polystyrene with salts of carboxylic acids (Figure 3.3). 

The hydroxyl version of the Rink amide linker, known as the Rink acid resin (25), was developed as a tool for the preparation of protected peptide fragments [13]. The peptide-linker ester bond is labile to extremely weak acids, such as HOBt or acetic acid, allowing peptides bearing t-butyl-based side-chain protection to be cleaved intact. Conversion of the hydroxyl group into chloride [66] or trifluoroacetyl [67] provides linkers that have been used for immobilization of various nucleophiles, including alcohols, N-protected hydroxylamines, phenols, purines, amines, anilines and thiols [66-68], The stability of the cation derived from this tinker is such that even thiols and amines can be cleaved from this tinker with TFA (Figure 14.12). 

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