Anchors cleaved by nucleophiles

The second synthesis strategy commonly used in peptide synthesis and combinatorial chemistry is based on base-labile anchors. The cleavage mechanism is based either on a p-elimination (Fig. 5.6) or a hydrolysis, re-esterification or aminolysis (Fig. 5.7). 

The reagents used and the products liberated are depicted in Table 5.1. From a single anchor structure and synthesis, different products can be generated with the use of different cleavage reagents providing a further source of diversity (e.g., with hydroxymethyl-benzoic acid as linker — five carboxylic acid derivatives). 

Other cleavage procedures listed in Section 5.3 include use of a Grignard reagent to generate alcohols, the synthesis of amines by cleavage with hydrazine (ADCC linker), and the generation of tertiary amines by Hoffmann-elimination (acrylic acid linker). 

4-AcetyI-3,5-dioxo-l-inethyI-cycIoliexyl-carboxylic acid 

Acrylic acid Cleavage Product after cleavage  

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Wang resin see Section 5.3. Anchors cleaved by nucleophiles. 

Benzyl-type linkers are the most common anchoring groups for various kinds of functionality. Esters, amides, amines, alcohols, and thiols, in particular, can be immobilized by this linker family. This was demonstrated by Merrifield [2] and Wang [19] and is the starting point of modern linker development. Benzylic linkers are typically cleaved by strong acids (for example trifluoroacetic acid, TFA), which cause protonation and subsequent elimination. A nucleophilic scavenger usually quenches the resonance-stabilized cation thus formed. 

Isonitrile solid support 8j functions as a safety-catch anchor for acyl-aminoamides formed by a Ugi 4CC reaction [356]. Boc derivatization of the secondary amide anchoring site causes activation toward nucleophilic attack, and thus products could be cleaved by reaction with alkoxide ion. 

Hindered esters which are difficult to hydrolyze by the standard methods may be cleaved utilizing soft nucleophiles which attack the alkoxy carbon atoms specifically. Alkane thiolates are very efficient agents for the hydrolysis of phenacyl (39), 9-anthrylmethyl (40), and methyl esters (41). The inertness of higher esters is largely due to steric effects, as it has been demonstrated that cu-haloalkyl esters can be cleaved by an anchoring method (42-44). 

Structural diagrams are oriented so that the resin or point of attachment to support is on the far right, and the site for anchoring the C-terminal amino acid residue is on the far left. Benzyl ester linkages may also be cleaved by a range of nucleophiles to create acids, esters, or other derivatives. Consult References 7,9, and 20 for further examples. 

The oxime resin 5z [255,256], which forms an acid-stable anchor for the carboxyl group of amino acids, has been used for some time for the synthesis of C-terminal modified peptides and homodetic cyclic peptides. The key step in lactam formation is intramolecular nucleophilic attack of the A-terminus at the anchoring group. The resin also reacts with isocyanates and the products undergo nucleophilic attack by amines resulting in the release of ureas [257], Resin-bound Boc-tryptophan has been used in the acid-catalyzed Pictet-Spengler synthesis with final products cleaved as primary amides by... 

The primary translation product of proteins destined to be anchored by GPI contains both an A-terminal secretory signal sequence and a C-terminal signal sequence that specifies GPI addition. The latter is cleaved and replaced by the GPI precursor in the ER (Figure 3A). This transfer reaction is mediated by a transamidase and involves a nucleophilic attack by the EtN amino group of the GPI precursor on a carbonyl of a specific amino acid residue near the C-terminus. This residue, residing at the co site , will become the new C-terminus of the GPI anchored protein (Figure 3B). In a cell free system that reconstitutes anchor attachment, an alternative nucleophile such as hydrazine or hydroxylamine can substitute for a GPI in this reaction [89]. In a T. brucei cell free system, GPI addition to VSG does not require ATP or other cofactors [90], In a mammalian system, the transfer of the GPI precursor to a protein seems to be enhanced by an ATP-dependent chaperone [91,92],... 

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