Base-labile resins

Kaiser oxime resin, 4-nitrobenzophenone oxime resin, a base-labile resin widdy used for the synthesis of Boc/Bzl-protected segments. Several methods have been de-... 

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. 

A special group of base-labile linkers for carboxylic acids rely on cleavage by 3-elimination. Here, the resin-bound alcohol must bear an electron-withdrawing group in the [3 position (Figure 3.8), which facilitates elimination by acidifying this position. Mechanistically, these linkers are closely related to the Fmoc protective group, and... 

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... 

For experimental cleavage procedures carried out with strong acids (e.g., liq HF, CF3SO3H) and high concentrations of TFA, see Section 4.3.5. The cleavage of peptides from photolabile-based resins is carried out as discussed above for acid handles, and from XAL and its A-alkyl-based resins as discussed for highly acid-labile resins. 

In order to remove products form the resin, the hydrazide is oxidized to the base-labile azo derivative. 

The linker is immobilized through the thiol group to form the 4-hydroxybenzene-thiomethyl-PS/DVB. In order to release the product from the resin the sulfide is oxidized with H202 to a base-labile sult one. 

Below, the usefulness of nucleophile- and base-labile linkers and resins is reviewed in the preparation of various organic compounds. First, intermolecular nucleophilic displacement (saponification, transesterification and amminolysis and related reactions) are analyzed. Finally, the obtention of cyclic products by intramolecular nucleophilic reactions is reviewed. 

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