A new chiral dipyridylphosphine ligand Xyl-P-Phos and its application in the Ru-catalyzed asymmetric hydrogenation of β-ketoesters

Article abstract of DOI:10.1016/S0040-4039(02)00062-X

A new chiral dipyridylphosphine ligand Xyl-P-Phos has been synthesized and the structure of (S)-Xyl-P-Phos oxide has been characterized by single crystal X-ray diffraction. The ruthenium complex of this ligand, Ru(R-Xyl-P-Phos)(C₆H₆)Cl₂, has been found to be a highly active, enantioselective and air-stable catalyst for the asymmetric hydrogenation of β-ketoesters and shows good potential for industrial applications.

Full text of DOI:10.1016/S0040-4039(02)00062-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1539–1543
A new chiral dipyridylphosphine ligand Xyl-P-Phos and its
application in the Ru-catalyzed asymmetric hydrogenation of
b-ketoesters
Jing Wu, Hua Chen, Wai Him Kwok, Kim Hung Lam, Zhong Yuan Zhou, Chi Hung Yeung* and
Albert S. C. Chan*
†
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis and
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
Received 8 November 2001; accepted 4 January 2002
Abstract—A new chiral dipyridylphosphine ligand Xyl-P-Phos has been synthesized and the structure of (S)-Xyl-P-Phos oxide has
been characterized by single crystal X-ray diffraction. The ruthenium complex of this ligand, Ru(R-Xyl-P-Phos)(C H )Cl , has
6
6
2
been found to be a highly active, enantioselective and air-stable catalyst for the asymmetric hydrogenation of b-ketoesters and
shows good potential for industrial applications. © 2002 Published by Elsevier Science Ltd.
The transition-metal-catalyzed asymmetric hydrogena-
tion reaction is one of the most efficient methods for
preparing a wide range of enantiomerically pure com-
achieved in the use of chiral arylphosphine ligands in
Rh- and Ru-catalyzed asymmetric reactions, chiral
phosphine ligands containing heterocyclic moieties such
as pyridyl groups have been relatively unexplored even
though the expansion of the scope of the metal phos-
phine chemistry with the rich chemistry of heterocyclic
functionalities is quite obvious. Some transition-metal
complexes with pyridylphosphine ligands have been
1
pounds. The quest for highly efficient chiral ligands
plays a crucial role in expanding the utility of this
strategy. Consequently, the number of novel chiral
ligands for catalytic asymmetric hydrogenation is grow-
ing rapidly and chiral bisphosphines (e.g. DIPAMP,
BINAP, BIMAP, DIOP, DuPhos, BDPP, etc.) have
proved to be among the most useful and versatile
synthesized and found to be inactive in homogeneous
3
hydrogenations. We have developed
a
class of
1
,2
4a,4b
ligands.
In contrast to the tremendous success
dipyridylphosphine ligands (Fig. 1), P-Phos 1
and
OCH3
OCH3
OCH3
CH3
N
N
N
N
N
P
CH3O
P
P
P
P
CH3
CH3
2
2
CH3O
CH3O
CH3O
CH3O
2
2
2
2
CH3
CH3
CH3O
P
N
OCH3
OCH3
CH3
OCH3
(R)-P-Phos (1)
(R)-Tol-P-Phos (2)
(R)-Xyl-P-Phos (3)
Figure 1.
Keywords: asymmetric hydrogenation; dipyridylphosphine ligands; ruthenium complex; b-ketoester.
*
Corresponding authors. Tel.: +00-852-27665607; fax: +00-852-23649932; e-mail: bcachan@polyu.edu.hk
University Grants Committee Area of Excellence Scheme (Hong Kong).
†
0
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00062-X

1
540
J. Wu et al. / Tetrahedron Letters 43 (2002) 1539–1543
4
c
Tol-P-Phos 2, and found their Ru(II) complexes to be
highly effective in the catalytic asymmetric hydrogena-
tion of 2-(6%-methoxy-2%-naphthyl)propenoic acid and
b-ketoesters.
The optical resolution of the racemate (±)-8 was carried
out via the formation of complexes with resolving
9
agents (2R,3R)-(−)- and (2S,3S)-(+)-DBT. The abso-
lute configuration of (−)-8 was established as S by a
single crystal X-ray analysis of the diastereoisomerically
10
Since steric hindrance effects are important in the devel-
opment of effective chiral ligands, in this study, we
have now synthesized a new P-Phos derivative 2,2%,
,6%-tetramethoxy-4,4%-bis[di(3,5-dimethylphenyl)phos-
phino]-3,3%-bipyridine (Xyl-P-Phos 3) by introducing
,5-dimethyl groups into the four phenyl rings in P-
pure 1:1 complex of (−)-8-(+)-DBT (Fig. 2). In the
complex, equimolar (−)-8 and (+)-DBT are connected
in a regularly alternating manner through two inter-
molecular hydrogen bonds between the hydrogen atoms
of the COOH groups of (+)-DBT and the oxygen atoms
[O(1) and O(2)] of the P=O groups in compound 8
thus building up infinite close-packed chains. The O
(1)···O (7) and O (2A)···O (10) distances are 2.505 and
6
3
Phos as a means to tune its electronic and steric proper-
ties. The results revealed that the new ligand 3 was even
more effective than 1 and 2 in the Ru-catalyzed hydro-
genation of b-ketoesters. Herein, we report the synthe-
sis of 3 (Scheme 1), the molecular structure of the
2.488 A
resolved by this method, was over 99.9% ee according
,
, respectively. The enantiomeric purity of (+)-8,
11
to HPLC analysis.
complex of (S)-3 oxide with (+)-dibenzoyl-D-tartaric
acid ((+)-DBT), as well as the application of this new
To examine the efficiency of the new chiral ligand 3 in
transition-metal-catalyzed asymmetric hydrogenation
reactions in comparison with those of 1 and 2, we first
prepared Ru(R-Xyl-P-Phos)(C H )Cl [(R)-9] using the
ligand in asymmetric hydrogenations.
Our synthetic approach to the enantiomerically pure
6
6
2
12
ligands (R)- and (S)-3 is depicted in Scheme 1. The
method of Mashima et al. (Scheme 2). The coordina-
tion of benzene to ruthenium makes the two phospho-
rus atoms of (R)-3 magnetically non-equivalent,
5
ortho-lithiation of 4 with lithium diisopropylamide
(
LDA) in THF at −78°C followed by the addition of
31
bis(3,5-dimethylphenyl)chlorophosphine (5) produced 6
in 56% yield. Substituted pyridine 4 was prepared
therefore the P NMR spectrum of (R)-9 displayed an
AB pattern centered at l 33.49 (JPA–PB=62.1 Hz) and
39.96 (JPA–PB1=62.5 Hz). The absorption observed at l
5.65 in the H NMR spectrum is assignable to the
4c,6
according to
a
literature method
whilst the
chlorophosphine species 5 was obtained by treating
6
(
(
(
Et N)PCl with
2
equiv. of ArMgBr (Ar=3,5-
h -coordinated benzene moiety.
2
2
CH ) C H ) followed by the treatment with dry HCl
3
2
6
3
7
88% yield). The oxidation of 6 with H O in acetone
(R)-9 was tested in the asymmetric hydrogenation of a
variety of b-ketoesters 10a–d to give optically active
b-hydroxy carboxylic esters, which are an important
class of intermediates for the synthesis of various com-
pounds such as carbacephems, tetrahydrolipstatin or
2
2
at 0°C provided 7 (99% yield) which was transformed
to the racemic oxide 8 of Xyl-P-Phos (85% yield) via an
Ullmann coupling reaction. Reduction of the resolved
phosphine oxide 8 by trichlorosilane in the presence of
triethylamine afforded optically pure ligand Xyl-P-Phos
13
(+)-brefeldin A. The experimental results are summa-
rized in Table 1. The hydrogenation of 10a as a stan-
dard substrate was attempted first and it was found
1
13
31
3
which was characterized by H, C, P8 NMR and
mass spectroscopy and elemental analysis.
Scheme 1. The synthetic route towards Xyl-P-Phos 3.

J. Wu et al. / Tetrahedron Letters 43 (2002) 1539–1543
1541
Figure 2. ORTEP drawing of the complex (S)-8-(+)-DBT with numbering schemes. Selected bond distances (A
,
): C(5)ꢀC(6)=
1
.500(4), O(1)···O(7)=2.505,
P(1)ꢀC(1)=1.813(3), P(2)ꢀC(10)=1.818(3),
P(1)ꢀO(1)=1.497(19),
P(2)ꢀO(2)=1.497(2),
O(2A)···O(10)=2.488.
Scheme 2.
that the reaction at 70°C under 200 psi of H was
may lead to a significant decrease of the catalyst activity
and enantioselectivity. The rigorous degassing of reac-
tion systems using nitrogen gas is essential to keep the
activities of many catalysts, which makes industrial
applications more difficult. In this study, we found the
Ru(R-Xyl-P-Phos)(C H )Cl catalyst system to be air-
2
completed in only 1 h with 97.1% ee (entry 1). Further
studies on the hydrogenation of other b-ketoesters confi-
rmed the consistently high activity and enantioselectivity
of 9 in these reactions (entries 2–7).
6
6
2
While enantioselectivity is a major concern in asymmetric
synthesis, the demonstration of high substrate-to-catalyst
ratio with consistently high enantioselectivity is an
important measure of the commercial feasibility of a
reaction. In this study, it was found that the high ee
values were essentially maintained when a high substrate-
to-catalyst ratio was used. The hydrogenation of 10d (30
g) catalyzed by (R)-9 with an S/C ratio of 7500 (M/M)
proceeded smoothly and afforded a useful pharmaceuti-
cal intermediate (S)-3-hydroxy-3-phenyl propionate
stable even in the solution state. When experimental
procedures prior to the introduction of hydrogen were
performed in air, the rate and enantioselectivity of the
hydrogenation of 10d showed no variation (100% conver-
sion, 96.1% ee, entry 7) from the air-purged system (100%
conversion, 96.2% ee, entry 8). Even when the solution
of (R)-9 was exposed to air for 10 h, its activity and
enantioselectivity remained essentially unchanged (100%
conversion, 95.5% ee, entry 9).
31
(
11d) with 93.2% ee in 98% yield (Table 1, entry 11),
A
P NMR study also supported the above results and
whereas, when using Ru(R-P-Phos)(C H )Cl and Ru(R-
proved the high air-stability of 9. The catalyst solution,
6
6
2
Tol-P-Phos)(C H )Cl as catalysts under identical reac-
which had been stirred for 10 h under air, had the same
6
6
2
31
tion conditions, the yields were 84% (90.6% ee, entry 12)
P NMR spectrum [CDCl , 500 MHz, l 33.49 (d,
3
4
c
and 90% (91.3% ee, entry 13), respectively.
J=62.9 Hz), 39.96 (d, J=62.5 Hz)] as that obtained
under N . The excellent air-stability of 9 makes the
experimental operation more convenient and shows a
good potential for its industrial application.
2
Most metal phosphine catalysts are air-sensitive in solu-
tion and even trace amounts of air in the reaction system

1
542
J. Wu et al. / Tetrahedron Letters 43 (2002) 1539–1543
a
Table 1. The asymmetric hydrogenation of b-ketoesters
Entry
Substrate
S/C (M/M)
PH2 (psi)
T (°C)
Time (h)
Conv. (%)
ee (%)
b,c
1
10a
10b
10b
10b
10c
10c
10d
10d
10d
10d
10d
400
400
800
2800
400
2800
800
800
800
5000
7500
200
300
300
300
300
300
300
300
300
350
350
70
80
80
80
80
80
90
90
90
90
90
1
2
3
15
2
13
2
2
2
10
15
100
100
100
100
100
100
100
100
100
100
98
97.1
96.6
96.1
94.5
94.8
93.7
96.2
96.1
95.5
93.3
93.2
b,c
2
b,c
3
b,c
4
b,c
5
b,c
6
b,d
7
d,e
8
d,f
9
d,g
10
1
d,g
1
d,g
d,g
1
1
2
3
10d
10d
7500
7500
350
350
90
90
15
15
84
90
90.6
91.3
a
Ru(R-Xyl-P-Phos)(C H )Cl was used as catalyst in entries 1–11; Ru(R-P-Phos)(C H )Cl was used as catalyst in entry 12; Ru(R-Tol-P-
6
6
2
6
6
2
Phos)(C H )Cl was used as catalyst in entry 13; the substrate and catalyst were added to the stainless steel autoclave under N and the solvents
6
6
2
2
were degassed and dried prior to use except when otherwise stated.
Reaction conditions: 100–400 mg substrate; substrate concentration=1.04–2.92 M in EtOH/CH Cl .
b
c
2
2
The conversion yield and the ee were determined by chiral GC with a Chrompack Chirasil-DEX CB column after converting the products to
the corresponding acetyl derivatives.
d
e
f
The conversion yield and the ee were determined by 500 MHz 1H NMR and HPLC analysis (Daicel Chiralcel OD column).
The substrate and catalyst were added to the stainless steel autoclave in air and the solvents were not degassed or dried prior to use.
The catalyst solution in EtOH and CH Cl was stirred for 10 h under air before the addition of substrate and H2.
2
2
g
3
0 g substrate; substrate concentration=4.11 M; the substrate and catalyst were added to the stainless steel autoclave under N and the solvents
2
were degassed and dried prior to use.
In summary, we have developed a new dipyridylphos-
Bhaduri, S.; Mukesh, D. Homogeneous Catalysis Mecha-
nisms and Industrial Applications; Wiley: New York,
2000; (e) Lin, G.-Q.; Li, Y.-M.; Chan, A. S. C. Principles
and Applications of Asymmetric Synthesis; Wiley: New
York, 2001.
phine ligand Xyl-P-Phos (3) and found its Ru complex
9
to be air-stable and highly effective in the asymmetric
hydrogenation of b-ketoesters. The unique air-stability
of this class of complexes makes the experiments conve-
nient to operate and shows a good potential for their
industrial application.
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We thank the Hong Kong Research Grants Council
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(
Project Number PolyU 5177/99P) and the Hong Kong
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1. The optical purities of the resolved 8 were determined by
HPLC analysis (Diacel-AD column, eluted by hexane:2-
propanol=4:96, flow rate=1.0 mL/min, umax=254 nm,
7
M. Organometallics 1999, 18, 4765.
1
8
. Spectral data for 3: H NMR (CDCl , 500 MHz): l 2.20
3
(
s, 12H, PhCH ), 2.25 (s, 12H, PhCH ), 3.37 (s, 6H,
3
3
OCH ), 3.83 (s, 6H, OCH ), 6.06 (d, J=1.5 Hz, 2H,
3
3
1
13
PyH), 6.79–6.92 (m, 12H, PhH). C NMR (CDCl , 500
3
MHz): l 21.54 (d, J=4.78 Hz), 53.06, 53.43, 105.47,
1
15.39 (t, J=37.07 Hz), 130.47 (d, J=33.81 Hz), 131.46
2
0
tR of (S)-8, 9.33 min; tR of R isomer, 15.25 min). [h] of
D
(t, J=20.99 Hz), 132.42 (t, J=21.74 Hz), 135.69 (t,
(
R)-8: +253.2° (c 1.01, CHCl3).
J=10.05 Hz), 136.88 (t, J=12.82 Hz), 137.39 (t, J=8.04
Hz), 137.71 (t, J=7.16 Hz), 154.64, 154.70, 154.75,
1
1
2. Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.;
Nozaki, K.; Kumobayashi, H.; Sayo, N.; Hori, Y.;
Ishizaki, T.; Akutagawa, S.; Takaya, H. J. Org. Chem.
3
1
1
60.76 (t, J=11.18 Hz), 162.30. P NMR (CDCl , 500
3
+
MHz): l −11.99. LSMS [M ] calcd C H N O P :
46
50
2
4 2
1
994, 59, 3064.
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862; (b) Pommier, A.; Pons, J. M. Synthesis 1994, 1294;
c) Case-green, S. C.; Davies, S. G.; Hedgecock, C. J. R.
7
7
3
56.85. Found: 757. Anal. calcd for C H N O P : C,
3.00; H, 6.66; N, 3.70. Found: C, 72.59; H, 6.89; N,
.27.
46 50 2 4 2
4
(
9
. (a) Takaya, H.; Akutagawa, S.; Noyori, R. Org. Synth.
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1