Synthesis of Enantiomerically Pure Diethylenetriaminepentaacetic Acid Analogues. L-Phenylalanine as the Educt for Substitution at the Central Acetic Acid

Article abstract of DOI:10.1021/jo00057a030

The enantiospecific synthesis of diethylenetriaminepentaacetic acid (DTPA) analogues from L-phenylalanine via a bis N-alkylation strategy is described.N-Alkylation of p-nitrophenylalanine benzyl ester (4) occurs readily with dibenzyl and di-tert-butyl diacetates 5a and 5b using a phosphate buffer/acetonitrile reaction medium.N,N-Dialkyl (2a,2b) and N-monoalkyl (3a,3b) derivatives of L-p-nitrophenylalanine thus are obtained directly in a single operation.Subjecting the monoalkylated material, N-(ethylamino)diacetic acid di-tert-butyl ester 3b, to a second alkylation with dibenzyl bromoethylaminediacetate 5a affords mixed pentaester 2c in which the terminal carboxyl groups are differentiated as benzyl esters at one end and tert-butyl at the other.Both complete and selective deprotections of the differentiated carboxyl groups in pentaesters 2a, 2b, and 2c are possible, allowing specific control of the carboxyl functionality at each terminus.The enantiomeric composition of monoalkyl amino acids 3a and 3b was evaluated by derivatizing with (+)-α-methylbenzyl isocyanate to afford the corresponding ureas.Analysis of the ureas by HPLC established the enantiomeric purity in each case as > 99 percent, thereby also establishing the enantiomeric purity of dialkyl compounds as > 99percent.Pentaacid 2d readily forms an optically active metal chelate with yttrium(III) as a single diastereomer.