Solid nucleophile-labile resins

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). 

The safety catch principle for the solid-phase preparation of C-ternninal modified peptides requires the bond between the handle and the first residue to be stable to the normal conditions of SPPS. However, at the end of the synthesis, a chennical transformation of the linker substituent makes the key bond labile to nucleophiles. The 4-sulfanylphenol 44b ti and the sulfonamide 45 (Kenner) resins are two examples of safety catch resins. Thus, in the first case, which is only compatible with the Boc/Bzl strategy, once the peptide chain is elongated, treatment of the peptide-resin with hydrogen peroxide converts the sulfide into the corresponding sulfone, which makes the bond labile to nucleophiles. In the second case, N-methylation with diazomethane leads to an N-methylated peptidyl-sulfonannide-resin, from which peptides can also be cleaved by nucleophiles. 

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