Stereochemically controlled synthesis of diethylenetriaminepentaacetic
acid (DTPA) analogues substituted on the ethylene backbones with meth
yl groups, the chiral center a to the terminal nitrogen being derived
from (S)- or (R)-alanine, has been achieved. The key intermediate (S)-
propylenediaminetriacetic acid triester was synthesized via selective
detosylation of the alkylation product derived from (S)-alanine and te
rt-butyl glycinate. Attaching the remaining modified alanine (or glyci
ne) fragment through acyl coupling and then selective reduction of the
amide followed by hydrolysis of the esters afforded the substituted D
TPA analogues. Ester differentiation has been accomplished through alk
ylation rather than acylation of the (S)-propylenediaminetriacetic aci
d triester. A byproduct from this alkylation is the oxazoloisoindole f
ormed by internal alkylation of the oxygen of the phthaloyl protecting
group. Phthaloyl deprotection followed by dialkylation afforded the e
ster-differentiated (S,S)-dipropylenetriaminepentaacetic esters. The e
nantiomeric purity of the chiral intermediates (S)-alaninol and (S)-pr
opylenediamines were determined by HPLC using epimeric standards.