Amides, cleavage methods

Partial hydrolysis by aqueous acid is a regioselective amide-cleavage process, although it does not relate to a particular amide bond the most easily hydrolysed amide bond in a polyamide is the one that is most exposed to reagents or otherwise enhanced in its propensity to hydrolysis. Partial hydrolysis was an important feature of the earliest structure determinations for peptides (e.g., by Sanger see Chapter 5), and currently features in a method for mass-spectrometric structure determination of peptides (Section 4.11). The alkylation of the amide bond in peptides, described in Chapter 5, assists mass-spectrometric study through increasing the volatility of peptides. 

As discussed in Section IV, photolysis is a mild cleavage method that is attractive for combinatorial drug discovery because products can be released into neutral aqueous solution suitable for direct screening. Amine analogues of the hydroxyl resins described earlier have been reported. Thus, (aminomethyl)-6>-nitrobenzyl supports 7n have been reported on which short peptide amides could be synthesized with cleavage occurring upon irradiation at 350 nm in the presence of ammonia [323]. 2-Nitrobenzhydryl (NBHA) supports 7o have also been used for peptide amide assembly using Boc-protected amino acids. The anchor was unaffected by 4 N HCl-dioxane... 

An alternative approach to peptide sequencing uses a dry method in which the whole sequence is obtained from a mass spectrum, thereby obviating the need for multiple reactions. Mass spec-trometrically, a chain of amino acids breaks down predominantly through cleavage of the amide bonds, similar to the result of chemical hydrolysis. From the mass spectrum, identification of the molecular ion, which gives the total molecular mass, followed by examination of the spectrum for characteristic fragment ions representing successive amino acid residues allows the sequence to be read off in the most favorable cases. 

Phosphate triesters (18) are iatermediates ia both the phosphotriester and phosphoramidite methods, and under appropriate conditions for deprotection of the bases and cleavage of the support, can be obtained directiy by usiag these approaches. The ethyl and isopropyl esters have been obtained directiy by usiag the phosphoramidite method because these are stable duting the normal deprotection procedure (62). By changing the oxidizing agent to Sg, both amidate and triester thiolates can be obtained. 

NO BF )" have also been used to cleave amides. Since only tertiary amides are cleaved by potassium r-butoxide (eq. 6), this method can be used to effect selective cleavage of tertiary amides in the presence of primary or secondary amides. " (Esters, however, are cleaved by similar conditions.) Photolytic cleavage of nitro amides (eq. 7) is discussed in a review. ... 

Protection of the amide — NH is an area of protective group chemistiy that has received little attention, and as a consequence few methods exist for amide — NH protection. Most of the cases found in the literature do not represent protective groups in the true sense, in that the protective group is often incoiporated as a handle to introduce nitrogen into a molecule rather than installed to protect a nitrogen which at some later time is deblocked. For this reason many of the following examples deal primarily with removal rather than with both formation and cleavage. 

Selective cleavage of peptides and proteins is an important procedure in biochemistry and molecular biology. The half-life for the uncatalyzed hydrolysis of amide bonds is 350 500 years at room temperature and pH 4 8. Clearly, efficient methods of cleavage are needed. Despite their great catalytic power and selectivity to sequence, proteinases have some disadvantages. Peptides 420,423,424,426 an(j proteins428 429 can be hydrolytically cleaved near histidine and methionine residues with several palladium(II) aqua complexes, often with catalytic turnover. 

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