Amino acids azide analogs

The azide procedure for peptide synthesis and particularly for fragment condensations is considered to be a mainly racemization free method. This low racemization tendency of azides was explained by several theories, which have been reviewed.t l The most plausible cause of racemization is the formation of oxazoles (Scheme 3) and the related enolization. In presence of bases the a-carbon proton is readily abstracted to form an anionic oxazol-5(4//)-one resonance system.For the formation of the oxazol-5(4//)-one the influence of the substituent Y on the a-carbonyl is essential. Since the a-carbonyl group of amino acid azides are less activated and thus relatively insensitive to oxygen containing nucleophiles such as water and alcohols, oxazol-5(4//)-one formation is largely prevented. It was proposed that the soft electron shell of the azide shields the a-carbonyl atom, so that only strong nucleophiles can attack it.t 1 The reactivity towards amines can be explained in a manner analogous to the aminolysis of anchimerically assisted active esters.h 1... 

Cells grown in the presence of azide analogs of certain amino acids or sugars will incorporate these derivatives into proteins or carbohydrates through enzymatic synthesis using... 

Fig. 14.45. Transformation of an a-phosphonylcarboxylic acid ester (B) via the related carboxylic acid azide F and its Curtius degradation in ethanol to furnish an ethoxycarbonyl-protected a-aminophosphonic acid ester E. The N- and 0-bound protective groups of the latter compounds are cleaved off under acidic conditions. In this manner a-aminophosphonic acids are synthesized. They are interesting analogs of the biologically important a-amino carboxylic acids.

Uronic acid azides constitute important precursors for A -glycosyl amino acids and their various peptide derivatives, and may be formed by a comparable pathway. Thus, the treatment of acetyl-protected uronic acid esters with tri-methylsilyl azide and SnCU gives the desired acetylated 1,2-trans methyl (o-glycopyranosyl azide)uronates in crystalline form. " Whereas the yields for the gluco 61 and galacto derivatives 62 are satisfactory, the manno analog 63 was obtained in only 11 % yield. Even with an excess of trimethylsilyl azide, the results could not be improved. ... 

BOP-Cl has been used quite extensively for the synthesis of peptides. " It is particularly useful for coupling fV-alkyl-a-amino acids with minimal racemization (eq 11), although the quality of BOP-Cl employed in these reactions can significantly affect yields, and the analogous azide, BOP-N3, has been proposed as an alternative reagent. Racemization can sometimes be suppressed by inclusion of additives such as 1-Hydroxybenzotriazole (HOBt) or Imidazole (eq 12), although under certain conditions HOBt can induce epimerization. ... 

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