One-step synthesis of chiral dimethyl 2-oxo-3-phenyl-glutarate in the asymmetric triple-carbonylation of styrene

Article abstract of DOI:10.1016/S1872-2067(10)60253-7

The in situ preparation of the novel chiral catalyst system, which are composed of (S)-2,2′,6,6′-tetramethoxy- 4,4′- bis(diphenylphosphine)-3,3′-bipyridine ((S)-P-PHOS) and palladium 2,4-pentanedionate, have been described. These complexes were found to be effective in the asymmetric triple-carbonylation of styrene, reaching up to [α]_D²⁰ = +27^o (c, 0.28, CH ₂Cl₂) for dimethyl 2-oxo-3-phenyl-glutarate using benzoquinone as oxidant, p-toluenesulfonic acid as co-catalyst, and methanol as solvent.

Full text of DOI:10.1016/S1872-2067(10)60253-7

CHINESE JOURNAL OF CATALYSIS
Volume 32, Issue 7, 2011
Online English edition of the Chinese language journal
Cite this article as: Chin. J. Catal., 2011, 32: 1143–1148.
SHORT COMMUNICATION
One-Step Synthesis of Chiral Dimethyl
2-Oxo-3-phenyl-glutarate in the Asymmetric
Triple-carbonylation of Styrene
WANG Lailai*, ZHANG Qinsheng, CUI Yuming
State Key Laboratory for Oxo Synthesis & Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, Gansu, China
Abstract: The in situ preparation of the novel chiral catalyst system, which are composed of (S)-2,2',6,6'-tetramethoxy-
4,4'-bis(diphenylphosphine)-3,3'-bipyridine ((S)-P-PHOS) and palladium 2,4-pentanedionate, have been described. These complexes were
found to be effective in the asymmetric triple-carbonylation of styrene, reaching up to [Į]D = +27o (c, 0.28, CH2Cl2) for dimethyl
20
2-oxo-3-phenyl-glutarate using benzoquinone as oxidant, p-toluenesulfonic acid as co-catalyst, and methanol as solvent.
Key words: styrene; asymmetric triple-carbonylation; chiral; dimethyl 2-oxo-3-phenyl-glutarate; palladium 2,4-pentanedionate;
dipyridlphosphines
As the intermediate of Rhizoxin synthesis [1] and the main
component of Sophora japonica [2], chiral 3-alkyl-glutaryl
ester has significant biological activity. Up to now, the syn-
thesis of chiral 3-alkyl-glutaryl ester is as follows, the racemic
3-alkyl-glutaric esters are synthesized using CuI as the catalyst
through the reaction of dimethyl glutarate and the Grignard
reagent in the presence of excessive trimethylchlorosilane [3],
and then the products are obtained through the hydrolysis of
resolution of racemic 3-alkyl-glutaric esters by catalytic hy-
drolysis using liver lipase [4–6]. Asymmetric triple-ꢀcarbon-
ylation of Į-olefin is shown in Scheme 1. 2-Oxo-3-alkyl-ꢀ
glutaryl ester and/or 2-oxo-4-alkyl-glutaric ester were synthe-
sized through triple-carbonylation with high activity, high
chemoselectivity, regioselectivity, and enantioselectivity using
Į-olefins as substrates and chiral metal complexes as catalysts.
Enantioselective triple-carbonylation of styrene was for the
first time reported by Sperrle et al [7] in 1996 using palladium
complexes [Pd(H2O)2{(S)-MeO-BIPHEP}](OTf)2 as chiral
catalyst and methanol as reactants and solvent. The structure of
ligand (S)-MeO-BIPHEP is shown in Scheme 1. Product di-
methyl 2-oxo-3-phenyl-glutarate was received. However, the
chemical selectivity of the reaction was low, and CO pressure
of reaction was up to 35 MPa. In 2000, Sperrle et al [8] used
palladium complex [Pd(H2O)2{(S)-MeO-BIPHEP}](BF4)2 as
catalyst precursor, and the selectivity for triple carbonylation
increased to 32%. The use of complex [Pd(H2O)2-
{(S)-MeO-BIPHEP}](OTf)2 as the catalyst and reducing the
amount of benzoquinone could make the selectivity increase to
37%, but the conversion of the reaction decreased. Using sty-
rene as substrate, the chemical selectivity of reaction was
higher than that of aliphatic Į-olefins. The chemical selectivity
of reactions could be improved by increasing CO pressure and
reducing the concentration of the catalyst. When 4-methyl-1-
pentene and 3-phenyl-1-propylene as substrates were used,
respectively, the conversion of reaction was significantly re-
duced, chemoselectivity and regioselectivity of triple carbon-
ylation were relatively low, and enantioselectivity of
2-oxo-3-methyl-glutaryl esters was moderate [8]. When pro-
pylene as the substrate was employed, ligand (S,S)-BDPP
afforded lower enantioselectivity of triple carbonylation than
enantiopure atropoisomeric bidentatephosphine ligands
(Scheme 1). In fact, ligand (S,S)-BDPP and Pd can form
six-membered ring complexes, while enantiopure atropoi-
someric bidentatephosphine ligands and Pd form
Received: 25 March 2011. Accepted 28 May 2011.
*Corresponding author. Tel: +86-931-4968161; Fax: +86-931-4968129; E-mail: wll@licp.cas.cn
This work was supported by the National Natural Science Foundation of China (20343005, 20473107, 20673130, 20773147, 21073211).
Copyright © 2011, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by Elsevier BV. All rights reserved.
DOI: 10.1016/S1872-2067(10)60253-7

WANG Lailai et al. / Chinese Journal of Catalysis, 2011, 32: 1143–1148
seven-membered ring intermediate. The rigidity of the former
is much less than that of the latter [9,10]. When the phenyl
group on the phosphorus of enantiopure atropoisomeric bi-
dentatephosphine ligands is substituted, chemoselectivity and
regioselectivity of triple carbonylation were reduced. As for
chiral ligands (R) (Sp)-JOSIPHOS and (R) (Sp)-PPF-PH2
(Scheme 2) based on ferrocenyl, the latter’s chemoselectivity
and regioselectivity is higher than that of the former. So far, the
chemical selectivity of the asymmetric triple-carbonylation
reaction catalyzed by palladium/bidentatephosphine ligands
complexes needs to be enhanced, and CO pressure needs to be
reduced. Therefore, the research on a novel catalytic system of
the asymmetric triple-carbonylation has a great significance.
Triple-carbonylation has the methodological importance.
More importantly, triple-carbonylation (Scheme 3) and
bis-alkoxycarbonylation (Scheme 4) have the same intermedi-
ates of reaction. This can be used as a basis to study the regio-
and enantioselectivity of triple-carbonylation. In contrast with
enantioselectivity
of
triple-carbonylation
and
bis-alkoxycarbonylation and the absolute configuration of
product, using various substrates such as styrene, propylene,
and 4-methyl-1-ene in the same chiral catalyst and selecting
the same substrate in different chiral catalyst systems, can
optimize the reaction conditions, and deduce the mechanism of
carbonylation [9,10]. For the first time this work employs
ligands (S)-P-PHOS (Scheme 2)/Pd complex as catalyst pre-
cursor to investigate triple-carbonylation of styrene.
Phosphine ligand (S)-P-PHOS as a white solid powder, sta-
ble in air, has been successfully applied in asymmetric catalytic
reactions [11–13], such as asymmetric hydrogenation of de-
hydrogenation amino acids and prochiral aromatic ketones.
When styrene was used as the substrate, ligand (S)-P-PHOS
and palladium acetate (Pd(OAc)2) were used to in situ prepare
the chiral catalysts, in the presence of p-benzoquinone as the
oxidant, p-toluenesulfonic acid as co-catalyst, and methanol as
solvent, triple-carbonylation of styrene did not occur. However,
O
R
O
Chiral Pd Cat.
H CO
3
OCH
+
3
R CH
H CO
OCH
3
+
CH
3CO/2CH OH
*
3
2
3
*
O
R
O
O
O
Enantioselectivity
Regioselectivity
S R
S R
2-oxo-4-alkyl-glutaric ester
bis-alkoxycarbonylation
2-oxo-3-alkyl-glutaryl ester
Chemoselectivity
triple-carbonylation
Scheme 1. Asymmetric triple-carbonylation of Į-olefins.
MeO
MeO
PPh2
PPh2
CH3
CH3
P(C6H5)2
P(C6H5)2
P(C6H5)2
P(C H )
P(c-C6H11)2
Fe
Fe P(C6H5)2
6
5 2
(R)(Sp)-PPF-PPh2
(R)(Sp)-JOSIPHOS
(S)-MeO-BIPHEP
OMe
(S,S)-BDPP
N
MeO
MeO
PPh2
PPh2
H
PPh2
PPh2
PPh2
PPh2
O
N
O
H
OMe
(S)-P-PHOS
(2S,3S)-DIOP
(R)-BINAP
Scheme 2. Chiral bidentatephosphine ligands.

WANG Lailai et al. / Chinese Journal of Catalysis, 2011, 32: 1143–1148
O
*
Pd(acac) , (S)-P-PHOS
2
H CO
3
OCH
+ 3CO + 2CH OH
3
3
CH OH
3
O
O
Scheme 3. Asymmetric triple-carbonylation of styrene.
O
Chiral catalyst
+ 2CO + 2CH OH
H CO
3
3
*
+"OX"
OCH
3
O
DMPS
Scheme 4. Enantioselective bis-alkoxycarbonylation of styrene.
when Pd(OAc)2 was replaced with acetylacetonate Palladium
(Pd(acac)2), it was interesting that triple-carbonylation of sty-
rene occurred, and chiral 2-oxo-3-phenyl dimethyl glutarate
was obtained by column chromatography of the crude product.
This may be due to various catalytic precursor using ligand
(S)-P-PHOS/Pd(OAc)2 or Pd(acac)2 formed in situ.
4.0), 3.20 (dd, 1H, CH2COOR; J = 16.0, J = 9.8), 3.50 (s, 3H,
OCH3), 3.58 (s, 3H, OCH3), 4.77 (m, 1H, CH; J = 4.0, J = 9.8);
7.18–7.22 (m, 5H, C6H5). 13C NMR: 35.0 (CH2COOR), 48.0
(CH), 50.0 (OCH3), 52.0 (OCH3), 125.8, 126.4, 128.0, 130.3
(C6H5), 157.3 (COCOOR), 169.5 (CH2COOR), 189.2 (CO).
MS (m/z, relative intensity (%)): 191 (43), 163 (37), 131 (11),
122 (11), 121 (100), 104 (21), 103 (16), 91 (11), 78 (8), 77 (13),
The typical reaction procedure of triple-carbonylation is as
follows [7,8], a mixture of Pd(acac)2 (0.025 mmol, 8.4 mg),
(S)-P-PHOS (0.025 mmol, 16.0 mg), styrene (5 mmol, 1 ml),
benzoquinone (5 mmol, 540 mg), p-toluenesulfonic acid
(0.05 mmol, 8.6 mg) in methanol (4 ml) was stirred under
nitrogen for 1 h at room temperature. A 100 ml stainless steel
autoclave was dried, purged with N2, the above methanol so-
lution was transferred into it. After sealing autoclave, CO (5.5
MPa) was introduced. The reaction mixture was heated to 50
ºC in oil bath and stirred for 38 h. At the end of tri-
ple-carbonylation, autoclave was cooled to room temperature,
and the residual gas was released safely. The reaction mixture
became brown and there existed a little black precipitate. The
autoclave was washed with methanol, and the washing liquid
was combined, which made the reaction mixture turbid. After
removing of the methanol from the reaction mixture under
reduced pressure, toluene was added, causing most of the hy-
droquinone to precipitate. The filtrate was evaporated, and oily
crude product (1.13 g) was purified by column chromatography
over silica (300 mesh) using petroleum ether (30–60 ºC)/ethyl
acetate as the eluent. The conversion of styrene is up to 90.4%.
A 50 mg of 2-oxo-3-phenyl dimethyl glutarate was obtained,
and the selectivity of the reaction was 4.4%.
20
59 (11), 51 (3). Specific rotation: [Į]D = +27o (c, 0.28,
CH2Cl2).
Catalyst precursor [Pd{(R)-P-PHOS}(H2O)2](OTf)2 was
synthesized in the presence of PdCl2(NCPh)2 and ligand
(R)-P-PHOS according to a reported procedure [14]. MS (5.68
× 104 eV) m/z (relative intensity (%)): 785(12), 787 (10) [M-(2
× OTf)]+, 861 (29), 862 (68), 863 (100), 865 (65), 867 (33),
868 (13). 1H NMR (CDCl3, 500 MHZ): į 3.57 (s, 6H, OCH3),
3.73 (d, 6H, OCH3), 6.19 (d, 2H, PyH), 7.41–7.92 (m, 20H,
PhH). 31P NMR (CDCl3, 202 MHZ): į 30.62. After several
attempts, bis-alkoxycarbonylation of styrene was realized
successfully (Scheme 4) and dimethyl 2-phenyl succinate
(DMPS) was synthesized using methanol as solvent.
A
typical procedure [14] for enantioselective
bis-alkoxycarbonylation of styrene is as follows, 50 mL
stainless steel autoclave was dried, purged with N2. It was
charged with 1.8 mmol of styrene, 1.8 mmol of
1,4-benzoquinone, and 1.8 × 10–3 mmol of [Pd{(R)-P-PHOS}
(H2O)2](OTf)2 catalyst precursors, and 1 ml of methanol under
an atmosphere of N2. It was pressurized with CO (15.2 MPa),
heated to 50 °C. The reaction mixture was stirred well with a
magnetic stirrer. After a prescribed period of 24 h, the reactor
was cooled to room temperature, and the remaining CO was
released safely. Solvent methanol was removed in vacuum,
followed by the addition of toluene causing the precipitation of
solid hydroquinone. The mixture was filtered, and the filtrate
was purified by column chromatography. The data on
conversion and selectivity were determined immediately by
GC on an AT-1 capillary column (25 m × 0.25 mm i.d.) using
acetophenone as an internal standard. The enantiomeric excess
1H NMR and 13C NMR were recorded on a Bruker AM400
NMR (TMS as internal standard). GC-MS was performed on a
HPG 1800CGCD equipped with FID detector to measure the
molecular weight. The specific rotation of the sample was
performed using the Perkin Elmer Polarimeter (Model 341
LC).
Characterization data of dimethyl 2-oxo-3-phenyl glutarate
is as follows, 1H NMR: 2.70 (dd, 1H, CH2COOR; J = 16.0, J =

WANG Lailai et al. / Chinese Journal of Catalysis, 2011, 32: 1143–1148
Table 1 The asymmetric carbonylation of Į-olefins catalyzed by palladium complexes
Entry
1a
2b
Substrate
styrene
Catalyst
Conversion (%)
90.7
Selectivity (%)
Regioselectivity (%)
100/0
[Į]D20 or ee
+27o (c, 0.28, CH2Cl2)
88% (R)
[Pd{(S)-P-P} (acac)2]
[Pd{(R)-P-P}(H2O)2](OTf)2
[Pd{(R)-P-P}(OAc)2]
4.4
styrene
24.0
16.0
MC 2.2, MP 1.9
3c
propene
24g/g-Pd
H-H/H-T/T-T (%) = 17:66:17
+1.4o (c, 0.5, CH2Cl2)
aReaction conditions: 0.025 mmol 8.4 mg Pd(acac)2, 0.025 mmol 16.0 mg (S)-P-PHOS, methanol 4 ml, styrene 5 mmol, benzoquinone 5 mmol,
p-toluenesulfonic acid 0.05 mmol, CO 5.5 MPa, 50 ºC, 38 h.
bReaction was operated according to a reported procedure[14]
.
cPd-catalyzed asymmetric alternating copolymerization of propene and CO was operated according to a reported procedure[15,16]
.
MC–Methyl cinnamate.
MP–Methyl 2-phenylpropionate and methyl 3-phenyl-propionate.
of triple-carbonylation of styrene was analyzed by GC using a
Chrompack Chirasil-DEX CB (50 m × 0.25 mm i.d.). The
absolute configuration of the product was determined by
measuring the specific rotations in comparison with literature
values. The conversion of styrene to dimethyl-2-
phenylsuccinate (DMPS) was only 24.0%. A 88.0% (R)
enantioselectivity and 16.0% chemoselectivity for DMPS,
2.2% chemioselectivity for ethyl cinnamate (MC) and 1.9%
chemoselectivity for methyl 2-phenylpropionate and MP were
received. By-product with low molecular weight such as
polyketone was formed [14].
[15,16], with Mn = 0.97 × 103, Mw/Mn = 4.4, and regioregularity
of HH/HT/TT (%) = 17:66:17 (Table 1, entry 3).
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