The synthesis and rotational isomerism of 1-amino-2-imidazol-4-ylethylphosphonic acid [phosphonohistidine, His(P)] and 1-amino-2-imidazol-2-ylethylphosphonic acid [phosphonoisohistidine, Isohis(P)]

Abstract

The synthesis of phosphonohistidine [His(P)] and phosphonoisohistidine [Isohis(P)] is described, in each case by a strategy in which the α-aminophosphonic acid grouping is assembled first and the imidazole ring is built last. The key α-aminophosphonic acid building block is phosphonoaspartic acid, protected as the N-acetyl phosphonate diethyl ester derivative. The n.m.r. spectra of histidine, isohistidine, phosphonohistidine, and phosphonoisohistidine are analysed at three pH values, using an iterative spin simulation program to confirm results where necessary. The preferred conformations of the four compounds are determined from vicinal H,H and H,P coupling constants. This allows prediction of the conformational differences to be expected in replacing carboxylate by phosphonate groups. In free energy terms, phosphonate appears to exert a larger steric effect than carboxylate by ca. 1 kcal mol^–1.