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

对我们最近开发的La(O-i-Pr)_3/(R)-BINOL/Ph_3PO/异丙苯不对称环氧化催化剂体系的制备条件和环氧化条件进行了微调。更准确地说，仔细考察了各种因素的影响，如(1)催化剂的组成比，(2)催化剂对每个底物的用量和浓度，(3)底物的加入时间，(4)反应温度。结果表明，在20 kg-80 kg底物的大规模实验中，以90%以上的化学产率和97%以上的ee成功地制备了所需的环氧酮。此外，合成的具有高光学纯度的环氧酮还成功地转化为相应的反α-氨基-β-羟基酸衍生物，这些化合物具有重要的药用或药用价值，没有异构化反应。另一方面，手性钪配合物SC[(R)-BNP]_3…此外，我们以前开发的新型Lewis酸催化剂，被发现能促进O-烷基羟胺与共轭烯酮的不对称Michael加成反应。因此，以较高的产率和对映体选择性(高达99%ee)合成了多种β-烷氧氨基酮。在NaO-t-Bu等碱性催化剂的作用下，Michael加合物被干净地转化为相应的氮杂环丙烷。由于这两个催化反应在室温下进行，并且几乎定量地提供了高光学纯度的产品，本两步工艺提供了一种非常实用的方法来光学提纯α-酮基氮杂环丙烷，这是另一类具有重要药学意义的合成中间体。我们还发现，在N-乙酰化条件下，α-酮基氮杂环丙烷可以转化为Synn-α-氨基-β-羟基酮。因此，利用本研究开发的手性La催化的环氧化反应和手性Sc催化的共轭烯酮的Michael反应，可以在同一底物上以光学纯的形式合成α-氨基-β-羟基酸衍生物的四种可能的非对映体。较少

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