【作者】 胡杨；

【导师】 张绪穆；

【作者基本信息】 武汉大学 ， 有机化学， 2018， 博士

【摘要】 手性醇类化合物由于具有独特的生物活性,因此不管是在医药合成还是在农业生产中均有着广泛的应用。不对称氢化法无疑是得到单一构型的手性化合物最为直接和有效的方法。尽管自Nyori报道了 Ru-BINAP经典催化体系以来,碳氧双键的不对称氢化领域已经得到了长足的发展,但是仍然存在很多急需解决的问题。比如直链脂肪酮,至今仍无法实现高选择性的不对称氢化。与此同时,部分在工业中有着重要作用的酮类底物虽然已经实现了高对映选择性的氢化,但是距离工业化需求仍然有一定的距离。因此,发展高催化活性、高对映选择性的碳氧双键不对称氢化技术不仅对于科学研究,对于工业生产和人们的日常生活都有着极为重要的意义。在本论文所报道的工作中,我们首先成功的将Ir/f-amphox体系应用于一系列α-氨基酮的不对称氢化,高效的制备了与底物相对应的手性1,2-氨基醇,取得了令人瞩目的成果。在TON=50 000的情况下,所有底物,不论是苯基上带有不同取代基的酮,还是氨基上带有不同取代基的酮,亦或是杂环芳香酮,均取得了>99%转化率和>99%的ee值;将TON提高到500 000转化率和ee值仍然能够保持>99%。同时,我们还提供了一条合成α-肾上腺素能受体激动剂(S)-phenylephrine的可行的路线。之后,我们又成功的开发了一条高效利用Ir/f-amphox催化体系不对称氢化多种前手性α-,β-,γ-,δ-酮酰胺来制备一系列底物之相对应的羟基酰胺的路线,取得了令人满意的结果。绝大多数底物得转化率和ee值均在99%以上。不仅如此,我们的催化体系还在对底物5-(4-氟苯基)-5-羰基-N-苯基戊酰胺的不对称氢化中体现出了极高的催化活性。在催化剂载量仅为0.002mol%(S/C = 50000)的情况下,Ir/f-amphox催化体系顺利实现了目标底物的不对称氢化,取得了>99%的转化率,98%的收率以及>99%的ee值。该反应的氢化产物是用于制备降血脂药物Ezetimibe的重要结构单元。最后为了克服原有的f-amphox催化体系无法高效催化氢化β-芳基酮酸衍生物该缺陷,我们设计并合成了一种新的f-amphox系列手性三齿配体indan-f-amphox。该新配体在Ir催化的β-芳基酮酸酯的不对称氢化中表现出了较高的催化活性和对映选择性。通过使用Ir/indan-f-amphox催化体系,我们实现了一系列β-芳基酮酸酯的高效不对称氢化,得到了与之相对应的羟基酮酸酯,取得了最高96%的ee值以及10 000的TON。更多还原

【Abstract】 Chiral alcohols are important building blocks in the fields of pharmaceutical,agrochemical industries,due to their distinct biological activities.In principle,preparation of chiral alcohols through catalytic asymmetric hydrogenation(AH)of readily available pre-chiral ketones is one of the most straightforward and operationally simple approaches.Although the homogeneous asymmetric hydrogenation of ketones has already achieved a great success,since the Noyori’s novel catalytic systems were reported,there are still many urgent problems in this field.For example,highly efficient catalytic system for the asymmetric hydrogenation of aliphatic ketone has not been found until now.Therefore,the asymmetric hydrogenation of ketones is still a research field that needs to be explored.In this dissertation,we performed the following work:1)Tridentate f-amphox ligands were successfully applied to the iridium-catalyzed asymmetric hydrogenation of various a-amino ketones to afford a series of chiral 1,2-amino alcohols with excellent results(all products up to>99%conversion and>99%ee,TON up to 500 000).The products chiral 1,2-amino alcohols are important motifs in many pharmaceuticals,chiral auxiliaries and ligands.Our catalytic system provided an efficient synthetic route to prepare important chiral intermediate of(S)-phenylephrine with practical industrial potential(up to 200 000 TON and>99%ee),which is the enantiomer of a famous a-adrenergic receptor agonist.2)Asymmetric synthesis of chiral hydroxy amides has been successfully accomplished by enantioselective catalytic hydrogenation of various prochiral α-,β-,γ,-8-keto amides in the presence of Ir/f-amphox catalyst with excellent results(almost all products with>99%conversion and>99%ee).Furthermore,a gram-scale asymmetric hydrogenation of 5-(4-fluorophenyl)-5-oxo-N-phenylpentanamide proceeded smoothly with only 0.001 mol%(S/C = 50 000)catalyst.The hydrogenation product was obtained with 98%yield and>99%ee,which is the important structural framework of an anti-hyperlipidemic drug Ezetimibe.3)A new chiral tridentate PNN ligand,[(RC,SC)-SC,RFC]-indan-f-amphox(a sister ligand of(SC,SC,RFC)-f-amphox),was synthesized and has formed an iridium catalyst for the direct hydrogenation of β-aryl β-ketoesters.A wide range of β-aryl β-ketoesters are reduced by Ir(III)-f-amphox catalyst with excellent enantioselectivities and reactivities(up to 99%ee,10 000 TON).更多还原