Development of Highly Efficient and Practical Chiral Rare Earth Catalysts and Its Use

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Fine-tuning of the preparation conditions of our recently developed catalyst system [La(O-i-Pr)_3/(R)-BINOL/Ph_3PO/cumene hydroperoxide] for the asymmetric epoxidation of conjugated enones as well as the epoxidation conditions was carried out. To be more precise, influence of various factors, such as (1) ratio of the components of the catalyst, (2) amount and concentration of the catalyst to each substrate, (3) addition time of the substrates, and (4) reaction temperatures, was carefully examined. As a result, we succeeded in the preparation of the desired epoxy ketones in over 90 % chemical yields with over 97 % ee in large-scale experiments using 20 kg - 80 kg of substrates. Furthermore, the resulting epoxy ketones with high optical purities were successfully converted into the corresponding anti-α-amino-β-hydroxy acid derivatives, which are medicinally or pharmaceutically important substances, accompanying no epimerization.On the other hand, the chiral scandium complex Sc[(R)-BNP]_3 … More , previously developed by us as a novel Lewis acid catalyst, was found to promote the enantioselective Michael addition of O-alkylhydroxylamines to conjugated enones. Thus, a variety of β-alkoxyamino ketones were synthesized in high yields and enantioselectivities (up to 99 % ee). The Michael adducts were cleanly converted into the corresponding aziridines by the treatment with a base catalyst like NaO-t-Bu. As these two catalytic reactions proceed at room temperature and almost quantitatively afford the products with high optical purities, the present two-step process provides a highly practical way to optically pure α-keto aziridines, another pharmaceutically important family of synthetic intermediates. We also found that the α-keto aziridines can be converted to the syn-α-amino-β-hydroxy ketones under the N-acetylation conditions.Therefore, the possible four diastereomers of α-amino-β-hydroxy acid derivatives may be prepared in optically pure forms from a common substrate by utilizing the chiral lanthanum-catalyzed epoxidation and the chiral scandium-catalyzed Michael reaction of conjugated enones developed in this study. Less