Angewandte
Chemie
DOI: 10.1002/anie.201411384
Asymmetric Catalysis
ZnCl2-Promoted Asymmetric Hydrogenation of b-Secondary-Amino
Ketones Catalyzed by a P-Chiral Rh–Bisphosphine Complex**
Qiupeng Hu, Zhenfeng Zhang, Yangang Liu, Tsuneo Imamoto, and Wanbin Zhang*
Abstract: A new catalytic system has been developed for the
asymmetric hydrogenation of b-secondary-amino ketones
using a highly efficient P-chiral bisphosphine–rhodium com-
plex in combination with ZnCl2 as the activator of the catalyst.
The chiral g-secondary-amino alcohols were obtained in 90–
94% yields, 90–99% enantioselectivities, and with high
turnover numbers (up to 2000 S/C; S/C = substrate/catalyst
ratio). A mechanism for the promoting effect of ZnCl2 on the
catalytic system has been proposed on the basis of NMR
spectroscopy and HRMS studies. This method was successfully
applied to the asymmetric syntheses of three important drugs,
(S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine, in high
yields and with excellent enantioselectivities.
(Figure 1).[6] A reason for the challenges facing the hydro-
genation of b-secondary-amino ketones is probably due to the
difficulty in finding an efficient catalyst system which has both
high catalytic activity and stereoselectivity.
Figure 1. Important drugs prepared from chiral g-secondary-amino
alcohols.
O
ver the last half century, remarkable progress has been
made in the area of asymmetric hydrogenation and it remains
an important topic of research because of its great potential
for industrialization.[1,2] Among the many substrates, b-amino
ketones have attracted considerable attention[3,4] because of
their use in the preparation of chiral g-amino alcohols, species
widely used as ligands and pharmaceutical intermediates.[5,6]
Unlike the extensive research on b-tertiary-amino ketones,[3]
only a few studies have focused on the asymmetric hydro-
genation of b-secondary-amino ketones for the preparation of
chiral g-secondary-amino alcohols.[3a,b,4] However, procedures
involving b-secondary-amino ketones have higher efficiency
and greater atom economy than those involving their tertiary
counterparts in the syntheses of a number of important drugs
such as (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine
Over the last several years, our research has focused on
the asymmetric hydrogenation of several types of substrates.[7]
During our continuing research interest in the synthesis of the
above-mentioned drug molecules, we have made encouraging
progress towards the asymmetric hydrogenation of b-tertiary-
amino ketones, a route through which (R)-fluoxetine and (R)-
atomoxetine could be synthesized with excellent enantiose-
lectivities.[7d] However, the application of this method to
thienyl-substituted substrates was unsuccessful, probably due
in part to the additional coordination ability of the sulfur
atom. To realize the synthesis of (S)-duloxetine and improve
the process efficiency, we have been searching for an efficient
catalytic system for the asymmetric hydrogenation of b-
secondary-amino ketones with both excellent enantioselec-
tivity and high yield and turnover number.
Electron-rich P-chiral bisphosphine ligands, including
BisP*, Miniphos, QuinoxP*, and BenzP*, have been utilized
since 1998 in the Rh-catalyzed asymmetric hydrogenation of
enamides with remarkably high stereoselectivities and reac-
tivities.[8] Considering their similar coordination configura-
tions, these ligands were tested in the Rh-catalyzed asym-
metric hydrogenation of b-methylamino ketones. Initially, 3-
(methylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride
(1a·HCl) was used as a model substrate (Table 1). The
hydrogen chloride is required to stabilize the free b-methyl-
amino ketone. In the absence of hydrogen chloride, the free
1a is unstable and can undergo a facile elimination to give an
a,b-unsaturated ketone which subsequently undergoes a con-
secutive Michael addition and cyclization with 1a to give
compound 3a. Hydrogenations involving the direct use of
freshly prepared 1a are also unsuccessful. However, the
hydrogenation of 1a·HCl also failed when performed under
H2 pressure (25 atm) and at room temperature. Only in the
[*] Q. Hu, Dr. Z. Zhang, Prof. Y. Liu, Prof. W. Zhang
School of Pharmacy, Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (P. R. China)
E-mail: wanbin@sjtu.edu.cn
Prof. W. Zhang
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (P. R. China)
Prof. T. Imamoto
Department of Chemistry, Graduate School of Science
Chiba University, Chiba 263-8522 (Japan)
[**] This work was partially supported by the National Natural Science
Foundation of China (No. 21172143, 21202096, 21232004, and
21472123), Science and Technology Commission of Shanghai
Municipality (No. 14XD1402300), and Shanghai Jiao Tong Univer-
sity (SJTU). We gratefully acknowledge the generous gifts of the four
P-chiral bisphosphine ligands from Nippon Chemical Industrial Co.
Ltd. and Dr. Masashi Sugiya for helpful discussion. We also thank
the Instrumental Analysis Center of SJTU for characterization.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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