二元活性酯胺解法合成米格列奈及其区域选择性的探讨

通过(S)-2-苄基丁二酸二元活性酯中间体选择性胺解的方法得到米格列奈, 实验中发现三个活性酯胺解反应中具有不同程度的区域选择性, 其中对硝基苯酚和N-羟基琥珀酰亚胺(HOSu)活性酯选择性非常高(100∶0, 98.9∶1.1), 而N-羟基苯并三氮唑(HOBt)活性酯的选择性则只有73.6∶26.4. 采用模拟退火方法得到了三个活性酯分子的低能构象, 并采用Hartree-Fock方法在6-31G*基组水平上对其进行全几何优化, 通过对构象的分析对产生区域选择性的因素进行了初步探讨, 发现分子一端的酯基团与侧链的苄基芳环之间存在着π-π堆积作用, 并导致了低能构象中相关原子对两端羰基形成不同程度的屏蔽, 并由此产生了反应的区域选择性.

Synthesis of KAD-1229 through Amidation of Bis-activated Esters and Discussion of Regioselectivity of the Reactions

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 re-gioselectivities; 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 n-n 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.