Solid‐phase synthesis of peptides with C‐terminal asparagine or glutamine

Attempts to anchor Fmoc‐asparagine or glutamine as p ‐alkoxybenzyl esters for solid‐phase peptide synthesis are fraught with difficulties. A convenient and effective method to prepare peptides with C ‐terminal asparagine or glutamine involves quantitative attachment of N x ‐Fmoc‐ C x ‐ tert. ‐butyl aspartate or glutamate via the free ω‐carboxyl groups to a tris(alkoxy)benzylamino (PAL) support. Chain elongation proceeds normally by standard Fmoc chemistry, and treatment with acid, e.g., CF 3 COOH—CH 2 Cl 2 , 90 min at 25°, releases the desired peptides in >95% yields without side reactions at the C ‐terminus. Feasibility of the approach has been demonstrated by the syntheses of the C ‐terminal octapeptide from human proinsulin, H‐Leu‐Ala‐Leu‐Glu‐Gly‐Ser‐Leu‐Gin‐OH, and the serum thymic factor pGlu‐Ala‐Lys‐Ser‐Gln‐Gly‐Gly‐Ser‐Asn‐OH.