Development of Asymmetric Acylation Reaction by Using Chiral Leaving Group and Its Application to the Synthesis of Useful Materials

本研究从手性离开基对不对称反应的研究开始。首先，从(R)-扁桃酸制备的光学活性苯并咪唑衍生物被发现在手性氨基烯醇酸的不对称酰化反应中作为有效的手性离开基团，在高达65%ee的情况下得到光学活性的α-烷基-β-草酰胺。尝试将该反应应用于β-内酰胺类抗生素的关键合成中间体的合成。虽然在β-内酰胺烯酸酯的酰化反应中没有观察到光学产率，但很明显，酰化产物3-酰基-β-内酰胺容易外消旋，与前一种情况不同。这一结果似乎暗示了手性BINAP-Ru络合物不对称还原外消旋3-酰基-β-内酰胺的可能性。尽管烯丙基铜是一种很好的酸性氯代烯丙基化试剂，但其不对称酰化反应是困难的。另一方面，利用含手性四氢吡喃基团的锂基咪唑与羰基化合物的烷基化反应合成手性咪唑类化合物的新方法。考察了新合成的咪唑类化合物作为手性配体在不对称反应中的应用。对恶唑硼烷不对称还原机理的初步研究，提出了不对称诱导的另一种可能性。在苯甲醛与二乙基锌和咪唑类化合物的手性配体的不对称烷基化反应中，通过在咪唑类化合物上引入蒽骨架，可获得高达73%的ee，从而成功地利用手性离开基团进行了不对称酰化反应，并取得了与不对称反应相关的各种新发现。进一步的研究正在进行中。

This research was commenced with the study on asymmetirc reaction by employing chiral leaving group. First, optically active benzimidazole derivative prepared from (R)-mandelic acid was found to serve as an effective chiral leaving group in the asymmetric acylation of achiral amide enolate affording optically active alpha-alkyl-beta-oxoamide in up to 65% ee. This reaction was attempted to apply to the synthesis of a key synthetic intermediate of beta-lactam antibiotics. Although no optical yield was observed in the acylation of beta-lactam enolate, it became obvious that the acylated product, 3-acyl-beta-lactam, racemized easily different from the previous case. This result seemed to suggest the possibility of asymmetric reduction of racemic 3-acyl-beta-lactam by using chiral binap-Ru complex. Asymmetric acylation of allylmetal was found to be difficult though allylcopper was found to be a good reagent for allylation of acid chloride.On the other hands, new synthetic method of chiral imidazole derivatives was developed by using alkylation of carbonyl compounds with the lithiated imidazole bearing chiral tetrahydropyranyl group on nitrogen. The newly prepared imidazole derivatives were examined as chiral ligand in asymmetric reactions. Preliminary study on the mechanism of asymmetric reduction using oxazaborolidine which was developed by Istuno and Corey, suggested another possibility of mechanism for asymmetric induction. In the asymmetric alkylation of benzaldehyde with diethylzinc and chiral ligand of imidazole derivatives, up to 73%ee was achieved by introducing anthracene framework on imidazole derivative.Thus we succeeded in the development of asymmetric acylation of amide enolate by using chiral leaving group along with various new findings concerned with asymmetric reaction. Further studies are in progress.