Linkers cleavage mechanisms

During solid phase synthesis peptides are bound to the solid support by means of the C-terminal carboxyl group. The properties of the anchor group positioned between the growing oligomer and the solid support are crucial for the success of a solid phase synthesis. Usually, specialised linkers are used which provide either peptide carboxylic acids or peptide carboxylic amides upon cleavage [4]. A cleavage mechanism that proceeds by a nucleophilic attack... 

Scheme 56 Cleavage mechanism of HASC linker by Procter [39,40]...

FIGURE 8.8 The two possible cleavage mechanisms for the orthogonal linker system. The top mechanism illustrates the acid-chemical cleavage process used for quality control of library production. The bottom mechanism illustrates the photocleavage process used to release the synthetic compound for biological assay. (QC = quality control.)... 

In addition to Woodward s scavenger treatment [18], the use of an a-substituted nitrobenzyl Hnker was used to solve the problem of aldehyde condensation, since the ketone photolysis byproduct is substantially less reactive than an aldehyde. On the basis of the accepted cleavage mechanism, though, photochemical deprotection should still be feasible with an a-substituted nitrobenzyl linker. 

Most photocleavable linkers for carboxylic acids used today are based on the photoisomerization of 2-nitrobenzyl esters and on the light-induced cleavage of phen-acyl esters (Figure 3.10). Several possible mechanisms have been proposed for the photolytic cleavage of benzoin esters. One of the most recent is the dissociation of the excited phenacyl ester into a carboxylate and a phenacyl cation ( photosolvolysis , Figure 3.10 [136]). 

In addition to the procedures listed in Table 3.38, further reactions have been used to generate halides upon cleavage. In Section 3.5.2, iodolactonization is presented as a method for the preparation of iodomethyl lactones from resin-bound pentenoic or hexenoic acid derivatives. Closely related to the iodolactonization is the iodine-mediated formation of 2-(iodomethyl)tetrahydrofurans from resin-bound isoxazoli-dines (Entry 9, Table 3.38 for the mechanism, see Figure 15.5). Nitriles can also be prepared by cleavage and simultaneous dehydration of amides RCONH2 from the Rink or Sieber linkers with TFA anhydride (Entry 10, Table 3.38). 

The high purity (>95%) of the released product from resin 14 prompted us to investigate the potential of radical release as a traceless linker concept. To our knowledge, thermolytic radical fragmentation of covalent bonds is a mechanism of bond dissociation that has not been exploited so far for linker chemistry and for solid-phase transformations. Cleavage yields, determined by releasing nonvolatile products, were found to be higher than 90%. 

Protiodesilylation has been exploited by many researchers as a mechanism for releasing arenes directly from the linker by cleavage of a C-Si bond (Figure 14.13) [94-99],... 

Physically cross-linked hydrogels can degrade by processes that reverse the gelation mechanism or disturb the noncovalent interactions of the cross-links. Chemically cross-linked hydrogels can be degraded via several mechanisms (Fig. 10.17) and include cleavage of the backbone chain, cross-linker, or pendant groups. 

---