EDUCATION 

2001.9 - 2005.6 Nankai University, College of Chemistry, B. S.

2005.9 - 2010.6 Nankai University, SKLEOC, Ph. D.

CONTACT

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Address: Zhejiang Jiuzhou Pharmaceutical Co. LTD, 99 Waisha Road, Jiaojiang District, Taizhou City, Zhejiang Province, PRC Postal (318000)

DISSERTATION

Abstract

    Chiral amines are indispensable building blocks for the synthesis of pharmaceuticals and natural products. Developing highly efficient asymmetric catalytic methods to synthesize chiral amines has drawn increasing attention in both academic research and industrial production.  Transition-metal-catalyzed asymmetric hydrogenation of prochiral enamines and imines represents one of the most efficient and atom-economic methods for preparing chiral amines. In the past decades, a variety of chiral catalysts have been developed for the hydrogenation of different enamines and imines in high enantioselectivities. However, the efficiency of the catalysts is highly substrate-dependent. Especially for the asymmetric hydrogenation of non-acyl enamine substrates, very few successful examples have been reported. Thus, more efficient chiral catalysts are highly desirable in this useful reaction. In this dissertation, we demonstrated that the iridium/monodentate phosphorus ligand complexes were highly efficient catalysts for the asymmetric hydrogenation of non-acyl enamines and isoquinoline-type imines, providing optically active amines in high activities and enantioselectivities under mild conditions.

    We reported a detailed investigation of asymmetric hydrogenation of tetrahydroisoquinoline-type enamines with an exocyclic double bond using chiral spiro iridium complexes as catalysts. Optimization of reaction conditions showed that the chiral spiro iridium/(Sa,R,R)-SIPHOS-PE complex was the most efficient catalyst. Using 1 mol% catalyst, a series of N-alkyl tetrahydroisoquinoline-type enamines could be hydrogenated under 1 atm H2, providing the corresponding chiral tetrahydroisoquinolines with excellent enantioselectivities (up to 98% ee). This was also the first example for the asymmetric hydrogenation of non-acyl enamines with exocyclic double bond. Furthermore, we found that a positive non-linear effect and an inverse isotope effect existed in this reaction. Two equivalent ligands were required for achieving high reactivity and enantioselectivity. These results demonstrated that the active catalyst containing two (Sa,R,R)-SIPHOS-PEs. A mechanism involving a catalytic cycle between IrI and IrIII promoted by iodine or iodide was also proposed. 

    We investigated the asymmetric hydrogenation of simple enamines which derived from ketones using chiral spiro iridium complexes as catalysts. A series of monophosphoramidite ligands with two aryl groups on the N atom were synthesized  and applied in the iridium-catalyzed asymmetric hydrogenation of simple enamines. The chiral spiro iridium/(R)-42 complex with I2 as additive was proved to be the most efficient catalysts. Under the optimal conditions, a variety of simple enamines was hydrogenated in moderate to good enantioselectivities (up to 90% ee).

    We also reported an investigation of asymmetric hydrogenation of isoquinoline-type imines using chiral spiro iridium complexes as catalysts. The chiral spiro iridium/(Ra,S,S)-SIPHOS-PE complex with 10 mol% KI as additive was the most efficient catalyst. Under the optimal conditions, a variety of isoquinoline-type imines was hydrogenated in excellent enantioselectivities (up to 99% ee), providing the optically active N-H tetrahydroisoquinolines. The deuterium-labeling study implied that an H/D exchang took place at the -position during the reaction.

Key Words: iridium, chiral spiro monophosphoramidite ligand, chiral amine, enamine, imine, asymmetric hydrogenation 

PUBLICATION

1.Pu-Cha Yan, Jian-hua Xie, Qi-Lin Zhou*, Asymmetric hydrogenation of unfunctionalized enamines catalyzed by iridium complexes of chiral spiro N,N-diarylphosphoramidites, Chinese J. Chem. 2010, 28, 1736-1742.

2.Pu-Cha Yan, Jian-Hua Xie, Guo-Hua Hou, Li-Xin Wang, Qi-Lin Zhou*, Enantioselective synthesis of chiral tetrahydroisoquinolines by iridium-catalyzed asymmetric hydrogenation of enamines, Adv. Synth. Catal. 2009, 351, 3243-3250.