An enantioselective synthesis of 3-aryl-4-phosphonobutyric acid esters via Cu-catalyzed asymmetric conjugate reduction

Article abstract of DOI:10.1016/j.tetasy.2011.12.009

The asymmetric conjugate reduction of 3-aryl-4-phosphonobutenoates has been demonstrated which provides an enantioselective synthesis of optically active 3-aryl-4-phosphonobutyric acid esters. A wide range of 3-aryl-4- phosphonobutenoate derivates are red

Full text of DOI:10.1016/j.tetasy.2011.12.009

Tetrahedron: Asymmetry 22 (2011) 2161–2164
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Tetrahedron: Asymmetry
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An enantioselective synthesis of 3-aryl-4-phosphonobutyric acid esters via
Cu-catalyzed asymmetric conjugate reduction
Wei-Lei Guo a,b, Chuan-Jin Hou a, , Zheng-Chao Duan b, Xiang-Ping Hu b,
⇑
⇑
a School of Light Industry and Chemical Engineering, 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:
Received 11 November 2011
Accepted 20 December 2011
The asymmetric conjugate reduction of 3-aryl-4-phosphonobutenoates has been demonstrated which
provides an enantioselective synthesis of optically active 3-aryl-4-phosphonobutyric acid esters. A wide
range of 3-aryl-4-phosphonobutenoate derivates are reduced with high enantioselectivities (up to 94%
ee) using an (S)-Segphos/Cu(OAc)2ꢀH2O catalyst system (1 or 5 mol %) in the presence of PMHS and
t-BuOH. The reduction is influenced by the steric and electronic effects of the substrates.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis. However, there are few reports on the enantioselective
synthesis of 4-phosphorobutyric acid derivatives18 although these
The catalytic asymmetric conjugate reduction of
a
,b-unsatu-
kinds of chiral compounds are very useful precursors to other
optically active phosphonic acid derivatives. Very recently, we19
reported the enantioselective synthesis of 3-aryl-4-phosphonobu-
tyric acid esters via the first Rh-catalyzed hydrogenation with a
P-stereogenic BoPhoz-type ligand. However, this method has the
disadvantages of demanding reaction conditions and the use of
expensive rhodium catalyst. These shortcomings prompted us to
seek an alternative method to prepare this compound. Herein,
we report the efficient synthesis of 3-aryl-4-phosphonobutyric
acid esters via copper-catalyzed asymmetric conjugate reduction
of the corresponding 3-aryl-4-phosphonobutenoates in which up
to 94% ee was obtained.
rated compounds offers an efficient and convenient preparation
of optically active compounds bearing a stereogenic center at
the b-position. Over the past decades, catalysts derived from var-
ious transition metals have been developed for achieving this
transformation, of which copper hydride species (Cu–H) ligated
by chiral ligands have proven to be the most successful.1 In
1999, Buchwald and co-workers reported the first asymmetric
conjugate reduction of
erated from Tol-BINAP/CuCl/NaOt-Bu in the presence of PMHS
(PMHS = polymethylhydrosiloxane).2 Since then, a series of
b-unsaturated compounds such as enones,3
,b-unsaturated
esters,2,4 ,b-unsaturated phosphonates,5
,b-unsaturated lactones
and lactams,6 ,b-unsaturated sulfones,7 ,b-unsaturated nitrile,8
a,b-unsaturated esters with a catalyst gen-
a,
a
a
a
a
a
2. Results and discussion
nitroalkenes9 and 2-alkenylheteroarenes10 have been subjected
to conjugate reduction with the Cu–H/diphosphine catalyst sys-
tem, giving the reduction products with excellent enantioselectiv-
ities. Despite these achievements, the development of a new
efficient catalyst system with high enantioselectivity, low catalyst
loading, and wide substrate scope is still highly desirable from
both scientific and practical viewpoints.
We started to investigate the asymmetric conjugate reduction of
(Z)-methyl 4-(dimethoxyphosphoryl)-3-phenylbut-2-enoate 1a by
surveying a number of diphosphine ligands, copper salts, silanes,
and solvents in order to identify a suitable catalyst system. The reac-
tions were carried out in the presence of PMHS (4 equiv) and t-BuOH
(4 equiv) under catalytic conditions: Cu(OAc)2ꢀH2O (1 mol %),
ligands (1.1 mol %) in Et2O for 24 h and the results are summarized
in Table 1. Initially, we screened several chiral diphosphine ligands
(Fig. 1). (S)-Tol-BINAP, which displayed an excellent performance
Phosphonates are important compounds because of their
biological and medical properties.11 In recent years, a variety of
phosphonic acid derivatives such as a
-hydroxyphosphonates,12 b-
hydroxyphosphonates,13
a a-alkylphospho-
-aminophosphonates,14
in the asymmetric conjugate reduction of
a
,b-unsaturated esters2
nates,15 b-alkyl-b-arylphosphonates16 and 3-phosphonopropanoic
was first tested. To our delight, we found that with (S)-Tol-BINAP,
the reaction proceeded smoothly and gave the desired product in
excellent conversion (98%) and enantioselectivity (92% ee) (entry
1). We then investigated some other chiral biphosphine ligands
which were proved to be successful in the asymmetric conjugate
reduction, such as (S)-BINAP, (R)-(S)-t-Bu-JosiPhos, (R)-(S)-XyliPhos,
acid derivatives17 have been synthesized by catalytic asymmetric
⇑
Corresponding authors.
E-mail addresses: houcj@dlpu.edu.cn (C.-J. Hou), xiangping@dicp.ac.cn (X.-P.
Hu).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.12.009

2162
W.-L. Guo et al. / Tetrahedron: Asymmetry 22 (2011) 2161–2164
Table 1
Cu-catalyzed asymmetric conjugate reduction of (Z)-methyl 4-(diethoxyphosphoryl)-3-phenylbut-2-enoate 1aa
CO2Me
CO2Me
P(O)(OMe)2
Cu/L* (1 mol %)
silane (4 equiv.)
P(O)(OMe)2
*
t-BuOH (4 equiv.)
solvent, RT
1a
2a
Entry
Ligand
Cu source
Silane
Solvent
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
(S)-Tol-BINAP
(S)-BINAP
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(PPh3)3ꢀ2MeOH
Cu(OTf)2
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
Et3SiH
PHSiH3
PHSiH2
TMDS
PMHS
PMHS
PMHS
PMHS
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Toluene
MeOH
THF
98
98
98
100
100
40
10
5
10
20
100
100
96
80
10
92
90
90
50
94
(R)-(S)-t-Bu-JosiPhos
(R)-(S)-XyliPhos
(S)-SegPhos
(S)-SegPhos
(S)-SegPhos
(S)-SegPhos
(S)-SegPhos
(S)-SegPhos
(S)-SegPhos
(S)-SegPhos
(S)-SegPhos
(S)-SegPhos
(S)-SegPhos
(S)-SegPhos
(S)-SegPhos
d
—
—
—
—
d
d
CuOAc
CuF2ꢀH2O
d
9
d
10
11
12
13
14
15
16
17
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
—
93
77
91
87
24
90
92
62
32
CH2Cl2
a
All reactions were performed at 1 mol % of catalyst loadings prepared in situ from Cu-precursor and 1.1 equiv of chiral diphosphine ligand with 0.5 mmol of substrate 1a
at room temperature in 2 mL of solvent for 24 h.
b
Degree of conversion was determined by GC.
Enantiomeric excesses were determined by chiral HPLC.
Not determined due to low conversion.
c
d
substrates with an ortho-methoxy in the phenyl ring tended to be
reduced with low reactivity and enantioselectivity than those with
a meta- or para-methoxy group (entries 2–4). The electronic prop-
erties of the para-substituent on the phenyl ring of the substrates
also had an important influence on the enantioselectivities. The
substrates with an electron-withdrawing group gave better enanti-
oselectivities than those with an electron-donating group (entries
4–8). However, the reduction of substrate 1h with a para-nitro
group on the phenyl ring required a larger catalyst loading and
higher temperatures in order to reach complete conversion (entry
8). Surprisingly, substrates with a meta- electron-withdrawing
group on the phenyl ring were reduced with moderate ee values
(entry 9). Reduction of 2-naphthyl substrate also gave excellent
ee values (entry 10). Meanwhile, a heteroaromatic derivative was
also suitable for this reaction (entry 11). However, low conversion
was achieved in the reduction of 3-alkyl-substituted substrate 1l
(entry 12). These results indicated that the 3-aryl-4-phosphonobut-
enoate derivates, which bear substituted groups such as methoxy,
fluoro, chloro, bromo, and nitro at the ortho, meta, and para posi-
tions, as well as naphthyl and heteroaromatic derivates, all reacted
smoothly to afford the corresponding 3-aryl-4-phosphonobutyric
acid esters in good to excellent ee values.
P
P(t-Bu)2
PPh2
Fe
2
PPh2
Fe
(R)-(S)-t-Bu-JosiPhos
(R)-(S)-XyliPhos
O
O
PPh2
PPh2
PPh2
Ptol2
Ptol2
PPh2
O
O
(S)-Tol-BINAP
(S)-BINAP
(S)-Segphos
Figure 1. Chiral diphosphine ligands evaluated in the asymmetric conjugate
reduction.
and (S)-SegPhos (entries 2–5). This study identified (S)-SegPhos as
the best ligand in terms of conversion and enantioselectivity; we
then retained it for the next round of optimization involving varia-
tion of copper salts, silanes, and solvents. Optimization of the copper
salts such as Cu(PPh3)3ꢀ2MeOH, Cu(OTf)2, CuF2ꢀH2O, and CuOAc was
unsuccessful, giving very low reaction activity (entries 6–9). Silanes
were then screened and then revealed that PMHS, PHSiH3, and
1,1,3,3-tetramethyldisiloxane (TMDS) gave similar results (entries
1, 11, and 13), although PMHS was slightly superior with respect
to enantioselectivity (entry 1). Solvent effects were also tested
(entries 14–17) and Et2O was proved to be the best solvent.
These promising results promoted us to investigate the sub-
strate scope and a variety of 3-aryl-4-phosphonobutenoates were
then examined. The details of the results are summarized in Table 2,
and clearly demonstrate that the enantioselectivities of the reaction
were influenced by steric and electronic effects. Generally speaking,
3. Conclusion
In conclusion, we have developed a copper-catalyzed asymmet-
ric conjugate reduction of 3-aryl-4-phosphonobutenoates that
provides an enantioselective synthesis of optically active 3-aryl-
4-phosphonobutyric acid esters. A wide range of 3-aryl-4-phos-
phonobutenoates were reduced with high enantioselectivities (up
to 94% ee) using a (S)-Segphos/Cu(OAc)2ꢀH2O catalyst system (1
or 5 mol %) in the presence of PMHS and t-BuOH. The reduction
was influenced by steric and electronic effects. Generally, sub-
strates having an electron-withdrawing group at the para-position
of the phenyl ring were reduced in higher ee value than those with
an electron-donating group. Further applications of this methodol-
ogy are in progress.

W.-L. Guo et al. / Tetrahedron: Asymmetry 22 (2011) 2161–2164
2163
7.27–7.33 (m, 2H); 31P NMR (162 MHz, CDCl3): d 31.8. ½a 2D0
ꢂ
¼ ꢃ0:5
Table 2
Cu-catalyzed asymmetric conjugate reduction of 3-aryl-4-phosphonobutenoates with
(c 1.58, CHCl3). HPLC analysis: Chiralcel AS-H column; flow rate:
1.0 mL/min; eluent: n-hexane/i-PrOH(90:10); detection at 210
nm; t1 = 42.85 min(major enantiomer), t2 = 47.56 min(minor enan-
tiomer); ee = 94%.
(S)-Segphosa
Cu(OAc)2·H2O (1 mol %)
CO2Me
O
CO2Me
O
(S)-Segphos (1.1 mol %)
*
P(OMe)2
P(OMe)2
silane (4 equiv.)
t-BuOH (4 equiv.)
Et2O, RT, 24h
R
R
2a-l
4.2.2. Methyl 4-(dimethoxyphosphoryl)-3-(2-methoxy-phenyl)-
butanoate 2b19
1a-l
1H NMR (400 MHz, CDCl3): d 2.25–2.35 (m, 2H), 2.80–2.86 (m,
1H), 2.91–2.96 (m, 1H), 3.55 (s, 3H), 3.57 (s, 6H), 3.72–3.79 (m,
1H), 3.84 (s, 3H), 6.85–6.91 (m, 2H), 7.18–7.22 (m 2H); 31P NMR
Entry
Substrate (R)
Yieldb (%)
eec (%)
1
Z-1a: R = C6H5
95
77
90
95
93
94
86
95
95
94
85
94 (ꢃ)
68 (ꢃ)
93 (ꢃ)
83 (ꢃ)
92 (ꢃ)
92 (S)
91 (ꢃ)
90 (ꢃ)
72 (ꢃ)
90 (ꢃ)
91 (ꢃ)
2d
3
Z-1b: R = 2-MeO-C6H4
Z-1c: R = 3-MeO-C6H4
Z-1d: R = 4-MeO-C6H4
Z-1e: R = 4-Br-C6H4
Z-1f: R = 4-Cl-C6H4
Z-1g: R = 4-F-C6H4
Z-1h: R = 4-NO2-C6H4
Z-1i: R = 3-Cl-C6H4
Z-1j: R = 2-naphthyl
Z-1k: R = 2-thienyl
Z/E-1l: R = Me
(162 MHz, CDCl3): d 32.9 ½a D20
¼ ꢃ1:5 (c 1.21, CHCl3). HPLC analy-
ꢂ
4
5
6
7
sis: Chiralcel AS-H column; flow rate: 1.0 mL/min; eluent: n-hex-
ane/i-PrOH(90:10); detection at 210 nm; t1 = 47.60 min(minor
enantiomer), t2 = 51.77 min(major enantiomer); ee = 68%.
8d
9e
10
11d
12
4.2.3. Methyl 4-(dimethoxyphosphoryl)-3-(3-methoxy-phenyl)-
butanoate 2c19
1H NMR (400 MHz, CDCl3): d 2.07–2.27 (m, 2H), 2.64–2.70 (m,
1H), 2.87–2.93 (m, 1H), 3.50–3.61 (m, 10H), 3.79 (s, 3H), 6.75–6.84
(m, 3H), 7.22 (t, J = 8.0 Hz 1H); 31P NMR (162 MHz, CDCl3): d 31.7
f
f
—
—
a
Reaction conditions: substrate 1 (0.5 mmol), Cu(OAc)2ꢀH2O (1 mol %), (S)-Seg-
phos (1.1 mol %), PMHS (4 equiv), t-BuOH (4 equiv) in Et2O at room temperature for
½
a 2D0
ꢂ
¼ ꢃ1:2 (c 1.61, CHCl3). HPLC analysis: Chiralcel AS-H column;
24 h.
b
flow rate: 1.0 mL/min; eluent: n-hexane/i-PrOH(90:10); detection
at 210 nm; t1 = 69.53 min(major enantiomer), t2 = 75.45 min(minor
enantiomer); ee = 93%.
Isolated yield.
c
The ee values were determined by HPLC on a Chiralcel AS-H chiral column. The
absolute configuration was determined by comparison of the sign of the specific
rotation with reported data.
d
Reaction was performed at 5 mol % catalyst loading and at 50 °C.
Reaction was performed at 5 mol % catalyst loading and at room temperature.
Not determined due to low conversion.
4.2.4. Methyl 4-(dimethoxyphosphoryl)-3-(4-methoxy-phenyl)-
butanoate 2d19
e
f
1H NMR (400 MHz, CDCl3): d 2.05–2.26 (m, 2H), 2.61–2.67 (m,
1H), 2.84–2.89 (m, 1H), 3.46–3.60 (m, 10H), 3.78 (s, 3H), 6.84 (d,
J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz 2H); 31P NMR (162 MHz, CDCl3): d
31.8 ½a 2D0
¼ ꢃ1:1 (c 1.35, CHCl3). HPLC analysis: Chiralcel AS-H col-
ꢂ
4. Experimental
4.1. General
umn; flow rate: 1.0 mL/min; eluent: n-hexane/i-PrOH(90:10);
detection at 210 nm; t1 = 66.24 min(major enantiomer), t2 = 80.29
min(minor enantiomer); ee = 83%.
All reactions were carried out under nitrogen atmosphere using
standard Schlenk techniques. The 3-aryl-4-phosphonobutenoate
substrates were synthesized according to a reported procedure.19
All solvents were dried and degassed by standard methods and
stored under nitrogen. All other chemicals were obtained commer-
cially. 1H NMR and 31P NMR was recorded at 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 chiralcel
AS-H chiral column.
4.2.5. Methyl 3-(4-bromophenyl)-4-(dimethoxy-phosphoryl)-
butanoate 2e19
1H NMR (400 MHz, CDCl3): d 2.05–2.24 (m, 2H), 2.62–2.68 (m,
1H), 2.86–2.91 (m, 1H), 3.50–3.62 (m, 10H), 7.13 (t, J = 8.0 Hz 2H),
7.43 (t, J = 8.0 Hz 2H); 31P NMR (162 MHz, CDCl3): d 31.2. ½a 2D0
¼
ꢂ
ꢃ3:9 (c 1.23, CHCl3). HPLC analysis: Chiralcel AS-H column; flow
rate: 1.0 mL/min; eluent: n-hexane/i-PrOH(90:10); detection at
210 nm; t1 = 41.23 min(major enantiomer), t2 = 50.63 min(minor
enantiomer); ee = 92%.
4.2. General procedure for the Cu-catalyzed asymmetric
conjugate reduction
4.2.6. Methyl 3-(4-chlorophenyl)-4-(dimethoxy-phosphoryl)-
butanoate 2f19
1H NMR (400 MHz, CDCl3): d 2.05–2.24 (m, 2H), 2.62–2.68 (m,
1H), 2.86–2.91 (m, 1H), 3.51–3.62 (m, 10H), 7.19(s, J = 8.0 Hz 2H),
Copper salt (0.005 mmol) and ligand (0.0055 mmol) were added
into an oven-dried Schlenk tube. Then, dry Et2O (2.0 mL) was added
under N2. The mixture was stirredat room temperature for 30 min to
7.27–7.29 (m, 2H); 31P NMR (162 MHz, CDCl3):
d 31.3.
½
a 2D0
ꢂ
¼ ꢃ3:6 (c 1.14, CHCl3). HPLC analysis: Chiralcel AS-H column;
give a solution. Next, PMHS (120
reaction mixture and stirred for 30 min. The substrate (0.50 mmol)
was then added, followed by t-BuOH (190 L, 2.0 mmol). The reac-
lL, 2.0 mmol) was added to the
flow rate: 1.0 mL/min; eluent: n-hexane/i-PrOH(90:10); detection
at 210 nm; t1 = 38.58 min(major enantiomer), t2 = 45.87 min(mi-
nor enantiomer); ee = 92%.
l
tion was sealed, and stirred for 24 h. The reaction mixture was
quenched with saturated aqueous ammonium chloride solution
and the aqueous layer was extracted with AcOEt (3 ꢁ 10 mL). The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated. The product was purified by chromatog-
raphy on silica gel.
4.2.7. Methyl 4-(dimethoxyphosphoryl)-3-(4-fluoro-phenyl)-
butanoate 2g19
1H NMR (400 MHz, CDCl3): d 2.06–2.24 (m, 2H), 2.61–2.67 (m,
1H), 2.85–2.90 (m, 1H), 3.52–3.61 (m, 10H), 7.00 (t, J = 8.0 Hz
2H), 7.20–7.22 (m, 2H); 31P NMR (162 MHz, CDCl3): d 31.5.
½
a 2D0
ꢂ
¼ ꢃ1:8 (c 1.10, CHCl3). HPLC analysis: Chiralcel AS-H column;
4.2.1. Methyl4-(dimethoxyphosphoryl)-3-phenyl-butanoate2a19
1H NMR (400 MHz, CDCl3): d 2.08–2.29 (m, 2H), 2.65–2.71 (m,
1H), 2.87–2.93 (m, 1H), 3.53–3.59 (m, 10H), 7.20–7.25 (m, 3H),
flow rate: 1.0 mL/min; eluent: n-hexane/i-PrOH(90:10); detection
at 210 nm; t1 = 42.49 min(major enantiomer), t2 = 47.96 min(mi-
nor enantiomer); ee = 91%.

2164
W.-L. Guo et al. / Tetrahedron: Asymmetry 22 (2011) 2161–2164
4.2.8. Methyl 4-(dimethoxyphosphoryl)-3-(4-nitro-phenyl)-
butanoate 2h19
References
1H NMR (400 MHz, CDCl3): d 2.00–2.20 (m, 2H), 2.54–2.60 (m,
1H), 2.77–2.83 (m, 1H), 3.38–3.45 (m, 1H), 3.50–3.56 (m, 9H), 6.59
(d, J = 8.0 Hz 2H), 6.98 (d, J = 8.0 Hz 2H); 31P NMR (162 MHz, CDCl3):
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¼ ꢃ3:4 (c 1.45, CHCl3). HPLC analysis: Chiralcel AS-H col-
ꢂ
umn; flow rate: 1.0 mL/min; eluent: n-hexane/i-PrOH(80:20);
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4.2.9. Methyl 3-(3-chlorophenyl)-4-(dimethoxy-phosphoryl)-
butanoate 2i
1H NMR (400 MHz, CDCl3): d 2.03–2.25 (m, 2H), 2.62–2.68 (m,
1H), 2.86–2.92 (m, 1H), 3.56–3.61 (m, 10H), 7.13–7.26 (m, 4H);
31P NMR (162 MHz, CDCl3): d 31.0; 13C NMR (100 MHz, CDCl3): d
31.0 (d, J = 139.2 Hz), 36.2 (d, J = 3.1 Hz), 41.0 (d, J = 11.0 Hz),
51.6, 52.0 (d, J = 6.5 Hz), 52.3 (d, J = 6.5 Hz), 125.5, 127.2, 127.4,
129.8, 134.2, 145.0 (d, J = 9.7 Hz), 171.4; ½a D20
¼ ꢃ2:4 (c 1.50,
ꢂ
CHCl3). HPLC analysis: Chiralcel AS-H column; flow rate: 1.0 mL/
min; eluent: n-hexane/i-PrOH(90:10); detection at 215 nm;
t1 = 47.34 min(major enantiomer), t2 = 50.83 min(minor enantio-
mer); ee = 72%.
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4.2.10. Methyl 4-(dimethoxyphosphoryl)-3-(2-naphthyl)-
butanoate 2j19
1H NMR (400 MHz, CDCl3): d 2.18–2.37 (m, 2H), 2.75–2.81 (m,
1H), 2.97–3.02 (m, 1H), 3.51–3.58 (m, 9H), 3.71–3.78 (m, 1H),
7.37 (d, J = 8.0 Hz 1H), 7.44–7.46 (m, 2H), 7.70 (s, 1H), 7.80 (d,
J = 8.0 Hz 3H); 31P NMR (162 MHz, CDCl3): d 31.8. ½a D20
¼ ꢃ2:4 (c
ꢂ
1.02, CHCl3). HPLC analysis: Chiralcel AS-H column; flow rate:
1.0 mL/min; eluent: n-hexane/i-PrOH(90:10); detection at 210
nm; t1 = 52.18 min(major enantiomer), t2 = 57.16 min(minor enan-
tiomer); ee = 90%.
4.2.11. Methyl 4-(dimethoxyphosphoryl)-3-(2-thienyl)-butanoate
2k19
1H NMR (400 MHz, CDCl3): d 2.16–2.34 (m, 2H), 2.69–2.75 (m,
1H), 2.93–2.98 (m, 1H), 3.57–3.66 (m, 9H), 3.86–3.93 (m, 1H),
6.91–6.92 (m, 2H), 7.16–7.17 (m, 1H); 31P NMR (162 MHz, CDCl3):
d 31.0. ½a 2D0
¼ ꢃ3:8 (c 1.86, CHCl3). HPLC analysis: Chiralcel AS-H
ꢂ
column; flow rate: 1.0 mL/min; eluent: n-hexane/i-PrOH(90:10);
detection at 210 nm; t1 = 40.88 min(minor enantiomer), t2 = 45.81
min(major enantiomer); ee = 91%.
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Acknowledgments
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Chem. 2006, 71, 6958–6974; (b) Selvam, C.; Goudet, C.; Oueslati, N.; Pin, J.-P.;
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The authors are grateful for the financial supports from the
Scientific Research Project of Department of Education of Liaoning
Province of China (L2010048) and the Planned Science and
Technology Project of Dalian (2011J21DW010).
19. Duan, Z.-C.; Hu, X.-P.; Zhang, C.; Zheng, Z. J. Org. Chem. 2010, 75, 8319–8321.