Synthesis of conformationally constrained DTPA analogues. Incorporation of the ethylenediamine units as aminopyrrolidines

Article abstract of DOI:10.1021/jo00092a022

The synthesis of conformationally constrained diethylenetriaminepentaacetic acid (DTPA) analogues is an effort to probe the relationship between ligand structure and metal complex stability. In the pursuit of this objective, diastereomerically and enantiomerically pure mono- and bis-pyrrolidine analogues of DTPA have been prepared from trans-4-hydroxy-L-proline. The mono-pyrrolidine chelator 1 was constructed from a single hydroxyproline unit and an ethylenediamine moiety while two hydroxyproline-derived fragments 4e or 14b and 9b were coupled by N-alkylation of a triflate to afford the core bis-pyrrolidine structures: optically active 10 and meso-15. Deprotection of the triamine pentaesters 12 and 17 afforded the triamine pentaacetic acids 2 and 3 as their hydrochloride salts. The stereochemical homogeneity of precursor esters 12 and 17 was determined by HPLC using authentic epimeric standards to establish that essentially no racemization of the original amino acid α-center had occurred. Some loss of stereochemical homogeniety was encountered in the synthesis of 10 and 15 by N-alkylation of aminoproline 9b with a hydroxyproline-derived triflate, which had proceeded with some retention of configuration. The diastereomeric impurities were removed by crystallization of the respective benzyl carbamates. Bis-pyrrolidine pentaacids 2 and 3 formed isolable chelates with gadolinium and lutetium. A comparision of the lutetium chelates of 2 and 3 by NMR revealed significant differences which were reflective of a rigid structure with 2, while metal complexation with 3 was structurally less defined.