Chiral ferrocenyl phosphine-phosphoramidite ligands for Cu-catalyzed asymmetric conjugate reduction of α,β-unsaturated esters

Article abstract of DOI:10.1016/j.tetasy.2011.01.022

Unsymmetrical hybrid chiral ferrocenyl phosphine-phosphoramidite ligands have been applied for the first time in the Cu-catalyzed asymmetric 1,4-reduction of β-aryl substituted α,β-unsaturated esters. The results show that the ligand bearing (S_c

Full text of DOI:10.1016/j.tetasy.2011.01.022

Tetrahedron: Asymmetry 22 (2011) 195–199
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral ferrocenyl phosphine-phosphoramidite ligands for Cu-catalyzed
asymmetric conjugate reduction of a,b-unsaturated esters
Chuan-Jin Hou a,b, Wei-Lei Guo a,b, Xiang-Ping Hu b, , Jun Deng b, Zhuo Zheng b,
⇑
⇑
a School of Chemical & Material, Dalian Polytechnic University, Dalian 116034, China
b Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Unsymmetrical hybrid chiral ferrocenyl phosphine-phosphoramidite ligands have been applied for the
first time in the Cu-catalyzed asymmetric 1,4-reduction of b-aryl substituted ,b-unsaturated esters.
The results show that the ligand bearing (Sc)-central, (Rp)-planar, and (Ra)-axial chiralities gave the best
Received 29 November 2010
Accepted 26 January 2011
Available online 2 March 2011
a
performance. The present catalytic system proved to be highly substrate-dependent, catalyzing the con-
jugate reduction of
a
,b-unsaturated esters in moderate to excellent enantioselectivities.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
modularity, and stability toward air and moisture, which make
them highly practical for both academic and industrial applica-
tions. Indeed, these ligands have been found to display wide utility
in asymmetric catalysis, and give excellent results in Rh-catalyzed
asymmetric hydrogenations,12 Rh-catalyzed asymmetric hydro-
formylations,13 Pd-catalyzed asymmetric allylic alkylations,14
Cu-catalyzed asymmetric conjugate additions of diethylzinc to
enones15 and Ag-catalyzed [3+2] cycloadditions of azomethine
ylides with dimethyl maleate.16 To the best of our knowledge,
however, there is no reported example of an asymmetric conjugate
reduction with a phosphine-phosphoramidite ligand. Herein, we
report our investigation on the use of a Cu/ferrocenyl phosphine-
phosphoramidite catalytic system in the asymmetric 1,4-reduction
The catalytic asymmetric 1,4-reduction of
a
,b-unsaturated
compounds is an important method for the construction of tertiary
stereogenic centers in organic synthesis. In the past decades, sig-
nificant progress has been made in the development of efficient
and economic protocols for achieving this transformation with
substantial emphasis on the use of transition metal catalysts, of
which copper hydride complexes ligated by non-racemic ligands
have arguably demonstrated the greatest synthetic utility.1 In
1999, Buchwald et al. reported for the first time that a catalyst
formed from p-tol-BINAP, CuCl, and NaOt-Bu could affect the
asymmetric conjugate reduction of
presence of 4 equiv of polymethylhydrosiloxane (PMHS) relative
to the substrate.2 Since then, a series of
,b-unsaturated com-
pounds (i.e., enones,3 ,b-unsaturated esters,2,4
,b-unsaturated
phosphonates,5 ,b-unsaturated lactones and lactams,6
,b-unsat-
urated sulfones,7 ,b-unsaturated nitrile,8 nitroalkenes,9 and 2-
a,b-unsaturated esters in the
of
a,b-unsaturated esters, in which up to 99% ee was obtained
a
although this reduction was found to be highly substrate-
dependent.
a
a
a
a
a
2. Results and discussion
alkenylheteroarenes10) has been subjected to the 1,4-reduction
with the Cu/diphosphine catalytic system, giving the reduction
products with excellent enantioselectivities. Despite these
achievements, chiral ligands employed in the Cu-catalyzed asym-
metric 1,4-reduction remain very limited, and only a few diphos-
phine ligand types, such as BINAP, BIPHEP, SEGPHOS, JosiPhos,
and Taniaphos, have been found to be efficient for this important
transformation. The search for new chiral ligands for the Cu-cata-
lyzed asymmetric 1,4-reduction is, therefore, of great interest.
Recently, we and some other groups developed a series of
unsymmetrical hybrid chiral phosphine-phosphoramidite li-
gands.11 These ligands have the advantages of easy accessibility,
As we have reported, these chiral ferrocene-based phosphine-
phosphoramidite ligands (PPFAPhos) can be easily prepared from
Ugi’s amine through a modular procedure.12c With these ligands
in hand (Fig. 1), we then examined their efficiency in the Cu-cata-
lyzed asymmetric conjugate reduction of
a,b-unsaturated esters.
Ethyl (E)-3-phenylbut-2-enoate 2a was selected as a model sub-
strate for the screening process, and the results are summarized
in Table 1. Initially, we examined a range of chiral ferrocenyl
phosphine-phosphoramidite ligands for effecting the conjugate
reduction of (E)-3-phenylbut-2-enoate 2a with polymethylhydro-
siloxane (PMHS) under catalytic conditions: Cu(OAc)2ꢀH2O
(5 mol %), ligand (6 mol %), and t-BuOH (4 equiv) in THF for 24 h.
At first was tested (Sc,Rp,Sa)-PPFAPhos, which was found to possess
the matched chiralities and display the best performance in the
⇑
Corresponding authors. Tel.: +86 411 84379276; fax: +86 411 84684746.
E-mail address: xiangping@dicp.ac.cn (X.-P. Hu).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.01.022

196
C.-J. Hou et al. / Tetrahedron: Asymmetry 22 (2011) 195–199
O
O
O
N
N
N
PPh2
PPh2
PPh2
P
P
P
Fe
Fe
Fe
O
O
O
(Sc,Rp,Sa)-PPFAPhos 1a
(Sc,Rp,Ra)-PPFAPhos 1b
(Rc,Rp,Sa)-PPFAPhos 1c
O
O
N
N
PPh2
P
O
P
P
O
Fe
Fe
(Rc,Rp,Ra)-PPFAPhos 1d
(Sc,Rp,Ra)-PPFAPhos* 1e
Figure 1. Ferrocene-based phosphine-phosphoramidite ligands, PPFAPhos 1a–e for Cu-catalyzed asymmetric conjugate reduction.
Table 1
Cu-catalyzed asymmetric conjugate reduction of ethyl (E)-3-phenylbut-2-enoate 2aa
Cu/L* (5 mol%)
CO2Et
CO2Et
*
silane (4 equiv.)
t-BuOH (4 equiv.)
solvent, rt
2a
3a
Entry
Ligand
Cu source
Silane
Solvent
Conversionb (%)
Eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(Sc,Rp,Sa)-1a
(Sc,Rp,Ra)-1b
(Rc,Rp,Sa)-1c
(Rc,Rp,Ra)-1d
(Sc,Rp,Ra)-1e
(Sc,Rp,Ra)-1b
(Sc,Rp,Ra)-1b
(Sc,Rp,Ra)-1b
(Sc,Rp,Ra)-1b
(Sc,Rp,Ra)-1b
(Sc,Rp,Ra)-1b
(Sc,Rp,Ra)-1b
(Sc,Rp,Ra)-1b
(Sc,Rp,Ra)-1b
Cu(OAc)2ꢀH2O
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PhSiH3
Ph2SiH2
TMDS
Et3SiH
PMHS
PMHS
PMHS
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
Toluene
CH2Cl2
100
100
56
32
31
95
100
70
96
44
25
79
46
6
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
32
81
82
74
62
56
CuCl/t-BuONa
CuF(PPh3)3ꢀ2MeOH
CuF(PPh3)3ꢀ2MeOH
CuF(PPh3)3ꢀ2MeOH
CuF(PPh3)3ꢀ2MeOH
CuF(PPh3)3ꢀ2MeOH
CuF(PPh3)3ꢀ2MeOH
CuF(PPh3)3ꢀ2MeOH
CuF(PPh3)3ꢀ2MeOH
d
<5
99
100
11
—
79
78
57
a
All reactions were performed at 5 mol % of catalyst loadings prepared in situ from Cu-precursor and 1.2 equiv of chiral diphosphine ligand with 0.25 mmol of substrate 2a,
4 equiv. of t-BuOH and 4 equiv of silanes at room temperature in 2 mL of solvent for 24 h.
b
Degrees of conversion were determined by GC.
Enantiomeric excesses were determined by chiral HPLC.
Not determined due to low conversion.
c
d
Rh-catalyzed asymmetric hydrogenation of various functionalized
olefins.12c However, only low enantioselectivity was achieved
although full conversions were observed (entry 1). Since the abso-
lute configuration of a chiral ligand normally affects the catalytic
activity and enantioselectivity, we then investigated the efficiency
of the diastereomeric ligands 1b–d of (Sc,Rp,Sa)-1a in this transfor-
mation. In most cases, the reduction proceeded very slowly, giving
only low enantioselectivity (entries 3 and 4). However, ligand 1b,
which holds (Sc)-central, (Rp)-planar, and (Ra)-axial chiralities, gave
an ee-value of 79% and full conversion (entry 2). The introduction
respect to the selectivity (entry 7). Silanes significantly affected the
reactivity and enantioselectivity, and the best results were
achieved with PMHS (entries 7–11). It is noteworthy that PhSiH2
showed greater reactivity than PhSiH3, which is different with
most other hydrosilylation reactions reported so far.5,17 For further
reaction optimization, the solvent effect was also investigated (en-
tries 12–14). The best result was obtained with a THF as solvent
(entry 7).
With the optimal catalyst combination and reaction conditions
in hand, the scope of the reduction of a series of b-aryl substituted
of a stereogenic P-donor atom into (Sc,Rp,Ra)-1b resulted in signif-
icantly decreased conversion and enantioselectivity (entry 5). An
optimization study with (Sc,Rp,Ra)-1b revealed that copper salts,
such as CuCl and CuF(PPh3)3ꢀ2MeOH, gave similar results (entries
6 and 7), but CuF(PPh3)3ꢀ2MeOH was slightly superior to CuCl with
a
,b-unsaturated esters was then investigated, and the results are
summarized in Table 2. The results disclosed that the ester func-
tional group had an important influence on the reactivity and
enantioselectivity. Thus, a modest change from an ethyl ester 2a
to a methyl ester 2b led to greatly decreased enantioselectivities

C.-J. Hou et al. / Tetrahedron: Asymmetry 22 (2011) 195–199
197
Table 2
sition of the phenyl ring were reduced in higher yields than those
with an electron-donating group. Further applications of chiral fer-
rocene-based phosphine-phosphoramidite ligands are currently in
progress.
Cu-catalyzed asymmetric 1,4-reduction of b-aryl substituted
a,b-unsaturated esters 2
with (Sc,Rp,Ra)-PPFAPhos 1ba
CuF(PPh3)3·2MeOH (5 mol%)
R1
O
R1
O
(Sc,Rp,Ra)-1b (6 mol%)
OR2
4. Experimental
4.1. General
Ar
OR2
PMHS (4 equiv)
t-BuOH (4 equiv)
THF, rt,24 h
Ar
2a-m
3a-m
Entry
Substrate (Ar, R1, R2)
Conversionb (%)
eed (%)
All reactions were carried out under a nitrogen atmosphere
using standard Schlenk techniques. All solvents were dried and de-
gassed by standard methods and stored under nitrogen. Ligands
1
2
3
4
5
6
7
8
9
10
11
12
13
2a (Ph, Me, Et)
2b (Ph, Me, Me)
2c (Ph, Me, i-Pr)
2d (Ph, Me, t-Bu)
2e (Ph, Et, Et)
2f (Ph, i-Pr, Et)
2g (4-CH3C6H4, Me, Et)
2h (4-CH3OC6H4, Me, Et)
2i (4-ClC6H4, Me, Et)
2j (4-BrC6H4, Me, Et)
2k (4-NO2C6H4, Me, Et)
2l (3-NO2C6H4, Me, Et)
2m (2-thienyl, Me, Et)
100 (95)c
100
55
61
100
93
75
87
100
100
100
49
82 (S)
44 (S)
50 (S)
38 (S)
86 (S)
81 (+)
77 (S)
76 (+)
>99 (+)
97 (+)
80 (+)
89 (+)
83 (+)
1a–e were prepared according to the literature.12c
a,b-Unsaturated
esters 2a–m were synthesized according to the literature method.2
All other chemicals were obtained commercially. 1H NMR was re-
corded on a Bruker DPX400 NMR spectrometer. Chemical shifts are
expressed in d value (ppm) using tetramethylsilane (TMS) as an
internal standard. HPLC analysis was performed on an Agilent
1100 series instrument with a chiral column (chiralcel OD-H, chi-
ralcel OJ-H or chiralpak AD-H).
88
a
Reaction conditions: substrate 2 (0.25 mmol), CuF(PPh3)3ꢀ2MeOH (5 mol %),
4.2. General procedure for Cu-catalyzed asymmetric conjugate
reduction of a,b-unsaturated esters
(Sc,Rp,Ra)-1b (6 mol %), PMHS (4 equiv), t-BuOH (4 equiv) in THF at room tempera-
ture for 24 h.
b
Degrees of conversion were determined by 1H NMR.
Isolated yield in parentheses.
The ee values were determined by HPLC on a chiral column (Chiralcel OD-H,
c
Copper salt (0.0125 mmol) and ligand (0.015 mmol) were
added into an oven-dried Schlenk tube. Then, dry THF (2.0 mL)
was added under nitrogen. The mixture was stirred at room tem-
d
chiralpak AD-H or Chiralcel OJ-H). The absolute configuration was determined by
comparison of the sign of the specific rotation with the reported data.
perature for 30 min to give
a solution. Next, PMHS (60 lL,
1.0 mmol) was added to the reaction mixture and stirred for
30 min. The substrate (0.25 mmol) was then added, followed by
t-BuOH (95 lL, 1.0 mmol). The reaction was sealed, and stirred
for 24 h. The reaction mixture was quenched with saturated aque-
ous ammonium chloride solution and the aqueous layer was ex-
tracted with Et2O (3 ꢁ 10 mL). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated. The prod-
uct was purified by chromatography on silica gel.
(entries 1 and 2). The introduction of a bulkier i-Pr ester or t-Bu es-
ter functional group also resulted in reduced conversion (entries 3
and 4). An alkyl group at the b-position had little effect on this
reaction, and all substrates 2a, 2e, and 2f were reduced with sim-
ilar enantioselectivities (entries 1, 5, and 6). It is noteworthy that
the substituent on the phenyl ring of the substrate had a major
influence on the conversion and enantioselectivity (entries 7–12),
and the substrates with an electron-donating group at the para-po-
sition of the phenyl ring (entries 7 and 8) tended to be reduced in
lower conversion and enantioselectivity than those with an elec-
tron-withdrawing group (entries 9–11). However, substrate 2l
bearing a meta-nitro group on the phenyl ring was reduced in
low conversion (entry 12). Goods results were also obtained in
the reduction of b-heteroaromatic-substituted substrate 2m (entry
13). These results indicate that the present catalytic system is effi-
4.2.1. Ethyl (S)-3-phenylbutanoate 3a2
1H NMR (400 MHz, CDCl3): d 1.18 (t, J = 7.1 Hz, 3H), 1.30 (d,
J = 7.0 Hz, 3H), 2.52–2.64 (m, 2H), 3.25–3.29 (m, 1H), 4.07 (q,
J = 7.1 Hz, 2H), 7.19–7.23 (m, 3H), 7.28–7.31 (m, 2H). ½a D20
¼ þ9:3
ꢂ
(c 1.43, CHCl3). HPLC analysis: chiralcel OD-H column; flow rate:
0.5 mL/min; eluent: n-hexane/i-PrOH (99.5:0.5); detection at
210 nm; t1 = 11.93 min, t2 = 22.87 min; ee = 82%.
cient for the asymmetric conjugate reduction of
a,b-unsaturated
4.2.2. Methyl (S)-3-phenylbutanoate 3b18,19
esters. However, in comparison with those traditional Cu/diphos-
phine catalytic systems,2,4 this catalyst displayed less generality
in terms of enantioselectivity and showed slightly lower enanti-
oselectivities for some substrates such as 2a.
1H NMR (400 MHz, CDCl3): d 1.30 (d, J = 7.0 Hz, 3H), 2.52–2.66
(m, 2H), 3.25–3.31 (m, 1H), 3.67 (s, 3H), 7.18–7.23 (m, 3H), 7.28–
7.32 (m, 2H). ½a 2D0
¼ þ7:3 (c 1.36, CHCl3). HPLC analysis: chiralcel
ꢂ
OD-H column; flow rate: 0.5 mL/min; eluent: n-hexane/i-PrOH
(99.5:0.5); detection at 215 nm; t1 = 11.97 min, t2 = 23.15 min;
ee = 44%.
3. Conclusion
In conclusion, we have demonstrated that chiral ferrocene-
based phosphine-phosphoramidite ligands are efficient for the
4.2.3. iso-Propyl (S)-3-phenylbutanoate 3c18,20
1H NMR (400 MHz, CDCl3): d 1.12 (d, J = 6.2 Hz, 3H), 1.17 (d,
J = 6.2 Hz, 3H), 1.30 (d, J = 6.9 Hz, 3H), 2.50–2.61 (m, 2H), 3.24–
3.27 (m, 1H), 4.93–4.96 (m, 1H), 7.17–7.21 (m, 3H), 7.26–7.31
Cu-catalyzed asymmetric 1,4-reduction of b-aryl substituted
a,b-
unsaturated esters, giving ee-values of up to >99%. The research
revealed that ligand 1b bearing (Sc)-central, (Rp)-planar, and (Ra)-
axial chiralities showed the best performance. The present cata-
lytic system proved to be highly substrate-dependent. With the
CuF(PPh3)3ꢀ2MeOH/(Sc,Rp,Ra)-1b catalytic system, a wide range of
(m, 2H). ½a 2D0
¼ þ5:2 (c 1.28, CHCl3). HPLC analysis: chiralcel OD-
ꢂ
H
column; flow rate: 0.5 mL/min; eluent: n-hexane/i-PrOH
(99.5:0.5); detection at 215 nm; t1 = 9.20 min, t2 = 10.29 min;
ee = 50%.
b-aryl substituted a,b-unsaturated esters were reduced in moder-
ate to excellent enantioselectivities in the presence of PMHS and
t-BuOH. The reduction was sensitive to the electronic properties
of the substituent on the phenyl ring of the substrate. Generally,
the substrates with an electron-withdrawing group at the para-po-
4.2.4. tert-Butyl (S)-3-phenylbutanoate 3d18
1H NMR (500 MHz, CDCl3): d 1.28 (d, J = 7.0 Hz, 3H), 1.35 (s, 9H),
2.45 (dd, J = 7.3, 14.7 Hz, 1H), 2.52 (dd, J = 8.1, 14.7 Hz, 1H),

198
C.-J. Hou et al. / Tetrahedron: Asymmetry 22 (2011) 195–199
3.18–3.26 (m, 1H), 7.17–7.22 (m, 3H), 7.25–7.30 (m, 2H).
2H), 7.45–7.49 (m, 1H), 7.57–7.59 (m, 1H), 8.07–8.11 (m, 2H). 13C
½
a 2D0
ꢂ
¼ þ8:3 (c 1.53, CHCl3). HPLC analysis: chiralcel OD-H column;
NMR (125 MHz, CDCl3): d 14.0, 21.5, 36.1, 42.3, 60.4, 121.5,
flow rate: 0.5 mL/min; eluent: n-hexane/i-PrOH (99.5:0.5); detec-
121.6, 129.3, 133.2, 147.7, 148.4, 171.5. ½a D20
¼ þ3:6 (c 1.36, CHCl3).
ꢂ
tion at 215 nm; t1 = 8.94 min, t2 = 9.77 min; ee = 38%.
HPLC analysis: chiralcel OD-H column; flow rate: 0.5 mL/min; elu-
ent: n-hexane/i-PrOH (99.5:0.5); detection at 215 nm;
t1 = 23.87 min, t2 = 25.38 min; ee = 89%.
4.2.5. Ethyl (S)-3-phenylpentanoate 3e20
1H NMR (400 MHz, CDCl3): d 0.79 (t, J = 7.4 Hz, 3H), 1.13 (t,
J = 7.1 Hz, 3H), 1.60–1.71 (m, 2H), 2.54–2.66 (m, 2H), 3.00 (m,
1H), 4.00–4.05 (m, 2H), 7.17–7.21 (m, 3H), 7.27–7.30 (m, 2H).
4.2.13. Ethyl (+)-3-(thiophen-2-yl)butanoate 3m24
1H NMR (400 MHz, CDCl3): d 1.21–1.28 (m, 3H), 1.38–1.41 (m,
3H), 2.52–2.58 (m, 1H), 2.65–2.71 (m, 1H),3.57–3.62 (m, 1H),
4.12 (q, J = 7.1 Hz, 2H), 6.83 (d, J = 3.2 Hz, 1H), 6.91 (t, J = 4.3 Hz,
½
a 2D0
ꢂ
¼ þ7:8 (c 1.18, CHCl3). HPLC analysis: chiralcel OD-H column;
flow rate: 0.5 mL/min; eluent: n-hexane/i-PrOH (99.5:0.5); detec-
tion at 215 nm; t1 = 10.54 min, t2 = 17.63 min; ee = 86%.
1H), 7.13 (d, J = 5.1 Hz, 1H). ½a D20
¼ þ10:4 (c 1.51, CHCl3). HPLC
ꢂ
analysis: chiralcel OD-H column; flow rate: 0.5 mL/min; eluent:
n-hexane/i-PrOH (99.5:0.5); detection at 215 nm; t1 = 14.49 min,
t2 = 20.14 min; ee = 83%.
4.2.6. Ethyl (+)-4-methyl-3-phenylpentanoate 3f20
1H NMR (400 MHz, CDCl3): d 0.77 (d, J = 5.7 Hz, 3H), 0.97 (d,
J = 5.7 Hz, 3H), 1.06 (t, J = 6.9 Hz, 3H), 1.85–1.88 (m, 1H), 2.55–
2.61 (m, 1H), 2.75–2.80 (m, 1H), 2.87–2.88 (m, 1H), 3.96 (q,
J = 6.8 Hz, 2H), 7.14–7.20 (m, 3H), 7.25–7.28 (m, 2H).
Acknowledgments
½
a 2D0
ꢂ
¼ þ13:4 (c 1.08, CHCl3). HPLC analysis: chiralcel OD-H col-
We are grateful for the generous financial supports from the
National Natural Science Foundation of China (20873145,
20972156, and 20802076), the Scientific Research Project of
Department of Education of Liaoning Province of China
(L2010048) and the Planned Science and Technology Project of
Dalian (2009E11SF132).
umn; flow rate: 0.5 mL/min; eluent: n-hexane/i-PrOH (99.5:0.5);
detection at 215 nm; t1 = 10.64 min, t2 = 20.36 min; ee = 81%.
4.2.7. Ethyl (S)-3-(4-methylphenyl)butanoate 3g19
1H NMR (400 MHz, CDCl3): d 1.19 (t, J = 7.1 Hz, 3H), 1.24–1.29
(m, 3H), 2.31 (s, 3H), 2.48–2.62 (m, 2H), 3.22–3.27 (m, 1H), 4.08
(q, J = 7.1 Hz, 2H), 7.11–7.26 (m, 5H). ½a D20
ꢂ
¼ þ8:8 (c 1.48, CHCl3).
References
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ent: n-hexane/i-PrOH (99.5:0.5); detection at 215 nm;
t1 = 19.76 min, t2 = 20.79 min; ee = 77%.
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4.2.8. Ethyl (+)-3-(4-methoxyphenyl)butanoate 3h21
1H NMR (400 MHz, CDCl3): d 1.18 (t, J = 6.8 Hz, 3H), 1.27 (d,
J = 6.8 Hz, 3H), 2.51–2.57 (m, 2H), 3.21–3.26 (m, 1H), 3.78 (s, 3H),
4.07 (q, J = 6.8 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.0 Hz,
2H). ½a 2D0
¼ þ11:6 (c 1.43, CHCl3). HPLC analysis: chiralcel OD-H
ꢂ
column; flow rate: 0.5 mL/min; eluent: n-hexane/i-PrOH
(99.5:0.5); detection at 215 nm; t1 = 15.82 min, t2 = 18.47 min;
ee = 76%.
4.2.9. Ethyl (+)-3-(4-chlorophenyl)butanoate 3i21
1H NMR (400 MHz, CDCl3): d 1.16–1.18 (m, 3H), 1.26–1.29 (m,
3H), 2.53–2.56 (m, 2H), 3.25–3.27 (m, 1H), 4.07 (q, J = 7.0 Hz,
2H), 7.15 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H). ½a D20
¼ þ16:5
ꢂ
(c 1.27, CHCl3). HPLC analysis: chiralcel OD-H column; flow rate:
0.5 mL/min; eluent: n-hexane/i-PrOH (99.5:0.5); detection at
215 nm; t1 = 11.34 min, t2 = 18.09 min; ee >99%.
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a 2D0
ꢂ
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4.2.11. Ethyl (+)-3-(4-nitrophenyl)butanoate 3k23
1H NMR (400 MHz, CDCl3): d 1.16–1.21 (m, 3H), 1.33–1.35 (m,
3H), 2.61–2.63 (m, 2H), 3.38–3.44 (m, 1H), 4.05–4.09 (m, 2H),
7.41 (d, J = 8.3 Hz, 2H), 8.17 (d, J = 8.6 Hz, 2H). ½a D20
¼ þ11:9 (c
ꢂ
1.63, CHCl3). HPLC analysis: chiralpak AD-H column; flow rate:
0.5 mL/min; eluent: n-hexane/i-PrOH (99.5:0.5); detection at
215 nm; t1 = 32.58 min, t2 = 35.43 min; ee = 80%.
4.2.12. Ethyl (+)-3-(3-nitrophenyl)butanoate 3l
1H NMR (400 MHz, CDCl3): d 1.16–1.20 (m, 3H), 1.30–1.36 (m,
3H), 2.58–2.68 (m, 2H), 3.39–3.46 (m, 1H), 4.09 (q, J = 6.3 Hz,

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