Solid-phase peptide synthesis acid labile linkers

Benzyl carbamate protection (Cbz or Z group see Table 10.15) was initially chosen by Merrifield for solid-phase peptide synthesis [255], The strongly acidic conditions required for its solvolysis (30% HBr in AcOH, 25 °C, 5 h) demanded the use of an acid-resistant nitrobenzyl alcohol linker. Z-protection of the a-amino group in solid-phase peptide synthesis was, however, quickly abandoned and replaced by the more acid-labile Boc protection. Benzyl carbamates can be cleaved by strongly ionizing... 

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). 

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... 

Chemical ligation methods for peptide synthesis using thioester chemistry in solution have been previously documented (see Vol. E 22a, Section 4.1.5). Generalized procedures for solid-phase ligation have been developed that simplify the overall procedure. One method uses a safety-catch acid labile linker at the C-terminus and was used for the synthesis of a 71-amino acid chemokine, vMIP I (Section 5.3.2.1). Another procedure uses a selectively cleavable glycolate ester linkage (Section 5.3.2.2). 

Sieber P (1987) A new acid-labile anchor group for the solid-phase synthesis of C-terminal peptide amides by the Fmoc method. Tetrahedron Lett 28 2107-2110 Mende F, Seitz O (2011) 9-Fluorenylmethoxycarbonyl-based solid-phase synthesis of peptide a-thioesters. Angew Chem Int Ed 50 1232-1240 Giiillier F, Grain D, Bradley M (2000) Linkers and cleavage strategies in solid-phase organic synthesis and combinatorial chemistry. Chem Rev 100 2091-2158... 

Dialkoxy- and trialkoxybenzyl esters are even more acid-labile than the Wang linker, and can, for example, be cleaved with dilute TFA, acetic acid, or hexafluoroiso-propanol without simultaneous acidolysis of Boc groups. These linkers thus enable the solid-phase synthesis of protected peptide fragments or other acid-sensitive products [33]. 

On the other hand, if the phosphopeptides are intended to be used in solution-phase assays, the synthesis can be carried out on a standard resin with common linkers. This includes the Rink amide or Wang-type linkers on polystyrene, TentaGel, or ChemMatrix supports. Upon completion of the peptide chain assembly, the peptides are released from the solid support by treatment with TFA-containing cocktails with concomitant removal of acid-labile side-chain protecting groups. Using these conditions robust protocols for rapid and efficient synthesis of phosphopeptides have been established. 

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