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

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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.