S-2-Amino-4-cyanobutanoic acid (β-cyanomethyl-l-Ala) as an atom-efficient solubilising synthon for l-glutamine

Glutamine (Gln) is often a difficult amino acid to incorporate during solution-phase peptide synthesis, owing to poor solubility and unwanted dehydrations as side-reactions. Current approaches to solving these problems are highly atom-inefficient. Nα-Cbz-β-cyanomethyl-l-Ala is readily accessible by dehydration of Cbz-l-Gln. β-Cyanomethyl-l-Ala can be incorporated into short peptides easily by conventional methods. The nitrile is stable to the hydrogenolysis conditions used to remove Cbz and to acidic deprotection but is quantitatively hydrated to the γ-carboxamide of l-Gln with hydrogen peroxide. Thus β-cyanomethyl-l-Ala may represent a new, soluble, perfectly atom-efficient synthon for l-Gln.