KAD-1229 was obtained through regioselective amidation of bis-activated esters of (S)-2-benzylsuccinic acid. It was found that amidation of three different activated esters yielded different regioselectivities; amidations of p-nitrophenyl ester and N-hydroxysuccinimide ester gave high regioselectivity (100∶0 and 98.9∶1.1) while N-hydroxybenzotriazole (HOBt) ester produced lower regioselectivity (73.6∶26.4). By the way of simulated annealing, the stable conformations of the three activated esters were obtained. The structures have been fully optimized using a Hartree-Fock method at 6-31G* level. The regioselectivity of these reactions was studied via analysis of these stable conformations, finding that there exists the π-π stacking interaction between the ester group and the benzyl aromatic-ring in the molecule. The π-π stacking interaction resulted in somewhat shield on the carbonyl group from related atoms in the stable conformations, thus different regioselectivities of these reactions were obtained.

Key words: KAD-1229, bis-activated ester, regioselectivity, molecular modeling, π-π stacking interaction