Safety-catch acid-labile

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). 

Two approaches for solid-phase chemical ligation have been described. Canne et al. have developed an elegant system that utilizes an oxime forming ligation to attach the first peptide to the resin, a selectively cleavable ester link to remove the peptide from the resin as a C-terminal carboxylic acid, and the Acm group to protect the N-terminal cysteine residue)311 A complementary approach has been developed by Brik et al. that utilizes native chemical ligation to attach the first peptide to the solid support, a safety-catch acid labile linker to remove the final polypeptide from the support as a C-terminal amide and either Acm or Msc group for N-terminal cysteine protection)32 ... 

Using the Safety-Catch Acid Labile Linker... 

Scheme 16.9 Safety-catch acid labile (SCAL) linker by Patek and Lebl.

SCAL, safety catch acid-labile linker or safety catch amide linker. 

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... 

A concept with attractive perspectives for increased flexibility in the choice of mutually compatible reaction conditions is termed safety catch. Here, particularly robust linkers are in their stable state during synthesis and are labilized by chemical transformation immediately prior to the final cleavage of the substrates. The SCAL linker [20] becomes acid labile only... 

An enzyme-labile so-called safety catch linker 452 was used successfully in various palladium-catalyzed cross-coupling reactions [592]. The linker 452, which releases a hydroxy or an amino functionality on enzymatic cleavage of its phenylacetamide moiety and subsequent rapid lactam formation, was attached to a soluble POE 6000 (polyethylene oxide) polymer and its free phenylacetic acid moiety was transformed to an m-iodobenzyl ester. The thus immobilized m-iodobenzyl alcohol was Heck-coupled with tert-butyl acrylate, and the coupling product 453 was cleaved off the solid support with penicillin G acylase under very mild conditions (pH 7, 37°C) (Scheme 8.84). 

As outlined above, a drawback of using acid or base labile linker units is that unwanted cleavage can occur when reagents employed in the synthetic sequence resemble the cleavage conditions. One elegant solution to this problem is the safety-catch linker... 

Finally, a safety-catch linker utilizing the acidic lability of the indole core was reported by Ley and colleagues (Scheme 1.7). Substrates attached to solid supports through the tosyl-protected indole (17) were stable in acidic conditions. However, deprotection of the tosyl group using TBAF provided activated intermediate 18. Treatment of the activated linker with 50% TFA in DCM was then sufficient to release the target amides 19. 

The acid-labile trityl ether, for example, is very easy to cleave off without interference of other protecting groups during synthesis. An interesting aspect of protecting and cleaving techniques is the introduction of a thioether as safety-catch moiety which is eliminated by oxidation to the sulfone [134]. 

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