Solid base-labile resins

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. 

Imidazo[2- ]pyridines bound to solid supports via acid or base labile linkers can be prepared by reaction of resin-bound a-bromoketones with 2-aminopyridines <2003TL6265>. 5-Azaindoles may be prepared by cyclization of ortho-alkynyl aminopyridines in moderate to high yield in the presence of catalytic amounts of Cul <1998TL5159> (Equation 58). 

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... 

Solid-phase peptide synthesis. The combination of the base-labile N-a-fluorenylmethoxycarbonyl (Fmoc) amino acids and the acid-labile /-butyl protecting group is valuable for solid-phase peptide synthesis, particularly with polar resins. Intermediate Fmoc-peptide resins are deprotected with 20% piperidine or 5% piperazine in DMF. Six amino acid groups can be added per day without difficulty. This new strategy was used for synthesis of human /3-endorphin (31 residues), with 29 residues added as the anhydrides of Fmoc-amino acids. The last residue was the N-a-Boc derivative of 0-/-butyltyrosine. The peptide resin was cleaved with anhydrous CF3COOH. The overall yield of isolated polypeptide was 41 %. This method does not require vigorous acidic conditions. 

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). 

In the design of a handle, the presence (once anchored to the solid support) of the carboxamido moiety has to be taken into account, because it can modify the conditions required for the cleavage step. This is especially important in those handles that are labile in the presence of acids and bases. Thus, the ester bond formed between the first amino acid and a 4-hydroxymethylphenoxyacetamidomethyl resin is more stable to TFA than when the first amino acid is anchored to the Wang resin, which also incorporates a 4-alkoxybenzyl alcohol.f In order to circumvent this effect, additional methylene groups should be added. 

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