Cleavage, acidolytic

The removal of the carbohydrate auxiliary group and the hydrolysis of the amino nitriles is achieved by acidolytic cleavage of the hemiaminal /V-glycosidic bond and the concomitant acid-catalyzed solvolysis of the nitrile using either hydrogen chloride in formic acid or hydrogen bromide in acetic acid56 57. 

A Karlstrom, K Rosenthal, A Unden. Study of the alkylation propensity of cations generated by acidolytic cleavage of protecting groups in Boc chemistry. J Pept Res 55, 36, 2000. 

The mild acidolytic cleavage procedure noted above is used to deprotect various side chain protected peptides synthesized in solution or on chlorotrityl-resin with tyrosine O-sulfate synthons as listed in Table 4. The overall yields are significantly superior to those obtained by postsynthetic sulfation of the purified peptides, since they are typical for synthetic peptides after the final deprotection and purification step. The additional main advantage of this approach derives from a facile analytical characterization, since sulfonated byproducts at the tyrosine and tryptophan level, as well as oxidation of the methionine residues resulting from postsynthetic sulfation of tyrosine peptides are avoided. 

Figure 3.3. Immobilization of carboxylic acids as benzyl esters and acidolytic cleavage. M Cs+, NMe4+, Na+, Zn2+ Y leaving group HX HBF4, HBr, HF, TFA, TfOH.

Figure 3.18. Acidolytic cleavage of aryl benzyl ethers as competing reaction during the acidolysis of N-benzylamides [212],...

Table 3.9. Acidolytic cleavage of resin-bound A-benzylamine derivatives.

Aromatic and heteroaromatic amines can be linked to insoluble supports using strategies similar to those used for aliphatic amines. Because of the lower basicities of aromatic amines, however, their /V-bcnzyl derivatives will usually be more susceptible to acidolytic cleavage than aliphatic /V-bcnzylamincs. For the same reason, N-acyl derivatives of aromatic amines will generally be more sensitive towards nucleophiles than the corresponding derivatives of aliphatic amines. 

Heterocycles containing an NH group, such as pyrroles, indoles, imidazoles, triazoles, etc., can be linked to insoluble supports as N-alkyl, N-aryl, or N-acyl derivatives (Table 3.29). The optimal choice depends mainly on the NH acidity of the heterocycle in question. Increasing acidity will facilitate the acidolytic cleavage of N-benzyl groups and the nucleophilic cleavage of /V-acyl groups from these heterocycles. 

Illustrative examples of the cleavage of support-bound ethers are listed in Tables 3.30 and 3.31. Acidolytic cleavage is the most commonly used strategy, but base-mediated, photolytic, and oxidative cleavage have also been reported. Wang linker... 

The degradation of support-bound a-amino acid amides has been used to prepare retro-inverso peptide mimetics ([226], second equation in Figure 10.6). These compounds are of interest because of their potentially improved metabolic stabilities, selectivities, and biological activities compared with peptides [226], Although retro-inverso peptides are aminals susceptible to acid-catalyzed hydrolysis, N,N -diacylated aminals can be sufficiently stable to withstand the conditions of Boc-group removal [227] or of acidolytic cleavage of peptides from Wang resin [226]. 

Examples of the preparation of oxazines and thiazines on insoluble supports are listed in Table 15.34. 3,l-Benzoxazin-4-ones can be prepared by intramolecular O-acy-lation of /V-aminocarbonyl anthranilic acids (Entry 1, Table 15.34). The resulting ben-zoxazinones are sufficiently stable towards acids to enable TFA-mediated cleavage from a Wang linker [410]. 1,3-Oxazines have also been obtained by acidolytic cleavage of functionalized 3-amino-l-propanols from Wang resin (Entry 4, Table 3.30). 

This preparation is analogous to the formation of diketopiperazines from dipeptide esters. In a similar approach, morpholine-2,5-diones were obtained by acidolytic cleavage of N-(bromoacety 1)am ino acids from Wang resin (Entry 3, Table... 

The first successful solid-phase synthesis of a peptide (H-Leu-Ala-Gly-Val-OH) was reported by Merrifield in 1963 [12]. The strategy used is outlined in Figure 16.1. The support was chloromethylated, partially nitrated (or brominated), 2% cross-linked polystyrene. Nitration was necessary to suppress acidolytic cleavage of the benzyl ester attachment during Z-group removal. Acylations of deprotected, support-bound amino acids were performed with DCC, and at the end of the synthesis the peptide was cleaved from the support by saponification with sodium hydroxide. 

O-tethered P-keto esters, through the intermediacy of aiylidene keto esters, have been efficiently utilized for the construction of immobilized dihydropyridines. Ceric ammonium nitrate (CAN) oxidation to pyridines followed by acidolytic cleavage provides a facile entry into nicotinic acid derivatives 57 [42], A three-component Biginelli cyclization of ureas on resin with a solution mixture of aldehydes and P-keto esters provides dihydropyrimidines 58 in high yield and purity [43], Heterocycles such as dihydropyridines and pyrimidines have historically proven to be a rich source of antimicrobial, antitumor, antiviral, and cardiovascular agents. 

For the synthesis of Thiangazole, Pattenden and co-workers prepared the oxa-zole derivative 25.3 [Scheme 5.25] from the a-methyl cysteine derivative 25.1 in four steps.55 The final step in the sequence involved acidolytic cleavage of both the N-Boc and S-Boc protecting groups with anhydrous HC1 in ether. However, in certain circumstances, an N-Boc group can be cleaved in the presence of an S-Boc group and a /erf-butyl ester [Scheme 5.26).56... 

An example of an acidolytic cleavage of a 2-(trimethytsi)yl)eLhyl phosphate together with an N-Boc group is shown in Scheme 7.42.w... 

Key Words Acidolytic cleavage backbone amide linkage bioconjugate chemical ligation combinatorial chemistry handle linker peptide alcohol peptide aldehyde peptide ester peptide thioester protecting group solid support. 

A -protected penultimate amino acid (3) protocol for introduction of the second and third residues when the sequence poses a risk of serious chain loss due to diketopiperazine (DKP) formation (4) stepwise chain elongation using Fmoc protocols to complete on-resin assembly of the desired C-terminal-modified peptide and (5) acidolytic cleavage to release the peptide into solution. 

Acidolytic Cleavage to Release C-Terminal Modified Peptide From Resin... 

Table 12 Acidolytic Cleavage of iV-Trityl Amino Acid and Peptide Derivatives ...

Table 4 Acidolytic Cleavage of N -Protected Diamino Acid Residuesl -...

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