Anchoring ester bond, cleavage

At this point we have to return to the problem of stability of the anchoring ester bond. Cleavage of the Boc blocking group with dilute HCl in acetic acid... 

In the design of a handle, the presence (once anchored to the solid support) of the carboxamido moiety has to be taken into account, because it can modify the conditions required for the cleavage step. This is especially important in those handles that are labile in the presence of acids and bases. Thus, the ester bond formed between the first amino acid and a 4-hydroxymethylphenoxyacetamidomethyl resin is more stable to TFA than when the first amino acid is anchored to the Wang resin, which also incorporates a 4-alkoxybenzyl alcohol.f In order to circumvent this effect, additional methylene groups should be added. 

In connection with different kinds of anchoring groups we should recall that numerous biologically active peptides have a carboxamide rather than a free carboxyl at their C-termini. As mentioned earlier, such peptide amides can be obtained by ammonolysis of the ester bond between peptide and polymer. A second possibility, to wit, acidolysis is equally useful and often practiced. In 1970 Pieta and Marshall constructed a new polymeric support in which the acid labile N—C bond in benzhydrylamine serves as the point of cleavage (Fig. 7). Of course, the bond s sensitivity to acids can be further increased by electron-releasing substituents such as methoxy groups. 

The alcohol content of the ammonolytic reagent indicates the consequence of several observations that the amide formation seems not to proceed by direct attack of ammonia on the polymer phase ester bond but on the corresponding alkyl esters intermediately released by base-catalyzed transesterification [87]. It has to be realized that this procedure often yields a mixture of peptide amide and methyl esters, the latter of which can be transformed into amides by extended exposure to ammonia. Direct ammonolytic cleavage with liquid ammonia itself, first, is hindered by the poor solvation of the lipophilic matrix in the polar medium. Second, if remaining anchor functions are still present like chloro-methyl- or bromoacetophenyl-sites, on 0.5% divinylbenzene containing supports, liquid... 

This type of modified lipopeptide cannot be deblocked under basic conditions because the labile palmitic acid thioester group would be preferentially hydrolyzed. The C-terminus of the peptide chain was selectively deprotected by removing the choline ester with choline esterase without affecting the palmitic acid thioester bond. The observed chemoselectivity here is exactly opposite to that found in nonenzymatic conversions. Some of the synthesized N-terminally deprotected lipopeptides, have been labeled with biotinand are expected to serve as anchors for a protein moiety in an artificial membrane. Butyrylcholine esterase mediated cleavage of the choline ester has been utilized l as the key step in the synthesis of S-palmitoylated peptides such as Myr-Gly-Cys(Plm)-Thr-Leu-Ser-Ala-OH, which represents the characteristic N-terminus of the a-subunit of human G o protein. 

The catalytic hydrogenolysis of benzyl esters — a well known and clean procedure in conventional peptide chemistry — recently was applied successfully to peptide cleavage from polystyrene supports [216]. The hydrogenation of the polymeric benzyl ester anchor bonds was performed in the presence of palladium II acetate with hydrogen at 60 psi,... 

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