新型手性PNO配体的合成及其在酮的不对称氢化中的应用

Ir-catalyzed asymmetric hydrogenation of ketones using novel PNO phosphine ligands

设计并合成了一种新型的PNO配体.该配体具有原料易得、合成简单、易于纯化等优点.通过市售的手性原料经过三步简单反应便可得到该配体.该配体与[Ir(COD)Cl]2(COD,1,5-环辛二烯)在四氢呋喃(THF)中混合可原位获得手性催化剂,催化苯乙酮及其衍生物的不对称氢化反应.该反应体系所得到的手性醇产物的产率最高可达>99%,ee值最高可达99%.该催化剂对烷基芳基酮能够展现出很好的催化效率,但是对于双烷基酮氢化的手性控并不理想.在一个较大规模的反应中(12 g底物),催化转化数(TON)可达100000.

The asymmetric hydrogenation of ketones continue to be a hot research topic because of the importance of secondary chiral alcohols in the production of pharmaceuticals and many other products.For example,based on the asymmetric hydrogenation of ketones,our group has synthesized Duloxetine and Ezetimibe,which were important and best selling antidepressant and antihyperlipidemic drugs.On the other hand,phosphine ligands were found to be the critical factor to increase the activity of metal catalysts.Thus,since the successful application of BINAP by Noyori and co-workers,hundreds of phosphine ligands have been developed for the more efficient transformation of ketones into chiral alcohols.For example,BPE ligand reported by Burk group in 1993,Miniphos ligand synthesized by Imamoto and coworkers in1999,series of SDP ligands developed by Zhou group since 2002,were both efficient and successful ligands for the asymmetric transformation of different ketones.Since 1997,our group also contributed many improved ligands for this reaction,such as,Binapine,f-amphox,et al.Despite significant achivements,there are still some questions to be solved in this area.For example,the synthesis of needed ligands demands hash reaction conditions and expensive starting materials,and sometimes the purification of the corresponding ligands was hard.Thus,new ligands or new synthetic methods are still in need for the more efficient transformation.Recently,we got interested in the introduction of prolinols as building blocks for the modification of ligands to control the enantioselectivity of this transformation.As a class of commercial available chiral building blocks,prolinol and its derivatives were increasingly applied as ligands or additives in the controls of enantioselectivity of organic transformations.In this context,combining our long standing interests in the developing of ferrocene based ligands,we designed and synthesized some novel PNO type phosphine ligands through three simple steps.Notably,the applied starting materials for these ligands were both commercially available chiral building blocks.The corresponding ligands have the advantages of easily available starting material,convenient synthesis,and simple purification.With these ligands in hand,we tested their catalytic activity on Ir-catalyzed asymmetric hydrogenation of acetophenone,which gave 99%conversion and high ee value of the product.Encourage by these positive result,we further optimized the reaction conditions including the solvent,base species,H2 pressure,and the catalyst loading.THF was the best solvent among the test solvents.Since most of the tested base species giving similar results,we assumed base has only slight effect on both the conversion of acetophenone and the enantioselectivity of corresponding product.In some additional reaction conditions screening experiments,we found that a higher H2 pressure or a higher catalyst loading was favorable for the conversion of acetophenone and the enantioselectivity of corresponding product.Thereafter,various different ketones were tested using the optimal reaction conditions.This catalytic system was compatible well with halides substitutions,methoxy gourps,and-CF3 gourps,and also possible for the application in the transformation of heterocycles.Herein,an efficient and practical protocol was developed for the asymmetric hydrogenation of ketones.The proposed catalytic system gave the corresponding chiral secondary alcohols in up to>99%yield,99%ee,and 100000 TON.In view of the high efficiency and easy synthesis of the ligand,we assume this work has remarkable potential regarding industrial process in the near future.