Asymmetric synthesis of chiral glutaric acid derivatives via Rh-catalyzed enantioselective hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2009.02.046

The first Rh-catalyzed enantioselective hydrogenation of dimethyl 2-methyleneglutarate and its derivatives has been reported. For the hydrogenation of dimethyl 2-methyleneglutarate with a chiral ferrocene-based monodentate phosphoramidite ligand (FAPhos), good enantioselectivity (over 90% ee) with full conversions was achieved. In contrast, the hydrogenation of substrates bearing an aryl substituent at a methylene moiety proved to be more difficult, in which the best enantioselectivity of up to 81% ee was obtained by the use of a P-stereogenic BoPhoz-type ligand.

Full text of DOI:10.1016/j.tetasy.2009.02.046

Tetrahedron: Asymmetry 20 (2009) 588–592
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Tetrahedron: Asymmetry
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Asymmetric synthesis of chiral glutaric acid derivatives via Rh-catalyzed
enantioselective hydrogenation
Zheng-Chao Duan a,b,c, Xiang-Ping Hu a, , Jun Deng a,b, Sai-Bo Yu a,b, Dao-Yong Wang a,b, Zhuo Zheng a,
*
*
a Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
b Graduate School of Chinese Academy of Sciences, Beijing 100039, China
c Hubei University for Nationalities, Enshi 445000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first Rh-catalyzed enantioselective hydrogenation of dimethyl 2-methyleneglutarate and its deriva-
tives has been reported. For the hydrogenation of dimethyl 2-methyleneglutarate with a chiral ferrocene-
based monodentate phosphoramidite ligand (FAPhos), good enantioselectivity (over 90% ee) with full
conversions was achieved. In contrast, the hydrogenation of substrates bearing an aryl substituent at a
methylene moiety proved to be more difficult, in which the best enantioselectivity of up to 81% ee
was obtained by the use of a P-stereogenic BoPhoz-type ligand.
Received 9 January 2009
Accepted 26 February 2009
Available online 22 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Chiral glutaric acid derivatives, in particular, 2-substituted glu-
taric analogs, are key structural elements of many natural products
and drug intermediates, as well as important building blocks in or-
ganic synthesis.1 Although some enantioselective synthetic meth-
ods and resolution procedures have been reported in the past
decades,2 a significantly smaller number of the catalytic methods
are known to date. An important advance was reported by Evans
et al. who have recently reported a highly enantioselective Michael
additions of enolsilanes to the unsaturated imide derivatives in
which the resulting adducts could be easily converted into chiral
2-methylglutaric acid.3 Nevertheless, the development of a cata-
lytic process for the enantioselective synthesis of chiral glutaric
acid derivatives is still a great challenge for chemists. Given its
inherent efficiency and atom economy, the catalytic asymmetric
hydrogenation of prochiral unsaturated precursors of glutaric acid
would seem to be an ideal approach to prepare such compounds.
Indeed, this method has proved to be a powerful tool for the intro-
duction of stereocenters.4 To the best of our knowledge, however,
the asymmetric synthesis of chiral glutaric acid derivatives via a
catalytic hydrogenation process is still an unexplored area. As a
part of our ongoing efforts toward the development of new and
practical methods for the preparation of optically active com-
pounds,5 herein, we wish to report our result on the enantioselec-
tive synthesis of chiral glutaric acid derivatives via the first
Rh-catalyzed asymmetric hydrogenation of 2-methylene-glutarate
and 2-benzylideneglutarates.
2.1. Asymmetric hydrogenation of dimethyl 2-methyleneglut-
arate 1
Over past decades, itaconate derivatives have been successfully
hydrogenated with a variety of chiral P-ligand/Rh complexes to
give enantiomerically pure 2-substituted succinate,4b,c which is
structurally similar to the 2-methylglutarate of interest.
It should be possible to synthesize a glutarate analog of itaconic
acid as a substrate for asymmetric hydrogenation (Fig. 1). There-
fore, the search for an efficient method to synthesize 2-methylene-
glutarate and its analogs is highly desirable. Gratifyingly, the
simplest member, dimethyl 2-methyleneglutarate 1, can be easily
prepared in good yields by the self-condensation of acrylates in
the presence of n-Bu3P as shown in Scheme 1.6
COOMe
COOMe
COOMe
2-methyleneglutarate 1
COOMe
dimethylitaconate
Figure 1. Itaconate and 2-methyleneglutarate 1.
With easy access to the substrate, the key to achieving an enan-
tioselective hydrogenation of methyl 2-methyleneglutarate 1 is
therefore to find an efficient catalyst. We focused our efforts on
searching for an appropriate chiral phosphorus ligand with a dem-
onstrated track record of affecting Rh-catalyzed asymmetric
hydrogenations. Exploratory ligand screening employed a diverse
array of chiral phosphorus-containing ligands, which are commer-
* Corresponding authors. Tel.: +86 411 84669077; fax: +86 411 84684746
(X.-P. Hu).
E-mail addresses: xiangping@dicp.ac.cn (X.-P. Hu), zhengz@dicp.ac.cn (Z. Zheng).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.046

Z.-C. Duan et al. / Tetrahedron: Asymmetry 20 (2009) 588–592
Table 1
589
COOMe
COOMe
CO2Me
n-Bu3P
Ligand and condition screening for Rh-catalyzed asymmetric hydrogenation of
dimethyl 2-methyleneglutarate 1a
1
COOMe
COOMe
COOMe
[Rh(COD)2]BF4/L*
*
Scheme 1. Synthesis of dimethyl 2-methyleneglutarate 1.
COOMe
1
2
cially available or developed within our group. Some representa-
tive ligands screened are shown in Figure 2.
Entry
Ligand
Solvent
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(R,R)-Me-DuPHOS
(S,R)-Me-BoPhoz
(S)-BINAP
(R,S)-FAPhos
MonoPhos
(R)-3
(R)-PipPhos
ManniPhos
(S,R,S)-PPFAPhos
(S,S)-PEAPhos
(R,S)-FAPhos
(R,S)-FAPhos
(R,S)-FAPhos
(R,S)-FAPhos
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
THF
89
100
93
100
74
<10
70
100
100
100
41
58
57
94
92
<10
—
15
46
25
P
PPh2
PPh2
PPh2
N
d
PPh2
Fe
P
(R,R)-Me-DuPHOS
(S,R)-Me-BoPhoz
(S)-BINAP
21
<10
<10
12
<10
100
O
d
Toluene
i-PrOH
—
O
N
P
<10
P
O
N
O
a
R
The reactions were performed with 0.25 mmol of substrate at room tempera-
ture under a H2 pressure of 20 bar in 2 mL of the indicated solvent for 12 h with
1 mol % of Rh catalyst.
Fe
b
MonoPhos: R = Me
(R)-3: R = (S)-1-phenylethyl
Conversion was determined by GC.
Ee was determined by GC using a capillary chiral column.
Not determined because of low conversion.
c
(R,S)-FAPhos
d
Ph
Ph
O
O
O
OMe
MonoPhos,14 (R)-PipPhos,15 and the phenyl analog of FAPhos, (R)-
3,16 gave poor results in this transformation (entries 5–7). There-
fore, ferrocene-based monophosphoramidite ligand, FAPhos, was
selected as the optimal ligand for the Rh-catalyzed asymmetric
hydrogenation of dimethyl 2-methyleneglutarate 1 in terms of
enantioselectivity and conversion. Subsequent experiments in an
effort to attain higher enantioselectivities by optimizing the reac-
tion conditions, proved unsuccessful. As shown in Table 1, a strong
solvent dependency was observed in the reaction. However, no re-
sults surpassed that obtained in CH2Cl2 (entries 4, 11–14).
O
P
O
O
N
O
P
O
O
(R)-PipPhos
ManniPhos
PPh2
O
O
O
N P
P
N
O
Fe
PPh2
2.2. Asymmetric hydrogenation of dimethyl 2-benzylidene-
glutarates 4
(S,S)-PEAPhos
(S,R,S)-PPFAPhos
Figure 2. Structure of some representative ligands for asymmetric hydrogenation.
The good results obtained in the hydrogenation of dimethyl
2-methyleneglutarate 1 prompted us to extend the scope of this
substrate class. A series of the substrates with an aryl substituent
in the methylene moiety were then prepared by a modified method
reported by Kim and Murthy et al. independently as outlined in
Scheme 2.17 Initially, the Baylis–Hillman acetates 6 were prepared
in good yields according to the standard methods by the treatment
of aromatic aldehydes with methyl acrylate, followed by acetyla-
tion of alcohol 5. The reaction of the Baylis–Hillman acetates 6
and (methoxycarbonyl-methylene)triphenylphosphorane in the
presence of Pd(OAc)2 in refluxing THF predominantly formed di-
methyl (E)-2-benzylideneglutarates in good yields. However, an at-
tempt to prepare 2-alkylmethyleneglutarate with the same
procedure failed.
With these substrates in hand, we set out to search for an effi-
cient catalyst for their hydrogenation, and some representative re-
sults are summarized in Table 2. Unlike the hydrogenation of
dimethyl 2-methyleneglutarate 1, most of phosphorus-containing
ligands including BINAP and FAPhos displayed moderate to low
activities for the hydrogenation of these 2-benzylidene substituted
substrates even under an H2 pressure of 60 bar and 2 mol % of cat-
alyst loading (entries 1 and 2). This phenomenon is very similar to
that observed in the hydrogenation of itaconic acid derivatives, in
Although having a similar structure, the hydrogenation of
dimethyl 2-methyleneglutarate 1 proved to be more difficult than
the corresponding dimethyl itaconate. The data summarized in
Table 1 revealed that most of the phosphorus-ligand/Rh com-
plexes, which have proved to be highly efficient for the asymmetric
hydrogenation of dimethyl itaconate, gave substantially low
enantioselectivities for the hydrogenation of dimethyl 2-methyl-
eneglutarate 1. For instance, DuPHOS7 only gave moderate enanti-
oselectivity and incomplete conversion (entry 1); while
unsymmetrical hybrid ligands such as Me-BoPhoz,8 PPFAPhos9
and PEAPhos10 showed low enantioselectivity although full con-
versions were observed in these cases (entries 2, 9, and 10). The
monodentate phosphite ligand, ManniPhos,11 gave only 46% ee
(entry 8).
To our delight, we found that bidentate BINAP12 and monoden-
tate FAPhos13 displayed good enantioselectivities despite the
incomplete conversion in the case of using BINAP (entries 3 and
4). More interestingly, subsequent investigations on the effect of
monophosphoramidite structure in this hydrogenation showed
that the ferrocene fragment in these monodentate ligands has a
crucial role in the reactivity and enantioselectivity. Thus, all of

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Z.-C. Duan et al. / Tetrahedron: Asymmetry 20 (2009) 588–592
R1
R1
OH
CHO
CO2Me
CO2Me
b
a
+
P
R
N
PPh2
N
R2
P
R
Fe
5
PPh2
R
Fe
OAc
c
CO2Me
CO2Me
CO2Me
1
2
3a
(Sc,RFc,RP)- : R = R = H;
(S,R)-Me-BoPhoz: R =Me;
(S,R)-Et-BoPhoz: R = Et
1
2
3b
3c
(Sc,RFc,RP)- : R = H, R = Me;
R
1
(Sc,RFc,RP)- : R = CF3, R2 = Me
R
4a
: R = H
6
4b: R = 4-Cl
Figure 3. BoPhoz ligands for asymmetric hydrogenation.
4c: R = 4-OMe
4d
: R = 3-OMe
Scheme 2. Synthesis of unsaturated precursors of glutarate 4a–d. Reagents and
conditions: (a) DABCO, rt; (b) AcCl, pyridine, DMAP, CH2Cl2; (c) Pd(OAc)2,
Ph3P@CHCOOMe, THF, reflux, 10–13 h.
3. Conclusion
In summary, we have reported the first asymmetric synthesis of
chiral 2-substituted glutarates via the Rh-catalyzed enantioselec-
tive hydrogenation. After an extensive ligand screening, the biden-
tate P-ligand BINAP and monodentate P-ligand FAPhos were found
to show good enantioselectivities (94% ee and 92% ee, respectively)
in the hydrogenation of dimethyl 2-methyleneglutarate. In con-
trast, the hydrogenation of 2-benzylideneglutarates was more dif-
ficult, and up to 81% ee was obtained by the use of a BoPhoz-type
ligand bearing a stereogenic P center in the phosphino moiety and
a 4-CF3 group in phenyl ring on aminophosphino moiety. These
observations are similar to that observed in the hydrogenation of
itaconate, in which the hydrogenation of b-substituted itaconic
acid derivatives is found to be less efficient than the hydrogenation
of the corresponding parent itaconic acid derivatives. Further
investigation of other chiral hydrogenation catalysts is underway
and should result in improved hydrogenation enantioselectivity.
which b-substituted substrates are found to be hydrogenated less
easily than the corresponding parent itaconic acid derivatives.18
Table 2
Rh-catalyzed asymmetric hydrogenation of dimethyl 2-benzylideneglutarates 4a
COOMe
CO2Me
CO2Me
*
[Rh(COD)2]BF4/L*
COOMe
CH2Cl2, H2 (60 bar)
rt, 24 h
R
R
7
4
Entry
Ligand
Substrate
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
9
(S)-BINAP
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
56
<5
8
—
66
61
—
71
76
75
78
81
d
(R,S)-FAPhos
(S,R)-Me-BoPhoz
(S,R)-Et-BoPhoz
(Sc,RFc,Rp)-3a
(Sc,RFc,Rp)-3b
(Sc,RFc,Rp)-3c
(Sc,RFc,Rp)-3c
(Sc,RFc,Rp)-3c
(Sc,RFc,Rp)-3c
100
100
<5
100
100
100
100
100
d
4. Experimental
4.1. General methods
10
All solvents were dried and degassed by standard methods
according to the literature19 and were stored under nitrogen. All
the commercially available catalysts and ligands were brought
from Strem Chemicals and used without further purification. All
reactions were carried out under an atmosphere of nitrogen using
the standard Schlenk techniques or in a nitrogen-filled glovebox,
unless otherwise noted. NMR spectra were recorded on BRUKER
DRX 400 spectrometers. Chemical shifts are reported in parts per
million (ppm) downfield from TMS with the solvent resonance as
the internal standard. Enantiomeric excess (ee) was determined
by GC on a HP 4890 or HPLC analysis on an Agilent HP-1100.
a
The reactions were performed with 0.25 mmol of substrate at room tempera-
ture under a H2 pressure of 60 bar in 2 mL of CH2Cl2 for 24 h with 2 mol % of Rh
catalyst.
b
Conversion was determined by GC.
Ee was determined by HPLC using a chiral column.
Not determined because of low conversion.
c
d
After extensively screening phosphorus-ligands, we delightedly
found that Me-BoPhoz showed a promising ee-value of up to 66%
and full conversions (entry 3). Since the synthetic methodology
of BoPhoz-type ligands is highly modular, the optimization of the
BoPhoz skeleton was therefore carried out (Fig. 3). After a system-
atic investigation of a number of BoPhoz-type ligands with varying
electronic and steric properties, we determined that (Sc,RFc,RP)-3c,
bearing a stereogenic P-center in the phosphino moiety and a 4-
CF3 group in phenyl ring of aminophosphino moiety, provided bet-
ter result than that obtained with Me-BoPhoz, in which up to 76%
ee was achieved (entry 7). The hydrogenation of a series of di-
methyl (E)-2-benzylideneglutarates 4 was examined with the Rh
complex of (Sc,RFc,RP)-3c subsequently. The results reveal that there
is no major effect on the electronic properties and substitution pat-
tern of the substituent on the phenyl ring of the substrates, and the
hydrogenation proceeded to completion and provided the corre-
sponding hydrogenated products with moderate enantioselectivi-
ties (entries 7–10). The best enantioselectivity was obtained in
the hydrogenation of 3-methoxyphenyl substituted substrate 4d,
in which up to 81% ee was achieved (entry 10).
4.2. Synthesis of dimethyl 2-methyleneglutarate 1
Methyl acrylate (21.5 g, 250 mmol) was cooled to ꢀ10 °C, fol-
lowed by the addition of tri-n-butylphosphine (5.1 g, 25 mmol).
The reaction was allowed to warm to room temperature, and after
stirring for 1.5 h, the solution was concentrated on a rotary evapo-
rator and the residue was distilled under reduced pressure to give
12.1 g (56%) of 1 as a colorless oil. 1H NMR (400 MHz, CDCl3): d
6.19 (s, 1H), 5.61 (s, 1H), 3.76 (s, 3H), 3.67 (s, 3H), 2.63–2.66 (m,
2H), 2.51–2.55 (m, 2H).
4.3. Synthesis of (E)-2-benzylideneglutarate derivatives 4
Methyl acrylate (15.0 g, 0.174 mol) and benzaldehyde (15.0 g,
0.141 mol) were stirred in the presence of DABCO (15.9 g,
0.141 mol) for 24 h at room temperature. The reaction mixture

Z.-C. Duan et al. / Tetrahedron: Asymmetry 20 (2009) 588–592
591
was diluted with ether and washed successively with HCl, NaHCO3,
and H2O. The organic layer was dried over Na2SO4, and then the ex-
cess methyl acrylate and solvent was removed. The crude product
was purified by flash chromatography to give the desired product
methyl 2-(1-hydroxybenzyl)acrylate 5a (23.1 g) in 85.1% yield.
Acetyl chloride (4.0 g, 3.72 mL, 52 mmol) was slowly dropped
into a solution of 5a (40 mmol) and pyridine (40 mL) in CH2Cl2
(20 mL), maintained at 0 °C and under nitrogen. After being stirred
overnight at room temperature, the solution was poured into ice-
water and extracted with ether (3 ꢁ 80 mL). The organic phase
was dried, and the solvent was evaporated. The crude product
was purified by column chromatography.
To a solution of the Baylis–Hillman acetate (16 mmol) in anhy-
drous benzene (80 mL) were added (methoxycarbonyl-methy-
lene)triphenylphosphorane (16 mmol) and Pd(OAc)2 (6 mol %)
and the solution was heated at reflux for 10–13 h (monitored by
TLC). After completion of the reaction, H2O (20 mL) was added to
the reaction mixture, which was extracted with EtOAc
(3 ꢁ 100 mL). The combined organic layer was washed with H2O
and brine, dried over anhydrous Na2SO4, concentrated in vacuum
and the crud product was purified by column chromatography.
meric excess was determined by GC or HPLC after purification on
silica gel.
4.4.1. Dimethyl 2-methylglutarate 2
Colorless oil. 92% ee, GC,
c
-DEX-225 column (0.25 mm ꢁ 30 m),
80 °C, t1 = 41.8 min, t2 = 43.6 min. ½a D25
ꢂ
¼ ꢀ8:1 (c 0.64, CHCl3); 1H
NMR (CDCl3): d 3.67–3.68 (m, 6H), 2.49 (m, 1H), 2.32–2.37 (m,
2H), 1.96 (m, 2H), 1.16–1.19 (m, 3H).
4.4.2. Dimethyl 2-benzylglutarate 7a
Colorless oil. 76% ee, HPLC (UV 260 nm, Chiralcel OJ-H
(0.46 cm ꢁ 25 cm), i-PrOH/hexane = 3/97, 1 mL/min), t1 = 16.7 min,
t2 = 18.7 min. ½a 2D0
ꢂ
¼ ꢀ4:8 (c 1.02, CHCl3); 1H NMR (400 MHz,
CDCl3): d 7.13–7.28 (m, 5H), 3.64 (s, 3H), 3.59 (s, 3H), 2.94–2.97
(m, 1H), 2.73–2.78 (m, 2H), 2.29–2.36 (m, 2H), 1.84–1.93 (m, 2H).
13C NMR (100 MHz, CDCl3): d 175.3, 173.2, 138.8, 128.9, 128.5,
126.5, 51.6, 51.6, 46.7, 38.4, 31.7, 26.8. HRMS (EI): calcd for
C14H18O4 [M+] 250.1205, found 250.1210.
4.4.3. Dimethyl 2-(4-chlorobenzyl)glutarate 7b
Colorless oil. 75% ee, HPLC (UV 260 nm, Chiralcel OJ-H
(0.46 cm ꢁ 25 cm), i-PrOH/hexane = 1/99, 0.8 mL/min), t1 = 37.6
min, t2 = 39.0 min. ½a D20
ꢂ
¼ ꢀ8:5 (c 1.18, CHCl3); 1H NMR (400 MHz,
4.3.1. Dimethyl (E)-2-benzylideneglutarate 4a
Colorless oil. 1H NMR (400 MHz, CDCl3): d 7.74 (s, 1H), 7.32–
7.39 (m, 5H), 3.81 (s, 3H), 3.64 (s, 3H), 2.86–2.90 (m, 2H), 2.54–
2.58 (m, 2H). 13C NMR (100 MHz, CDCl3): d 173.11, 168.25,
140.54, 135.21, 131.07, 129.14, 128.66, 52.09, 51.63, 33.28, 23.09.
HRMS (EI): calcd for C14H16O4 [M+] 248.1049, found 248.1049.
CDCl3): d 7.22–7.27 (m, 2H), 7.07–7.09 (m, 2H), 3.65 (s, 3H), 3.60
(s, 3H), 2.90–2.93 (m, 1H), 2.69–2.76 (m, 2H), 2.29–2.37 (m, 2H),
1.87–1.94 (m, 2H). 13C NMR (100 MHz, CDCl3): d 174.99, 173.16,
137.28, 132.31, 130.21, 128.58, 51.66, 46.54, 37.69, 31.62, 26.85.
HRMS (EI): calcd for C14H17ClO4 [M+] 284.0815, found 284.0816.
4.3.2. Dimethyl (E)-2-(4-chlorobenzylidene)glutarate 4b
Colorless oil. 1H NMR (400 MHz, CDCl3): d 7.67 (s, 1H), 7.36–
7.38 (m, 2H), 7.28–7.31 (m, 2H), 3.82 (s, 3H), 3.67 (s, 3H), 2.82–
2.86 (m, 2H), 2.53–2.57 (m, 2H). 13C NMR (100 MHz, CDCl3): d
172.97, 167.99, 139.14, 134.63, 131.69, 130.45, 129.52, 128.91,
52.17, 51.69, 33.12, 23.04. HRMS (EI): calcd for C14H15ClO4 [M+]
282.0659, found 282.0620.
4.4.4. Dimethyl 2-(4-methoxybenzyl)glutarate 7c
Colorless oil. 78% ee, HPLC (UV 254 nm, Chiralcel OD-H
(0.46 cm ꢁ 25 cm), i-PrOH/hexane = 1/99, 1 mL/min), t1 = 15.4
min, t2 = 16.6 min. ½a D20
ꢂ
¼ ꢀ8:6 (c 1.14, CHCl3); 1H NMR (400 MHz,
CDCl3): d 7.04–7.07 (m, 2H), 6.80–6.82 (m, 2H), 3.77 (s, 3H), 3.65
(s, 3H), 3.61 (s, 3H), 2.88–2.91 (m, 1H), 2.69–2.73 (m, 2H), 2.28–
2.36 (m, 2H), 1.87–1.91 (m, 2H). 13C NMR (100 MHz, CDCl3): d
175.3, 173.3, 158.2, 130.8, 129.8, 113.8, 55.2, 51.6, 51.6, 46.9, 37.6,
31.7, 26.7. HRMS (EI): calcd for C15H20O5 [M+] 280.1311, found
280.1309.
4.3.3. Dimethyl (E)-2-(4-methoxybenzylidene)glutarate 4c
Colorless oil. 1H NMR (400 MHz, CDCl3): d 7.68 (s, 1H), 7.34–
7.37 (m, 2H), 6.91–6.94 (m, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 3.68 (s,
3H), 2.88–2.92 (m, 2H), 2.55–2.59 (m, 2H). 13C NMR (100 MHz,
CDCl3): d 173.29, 160.06, 140.16, 131.11, 128.77, 127.63, 114.16,
55.31, 52.02, 51.66, 33.19, 23.13. HRMS (EI): calcd for C15H18O5
[M+] 278.1154, found 278.1150.
4.4.5. Dimethyl 2-(3-methoxybenzyl)glutarate 7d
Colorless oil. 81% ee, HPLC (UV 254 nm, Chiralcel OJ-H
(0.46 cm ꢁ 25 cm), i-PrOH/hexane = 1/99, 0.8 mL/min), t1 = 45.0
min, t2 = 49.4 min. ½a D20
ꢂ
¼ ꢀ2:7 (c 1.16, CHCl3); 1H NMR (400 MHz,
CDCl3): d 7.17–7.21 (m, 1H), 6.70–6.75 (m, 3H), 3.80 (s, 3H), 3.65
(s, 3H), 3.62 (s, 3H), 2.92–2.96 (m, 1H), 2.69–2.76 (m, 2H), 2.29–
2.37 (m, 2H), 1.88–1.94 (m, 2H). 13C NMR (100 MHz, CDCl3): d
175.2, 173.2, 159.7, 140.4, 129.5, 121.2, 114.5, 111.9, 55.1, 51.6,
46.5, 38.4, 31.7, 26.8. HRMS (EI): calcd for C15H20O5 [M+] 280.1311,
found 280.1319.
4.3.4. Dimethyl (E)-2-(3-methoxybenzylidene)glutarate 4d
Colorless oil. 1H NMR (400 MHz, CDCl3): d 7.71 (s, 1H), 7.28–
7.32 (m, 1H), 6.88–6.95 (m, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.66 (s,
3H), 2.86–2.90 (m, 2H), 2.54–2.58 (m, 2H). 13C NMR (100 MHz,
CDCl3): d 173.06, 168.18, 159.65, 140.42, 136.49, 131.28, 129.65,
121.51, 114.45, 55.20, 52.06, 51.59, 33.29, 23.20. HRMS (EI): calcd
for C15H18O5 [M+] 278.1154, found 278.1147.
Acknowledgments
4.4. General procedure for asymmetric hydrogenation
We are grateful for financial support from the National Natural
Science Foundation of China (20873145, 20802076) and the
Knowledge Innovation of the Chinese Academy of Sciences (DICP-
S200802).
In a nitrogen-filled glovebox, to a solution of [Rh(COD)2]BF4
(1.0 mg, 0.0025 mmol) in anhydrous and degassed CH2Cl2 (1 mL)
was added ligand (0.00275 mmol for bidentate ligands or
0.005 mmol for monodentate ligands). After stirring the mixture
for 30 min, a substrate (0.25 mmol) dissolved in CH2Cl2 (1 mL)
was added. The reaction mixture was transferred to a Par stainless
autoclave. The autoclave was purged three times with hydrogen
and the pressure was set to the desired pressure. The hydrogena-
tion was performed at room temperature for 24 h. After carefully
releasing the hydrogen, the solvent was removed. The enantio-
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