Phenylacetamide linker

Fig. 6. An enzyme labile phenylacetamide linker. Penicillin acylase cleaves the acetamide group of polymer-supported linker 28. The benzylamine derivative 29 then cyclizes to release the target compound.

An exo-linker according to Fig. 10.1 must contain an enzyme labile group R, which is recognized and attacked by the biocatalyst Possible combinations could be phenylacetamide/penicillin amidase, ester/esterase, monosaccharide/glycosid-ase, phosphate/phosphatase, sulfate/sulfatase and peptides/peptidases [41]. The following systems have been worked out (Tab. 10.2). 

Penicillin acylase catalyzes the hydrolysis of phenylacetamides and has been used in peptide synthesis for the cleavage of protecting groups [46—47]. In linker (40) developed by Flitsch et al. [41—42] (Scheme 10.8) the group -XR represents the alcohol or amine group of the target molecule. Hydrolysis of the phenylaceta-... 

Table 3.26 lists illustrative examples of cleavage reactions of support-bound N-aryl-carbamates, anilides, and /V-arylsulfonamidcs. /V-Arylcarbamatcs are more susceptible to attack by nucleophiles than /V-alkylcarbamates, and, if strong bases or nucleophiles are to be used in a reaction sequence, it might be a better choice to link the aniline to the support as an /V-bcnzyl derivative. Entry 7 (Table 3.26) is an example of a safety-catch linker for anilines, in which activation is achieved by enzymatic hydrolysis of a phenylacetamide to liberate a primary amine, which then cleaves the anilide. 

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). 

Overview Waldmann and his group recently reported the development of a penicillin G acylase sensitive safety catch linker for the attachment of alcohols and anilines to a polymeric support (Fig. 6) (20). The release of the synthesized target molecule from the support is initiated by the hydrolysis of the phenylacetamide moiety contained in the linker 28 under extremely mild conditions (pH 7.0, room temperature or 37°C). The liberated benzylamine 29 intermediate cyclizes instantaneously to release the desired target molecule with the tetrahydroisoquinolinone 30 formed in the course of this process remaining on the polymer. 

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