Orthogonally cleavable linker

Figure 16.1. Synthesis of tree-type carbohydrate clusters using orthogonally cleavable linkers.

Over the years, a number of cleavable linkers that are acid labile, base labile, or photol-abile have been developed for solid-phase peptide synthesis. (This topic has been covered in detail by several review papers [34-36].) For libraries that require the linker to be cleaved before screening, most of these conventional linkers can be used. Several unconventional linkers have been found to be particularly useful and user-friendly for combinatorial applications (see Fig. 1). Among them are methionine-containing linker [37] and safety-catch benzylhydrylamine linker 1 [38], Bray et al. [39] have utilized an orthogonal peptide-resin linker 2 which allows the final deprotection and removal of contaminating chemicals and the peptide is later released into an aqueous buffer. Hoffmann and Frank [40] recently described a novel safety-catch linker 3 based on the intramolecular catalytical... 

Trityl resins are particularly suitable for immobilization of nucleophilic substrates such as acids, alcohols, thiols, and amines. They are quite acid-sensitive and are cleavable even with acetic acid this is useful when acid-labile protecting groups are used. The stability of trityl resin can be tailored by use of substituted arene rings, as shown by chlorotrityl resin, which furnishes a more stable linker than the trityl resin itself. Steric hindrance also prohibits formation of diketopiperazines during the synthesis of peptides. Orthogonality toward allyl-based protective groups was demonstrated in the reverse solid-phase peptide synthesis of oligopeptides [30] (Scheme 6.1.4). 

Many other handles exist that are cleavable by orthogonal mechanisms for the synthesis of protected peptide fragments these are also summarized in Table 5. A novel strategy for the synthesis of cyclic peptides on resin is to attach the peptide to the resin by a backbone nitrogen rather that the C -carboxyl. The N-and C-termini then remain free for further functionalization such as cyclization, esterification, or thioester formation. This backbone amide linker (BAL) is listed in Table 5. Other strategies such as attaching the peptide to the resin via the side chain of trifunctional amino acids and more comprehensive listings of linkers and handles are covered in References 9,12, and 109-111. 

---