The Carboxamide Groups of Asparagine and Glutamine

FIGURE 6.16 Protecting groups for carboxamides. Derivatives are obtained by reaction of the carboxamide with an alcohol or the acid with an amine. Mbh = 4,4 -dimethoxybenzhydryl64 Trt = trityl [Sieber Iselin, 1991] Xan = 9-xanthenyl63 Dmb = 2,4-dimethoxybenzyl66 Tmb = 2,4,6-trimethoxybenzyl65 BHR = benzhydryl-resin.68 

S Akabori, S Sakakibara, Y Shimonishi. Protection of amide nitrogen for peptide synthesis. A novel synthesis of peptides containing C-terminal glutamine, (xanthenyl) Bull Chem Soc Jpn 34, 739, 1961. 

W Konig, R Geiger. A new amide protecting group, (methoxybenzhydryl) Chem Ber 103, 2041, 1970. 

PG Pietta, P Cavallo, GR Marshall. 2,4-Dimethoxybenzyl as a protecting group for glutamine and asparagine in peptide synthesis. J Org Chem 36, 3966, 1971. 

P Sieber, B Riniker. Protection of carboxamido functions by the trityl residue. Application to peptide synthesis. Tetrahedron Lett 32, 739, 1991. 

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The carboxamide groups of asparagine and glutamine derivatives 26 are susceptible to dehydration during carbodiimide-mediated esterification at the a-carboxy groups (Scheme 4).[64] reaction probably involves formation of aspartyl- or glutamylisoimide 28 by attack... 

The side chain carboxamide groups of asparagine and glutamine can lose water during activation. There are several ways to avoid this side reaction. For instance, no significant amount of nitrile forms if the lifetime of the reactive intermediate is cut short by the addition of an auxiliary nucleophile such as 1-hydroxybenzotriazole (HOBt) ... 

Heating proteins in a dry state at neutral pH results in the formation of isopeptide bonds between the e-amino groups of lysine residues and the P- or y-carboxamide groups of asparagine and glutamine residues ... 

The general approach for carboxyl protection is esterification. The simplest solution, the use of methyl or ethyl esters, is suitable for semipermanent blocking, although the commonly applied process of unmasking, alkaline hydrolysis, is far from unequivocal. It is accompanied by racemization, partial hydrolysis of carboxamide groups in the side chain of asparagine and glutamine residues and by several other side reactions which are initiated by proton abstraction (Cf. Chapter VII). Nevertheless, perhaps because of the attractively simple esterification of amino acids... 

Tetrazole analogues of amino acids have been prepared from Z-protected amino acids, and Z-protected amino nitriles." More recently, the group of Sureshbabu et al. extended this formal [3 -r 2] cycloaddition between a nitrile-containing protected -amino acid 11 and azide to also include Fmoc-amino acids and prepared and y-tetrazolyl -amino acids 12 for incorporation into peptides (see Scheme 10.2). ° The carboxamide side-chains of asparagine and glutamine were dehydrated and converted to the tetrazole by treatment with sodium azide and zinc bromide to afford tetrazole-isosteres of aspartic acid and... 

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