Chiral biphosphine ligands for the Ru-catalyzed enantioselective hydrogenation of β-ketoesters

Article abstract of DOI:10.1016/j.tetasy.2004.04.034

Three new biaryl phosphine ligands 4a-c have been prepared and their application in the Ru-catalyzed asymmetric hydrogenation of β-ketoesters investigated. Ruthenium catalysts containing these ligands are highly effective in the hydrogenation of β-ketoesters with up to 99.9% ee being obtained.

Full text of DOI:10.1016/j.tetasy.2004.04.034

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2185–2188
Chiral biphosphine ligands for the Ru-catalyzed
enantioselective hydrogenation of b-ketoesters
Yanhui Sun,a Xiaobing Wan,b Minjie Guo,b Donghui Wang,b Xicheng Dong,b
Yi Pana and Zhaoguo Zhangb,*
aDepartment of Chemistry, Nanjing University, Nanjing 210093, China
bState Key Laboratory of Organometallic Chemistry and Key Laboratory of Computer Science,
Shanghai Institute of Organic Chemistry, Shanghai 200032, China
Received 24 March 2004; accepted 8 April 2004
Available online 4 June 2004
Abstract—Three new biaryl phosphine ligands 4a–c have been prepared and their application in the Ru-catalyzed asymmetric
hydrogenation of b-ketoesters investigated. Ruthenium catalysts containing these ligands are highly effective in the hydrogenation of
b-ketoesters with up to 99.9% ee being obtained.
Ó 2004 Elsevier Ltd. All rights reserved.
Transition metal-catalyzed reactions are widely
employed in the preparation of enantiomerically pure
MeO
MeO
PPh2
PPh2
PPh2
PPh2
OMe
compounds, in which the chiral ligands play an impor-
tant role.1 Much effort has been devoted to the design
and synthesis of numerous chiral ligands. Since Knowles
N
N
3
and Sabacky2 and Horner etal. firstuitlized chiral
MeO
MeO
PPh2
PPh2
BIPHEMP
O
MeO-BIPHEP
phosphines in asymmetric hydrogenation in 1968,
Kagan and Dang have reported the asymmetric hydro-
genation of a-dehydroamino acid esters (up to 85% ee)
with DIOP,4 derived from tartaric acid. These results
gave us the idea for the development of new biphosphine
ligands. Atropoisomeric C2-symmetric biphosphines are
amongst the most important ligands, BINAP,5 BIP-
HEMP,6 MeO-BIPHEP,6 TunePhos,7 P-Phos,8 SEG-
Phos,9 difluorphos10 (Scheme 1) and other important
biaryl phosphine ligands11 have been developed over the
past 20 years. It is not rare to obtain very decent ee with
the reported ligands; however, developing easily-prepa-
rable, fine-tunable, easy-handable, inexpensive yet effi-
cientligands is sitll a challenging issue.
F
O
OMe
PPh2
PPh2
O
O
F
F
PPh2
PPh2
n
O
P-phos
O
F
n=1-6, TunePhos
difluorphos
Scheme 1. Some atropoisomeric phosphine ligands.
in transition metal-catalyzed refractions.7;9;10;12 Itis
understandable that when biphosphine ligands with
different dihedral angles coordinate a transition metal
with multiple coordination numbers, the two phospho-
rus atoms may locate either at the equatorial–equatorial
or at equatorial–axial positions (Fig. 1);12c this results in
the difference in regio- and/or enantioselectivity. Zhang
et al. have studied the asymmetric hydrogenation of b-
ketoesters with Cn-TunePhos as a model;7 Saito et al.
designed the SEGPhos series ligands with small dihedral
Geometric, steric and electronic properties of the chiral
ligand are important to the enantioselectivity and reac-
tivity. The dihedral angles of the biaryl phosphine
ligands have also been proven to be predominant in
controlling the regioselectivity and/or enantioselectivity
angles and applied them to the asymmetric hydrogena-
9
* Corresponding author. Tel.: +86-21-64163300-3435; fax: +86-21-64-
166128; e-mail: zhaoguo@mail.sioc.ac.cn
^
tion of ketones. Genetetal. prepared difluorphos and
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.04.034

2186
Y. Sun et al. / Tetrahedron: Asymmetry 15 (2004) 2185–2188
O
R
O
O
L
M
L
L
M
P
R
a
b
P
P
L
P
L
L
R
O
R
Br
P(O)Ph2
1
2
M: transition metal L: other ligand or substrate or solvent
O
R
O
R
Figure 1. Possible coordination model of biphosphine ligands with
differentdihedral angles.
c
O
O
R
R
R
P(O)Ph2
P(O)Ph2
O
O
P(O)Ph2
P(O)Ph2
+ (R)-(+)-3
R
studied the dihedral angle effect in asymmetric hydro-
genation reactions.10 The results revealed that the dihe-
dral angle is crucial in achieving high enantioselectivity.
R
O
O
R
(S)-(-)-3
racemic-3
Although SEGPhos (Fig. 2) has been proved excellent
ligand in asymmetric hydrogenation reactions, it is not
an ideal model to investigate the dihedral angle effect in
asymmetric hydrogenation reactions, since the coordi-
nation environment for the phosphorus atoms has been
changed when modifying the substituents at the phos-
phorus atoms (Fig. 2). We designed a working model
bearing a SEGPhos backbone by introducing substitu-
ents at the 1,3-dioxole ring to investigate the dihedral
angle effect. MM2 calculation showed that when the
substituents at the 1,3-dioxole ring change, the dihedral
angles for the free ligands also change remarkably (Fig.
2).
O
R
(S)-4a, R= CH3
O
O
R
d
PPh2
PPh2
(S)-4b, R-R= -(CH2)4-
(S)-4c, R-R= -(CH2)5-
+ (R)-(+)-4
R
R
O
(S)-(-)-4
Scheme 2. Synthesis of ligands 4a–c. Reagents and conditions: (a)
(i) Mg, THF, (ii) Ph2PCl, (iii) H2O2; (b) (i) LDA, )15 to 2 °C, 4 h;
(ii) FeCl3, 0 °C; (c) (i) )DBTA, EtOAc or CH2Cl2, (ii) NaOH; (d)
HSiCl3, PhNMe2, reflux, 10 h.
good yields for the lithiation of 2b ()5 °C) and 2c
()2 °C), with 3b and 3c being obtained in 81.5% and
79.3% yields, respectively.
Herein, we report the synthesis, resolution (Scheme 2)
and determination of the absolute configurations of
three new biaryl ligands 4a–c and their applications in
asymmetric hydrogenation reaction.
Resolutions of 3a and 3b were both performed by
employing ())-2,3-dibenzoyl tartaric acid [())-DBTA] as
the resolving agent in ethyl acetate, while the resolution
of 3c was performed in CH2Cl2. The phosphine oxides
())-3a, ())-3b and ())-3c were reduced to ())-4a, ())-4b
and (+)-4c with HSiCl3, respectively. The absolute
configurations of ())-3a and ())-3b were defined to be S
by means of single crystal X-ray diffraction of their salts
of ())-DBTA. The enantiomeric purity of the ligands
was determined either by HPLC on a chiral column (for
4b, the precursor 3b can be separated on a Chiralpak
AD-H column) or by measuring the 31P NMR of
The racemic ligands can be prepared according to a
procedure similar to that reported in the synthesis
of SEGPhos (Scheme 2). Treatment of 5-(diphenyl-
phosphinoyl)-2,2-dimethyl-benzo[1,3]dioxole 2a with
1.2 equiv of LDA at low temperature ()15 °C) for 4 h
and then oxidative coupling with anhydrous ferric
chloride affords 3a in moderate yield (67.5%). Com-
pounds 3b and 3c were obtained in similar way except
for the lithiation step. Up to 2.4 equiv of LDA and a
higher reaction temperature were needed to achieve
O
R
O
R
O
O
O
O
1
4
5
6
1 PPh2
4 PPh2
PAr2
PAr2
5
6
2
3
2
3
R
R
O
O
SEGPhos:
Our working model:
Coordination environment
changes
Coordination environment does not
change when R changes (only
dihedral angle changes)
when Ar changes (dihedral angle
also changes)
Dihedral angle (o)
C1-C2-C3-C4
C5-C2-C3-C6
79.9
82.2
91.4
83.5
SEGPHOS
R=CH3
R,R=-(CH2)4
R,R=-(CH2)5
73.6
74.7
81.7
75.5
-
-
Figure 2. A working model to investigate dihedral angle effect (dihedral angles were obtained by MM2 calculation, Cache 6.1.1).

Y. Sun et al. / Tetrahedron: Asymmetry 15 (2004) 2185–2188
2187
the complexes of biphosphines (4a or 4c) and (+)-bis-
(l-chloro)bis[(R)-dimethyl(a-methyl-benzyl)aminato-
C2N]dipalladium(II).6b;13
These ligands were also successful in the asymmetric
hydrogenation of 3-oxo-3-arylpropionic acid ethyl esters
5; good enantioselectivity was obtained. The enantio-
meric excess of 6 was comparable to when SEGPhos9
was employed as ligand, and better than when BINAP
(89.3% ee)11c or MeO-BIPHEP (74.8% ee)9 was used as
the ligand. Hydrogenation of 5 was not sensitive to the
substituents (m, o, p and electron donating or electron
withdrawing) on the aromatic ring (Table 2).
We chose the asymmetric reduction of b-ketoesters as
the model reaction for studying the dihedral angle effect
of the ligands. The reaction was performed in an alcohol
solvent with [Ru(L*)(benzene)Cl]Cl complex as cata-
lyst.14
Ligands 4a–c are excellent ligands for the asymmetric
reduction of alkyl acetoacetates, with up to 99.9% ee
being obtained, regardless of the bulkiness of the alkyl
group (Table 1, entries 1–8). When 4,4-dimethyl-3-oxo-
pentanoic acid ethyl ester 7d was employed as the sub-
strate for the asymmetric reduction, 4a proved best(ee
was up to 97.9%), while 4c was inferior to 4a and 4b
(Table 1, entries 9–11). 4-Chloro-3-oxo-butyric acid
ethyl ester is different from other substrates. Its ee value
is highly dependent on the reaction temperature: if the
reaction was carried out at a lower temperature, the ee
was lower (Table 1, entries 12, 13); however, if the
temperature was increased, the ee values also increased
(Table 1, entries 14–17).15 The reduction was very
effective with no ee decrease when the reaction was
carried out with 0.1 mol % catalyst (Table 1, entries 18–
20).
Table 2. Asymmetric hydrogenation of ArCOCH2CO2Eta
O
OH
(Ru(L*)(benzene)Cl)Cl
H2
CO2Et
CO2Et
Ar
Ar
*
5
6
Entry
Ar
Ee
4a
4b
4c
1
2
Ph 5ab
97.9
97.4
95.7
96.8
96.2
96.3
96.6
96.5
94.4
96.4
96.2
96.7
93.0
95.7
95.1
95.3
96.0
95.2
93.3
96.7
96.3
95.2
95.8
––
4-Me–C6H4 5bc
4-MeO–C6H4 5cc
4-F–C6H4 5db
4–Cl–C6H4 5ed
4-Br–C6H4 5fd
3-Me–C6H4 5gb
3–Cl–C6H4 5hd
2-Me–C6H4 5gd
2–Cl–C6H4 5hc
3
4
5
97.0
––
6
7
––
8
96.6
91.9
96.7
9
10
Table 1. Asymmetric hydrogenation of R1COCH2CO2R2 with
(Ru(L*)(benzene)Cl)Cla
a All of the reactions were carried out at 65 °C with a substrate con-
centration of 0.5 M, under 30 atm of H2 in EtOH for 20 h. Substrate/
[Ru(benzene)Cl2]2/ligands ¼ 200/0.5/1.1, conversion 100%.
O
OH
(Ru(L*)(benzene)Cl)Cl
H2
CO2R2
CO2R2
R1
R1
b Ee values were determined by HPLC on a Chiralcel OD-H column.
c Ee values were determined by HPLC on Chiralpak AS-H column.
d Ee values were determined by HPLC on Chiralpak AD-H column.
*
8
7
Entry
R1/R2
7
Temp.
(°C)
Time
(h)
4
8 %eeb
The dihedral angles of the [Ru(L*)(benzene)Cl]Cl com-
plex were also calculated by MM2, Cache 6.1.1 software
and PM3 (semi-empirical), Spartan software. MM2
calculations revealed that the dihedral angles (C1–C2–
C3–C4) of the three ligands were smaller than SEGPhos,
with 4a having the smallest dihedral angle. PM3 (semi-
empirical) calculations indicated that 4a and 4c had
smaller dihedral angles than SEGPhos did, though the
difference was notsignificant(Fig. 3). The difference did
not make a remarkable change in enantioselectivity in
1
Me/Et 7a
Me/Et 7a
65
65
65
65
65
65
65
65
65
65
65
60
60
85
85
95
95
95
95
95
20
20
20
20
20
20
20
20
20
20
20
20
20
3
4a
4b
4c
4a
4b
4c
4a
4b
4a
4b
4c
4a
4b
4a
4b
4a
4b
4a
4b
4c
99.9
99.9
99.9
99.4
99.9
99.6
99.5
99.4
97.9
96.7
92.3
88.2c
89.3c
95.9c
95.8c
96.2c
96.4c
96.5c
95.3c
96.8c
2
3
Me/Et 7a
Me/iPr 7b
Me/iPr 7b
Me/iPr 7b
Me/tBu 7c
Me/tBu 7c
tBu/Et 7d
tBu/Et 7d
tBu/Et 7d
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18d
19d
20d
ClCH2/Et 7e
ClCH2/Et 7e
ClCH2/Et 7e
ClCH2/Et 7e
ClCH2/Et 7e
ClCH2/Et 7e
ClCH2/Et 7e
ClCH2/Et 7e
ClCH2/Et 7e
O
R
1
3
PPh2
R
O
O
5
6
2
3
Cl
Ru(benzene)Cl
PPh2
3
3
R
4
3
R
O
3
Dihedral angle (o)
3
C1-C2-C3-C4 C5-C2-C3-C6
a All of the reactions were carried out in EtOH with a substrate con-
centration of 0.5 M, under 30 atm of H2. Substrate/[Ru(benzene)Cl2]2/
ligands ¼ 200/0.5/1.1, conversion: 100%.
73.5 (74.7)
66.2 (67.6)
R=H
R=CH3
72.8 (72.6)
73.9 (73.8)
72.5 (73.9)
61.4 (67.5)
64.0 (68.5)
61.5 (68.4)
-
-
R,R=-(CH2)4
R,R=-(CH2)5
b Ee values were determined by GC on a b-DEX 325 capillary column.
c The product was acylated to 3-acetoxy-4-chloro-butyric acid ethyl
ester 9e in pyridine and acetic anhydride. Ee (%) of 9e was determined
by GC on a b-DEX 325 capillary column.
Figure 3. Spartan PM3 (semi-empirical) calculation of [RuCl(benz-
ene)L]Cl (data in the parenthesis refer to the dihedral angles calculated
by MM2, Cache 6.1.1).
d Substrate/[Ru(benzene)Cl2]2/ligands ¼ 1000/0.5/1.1.

2188
Y. Sun et al. / Tetrahedron: Asymmetry 15 (2004) 2185–2188
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€
6. (a) Schmid, R.; Cereghetti, M.; Heiser, B.; Schonholzer,
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the asymmetric hydrogenation of b-ketoesters, however,
these finely tunable ligands could provide the opportu-
nity for better enantioselectivity in asymmetric hydro-
genation where narrow dihedral angles are needed.
€
Schmid, R.; Foricher, J.; Cereghetti, M.; Schonholzer, P.
Helv. Chim. Acta 1991, 74, 370; (c) Schmid, R.; Broger, E.
In conclusion, we have developed three novel biphos-
phine ligands and set up a model to investigate the
dihedral angle effect in Ru-catalyzed enantioselective
hydrogenation of aryl, alkyl substituted b-ketoesters
with high enantioselectivity was achieved. Applications
of these ligands to extend the scope of asymmetric
reductions and asymmetric C–C bond forming reactions
are currently in progress.
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Acknowledgements
We thank Mr. M. S. He for the MM2 calculations of the
dihedral angles for the free ligands and the
[RuLCl(benzene)]Cl complexes. We also thank the Na-
tional Natural Science Foundation of China, Chinese
Academy of Sciences, and the Science and Technology
Commission of Shanghai Municipality for financial
support.
10. Jeulin, S.; Dupratde Paule, S.; Raotvelomanana-Vidal,
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Tetrahedron Lett. 2002, 43, 2789; (b) Qiu, L.; Qi, J.; Pai,
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