Development of 5-Amino-2,4,6-triiodoisophthalic Acid Derivatives for Carbamoylation of Amino Acids

In this study, the authors used 5-amino-2,4,6-triiodoisophthalic acid (ATIIPA) as a nucleophile to produce the corresponding 1,3-diesters. Two types of 1,3-diesters, (i) diethyl 5-amino-2,4,6-triiodoisophthalate (DEtTIIP) and (ii) diacetoxyethyl 5-amino-2,4,6-triiodoisophthalate (DAcOEtTIIP), were mostly prepared in quantitative yields. The 1,3-esters were tested as a carbamoylation agent towards the amino groups of the Ala esters via isocyanation of the 5-amino group. The addition reaction of DEtTIIP-NCO and betaAla-OEt yielded DEtTIIP:CO-betaAla-OEt, and the 1,3-diethyl ester is highly resistant to alkaline hydrolysis due to the steric shielding by the adjacent 2,4,6-iodines, while the -ethyl ester of the Ala substructure was easily removed. Alkaline hydrolysis of another adduct, DAcOEtTIIP:CO-betaAla-OtBu, removed only the 1,3-acetoxy ethyl groups to form the product DAcOHTIIP:CO-betaAla-OtBu, as well as the acidic fission of the -OtBu ester was quantitative to give DAcOEtTIIP:CO-betaAla. These results indicated that the DAcOEtTIIP is a feasible precursor for the N-carbamoylation of the amino acid ester, preserving the freedom for selective ester deprotection, which further inspired the contrast molecule design using amino acids and peptides.