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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DISSERTION

Abstract

Catalytic asymmetric hydrogenation is one of the most efficient and convenient methods for the preparation of optically active compounds such as chiral alcohols, amines, and amino acids, and has been widely applied in pharmaceuticals and fine chemical. Many efficient asymmetric hydrogenations have been developed in the past decades. However, there are still a large number of hydrogenation reactions which gave low enantioselectivities due to the lack of efficient chiral catalysts. Recently, in the search for highly efficient "bifunctionalized" chiral catalysts for catalytic asymmetric hydrogenations, several types of chiral amino-phosphine ligands have been developed, but none of them provided satisfied results. Thus, efficient chiral amino-phosphine ligands are still highly desirable for catalytic asymmetric hydrogenations.                                                                                                                                                    

In this dissertation, we introduced "privileged" chiral spiro backbone into amino-phosphine ligands to develop a series of chiral spiro amino-phosphine ligands SpiroAP. These spiro amino-phosphine ligands were prepared from optically pure 1,1′-spirobiindane-7,7′-diol via 7-bisarylphosphino-7′-carboxy-1,1′-spirobiindane intermediates, which were easily converted to spiro aminophosphine ligands in excellent yields using a Schmidt reaction. The iridium complexes of spiro aminophosphines were characterized by X-ray analyses of single crystal.

The iridium complexes of SpiroAPs were applied in asymmetric hydrogenation of simple ketones, and very high reactivity (TOF up to 37200 h^-1 and TON up to 10000) and high enantioselectivities (up to 97% ee) have been achived. Deuteration experiment gave the product with a deuterium at the a-position to hydroxy group, indicating that the hydrogenation took place directly at the carbonyl group of the ketone.

Employing iridium complex of chiral spiro aminophosphines we studied the asymmetric hydrogenation of exo-cyclic α,β-unsaturated ketone, and found that Ir-(R)-6e complex was also an highly efficient catalyst for this hydrogenation, offering a series of chiral cyclic allylic alcohols with up to 97% ee. This is the first example of highly efficient catalytic asymmetric hydrogenation of cyclic α,β-unsaturated ketone with an exo-double bond. Futhermore, this iridium catalytic system was also effective for the asymmetric hydrogenation of acyclic unsaturated ketones, providing the corresponding chiral acyclic alcohols in up to 92% ee.

Finally, the Ir-catalyzed α,β-unsaturated ketone hydrogenation reaction was applied to the synthesis of the active forms of loxoprofen, a non-steroidal anti-inflammatory drug. The (E)-2-(4-bromobenzylidene)cyclopentanone was firstly hydrogenated to the corresponding allylic alcohol (R)-23m in 97% yield with 93% ee. The finally chiral center was generated by asymmetric hydrogenation of the corresponding α,β-unsaturated carbonyl acid with Ir-SIPHOX catalyst. Thus, a practical method for the asymmetric synthesis of the active form of loxoprofen was developed by using two steps of asymmetric hydrogenation with chiral spiro Ir-catalysts.

In this study, 9 spiro chiral aminophosphine ligands and 29 new compounds were synthesized and confirmed by ¹H NMR, ¹³C NMR, HRMS analyses. And three iridium complexes bearing chiral aminophosphine ligands were determined by X-ray diffraction analyses. 

Key Words: spiro aminophosphine, iridium complex, asymmetric hydrogenation, ketones, α,β-unsaturated ketone, Loxoprofen

PUBLICATION

1.Jian-Bo Xie, Jian-Hua Xie*, Xiao-Yan Liu, Qian-Qian Zhang, Qi-Lin Zhou*, Chiral iridium spiro aminophosphine complexes: asymmetric hydrogenation of simple ketones, structure and plausible mechanism, Chem. Asian J. 2011, 6, 899-908.

2.Jian-Βo Xie, Jian-Hua Xie*, Xiao-Yan Liu, Wei-Ling Kong, Shen Li, and Qi-Lin Zhou*, Highly enantioselective hydrogenation of α-arylmethylene cycloalkanones catalyzed by iridium complexes of chiral spiro aminophosphine ligands, J. Am. Chem. Soc. 2010, 132, 4538-4539.