Enantioselective synthesis of chiral γ-aryl α-keto ester by copper-catalyzed 1,4-conjugate addition using D2-symmetric biphenyl phosphoramidite ligand

Article abstract of DOI:10.1016/j.tet.2011.06.059

Cu-catalyzed enantioselective 1,4-conjugate addition of β,γ-unsaturated α-keto ester compound was carried out to afford chiral γ-substituted γ-aryl α-keto ester, which could be conveniently converted to the potential skeleton of new Pril drugs. Up to 81%

Full text of DOI:10.1016/j.tet.2011.06.059

Tetrahedron 67 (2011) 6197e6201
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective synthesis of chiral g-aryl a-keto ester by copper-catalyzed
1,4-conjugate addition using D2-symmetric biphenyl phosphoramidite ligand
*
Bo Yang, Fang Xie, Han Yu, Kaiji Shen, Zhenni Ma, Wanbin Zhang
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 April 2011
Received in revised form 11 June 2011
Accepted 21 June 2011
Available online 25 June 2011
Cu-catalyzed enantioselective 1,4-conjugate addition of
carried out to afford chiral g-substituted g-aryl a-keto ester, which could be conveniently converted to
the potential skeleton of new Pril drugs. Up to 81% ee and 99% yield were afforded for the 1,4-conjugate
addition using D2-symmetric biphenyl phosphoramidite ligand.
Ó 2011 Elsevier Ltd. All rights reserved.
b,g-unsaturated a-keto ester compound was
Keywords:
Phosphoramidite ligand
Asymmetric catalysis
Copper
Conjugate addition
g-Aryl-b,g-unsaturated a-keto ester
1. Introduction
the most efficient ones with good to excellent results (Fig. 1). Re-
cently, our group have developed a new type of D2-symmetric bi-
Inhibitors of angiotensin converting enzyme (ACE-inhibitors),
also known as Pril drugs, were efficient for treating high blood
pressure (hypertension), congestive heart failure, and preventing
strokes. Lots of Pril drugs have been developed in the past few
decades due to their high efficiency versus low kidney damage in
people with hypertension.1,2 Typically, almost all the Pril drugs
were made of two parts, a peptide moiety and an (S)-homophenyl-
alanine moiety, which could be introduced starting from (R)-2-
hydroxy-4-phenylbutyrate.2 For the development of new Pril
drugs, many efforts have been focused on the modification of their
peptide moiety so far, while no example was reported on the
modification of (S)-homophenyl-alanine moiety.1,2 In fact, the in-
troduction of new functional group to the later could enhance the
drug effect and broaden the scope of ACE-inhibitors.
phenyl phosphoramidite ligand L4, which afforded one of the best
asymmetric catalytic results in the asymmetric 1,4-conjugate ad-
dition of diethylzinc to
a,b-unsaturated ketones and nitroalkene
due to their symmetry and easier modification on 3,30,5,50-posi-
tions of biphenol backbone.7
Ph
N
Ph
N
O
O
O
O
O
O
O
O
P
P
P
N
Ph
Ph
On the other hand, the copper-catalyzed 1,4-conjugate addition
of
a
,
b
-unsaturated carbonyl and/or nitro compounds is a powerful
-substituted carbonyl and/or nitro com-
L3
way to construct chiral
b
L2
L1
pounds.3e6 Amongst the reported catalyst systems in the asym-
metric 1,4-conjugate addition, chiral phosphoramidite ligands,
such as central chiral ligands L1 derived from TADDOL backbone4
and C2-symmetric chiral ligands L2 and L3 with biaryl backbones
derived from BINOL5 and Biphenol,6 respectively, were tested to be
R
R
a: cis R = H,
Ph
N
Ph
N
b: trans R = H,
c: trans R = Me,
d: trans R = Et,
e: trans R = Br,
f: trans R = Ph,
g: trans R = Allyl,
O
O
O
O
P
P
Ph
Ph
R
R
(S, S, aR, S, S)-L4
* Corresponding author. Tel./fax: þ86 21 54743265; e-mail address: wanbin@
sjtu.edu.cn (W. Zhang).
Fig. 1. Some chiral phosphoramidite ligands.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.059

6198
B. Yang et al. / Tetrahedron 67 (2011) 6197e6201
Therefore, we want to carry out the copper-catalyzed enantio-
selective 1,4-conjugate addition of -unsaturated -keto ester
compound 1 to afford -substituted -aryl -keto ester compound
2, which could be easily converted to series of chiral 4-substituted
2-hydroxy-4-arylbutyrate 3 (Scheme 1).2a Compound 3 may be
a potential important intermediate for new Pril drug development
as mentioned above. Here, we report our results on the copper-
catalyzed asymmetric 1,4-conjugate addition of 1 with a series of
chiral phosphoramidite ligands including our D2-symmetric ones.
Next, different solvents were screened with the above optimal
b
g
,g
a
reaction conditions (Table 1, entries 15e20). The results showed
that high yields and enantioselectivities were obtained with sol-
vents, such as toluene, Et2O, THF (entries 15e17). On the contrary,
when the reaction carried out in solvents, such as DCM, PhCF3, DMF,
very low yields or very low ee values were given (entries 18e20).
Based on the above results, the optimal reaction conditions were
that Cu(I)(MeCN)4ClO4 was used as copper source, toluene was
used as solvent and the reaction was conducted at ꢀ20 ꢁC.
Finally, a series of phosphoramidite ligands were applied in the
catalytic reaction using the above optimized reaction conditions
(Table 2). Moderate catalytic activities and low enantioselectivities
were provided with (ꢀ)-TADDOL-derived central chiral mono-
phosphoramidite ligand L1, axial chiral monophosphoramidite li-
gand L2 and L3 (entries 1e3). To our delight, much better results
were achieved by using D2-symmetric axial dibridged phosphor-
amidite ligand L4 (entries 4e10). The ligand L4 with trans config-
uration has better catalytic effect compared to that with cis
configuration (entries 4 and 5). It was found that the substituted
group on 3,30,5,50-positions had a very important effect not only on
enantioselectivity but also on absolute configuration of the prod-
ucts. When the substituted group on 3,30,5,50-positions was H,
ꢀ60% ee value was obtained (entry 5). As increased size of
substituted group to methyl, the steric hindrance increased. It was
interesting to find that the configuration of product reversed and
74% ee value was obtained (entry 6). When the size of substituted
group continuously increased to ethyl, the steric hindrance in-
creased further and a ꢀ54% ee value was obtained (entry 7). These
results were also consistent with our previous research.7 If the
substituted groups were changed to Br and Ph, 32% and 30% ee
values were obtained, respectively (entries 8 and 9). When the
substituted group was changed to allyl, a nearly racemic catalytic
product was obtained (entry 10). These results suggest that the
reversal of the product’s configuration could be controlled by
adjusting different functional group, which were rarely
reported.7,10
g
a
Scheme 1.
2. Results and discussion
Compound 1 could be easily prepared from pyruvic acid and
corresponding aromatic aldehyde through aldol reaction.8 Then we
used compound 1 as the substrate in the copper-catalyzed asym-
metric 1,4-conjugate addition with Et2Zn (Table 1, entry 1). Firstly,
different temperatures were screened in the asymmetric 1,4-
conjugate addition with Cu(II)(OAc)2-L4c as catalytic system in
toluene (Table 1, entries 1e5). The catalytic system showed high
reactivity and the reaction completed in 2 h. The enantioselectivity
increased gradually with decreasing the temperature from rt to
ꢀ20 ꢁC (Table 1, entries 1e3). Further decreased the temperature,
however, the enantioselectivity declined (entry 4). It is interesting
that the configuration was reversed at ꢀ78 ꢁC (entry 5). This phe-
nomenon had also been reported by Sibi and Casey groups.9
Table 1
Condition optimization of 1,4-conjugate addition reactiona
O
Et
O
Cu(I) or Cu(II)
∗
O
O
+
ZnEt2
L4c
O
O
Table 2
1a
2a
Optimization of ligands used in 1,4-conjugate addition reaction to 1aa
O
Et
O
Entry
Cu salt
Solvent
Toluene
Temp (ꢁC)
Yieldb(%)
ee(%)c
L*
Cu(I)(MeCN)4ClO4,
∗
O
O
+
ZnEt2
toluene, -20 oC, 2 h
1
2
3
4
5
6
7
8
Cu(II)(OAc)2$H2O
Cu(II)(OAc)2$H2O
Cu(II)(OAc)2$H2O
Cu(II)(OAc)2$H2O
Cu(II)(OAc)2$H2O
Cu(II)Br2
Cu(II)ClO4$6H2O
Cu(II)(OTf)2
Cu(II)(acac)2
rt
0
81
85
88
92
16
70
96
87
96
99
92
92
79
99
100
90
88
71
92
20
58
64
68
66
ꢀ19
29
66
63
64
68
62
66
65
67
74
69
67
6
O
O
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Et2O
ꢀ20
ꢀ30
ꢀ78
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
1a
2a
Entry
Ligand
Yield(%)b
ee(%)c
1
2
3
4
5
6
7
8
9
L1
L2
L3
45
52
62
48
90
100
67
57
55
18
6
29
48
9
cis-aR-L4a
ꢀ39
ꢀ60
74
ꢀ54
10
11
12
13
14
15
16
17
18
19
20
Cu(II)(Me3CCO2)2
Cu(I)TC
trans-aR-L4b
trans-aR-L4c
trans-aR-L4d
trans-aR-L4e
trans-aR-L4f
trans-aR-L4g
Cu(I)(C6H6)OTf
Cu(I)(MeCN)4PF6
Cu(I)(MeCN)4BF4
Cu(I)(MeCN)4ClO4
Cu(I)(MeCN)4ClO4
Cu(I)(MeCN)4ClO4
Cu(I)(MeCN)4ClO4
Cu(I)(MeCN)4ClO4
Cu(I)(MeCN)4ClO4
32
30
2
10
a
THF
DCM
PhCF3
DMF
Cu salt (2 mol %), 4 mol % ligand, 1.5 equiv ZnEt2.
Determined by 1H NMR spectroscopy.
Determined by HPLC, Chiralcel OJ-H column: i-PrOH/hexane 10/90, 1 mL/min,
b
c
25
67
210 nm.
a
Cu salt (2 mol %), 4 mol % L4c, 1.5 equiv ZnEt2, the reaction completed in 2 h.
b
c
Determined by 1H NMR spectroscopy.
Determined by HPLC, Chiralcel OJ-H column: i-PrOH/hexane 10/90, 1 mL/min,
With the optimized reaction conditions in hand, we investigated
210 nm.
the scope of substrates using Cu(I)(MeCN)4ClO4-L4c as catalytic
system in toluene at ꢀ20 ꢁC and the results were shown in Table 3.
With the increase of the size of alkyl groups R at keto ester side,
the enantioselectivity decreased (Table 3, entries 1 and 2). When
the R group was changed to benzyl, the configuration of the product
Then, the effects of copper salts on the reaction were in-
vestigated at ꢀ20 ꢁC with toluene as solvent (Table 1, entries 6e15).
Among the examined copper salts, Cu(I)(MeCN)4ClO4 was the best
one according to the yield and enantioselectivity (entry 15).

B. Yang et al. / Tetrahedron 67 (2011) 6197e6201
6199
run on silica gel (100e200 mesh). 1H NMR (400 MHz) spectra and
13C NMR (100 MHz) spectra were obtained on a Varian MERCURY
plus-400 spectrometer. HRMS was performed on a Micromass LCT
TM at the Instrumental Analysis Center of Shanghai Jiao Tong
University.
Table 3
Substrates scope of enantioselective 1,4-addition reactiona
O
Et
O
∗
Cu(I)(MeCN)4ClO4, L4c
toluene, -20 oC, 2 h
O
O
+
ZnEt2
Ar
R
Ar
R
O
1a~1m
O
2a~2m
4.2. Procedures and analytical data
Entry
Substrate
Ar
R
Yieldb(%)
ee(%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
Ph
Ph
4-MePh
3-MePh
2-MePh
4-OMePh
4-ClPh
Me
Et
Bn
100
50
84
99
99
49
78
88
99
97
96
72
61
74
46
4.2.1. Preparation of the substrates. All substrates 1 were prepared
according to literature.8
ꢀ71
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
59
60
18
61
71
4.2.2. General procedure for copper-catalyzed conjugate addition by
ZnEt2. General procedures for conjugate addition: the flame dried
Schlenk tube was charged with Cu(MeCN)4ClO4 1.64 mg
(0.010 mmol) and 2 equiv of ligand (0.020 mmol) under nitrogen,
and the mixture was dissolved in dry toluene (0.5 mL), resulting
a colorless solution. The solution was stirred at 25 ꢁC for 2 h and
then cooled to ꢀ20 ꢁC. The substrate 1 (1.0 mmol dissolved in
1.0 mL dry toluene) was then added dropwise within 3 min. The
solution was stirred for 5 min at ꢀ20 ꢁC and gradually turned to
light yellow. Diethylzinc (1.5 mmol, 3.4 mL of 1 M sol in hexane)
was added dropwise within 3 min. The reaction mixture was stirred
at ꢀ20 ꢁC for 2 h till full conversion monitored by TLC. Then the
system was quenched by aqueous satd NH4Cl and extracted with
ethyl acetate (5 mLꢂ2), the organic solution was concentrated and
the residue was purified by silica gel column chromotography to
afford the product 2. Enantiomeric excess was determined by chiral
HPLC.
9
4-BrPh
4-FPh
4-NO2Ph
81
10
11
12
13
1j
1k
1l
71
NDd
57
b
-Naph
1m
Furan
6
a
Cu salt (2 mol %), 4 mol % L4c, 1.5 equiv ZnEt2.
b
c
Determined by 1H NMR spectroscopy.
Determined by HPLC, Chiralcel OJ-H column: i-PrOH/hexane 10/90, 1 mL/min,
210 nm.
d
ND¼Not Detected.
even reversed and up to ꢀ71% ee was obtained (entry 3). It was
worth noting that the steric hindrance on the aryl group had an
obvious impact on catalytic reactivity and enantioselectivity (en-
tries 4e6). The para and meta orientated substrates provided good
reactivities and moderate enantioselectivities, respectively (entries
4 and 5), while ortho orientated substrate 1f resulted in 49% yield
and 18% ee value (entry 6). Then substrates possessing substituted
benzene ring with different electron natures were examined (en-
tries 4e11). The substrate with electron donating group achieved
slightly lower enantioselectivity (entries 4, 7). However, substrates
with electron withdrawing groups gave an obviously increase on
enantioselectivities (entries 8e10). When the para position of the
benzene ring was substituted by Br, up to 81% ee was achieved
(entry 9). For the naphthyl substrate 1l, only a moderate enantio-
selectivity was obtained (entry 12). Unfortunately, for the furan
substrate 1m, only low enantioselectivity was provided with
a moderate yield (entry 13). Pyridine substrate was also in-
vestigated, but the reaction did not occur since its poor solubility.
4.2.2.1. Methyl 2-oxo-4-phenylhexanoate (2a). Light yellow oil;
100% yield and 74% ee; 1H NMR (400 MHz, CDCl3):
d
7.30e7.09 (m,
5H), 3.78 (s, 3H), 3.22 (m, 2H), 3.15e3.09 (m, 1H), 1.70e1.52 (m, 2H),
0.78 (q, 3H); 13C NMR (100 MHz, CDCl3):
193.41, 143.27, 128.69,
d
128.57,128.28, 126.78, 53.14, 46.14, 42.50, 29.48, 20.74, 12.13; HRMS
(Q-TOF Premier) calcd for C13H16O3 [MꢀH]ꢀ 219.1021, found:
219.1007. HPLC conditions: Chiralcel OJ-H column, i-PrOH/hexane
10/90, flow rate: 1 mL/min, UV detection at 210 nm; Retention
time: tmajor¼20.2 min, tminor¼32.0 min.
4.2.2.2. Methyl 2-oxo-4-phenylhexanoates (2b). Light yellow oil;
50% yield and 46% ee; 1H NMR (400 MHz, CDCl3):
d 7.29e7.26 (m,
2H), 7.21e7.17 (m, 3H), 4.23 (q, J¼7.06 Hz, 2H), 3.19e3.14 (m, 2H),
3.15e3.09 (m, 1H), 1.71e1.57 (m, 2H), 1.30 (q, 3H), 0.79 (q, 3H); 13C
NMR (100 MHz, CDCl3):
d 193.82, 161.28, 143.70, 128.67, 127.82,
3. Conclusion
126.75, 62.57, 46.09, 42.59, 29.49, 14.15, 12.12; HRMS (Q-TOF Pre-
mier) calcd for C14H18O3 [MþNa]þ 257.1154, found: 257.1158. HPLC
conditions: Chiralcel OJ-H column, i-PrOH/hexane 10/90, flow rate:
In conclusion, we have developed a new method to prepare
series of chiral
g-substituted g-aryl a-keto ester 2 via copper-
1
mL/min, UV detection at 210 nm; Retention time:
catalyzed asymmetric 1,4-conjugate addition with optimized re-
action system. Up to 81% ee and 99% yield were obtained by using
D2-symmetric phosphoramidite ligand L4c. The chiral product
could be easily converted to series of 4-substituted chiral (S)-a-
hydroxyl-4-phenylbutyrate, a potential skeleton of new Pril drugs.
tmajor¼13.30 min, tminor¼19.83 min.
4.2.2.3. Benzyl 2-oxo-4-phenylhexanoate (2c). Light yellow oil;
84% yield and ꢀ71% ee; 1H NMR (400 MHz, CDCl3):
d
7.36 (s, 5H),
7.28e7.25 (m, 2H), 7.2e7.14 (m, 3H), 5.20 (s, 2H), 3.19e3.13 (m, 2H),
3.14e3.04 (m, 1H), 1.72e1.58 (m, 2H), 0.78 (q, 3H); 13C NMR
4. Experimental section
4.1. General
(100 MHz, CDCl3): d 193.41, 143.61, 128.97, 128.89, 128.84, 128.69,
127.80, 126.78, 68.08, 46.26, 42.60, 29.49, 12.12; HRMS (Q-TOF
Premier) calcd for C19H20O3 [MꢀH]ꢀ 295.1334, found: 295.1350.
HPLC conditions: Chiralcel OJ-H column, i-PrOH/hexane 10/90, flow
Commercially available reagents were used without further
purification other than those detailed below. Substrates 1 were
prepared according to modified methods of reported proceedings.8
All air- and moisture-sensitive manipulations were carried out
with standard Schlenk techniques under nitrogen. Toluene, DMF,
THF, Et2O, dichloromethane, and CF3Ph were dried according to
published procedures. The commercially available reagents were
used without further purification. Column chromatography was
rate: 1 mL/min, UV detection at 210 nm; Retention time:
tminor¼42.88 min, tmajor¼45.76 min.
4.2.2.4. Methyl 2-oxo-4-p-tolylhexanoate (2d). Light yellow oil;
99% yield and 59% ee; 1H NMR (400 MHz, CDCl3):
d 7.26e7.04 (m,
4H), 3.79 (s, 3H), 3.19e3.11 (m, 2H), 3.10e3.04 (m, 1H), 2.30 (s, 3H),
1.70e1.57 (m, 2H), 0.78 (q, 3H); 13C NMR (100 MHz, CDCl3):
d
193.47, 161.64, 140.55, 136.25, 129.37, 127.65, 53.07, 46.26, 42.13,

6200
B. Yang et al. / Tetrahedron 67 (2011) 6197e6201
29.51, 21.22, 12.13; HRMS (Q-TOF Premier) calcd for C14H18O3
[MþNa]þ 257.1154, found: 257.1158. HPLC conditions: Chiralcel OJ-
H column, i-PrOH/hexane 10/90, flow rate: 1 mL/min, UV detection
at 210 nm; Retention time: tmajor¼12.38 min, tminor¼20.48 min.
261.0905. HPLC conditions: Chiralcel OJ-H column, i-PrOH/hexane
10/90, flow rate: 1 mL/min, UV detection at 210 nm; Retention
time: tmajor¼13.83 min, tminor¼18.25 min.
4.2.2.11. Methyl 4-(4-nitrophenyl)-2-oxohexanoate (2k). Light
4.2.2.5. Methyl 2-oxo-4-m-tolylhexanoate (2e). Light yellow oil;
yellow oil; 96% yield, the ee has not been detected; 1H NMR
99% yield and 60% ee; 1H NMR (400 MHz, CDCl3):
d
7.19e7.15 (t,
(400 MHz, CDCl3):
d
8.15e8.13 (d, J¼8.4 Hz, 2H), 7.36e7.34 (d,
J¼7.6 Hz, 1H), 7.01e6.96 (m, 4H), 3.79 (s, 3H), 3.19e3.12 (m, 2H),
J¼8.4 Hz, 2H), 3.81 (s, 3H), 3.25e3.20 (m, 2H), 3.20e3.10 (m, 1H),
3.10e3.02 (m, 1H), 2.32 (s, 3H), 1.71e1.57 (m, 2H), 0.79 (q, 3H); 13C
1.79e1.70 (m, 2H), 0.79 (q, 3H); 13C NMR (100 MHz, CDCl3):
NMR (100 MHz, CDCl3):
d
193.42, 161.64, 143.61, 138.19, 128.61,
d 192.33,161.27, 151.62, 134.87, 128.73, 128.30, 127.47, 124.17, 124.00,
128.55, 127.52, 124.76, 53.07, 46.18, 42.44, 29.46, 21.68, 12.17; HRMS
(Q-TOF Premier) calcd for C14H18O3 [MþNa]þ 257.1154, found:
257.1154. HPLC conditions: Chiralcel OJ-H column, i-PrOH/hexane
10/90, flow rate: 1 mL/min, UV detection at 210 nm; Retention
time: tmajor¼10.05 min, tminor¼12.28 min.
53.31, 45.54, 42.12, 29.29, 12.01; HRMS (Q-TOF Premier) calcd for
C13H15NO5 [MꢀH]ꢀ 264.0872, found: 264.0880.
4.2.2.12. Methyl 4-(naphthalen-2-yl)-2-oxohexanoate (2l). Light
yellow oil; 72% yield and 57% ee; 1H NMR (400 MHz, CDCl3):
d
7.81e7.78 (m, 3H), 7.63 (s, 1H), 7.48e7.41 (m, 2H), 7.35e7.33 (dd,
4.2.2.6. Methyl 2-oxo-4-o-tolylhexanoate (2f). Light yellow oil;
J1¼1.2 Hz, J2¼2 Hz,1H), 3.75 (s, 3H), 3.35e3.26 (m, 2H), 3.25e3.16 (m,
49% yield and 18% ee; 1H NMR (400 MHz, CDCl3):
d 7.17e7.08 (m,
1H), 1.82e1.72 (m, 2H), 0.82 (q, 3H); 13C NMR (100 MHz, CDCl3):
4H), 3.79 (s, 3H), 3.44 (m, 1H), 3.24e3.06 (m, 2H), 2.37 (s, 3H),
d 193.29,141.04,133.65,132.62,128.46,127.86,127.81,126.61,126.24,
1.71e1.58 (m, 2H), 0.79 (q, 3H); 13C NMR (100 MHz, CDCl3):
125.91, 125.70, 53.10, 46.14, 42.64, 29.38, 12.21; HRMS (Q-TOF Pre-
mier) calcd for C17H18O3 [MꢀH]ꢀ 269.1178, found: 269.1158. HPLC
conditions: Chiralcel OJ-H column, i-PrOH/hexane 10/90, flow rate:
1 mL/min, UV detection at 210 nm; Retention time: tmajor¼27.27 min,
tminor¼31.89 min.
d
193.51, 161.59, 142.02, 136.53, 130.59, 126.45, 126.33, 125.78,
53.09, 45.92, 36.82, 29.52, 20.02, 11.93; HRMS (Q-TOF Premier)
calcd for C14H18O3 [MþNa]þ 257.1154, found: 257.1149. HPLC con-
ditions: Chiralcel OJ-H column, i-PrOH/hexane 10/90, flow rate:
1
mL/min, UV detection at 210 nm; Retention time:
tmajor¼13.42 min, tminor¼28.40 min.
4.2.2.13. Methyl 4-(furan-2-yl)-2-oxohexanoate (2m). Light yel-
low oil; Obtained 61% yield and 6% ee; 1H NMR (400 MHz, DMSO):
4.2.2.7. Methyl 4-(4-methoxyphenyl)-2-oxohexanoate (2g). Light
d
7.60e7.57(d, J¼12Hz,1H), 6.53e6.42(m,1H), 6.19e6.15(d, J¼16Hz,
1H), 3.78 (s, 3H), 3.32e3.30 (m, 1H), 1.71e1.65 (m, 2H), 0.80 (s, 3H);
13C NMR (400 MHz, DMSO):
174.89, 152.37, 143.30, 130.45, 118.28,
yellow oil; 78% yield and 61% ee; 1H NMR (400 MHz, CDCl3):
d
7.10e7.06 (m, 2H), 6.84e6.8 (m, 2H), 3.78 (s, 3H), 3.77 (s, 3H),
3.16e3.07 (m, 2H), 3.08e3.02 (m, 1H), 1.69e1.54 (m, 2H), 0.78 (q,
3H); 13C NMR (100 MHz, CDCl3):
193.51, 161.64, 158.39, 135.61,
d
112.30,109.39, 77.74, 52.77, 32.91, 8.49; HRMS (EI) calcd for C11H14O4
[MꢀH]þ 209.0814, found: 209.0753. HPLC conditions: Chiralcel OJ-H
column, i-PrOH/hexane 10/90, flow rate: 1 mL/min, UV detection at
210 nm; Retention time: tmajor¼11.14 min, tminor¼12.59 min.
d
128.71, 128.68, 114.04, 55.41, 53.08, 53.07, 46.37, 41.79, 29.64, 12.13;
HRMS (Q-TOF Premier) calcd for C14H18O4 [MꢀH]ꢀ 249.1127, found:
249.1124. HPLC conditions: Chiralcel OJ-H column, i-PrOH/hexane
10/90, flow rate: 1 mL/min, UV detection at 210 nm; Retention
time: tmajor¼25.61 min, tminor¼31.12 min.
Acknowledgements
This work was supported by the National Nature Science
Foundation of China (No. 20872091 and 20972095), Science and
Technology Commission of Shanghai Municipality (No.
09JC1407800), Shanghai Jiao Tong University (interdisciplinary
fund) and Nippon Chemical Industrial Co., Ltd. We thank Professor
T. Imamoto and Dr. M. Sugiya for the helpful discussion and In-
strumental Analysis Center of Shanghai Jiao Tong University.
4.2.2.8. Methyl 4-(4-chlorophenyl)-2-oxohexanoate (2h). Light
yellow oil; 88% yield and 71% ee; 1H NMR (400 MHz, CDCl3):
d 7.25
(s, 2H), 7.11e7.06 (m, 2H), 3.78 (s, 3H), 3.17e3.10 (m, 2H), 3.10e3.03
(m, 1H), 1.78e1.58 (m, 2H), 0.77 (q, 3H); 13C NMR (100 MHz, CDCl3):
d
192.97, 161.48, 142.14, 132.42, 129.18, 128.84, 128.81, 53.19, 45.98,
41.86, 29.44, 12.06; HRMS (Q-TOF Premier) calcd for C13H15ClO3
[MꢀH]ꢀ 253.0653, found: 253.0648. HPLC conditions: Chiralcel OJ-
H column, i-PrOH/hexane 10/90, flow rate: 1 mL/min, UV detection
at 210 nm; Retention time: tmajor¼12.13 min, tminor¼14.47 min.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.06.059.
4.2.2.9. Methyl 4-(4-bromophenyl)-2-oxohexanoate (2i). Light
yellow oil; 99% yield and 81% ee; 1H NMR (400 MHz, CDCl3):
d 7.41
(d, J¼8.8 Hz, 2H), 7.06e7.04 (d, J¼8.4 Hz, 2H), 3.79 (s, 3H), 3.17e3.10
References and notes
(m, 2H), 3.11e3.05 (m,1H), 1.68e1.58 (m, 2H), 0.77 (q, 3H); 13C NMR
(100 MHz, CDCl3):
d 192.93, 161.47, 142.68, 131.79, 131.76, 129.58,
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1
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