Synthesis of chiral 1,3-bis(1-(diarylphosphoryl)ethyl)-benzenes via Ir-catalyzed double asymmetric hydrogenation of bis(diarylvinylphosphine oxides)

Article abstract of DOI:10.1007/s11426-014-5134-7

A class of chiral 1,3-bis(diarylphosphinoethyl)benzenes, which are key intermediates for the synthesis of PCP-type chiral pincer ligands, were prepared in high diastereomeric ratios and excellent ee values via double asymmetric hydrogenation of the corresponding bis(diarylvinylphosphine oxide) substrates using a SpinPhox/Ir(I) complex as the catalyst. The hydrogenation product 5a was readily transformed into the corresponding borane-protected chiral PCP-type pincer ligand 7a with high enantiomeric excess, exemplifying a viable synthetic route to optically active chiral PCP pincer ligands.

Full text of DOI:10.1007/s11426-014-5134-7

SCIENCE CHINA
Chemistry
August 2014 Vol.57 No.8: 1073–1078
doi: 10.1007/s11426-014-5134-7
• ARTICLES •
Synthesis of chiral 1,3-bis(1-(diarylphosphoryl)ethyl)-benzenes
via Ir-catalyzed double asymmetric hydrogenation of
bis(diarylvinylphosphine oxides)
LIU Xu, HAN ZhaoBin, WANG Zheng & DING KuiLing*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
Received March 31, 2014; accepted April 17, 2014; published online July 1, 2014
A class of chiral 1,3-bis(diarylphosphinoethyl)benzenes, which are key intermediates for the synthesis of PCP-type chiral pin-
cer ligands, were prepared in high diastereomeric ratios and excellent ee values via double asymmetric hydrogenation of the
corresponding bis(diarylvinylphosphine oxide) substrates using a SpinPhox/Ir(I) complex as the catalyst. The hydrogenation
product 5a was readily transformed into the corresponding borane-protected chiral PCP-type pincer ligand 7a with high enan-
tiomeric excess, exemplifying a viable synthetic route to optically active chiral PCP pincer ligands.
bis(diarylvinylphosphine oxide), iridium, asymmetric hydrogenation, PCP-type chiral pincer ligands
PCP-type ligands is relatively slow, presumably hampered
1 Introduction
by their tedious multistep syntheses and difficulties in ste-
reochemical manipulations. So far, chiral PCP-type ligands
were usually prepared by resolution or the use of stoichio-
metric chiral auxiliaries. In 1994, Venanzi and coworkers [7]
reported a multistep synthesis of the first optically pure PCP
ligand, and the use of its platinum pincer complex in the
aldol condensation of aldehydes with methyl isocyanate. In
late 1990s, Zhang and coworkers [8, 9] developed a general
method for the synthesis of chiral PCP-type ligands, by us-
ing (+)-DiPCl as a stoichiometric reagent in the key step of
1,3-diacetylbenzene asymmetric reduction. Kirchner and
coworkers [19] reported a modular synthesis of some chiral
PCP-type bis-phosphoramidite ligands containing chiral
phosphite units in 2006. There have also been several recent
literature reports on the catalytic asymmetric synthesis of
chiral diphosphine ligands, however, the examples of PCP
are only sporadical in most cases. Bergman and coworkers
[20] reported a Ru-catalyzed enantioselective synthesis of
P-stereogenic phosphine-boranes, with an example of a
bisborane protected PCP pincer ligand being obtained in
Over the past several decades, transition metal complexes
with PCP-type pincer ligands (Figure 1) have gained much
attention because of their extensive applications in various
fields of chemistry [1, 2]. The neighboring phosphine units
on the pincer-type ligands can facilitate the metal insertion
into the middle C–H bond, leading to the formation of ro-
bust metal complexes with well-defined structures and in-
teresting physicochemical properties [3]. By this way, the
PCP pincer ligands adopt tridentate coordination with tran-
sition metals, thus providing excellent opportunities to fine
tune the metal complex properties for catalysis [4–6]. Par-
ticularly, the chiral PCP-type pincer ligands can offer a
unique chiral environment and stereoelectronic features for
the resident metal, and have found successful applications
in a variety of catalytic asymmetric reactions in recent dec-
ades [7–18]. Despite the progress, the development of chiral
Dedicated to Professor Qian Changtao on the occasion of his 80th birthday.
*Corresponding author (email: kding@mail.sioc.ac.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2014
chem.scichina.com link.springer.com

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Liu X, et al. Sci China Chem August (2014) Vol.57 No.8
All solvents were purified and dried using standard proce-
dures. Melting points were measured on a RY-I apparatus
1
and uncorrected. H, 13C, 31P and 19F NMR spectra were
recorded on Varian Mercury 300 or 400 MHz spectrometers.
Chemical shifts ( values) were reported in ppm downfield
from internal TMS (1H NMR), CDCl3 (13C NMR), external
85% H3PO4 (31P NMR), and external CF3CO2H (19F NMR),
respectively. Optical rotations were determined using a Per-
kin Elmer 341 MC polarimeter. The IR spectra were meas-
ured on a BRUKER TENSOR 27 FT-IR spectrometer.
EI-MS (70 eV) and ESI-MS spectra were obtained on an
Agilent 5973N or a Shimadzu LCMS-2010EV spectrometer,
respectively. HRMS (EI), HRMS (ESI), and HRMS
(MALDI/DHB) were determined on Bruker APEXIII 7.0
TESLA FT-MS, Agilent Technologies 6224 TOF LC/MS,
or IonSpect 4.7 TESLA FTMS spectrometers, respectively.
HPLC analyses were performed on a JASCO 2089 liquid
chromatograph.
Figure 1 PCP-type pincer ligands and their metal complexes.
95% ee via asymmetric alkylation. Duan and coworkers [10,
11] reported the synthesis of a chiral PCP pincer ligand or
its Pd complex via a Pd-catalyzed double asymmetric con-
jugate addition of diarylphosphines to a phenyl-based
bisenal or bisenone compound. Leung and coworkers [21]
reported a highly diastereo- and enantioselective synthesis
of chiral PCP pincer ligands via Pd-catalyzed hydrophos-
phination of dienones with diphenylphospine. Given the
significance and challenges in PCP- type chiral ligand syn-
thesis, development of efficient, general, and enantioselec-
tive routes to these compounds are highly desirable. We
envisioned that metal catalyzed double asymmetric hydro-
genation (AH) [22–24] of 1,3-bis(1-(diarylphosp horyl)
vinyl)benzene derivatives would provide a viable route to
PCP-type chiral pincer ligands via the formation of optically
active 1,3-bis(diarylphosphinoyl) benzenes, since diphos-
phine oxides can be used as key synthetic precursors for the
diphosphine ligands [25]. In this context, Matteoli and
coworkers [26] reported in 2000 the synthesis of chiraphos,
a chiral chelating diphosphine ligand, via Ru-(S)-BINAP
catalyzed asymmetric hydrogenation of 2,3-bis(diphenylph-
osphinoyl)buta-1,3-diene. Andersson and coworkers [27]
have also disclosed a highly enantioselective synthesis of
diphenylphosphine oxides via chiral N,P-Ir catalyzed asym-
metric hydrogenation [28–38]. We have previously reported
the use of SpinPHOX/IrI catalysts 1, for efficient asymmet-
ric hydrogenation of ketimines [39], α,β-unsaturated car-
boxylic acids [40], α,β-unsaturated Weinreb amides [41],
α,α′-bis(2-hydroxyarylidene)ketones [42, 43], as well as a
range of cyclic α-alkylidene carbonyl compounds [44].
Herein, we report the first application of SpinPHOX/IrI cat-
alysts in the asymmetric hydrogenation of the challenging
1,3-bis(1-(diarylphosphoryl)vinyl)benzene derivatives, giv-
ing 1,3-bis(diarylphosphinoyl)benzenes in high diastereo-
meric ratios and excellent ee values. The synthetic utility of
the procedure was exemplified by the ready conversion of a
hydrogenation product into the corresponding enantiopure
borane-protected chiral PCP-type pincer ligand.
2.2 Synthesis of the SpinPHOX/IrI complexes (R,S)-1a–
e and (S,S)-1a–d
The Ir complexes (R,S)-1a–e and (S,S)-1a–d (Figure 2), for
the asymmetric hydrogenation reactions were synthesized by
following our previously reported procedures [39].
2.3 General procedure for the synthesis of 1,3-bis(1-
(diarylphosphoryl)vinyl)benzenes 4a–i
A reaction tube under argon atmosphere was charged with
diphenylphosphine oxide (5.2 mmol), Pd(OAc)2 (0.25
mmol), 1,2-bis(diphenylphosphino)ethane (dppe, 0.375
mmol), 1,3-diethynyl-5-substituented benzene (2.6 mmol)
and chlorobenzene (20 mL). The mixture was heated at
130 °C for 10 h. The reaction mixture was allowed to cool
to room temperature, and the solvent was evaporated in
vacuo. The residue was purified by column chromatography
on silica gel using CH2Cl2/MeOH (60:1–20:1, v/v) as the
eluents.
The characterization of compounds 4a–i were shown in
the Supporting Information online.
2.4 General procedure for asymmetric hydrogenation
of the 1,3-bis(1-(diarylphosphoryl)vinyl)benzene sub-
strates 4a–i
To a vial containing CH2Cl2 (1.5 mL) and a magnetic stir-
ring bar were added the SpinPHOX/Ir precatalyst (R,S)-1 or
2 Experimental
2.1 General information
Unless otherwise noted, all reactions and manipulations
involving air- or moisture-sensitive compounds were per-
formed using standard Schlenk techniques or in a glovebox.
Figure 2 SpinPHOX/IrI catalysts (R,S)-1a–e and (S,S)-1a–d.

Liu X, et al. Sci China Chem August (2014) Vol.57 No.8
1075
(S,S)-1 (0.015 mmol) and the substrate 4 (0.15 mmol) under
an argon atmosphere. The vial was transferred in a glove
box to a Parr steel autoclave, which was purged three times
with hydrogen and finally pressurized to the specified pres-
sure. The reaction mixture was stirred at 50 °C for 20 h. The
residual hydrogen gas was released in a hood, and the con-
using AH of diphenyl(1-phenylvinyl)phosphine oxide 2 as
the model reaction [27] and 1.0 mol% of (R,S)- or (S,S)-1 as
the catalyst. The reactions were conducted under 50 atm of
H2 at room temperature for 12 h, and the results are shown
in Table 1. For the reactions performed in dichloromethane,
large variations were observed in both the catalytic activity
(39%–>99% conversions) and the enantioselectivity (19%–
91% ee), depending on the (R,S)- or (S,S)-configu- rations
and the oxazolyl substituent of the catalyst (entries 1–9).
Under these conditions, catalysts (R,S)-1b and (S,S)-1b, both
bearing a Ph group on the (S)-oxa-zolyl moiety, turned out
to be optimal for the reaction in terms of both enantiocon-
trol and reactivity, both resulting in full substrate conver-
sions to afford the hydrogenation product 3 with 91% ee
albeit in opposite absolute configuration (entries 2 and 7).
Further screening of the reaction conditions using catalyst
(R,S)-1b revealed a profound solvent effect, as the AH of 2
in several other types of solvents all gave results inferior to
those in dichloromethane (entries 10–14 vs 2).
1
version was determined by H NMR analysis of an aliquot
of the crude mixture. The reaction mixture was filtered
through a short pad of silica gel, and the solvent of the fil-
trate was removed in vacuo to afford the product. The dia-
stereomeric ratios (dr = dl/meso) and ee values of the dou-
ble asymmetric hydrogenation products 5a–i were deter-
mined by chiral HPLC, while the 1H, 13C, 31P and 19F NMR,
and FT-IR spectral data were recorded on diastereomeric
(racemic/meso) 5a–i obtained by Pd/C catalyzed hydro-
genation of 4a–i, respectively.
The characterization of compounds 5a–i were shown in
the Supporting Information online.
2.5 Procedure for the synthesis of [(1R,1′R)-1,3-bis[1-
(diphenylphosphino)ethyl]benzene]-bisborane 7
3.2 Substrate synthesis and initial test for double
asymmetric hydrogenation of 1,3-bis(1-(diphenylpho-
sphoryl)vinyl)benzene
A reaction tube under nitrogen atmosphere was charged
with 1,3-bis(1-(diphenylphosphoryl)ethyl)benzene 5a (270
mg, 0.5 mmol), Ti(OiPr)4 (0.05 mL, 0.1 mmol), tetrame-
thyldisilazane (TMDS, 0.7 mL, 3.5 mmol), and toluene (10
mL). The reaction mixture was heated at 80 °C for 12 h,
then allowed to cool to room temperature. A solution of
BH3/THF (1.0 mol/L, 1.3 mL, 1.3 mmol) was added, and
the resulting mixture was stirred further for 12 h. The sol-
vent was evaporated in vacuo, and the residue was purified
by column chromatography on silica gel with EtOAc/hex-
ane (1:10, v/v) as the eluent to afford [(1R,1′R)-1,3-bis[1-
(diphenylphosphino)ethyl]benzene]-bisborane 7 as a white
solid. Yield: 95%; m.p. 155–156 °C ( lit. m.p. 157–159 °C)
Encouraged by the excellent preliminary results attained in
the hydrogenation of 2 with catalysts (R,S)- and (S,S)-1b,
we sought to extend this procedure to the AH of 1,3-bis(1-
(diphenylphosphoryl)vinyl)benzenes 4, a type of bisolefins
with two (diphenylphosphoryl)vinyl units on the meta-po-
sitions of a phenyl backbone. Pd/CuI catalyzed Sonogashira
Table 1 SpinPHOX/IrI (1) catalyzed AH of diphenylvinylphosphine
oxide 2 a)
[9], 99% ee, 91:9 dr, []2D0 = +189.1 (c = 1.0, CHCl3). H
1
NMR (400 MHz, CDCl3)  7.87–7.82 (m, 4H), 7.54–7.47
(m, 6H), 7.34–7.30 (m, 6H), 7.23–7.19 (m, 4H), 7.00 (s, br,
Entry
1
Cat.
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
Conv. (%) b)
> 99
> 99
> 99
> 99
> 99
72
ee (%) c)
88 (R)
91 (R)
71 (R)
83 (S)
88 (R)
67 (S)
91 (S)
19 (S)
49 (S)
88 (R)
87 (R)
80 (R)
75 (R)

(R,S)-1a
(R,S)-1b
(R,S)-1c
(R,S)-1d
(R,S)-1e
(S,S)-1a
(S,S)-1b
(S,S)-1c
(S,S)-1e
(R,S)-1b
(R,S)-1b
(R,S)-1b
(R,S)-1b
(R,S)-1b
1H), 6.89 (s, br, 3H), 3.72–3.63 (m, 2H), 1.48 (dd, JP–H
=
2
16.0 Hz, JH–H = 7.2 Hz, 6H) ppm. The enantiomeric excess
and diatereomeric ratio were determined by HPLC on
Chiralcel ID-3 column, hexane:isopropanol = 80:20, flow
rate = 0.7 mL/min, UV detection at  = 230 nm, tR = 14.5
min (major), tR = 17.0 min (meso), tR = 33.2 min (minor).
The diastereomeric mixture was further purified by
recrystallization from ethyl acetate/petroleum ether to give
(1R,1′R)-7 as a single isomer (> 99% ee).
3
4
5
6
> 99
43
7
8
39
9
74
10
11
12
13
14
CHCl3
toluene
THF
71
> 99
> 99
22
3 Results and discussion
MeOH
a) Unless otherwise noted, all reactions were conducted under 50 atm
3.1 SpinPHOX/IrI catalyzed asymmetric hydrogena-
tion of diphenyl(1-phenylvinyl)phosphine oxide 2
of H2 at 25 °C for 12 h with [2] = 0.1 mol/L and [1] = 1 mmol/L (1 mol%);
1
b) determined by H NMR spectroscopy; c) determined by HPLC, and the
absolute configurations were assigned by comparing their specific rotations
with the literature reported values [27].
The initial test for the viability of the catalysis was performed

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Liu X, et al. Sci China Chem August (2014) Vol.57 No.8
Scheme 1 Synthesis of 1,3-bis(1-(diarylphosphoryl)vinyl)benzene substrates 4a–i.
Table 2 1b-Catalyzed AH of 1,3-bis(1-(diphenylphosphoryl)vinyl) ben-
zene 4a a)
cross-coupling of 1,3-dibromo-5-substituented benzenes
with two equivalents of ethynyltrimethylsilane, followed by
desilylation of the resulting 1,3-bis ((trimethylsilyl)ethynyl)
substituted benzenes with aqueous potassium carbonate,
readily afforded the 1,3-diethynyl-5-substituted benzenes in
good overall yields (Supporting Information). Pd/dppe cata-
lyzed regioselective double Markovnikov addition of di-
phenylphosphine oxide to the meta-diethynylbenzenes [45]
proceeded smoothly in refluxing chlorobenzene, giving the
1,3-bis(1-(diarylphosphoryl) vinyl)benzene substrates 4a–i
in moderate to high yields (Scheme 1).
Cat.
(x mol%)
(R,S)-1b (2)
Conv.
(%) b)
50
ee
dr
Entry
T (°C)
5a:6 b)
(%) c)
(%) c)
25
25
25
40
50
50
50
50
1:2.9 N.D. e) N.D.
1
(S,S)-1b (2)
(R,S)-1b (5)
(R,S)-1b (5)
(R,S)-1b (5)
(R,S)-1b (5)
(R,S)-1b (10)
(S,S)-1b (10)
trace
74
N.D.
1:1.6
1:1.5
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
2
3
80
4
Subsequent efforts were made to extend the AH protocol
to 1,3-bis(1-(diphenylphosphoryl)vinyl)benzene 4a using
either (R,S)- or (R,S)-1b as the catalyst (Table 2). The reac-
tion under the conditions optimized for diphenylvinylphos-
phine oxide 2 using 2.0 mol% of (R,S)-1b as the catalyst,
however, only resulted in partial conversion (50%) of the
substrate to give compound 5a as a minor product, along
with a substantial amount of the mono-hydrogenated prod-
uct 6 (entry 1). This observation suggested that the double
asymmetric hydrogenation of 4a to 5a is most likely to pro-
ceed in a stepwise fashion via the formation of 6 as the in-
termediate. Even worse results were obtained using catalyst
(S,S)-1b under otherwise identical conditions (entry 2),
suggesting that the catalyst might be deactivated to some
extent by the weak coordination of the hydrogenation prod-
uct, and that a higher catalyst loading and/or more forcing
conditions should be resorted for double AH of 4a. Indeed,
increasing the catalyst loading of (R,S)-1b to 5.0 mol%
while gradually elevating the temperature to 50 °C, led fi-
nally to a full conversion of 4a and disappearance of 6 (en-
tries 3–5). In the last case, the double AH product 5a was
obtained quantitatively with an excellent enantiopurity
(96% ee), but the diastereomeric ratio (dl/meso) was only
moderate (70:30, entry 5). Changing the reaction medium to
toluene gave rise to essentially comparable catalytic per-
formance as that in dichloromethane (entry 6 vs 5). Grati-
fyingly, further increment of the catalyst loading of (R,S)-1b
to 10 mol% afforded complete conversion to (R,R)-5a with
> 99
> 99
> 99
> 99
1:0 96 (R,R) 70:30
1:0 96 (R,R) 66:34
1:0 98 (R,R) 85:15
1:0 97 (S,S) 83:17
5
6 d)
7
8
a) Unless otherwise specified, the reactions were conducted in di-
chloromethane in a Parr autoclave under 50 atm of H2 for 20 h with [4a] =
0.1 mol/L; b) determined by 1H NMR spectroscopy; c) the dr (dl/meso) and
ee values of 5a were determined by chiral HPLC, and the absolute config-
uration of chiral 5a was deduced to be (R,R) by comparing the optical
rotation with that of its borane protected reduction derivative (1R,1′R)-7
(vide infra); d) the reaction was conducted in toluene; e) N.D. represents
not determined.
3.3 AH of 1,3-bis(1-(diarylphosphoryl)vinyl)benzenes
and the synthesis of a PCP-type chiral pincer ligand
Under the optimized conditions, the double AH protocol
was successfully extended to a number of 5-substituted 1,3-
bis(1-(diarylphosphoryl)vinyl)benzene derivatives 4a–i. As
shown in Table 3, in each case the reaction proceeded
smoothly under the catalysis of (R,S)-1b, to afford the cor-
responding chiral bisphosphine oxides 5a–i in high dl/meso
ratios (dr 85:15–98:2). The enantioselectivities for 5a–i are
uniformly excellent (91%99% ee), irrespective of the elec-
tron-donating (entries 2 and 3) or -withdrawing (entries 4–6)
nature of the 5-substituent on the phenyl backbone. It is
noteworthy that apart from the methoxy (entry 3), fluoro
(entry 4), and carbomethoxy (entry 6) groups, the reaction
with substrate 4h bearing a free 5-hydroxymethyl group
also proceeded well with good dr and excellent ee values
(entry 8), suggesting a high functional group tolerance of
the double AH protocol.
excellent ee
(98%) and good dr (85:15) values (entry 7). It
is also interesting to note that catalyst (S,S)-1b afforded
(S,S)-5a in good dr (87:13) and 97% ee under otherwise
identical conditions, demonstrating asymmetric induction
complementary to (R,S)-1b in the double AH of 4a.
To demonstrate the synthetic utility of the present pro-
cedure, the product (+)-5a was reduced to the corresponding

Liu X, et al. Sci China Chem August (2014) Vol.57 No.8
1077
Table 3 1b-Catalyzed AH of 1,3-bis(1-(diarylphosphoryl)vinyl)benzenes
4a–i a)
This work was financial supported by the Basic Research Development
Program of China (2010CB833300), the National Natural Science
Foundation of China (21121062, 21232009), the Chinese Academy of
Sciences, and the Science and Technology Commission of Shanghai
Municipality.
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Entry
Substrate
R
H
Ar
Ph
ee (%) b)
98 (+)
98 (+)
98 (+)
98 (+)
99 (+)
98 (+)
95 (+)
91 (+)
99 (+)
dr (%) b)
85:15
92:8
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
Me
Ph
OMe
F
Ph
85:15
86:14
90:10
90:10
93:7
Ph
4
5
Cl
Ph
COOMe
Ph
Ph
Ph
4g
4h
4i
CH2OH
H
Ph
93:7
p-Tol
98:2
6
7
a) The reactions were performed in a Parr autoclave under 50 atm of H2
with 0.15 mmol of 4a–i in CH2Cl2 (1.5 mL) in the presence of 10 mol% of
(R,S)-1b at 50 °C, and the conversion in each case was determined to
be > 99% by H NMR analysis; b) the dr and ee values of 5a–i were de-
termined by chiral HPLC.
1
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3126
bisphosphine by treatment with TMDS in THF, which upon
in situ borylation with BH3·THF gave the corresponding
air-stable bisborane-protected chiral PCP-type pincer ligand
(R,R)-7 in 99% ee with 9% meso isomer (Scheme 2). Puri-
fication of 7 by recrystallization from ethyl acetate/petro-
leum ether gave a single optically pure (R,R)-enantiomer,
which would allow for a facile access to the corresponding
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In summary, we have developed an efficient procedure for
the synthesis of chiral 1,3-bis(diarylphosphinoethyl)ben-
zenes, via double asymmetric hydrogenation of 1,3-bis(1-
(diarylphosphoryl)vinyl)benzenes using the Ir(I) complexes
1 as catalysts. Good to high diastereomeric ratios (up to
98:2) and excellent ee values (91%–99%) were achieved for
the resulting chiral bisphosphine oxides, which can be read-
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cer ligands via simple synthetic manipulations. Further
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DING KuiLing was born in Henan Province (China) in 1966. He received his B.Sc. degree from
Zhengzhou University in 1985 and Ph.D. degree from Nanjing University in 1990 under the supervi-
sion of professor Yangjie Wu. He became an assistant professor at Zhengzhou University in 1990
and full professor at the same place in 1995. During 1993–1994 he was engaged in postdoctoral re-
search with professor Teruo Matsuura at Ryukoku University (Japan). In the period from 1997 to
1998 he was a UNESCO research fellow with Professor Koichi Mikami at Tokyo Institute of Tech-
nology (Japan). He joined the Shanghai Institute of Organic Chemistry in 1999, where he is currently
a professor of chemistry. His research interests include development of new chiral catalysts and
methodologies for asymmetric catalysis.