Enantioselective hydrogenation of β-ketophosphonates with chiral Ru(II) catalysts

Article abstract of DOI:10.1021/jo301532t

Highly effective asymmetric hydrogenation of β-ketophosphonates in the presence of Ru-(S)-SunPhos as catalyst was realized; good to excellent enantioselectivities (up to 99.9% ee) and excellent diastereoselectivities (96:4) were obtained.

Full text of DOI:10.1021/jo301532t

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pubs.acs.org/joc
Enantioselective Hydrogenation of β‑Ketophosphonates with Chiral
Ru(II) Catalysts
Xiaoming Tao,† Wanfang Li,† Xin Ma,† Xiaoming Li,† Weizheng Fan,† Lvfeng Zhu,† Xiaomin Xie,†
and Zhaoguo Zhang*,†,§
†School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
§State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032,
China
S
* Supporting Information
ABSTRACT: Highly effective asymmetric hydrogenation of
β-ketophosphonates in the presence of Ru−(S)-SunPhos as
catalyst was realized; good to excellent enantioselectivities (up
to 99.9% ee) and excellent diastereoselectivities (96:4) were
obtained.
Investigation of catalytic procedures mainly focused on the
hydrogenation reactions using chiral ruthenium catalysts. In the
1990s, Noyori and co-workers first reported the asymmetric
hydrogenation of several β-ketophosphonates with Ru−BINAP
systems and applied this method to furnish a facile synthesis of
INTRODUCTION
■
Chiral β-hydroxyphosphonates have attracted considerable
attention in recent years because of their wide biological
applications as well as their ability to mimic the corresponding
hydroxyl carboxylic acids or amino acids.1 They are also
intermediates in the syntheses of potentially significant
antibacterial agents, enzyme inhibitors, peptide analogues, and
phosphonic acid-based antibiotics (Figure 1).2 Chiral β-
fosfomycin.4 Genet
̂
et al. also hydrogenated several β-
ketophophonates including a β-(3-thienyl) derivative with
Ru−MeO-Biphep systems.5 Recently, Pizzano et al. reported
the highly enantioselective hydrogenation of enol phosphonates
to give masked (or protected) chiral β-hydroxyphosphonates.6
This feature is of much practical interest because the separation
of geometric isomers is avoided and it confers a challenging
aspect to the hydrogenation of these olefins, since structurally
related Z isomers usually undergo slower and less enantiose-
lective reactions than their E counterparts.7 In addition, steric
effects, resulting from the size of the phosphonate group, can
further reduce the reactivity of these alkenes.8 Therefore,
further study of β-ketophosphonates hydrogenation is still of
considerable interest.
In the past few years, our group has studied asymmetric
hydrogenation of various functionalized ketones and applied
the Ru−(S)-SunPhos catalytic system in the synthesis of some
useful chiral blocks.9 In this paper, we will disclose a general
and highly enantioselective hydrogenation reaction of β-
ketophosphonates.
Figure 1. Chiral β-hydroxyphosphonates in pharmaceuticals.
RESULTS AND DISCUSSION
■
It has been well-known that subtle changes in geometric, steric,
and/or electronic properties of chiral ligands can lead to
dramatic variations of reactivity and enantioselectivity,10 thus
the ligands (L1−L10, Figure 2) effects were examined initially
with dimethyl (2-oxo-2-phenylethyl)phosphonate (1a) as the
hydroxyphosphonates have been previously produced by either
enzymatic, nonenzymatic kinetic resolution of the racemates or
oxazaborolidine-catalyzed reduction of ketones.3 However,
these synthetic routes suffered from either low enantioselectiv-
ity or poor efficiency. Accordingly, the need for the
development of versatile and efficient methods for the
preparation of enantiopure β-hydroxyphosphonates is of great
significance.
Received: July 24, 2012
Published: September 7, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
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steric effect. On the basis of the above results, (S)-SunPhos was
the ligand of choice.
Optimization of solvents, hydrogen pressure, and reaction
temperatures are summarized in Table 2. Enantioselectivity in
Table 2. Optimization of Solvent, Pressure, and
a
Temperature
b
entry
solvent
P (bar)
T (°C)
ee (%)
1
2
3
4
5
6
7
8
MeOH
EtOH
10
10
10
10
30
50
10
10
50
50
50
50
50
50
30
70
99.7
97.5
97.9
99.1
97.3
95.4
89.5
99.1
i-PrOH
n-PrOH
MeOH
MeOH
MeOH
MeOH
Figure 2. Structures of chiral bidentate ligands.
standard substrate. The catalyst was prepared from
[RuCl2(benzene)]2 and a diphosphine ligand by refluxing
them in degassed dichloromethane/ethanol (v/v = 1:1) for 1.5
h and then dried under reduced pressure.9a The reaction was
carried out with an S/C = 200:1 under 10 bar of hydrogen
pressure at 50 °C in MeOH for 19 h. All of the tested ligands
show similar activity, but the enantioselectivity varied to some
extent. As illustrated in Table 1, (R)-BINAP, (S)-SegPhos, (S)-
a
All reactions were carried out with a substrate (1 mmol)
concentration of 0.5 M in solvent for 19 h. S/C = 200:1. Conversion:
> 99%. ee values were determined by HPLC on a ChiralPak OB-H
column.
b
MeOH (entry 1, 99.7% ee) was superior to that in EtOH (entry
2, 97.5% ee) or i-PrOH (entry 3, 97.9% ee). The results
depicted in Table 2 showed that the stereochemical outcome of
the hydrogenation was dependent on the hydrogen pressure
(entries 5 and 6, 97.3% at 30 bar vs 95.4% at 50 bar), higher
hydrogen pressure decreased the enantioselectivity. Temper-
atures also influenced the enantioselectivities (entry 1 vs 7, 8).
Lower reaction temperature remarkably decreased the
enantioselectivity and reaction rate while higher reaction
temperature increased the reaction rate with slightly decreased
enantioselectivity.11 Reaction time remarkably influenced the
conversion and enantiomeric excesses (Table 5, see the
Supporting Information). Lower conversion and enantioselec-
tivity were obtained when the reaction time was shortened
(entries 1 and 2), and the enantioselectivity remained
unchanged when longer reaction times were tested (entry 4).
On the basis of these results, the optimized reaction
conditions were therefore set as follows: 0.5 mol % of
[RuCl(benzene)(S)-SunPhos]Cl as the catalyst, MeOH as the
solvent with a substrate concentration of 0.5 M, and 10 bar of
H2 at 50 °C.
Under the optimized reaction conditions, a variety of β-
ketophosphonates were hydrogenated, and the results are
presented in Table 3. When a series of alkyl (2-oxo-2-
phenylethyl)phosphonates were hydrogenated at the optimized
reaction conditions, methyl, ethyl, and isopropyl (2-oxo-2-
phenylethyl)phosphonates afforded the corresponding alcohols,
2a, 2b, and 2c in 99.7, 95.5, and 90.0% ee, respectively.
Obviously, the bulkiness of the alcohol plays an important role
in achieving good enantioselectivity. Because methyl phospho-
nate is superior to ethyl or isopropyl phosphonate (Table 3,
entry 1 vs 3 or 4), methyl phosphates were chosen in the
following investigation. Most methyl (2-oxo-2-phenylethyl)-
phosphonates gave excellent enantioselectivities (entries 1−
12). Furthermore, the reaction proceeded smoothly on
multigrams scale with excellent enantiofacial discrimination,
up to 99.3% ee under 15 bar of hydrogen pressure and 50 °C
Table 1. Screening of Ligands in Asymmetric Hydrogenation
of 1a
a
b
b
entry
ligand
ee (%)
config
1
2
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
99.7
97.7
92.3
91.8
49.7
94.5
94.9
94.1
96.5
20.9
S
R
R
R
R
R
S
3
4
5
6
7
8
S
9
R
R
10
a
All reactions were carried out with a substrate (1 mmol)
concentration of 0.5 M in MeOH under 10 bar of H2 at 50 °C for
b
19 h, S/C = 200:1. Conversion: >99%. ee values were determined by
HPLC on a Chiralpak OB-H column; absolute configuration was
assigned on the basis of its optical rotation or HPLC.
MeO-Biphep, and (R)-SynPhos were workable ligands;
however, they are inferior to (S)-SunPhos (Table 1, entries 1,
6−9, 94.1−96.5% ee vs 99.7% ee). (R)-4-CF3-SynPhos, a less
electron-rich ligand, resulted in only a 20.9% ee of 2a. When
L2−L5 were used as ligands, corresponding ee values of 97.7%,
92.3%, 91.8%, and 49.7% were achieved (Table 1, entries 2−5),
revealing that the modifications of SunPhos on P atom did
impose remarkable changes in enantioselectivity of the
asymmetric hydrogenation of β-ketophosphonates (1a):
substituents on the phenyl appendages of the ligands had an
adverse effect on the ee’s, which might have resulted from the
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(entry 12). Electronic influences of the para substituents were
presumed to affect the coplanarity of the benzene rings with
CO in the transition state,12 thereby generating an
asymmetric bias. Simple meta-substituted substrates gave
excellent enantiomeric excesses up to 99.8% (entry 6).
Hydrogenation of aliphatic analogues also gave excellent
enatioselectivities (entry 13, 97.2% ee, R1 = Me), even for the
more hindered carbonyl groups (entry 15, 95.7% ee, R1 = i-Pr
and entry 18, 96.4% ee, R1 = Cy).
Our catalyst was also fruitful in the asymmetric hydro-
genation of N-Boc-γ-amino substituted β-ketophosphonate
(1s), giving excellent ee values of 2s (entry 19, 97.3% ee).
When three β-ketophosphonates with a alkyl substituent at the
α-position were used, syn/anti ratio ca. 94:6 to 96:4 were
observed with the acyclic substrate (entries 21−23).13
Asymmetric hydrogenation of dimethyl 1-bromo-2-oxopropyl-
phosphonate (1u) afforded the corresponding alcohol (2u) in
99.7% ee and a syn/anti ratio of 96:4. Enantiopure 2u has been
applicated in the practical synthesis of fosfomycin.14
Table 3. Asymmetric Hydrogenation of β-
Ketophosphonates
a
2
b
b
entry
1
1
R1
R2
R3
ee (%)
config
1a
1a
1b
1c
1d
1e
1f
C6H5
C6H5
C6H5
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
Me
Br
Me
Me
Et
99.7
99.3
95.5
90.0
96.6
85.5
99.8
99.8
99.6
88.7
98.7
99.9
96.7
S
d
2
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
3
4
i-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
5
o-OMe-C6H4
o-Me-C6H4
m-Me-C6H4
p-Me-C6H4
p-OMe-C6H4
p-F-C6H4
p-Cl-C6H4
p-Br-C6H4
p-CF3-C6H4
CH3
6
7
8
1g
1h
1i
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1j
CONCLUSION
1k
1l
■
In conclusion, we have developed a convenient and general
protocol for the asymmetric hydrogenation of a variety of alkyl-
and aryl-substituted β-ketophosphonates with excellent enan-
tioselectivities. SunPhos was the best chiral ligand among
screened all ligands, while electron-withdrawing ligands
remarkably decreased the enantiomeric excesses. An ortho
substituent on the aromatic rings had a negative effect on the
enantioselectivity of the phenyl phosphonates. Electron-
donating groups on the para-positions of the phenyl rings
usually led to higher ee values, while electron-withdrawing
groups drastically decreased the enantioselectivities of the
hydrogenation products. Notably, α-alkyl- or bromo-substituted
β-ketophosphonates can be hydrogenated through DKR to
produce the corresponding syn products with excellent
diastereo- and enantioselectivity.
c
1m
1n
1o
1p
1q
1r
97.2
c
C2H5
95.3
c
CH(CH3)2
C5H11
95.7
c
96.3
c
C11H23
94.1
c
Cy
96.4
c
1s
1t
BocNHCH2
CH3
97.3
c
98.6
(1R, 2S)
(1R, 2S)
(1R, 2S)
(1R, 2S)
c
1u
1v
1w
CH3
99.8
c
CH3
99.5
e
c
24
CH3
Me
99.7
a
Unless otherwise stated, all reactions were carried out with a substrate
(1 mmol) concentration of 0.5 M in MeOH under 10 bar of H2 at 50
°C for 19 h, S/C = 200:1. Conversion: > 99%. ee values were
determined by HPLC on a Chiralpak OB-H column or AD-H column;
b
absolute configuration was assigned on the basis of its optical rotation
c
EXPERIMENTAL SECTION
or HPLC. ee values were determined through their corresponding p-
■
d
nitrobenzoyl derivatives 3m−w. Reaction using 23.0 g of 1a at 15 bar
General Methods. Commercially available reagents were used
throughout without further purification other than those detailed
below. The solvents used in catalyst preparation and hydrogenation
reactions were pretreated by the following procedures: MeOH and
EtOH were distilled over magnesium under nitrogen. i-PrOH was
distilled over calcium hydride. All reactions were carried out under an
atmosphere of nitrogen using standard Schlenk techniques or in a
nitrogen-filled glovebox, unless otherwise noted. 1HNMR spectra were
recorded at 400 MHz, with TMS as internal standard. 13CNMR
spectra were obtained at 101 MHz and referenced to the central peak
of 77.0 ppm for CDCl3. Coupling constants (J) are reported in hertz
and refer to apparent peak multiplications. Mass spectroscopy data
were collected on an HRMS-EI instrument. Flash column chromatog-
raphy was performed on silica gel (300−400 mesh).
e
of H2 for 48 h at 50 °C. S/C = 10000:1. An 87:13 mixture of 2u and
2m, syn/anti = 96:4. (The optimization of the reaction conditions is
provided in the Supporting Information.)
using a low catalyst loading of 0.01 mol % of [RuCl(benzene)-
(S)-SunPhos]Cl (entry 2) were obtained. For the phospho-
nates possessing an ortho substituent on the aromatic ring, the
hydrogenation results were dependent on the nature of the
substituents: for a noncoordinating ortho-substituent, the ee
dropped dramatically (entry 5 vs 1, 85.5 vs 99.7% ee); for a
coordinating ortho-substituted substrate, the ee dropped slightly
(entry 4 vs 1, 96.6 vs 99.7% ee). A range of para-substituted
aryl substrates were also studied, and the results showed that
the electron density of the aromatic ring also had a dramatic
effect on the enantioselectivity. Substrates with electron-
donating groups on the aromatic rings usually gave higher ee
values (entries 7−11, 98.7−99.9% ee), while substrates with an
electron-withdrawing substitution group, such as the fluoro in
1i, the ee of hydrogenation product 2i (88.7% ee), which is an
important intermediate of the synthesis of cholesterol inhibitor,
was drastically decreased.2g Enantioselective hydrogenation of
dimethyl 2-(p-trifuoromethylphenyl)-2-oxoethylphosphonate
(1l) afforded the corresponding alcohol (2l) in 96.7% ee
Typical Procedure for the Preparation 1a−r.15 A three-necked,
round-bottomed flask equipped with a nitrogen inlet adapter, addition
funnel, thermocouple, and mechanical stirrer was charged with the
ester (1.0 equiv), dimethyl or diethyl or diisopropyl methylphosph-
onate (1.2 equiv), and THF. The reaction mixture was cooled at −5
°C while LDA (2.1 equiv) was added dropwise via addition funnel
keeping the internal temperature below 0 °C. After complete addition,
the reaction mixture was stirred at 0 °C until complete consumption of
the ester as determined by TLC analysis. The reaction mixture was
then carefully quenched with 6 M HCl to adjust the pH to ca. 4−5 and
diluted with CH2Cl2. The aqueous layer was separated and extracted
with CH2Cl2. The combined organic layers were washed with water
and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The
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The Journal of Organic Chemistry
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residue was purified by column chromatography with petroleum ether
and ethyl acetate.
Dimethyl [2-(p-Chlorophenyl)-2-oxoethyl]phosphonate
(1j).19 The crude material was purified by column chromatography
on silica gel (eluting with ethyl acetate/petroleum ether 1:2) to give 1j
(7.5 g, 88.9%) as a yellow liquid: 1H NMR (400 MHz, CDCl3) δ 7.95
(d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H), 3.76 (s,
3H), 3.60 (d, J = 22.8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 190.3,
140.8, 134.8, 130.2, 128.7, 52.9, 37.9, 36.6.
Dimethyl [2-(p-Bromophenyl)-2-oxoethyl]phosphonate
(1k).17 The crude material was purified by column chromatography
on silica gel (eluting with ethyl acetate/petroleum ether 1:1) to give 1k
(10.8 g, 86.3%) as a yellow liquid: 1H NMR (400 MHz, CDCl3) δ 7.87
(d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 3.76 (s,
3H), 3.60 (d, J = 22.8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 190.6,
134.9, 131.8, 130.4, 129.0, 53.0, 38.0, 36.7.
Dimethyl (2-Oxo-2-phenylethyl)phosphonate (1a).15 The
crude material was purified by column chromatography on silica gel
(eluting with ethyl acetate/petroleum ether 1:1) to give 1a (12.2 g,
1
86.7%) as a colorless liquid: H NMR (400 MHz, CDCl3) δ 8.02 −
7.89 (m, 2H), 7.58−7.50 (m, 1H), 7.36−7.45 (m, 2H), 3.74 (s, 1H),
3.70 (s, 3H), 3.59 (d, J = 22.6 Hz, 2H); 13C NMR (101 MHz, CDCl3)
δ 191.7, 136.3, 133.7, 128.9, 128.6, 53.0, 38.0, 36.7.
Diethyl (2-Oxo-2-phenylethyl)phosphonate (1b).16 The crude
material was purified by column chromatography on silica gel (eluting
with ethyl acetate/petroleum ether 1:4) to give 1b (5.7 g, 82.2%) as a
1
colorless liquid: H NMR (400 MHz, CDCl3) δ 8.01−7.96 (m, 2H),
7.59−7.53 (m, 1H), 7.54−7.26 (m, 2H), 4.15−4.06 (m, 4H), 3.60 (d, J
= 23.6 Hz, 2H), 1.27−1.22 (m, 6H); 13C NMR (101 MHz, CDCl3) δ
143.9, 127.8, 126.9, 125.3, 68.2, 61.3, 61.1, 36.2, 34.8, 15.8.
Dimethyl [2-(p-Trifluoromethylphenyl)-2-oxoethyl]-
phosphonate (1l).18 The crude material was purified by column
chromatography on silica gel (eluting with ethyl acetate/petroleum
Diisopropyl (2-Oxo-2-phenylethyl)phosphonate (1c).17 The
crude material was purified by column chromatography on silica gel
(eluting with ethyl acetate/petroleum ether 1:2) to give 1c (6.8 g,
83.7%) as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 7.95−7.99
(m, 2H), 7.58−7.51 (m, 1H), 7.47−7.40 (m, 2H), 4.75−4.64 (m, 2H),
3.54 (d, J = 26.0 Hz, 2H), 1.24 (dd, J = 6.1, 3.0 Hz, 12H); 13C NMR
(101 MHz, CDCl3) δ 192.1, 136.6, 133.5, 129.1, 128.5, 71.5, 40.3,
39.0, 24.0, 23.8.
1
ether 1:1) to give 1l (8.2 g, 91.0%) as a yellow liquid: H NMR (400
MHz, CDCl3) δ 7.97 (t, J = 1.7 Hz, 1H), 7.88 (ddd, J = 8.0, 2.1, 1.1
Hz, 1H), 7.57 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.44 (t, J = 1.7 Hz, 1H),
3.80 (s, 3H), 3.77 (s, 3H), 3.60 (d, J = 22.8 Hz, 2H); 13C NMR (101
MHz, CDCl3) δ 190.8, 138.8, 134.9, 134.6, 134.3, 133.9, 129.8, 129.1,
125.4, 121.9, 52.9, 38.2.
Dimethyl (2-oxopropyl)phosphonate (1m).4a The crude
material was purified by column chromatography on silica gel (eluting
with ethyl acetate/petroleum ether 1:5) to give 1m (26.7 g, 56.7%) as
a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 3.79 (s, 3H), 3.77 (s,
3H), 3.09 (d, J = 22.8 Hz, 2H), 2.32 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 199.2, 52.6, 42.3, 37.6, 30.9.
Dimethyl [2-(o-Methoxyphenyl)-2-oxoethyl]phosphonate
(1d).18 The crude material was purified by column chromatography
on silica gel (eluting with ethyl acetate/petroleum ether 1:1) to give
1d (12.0 g, 88.5%) as a yellow liquid: 1H NMR (400 MHz, CDCl3) δ
7.73 (dd, J = 7.8, 1.7 Hz, 1H), 7.49 (dd, J = 7.8, 1.7 Hz, 1H), 6.99
(ddd, J = 12.0, 9.2, 4.7 Hz, 2H), 3.93 (s, 3H), 3.80 (d, J = 21.6 Hz,
2H), 3.75 (s, 3H), 3.72 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
192.9, 158.6, 134.4, 130.9, 127.2, 120.7, 111.5, 55.5, 52.7, 42.2, 40.9.
Dimethyl [2-(o-Methylphenyl)-2-oxoethyl]phosphonate
(1e).18 The crude material was purified by column chromatography
on silica gel (eluting with ethyl acetate/petroleum ether 1:2) to give 1e
(6.7 g, 85.2%) as a light yellow liquid: 1H NMR (400 MHz, CDCl3) δ
7.74 (d, J = 7.8 Hz, 1H), 7.42−7.38 (m, 1H), 7.31−7.25 (m, 2H), 3.77
(s, 3H), 3.74 (s, 3H), 3.60 (d, J = 22.4 Hz, 2H), 2.52 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 194.5, 138.7, 136.7, 131.8, 129.3, 125.5,
52.7, 40.4, 21.0.
Dimethyl [2-(m-Methylphenyl)-2-oxoethyl]phosphonate
(1f). The crude material was purified by column chromatography on
silica gel (eluting with ethyl acetate/petroleum ether 1:2) to give 1f
(4.6 g, 86.7%) as a yellow liquid: 1H NMR (400 MHz, CDCl3) δ 7.87
(d, J = 8.3 Hz, 2H), 7.28−7.21 (m, 2H), 3.76 (s, 3H), 3.73 (s, 3H),
3.59 (d, J = 22.6 Hz, 2H), 2.39 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 191.5, 138.1, 136.6, 134.1, 128.9, 128.2, 125.9, 52.7, 37.6, 20.8;
HRMS (collected on an UPLC and Q-TOF MS spectrometer) calcd
for C11H15O4P (M + Na)+ 265.0606, found 265.0612.
Dimethyl [2-(p-Methylphenyl)-2-oxoethyl]phosphonate
(1g).18 The crude material was purified by column chromatography
on silica gel (eluting with ethyl acetate/petroleum ether 1:1) to give 1g
(12.2 g, 86.5%) as a light yellow liquid: 1H NMR (400 MHz, CDCl3)
δ 7.87 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 3.76 (s, 3H), 3.73
(s, 3H), 3.59 (d, J = 22.6 Hz, 2H), 2.38 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 191.2, 144.8, 133.9, 129.4, 129.3, 53.1, 38.1, 21.7.
Dimethyl [2-(p-Methoxyphenyl)-2-oxoethyl]phosphonate
(1h).18 The crude material was purified by column chromatography
on silica gel (eluting with ethyl acetate/petroleum ether 1:1) to give
1h (10.1 g, 78.9%) as a colorless liquid: 1H NMR (400 MHz, CDCl3)
δ 7.98 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H), 3.78
(s, 3H), 3.75 (s, 3H), 3.58 (d, J = 22.6 Hz, 2H); 13C NMR (101 MHz,
CDCl3) δ 189.7, 163.7, 131.0, 129.1, 113.5, 55.1, 52.7, 37.4, 36.4.
Dimethyl [2-(p-Fluorophenyl)-2-oxoethyl]phosphonate
(1i).19 The crude material was purified by column chromatography
on silica gel (eluting with ethyl acetate/petroleum ether 1:3) to give 1i
(6.3 g, 88.0%) as a light yellow liquid: 1H NMR (400 MHz, CDCl3) δ
8.06−8.02 (m, 2H), 7.18−7.13 (m, 2H), 3.80 (s, 3H), 3.77 (s, 3H),
3.60 (d, J = 22.8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 190.0,
167.2, 132.7, 131.6, 115.5, 52.9, 38.0, 36.7.
Dimethyl (2-Oxobutyl)phosphonate (1n).20 The crude material
was purified by column chromatography on silica gel (eluting with
ethyl acetate/petroleum ether 1:5) to give 1n (7.5 g, 67.0%) as a
colorless liquid: 1H NMR (400 MHz, CDCl3) δ 3.62 (s, 3H), 3.59 (s,
3H), 2.93 (d, J = 22.8 Hz, 2H), 2.47 (q, J = 7.2 Hz, 2H), 0.88 (t, J =
7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 201.9, 59.8, 52.6, 41.1,
7.1.
Dimethyl (3-Methyl-2-oxobutyl)phosphonate (1o).21 The
crude material was purified by column chromatography on silica gel
(eluting with ethyl acetate/petroleum ether 1:5) to give 1o (7.9 g,
1
88.0%) as a colorless liquid: H NMR (400 MHz, CDCl3) δ 3.79 (s,
3H), 3.76 (s, 3H), 3.12 (d, J = 22.4 Hz, 2H), 2.81 (dd, J = 13.8, 6.9 Hz,
1H), 1.12 (s, 3H), 1.11 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
205.7, 52.9, 41.7, 39.5, 17.7.
Dimethyl (2-Oxoheptyl)phosphonate (1p).20 The crude ma-
terial was purified by column chromatography on silica gel (eluting
with ethyl acetate/petroleum ether 1:5) to give 1p (7.9 g, 87.1%) as a
colorless liquid: 1H NMR (400 MHz, CDCl3) δ 3.79 (s, 3H), 3.77 (s,
3H), 3.08 (d, J = 22.5 Hz, 2H), 3.05 (s, 1H), 2.60 (t, J = 7.3 Hz, 2H),
1.62−1.54 (m, 2H), 1.34−1.22 (m, 5H), 0.88 (t, J = 6.9 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 201.9, 52.8, 43.9, 41.7, 40.4, 30.8, 22.8,
22.2, 13.7.
Dimethyl (2-Oxotridecyl)phosphonate (1q).22 The crude
material was purified by column chromatography on silica gel (eluting
with ethyl acetate/petroleum ether 1:5) to give 1q (5.4 g, 78.1%) as a
colorless liquid: 1H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 3.63 (s,
3H), 2.95 (d, J = 22.7 Hz, 2H), 2.47 (t, J = 7.3 Hz, 2H), 1.11 (s, 18H),
0.73 (t, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 201.6, 52.7,
52.6, 43.8, 41.5, 40.2, 31.5, 29.3, 29.2, 29.1, 29.0, 28.6, 23.6, 22.6, 13.8.
Dimethyl (2-Cyclohexyl-2-oxoethyl)phosphonate (1r).20 The
crude material was purified by column chromatography on silica gel
(eluting with ethyl acetate/petroleum ether 1:4) to give 1r (5.6 g,
1
87.0%) as a yellow liquid: H NMR (400 MHz, CDCl3) δ 3.79 (s,
3H), 3.77 (s, 3H), 3.12 (d, J = 22.2 Hz, 2H), 2.60−2.51 (m, 1H),
1.89−1.83 (m, 2H), 1.81−1.75 (m, 2H), 1.38−1.14 (m, 6H); 13C
NMR (101 MHz, CDCl3) δ 204.2, 52.0, 50.6, 38.9, 27.4, 25.1, 24.7.
Dimethyl [2-Oxo-3-(N-tert-butoxycarbonylamino)propyl]-
phosphonate (1s).23 The crude material was purified by column
chromatography on silica gel (eluting with ethyl acetate/petroleum
ether 1:1) to give 1s (7.8 g, 89.0%) as a colorless liquid: 1H NMR (400
MHz, CDCl3) δ 5.27 (s, 1H), 4.13 (d, J = 5.2 Hz, 2H), 3.80 (s, 3H),
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3.77 (s, 3H), 3.73 (d, J = 10.7 Hz, 1H), 3.12 (d, J = 22.8 Hz, 2H), 1.43
(s, 9H); 13C NMR (101 MHz, CDCl3) δ 197.7, 155.5, 79.9, 53.1, 51.1,
39.2, 37.9, 28.1.
opened and the solvent was evaporated. The enantiomeric excess was
determined by HPLC after passing the residue through a short pad of
silica gel column with petroleum ether and ethyl acetate.
Dimethyl (1-Methylacetonyl)phosphonate (1t).24 Iodome-
thane (4.7 g, 33.11 mmol) was added to a mixture of potassium
carbonate (5.4 g, 39.13 mmol) and dimethyl (2-oxopropyl)-
phosphonate (5.0 g, 30.10 mmol) in acetone (20 mL) at 0 °C. The
mixture was stirred at 0 °C for 1 h, allowed to warm to room
temperature, and stirred for a further 19 h. Aqueous saturated
ammonium chloride solution (15 mL) was added, the organic solvents
were removed by rotary evaporation, and the aqueous phase was
extracted with ethyl acetate (4 × 30 mL). The combined organic
solvents were dried over Na2SO4, filtered and concentrated in vacuo.
The residue was purified by column chromatography with petroleum
ether and ethyl acetate to afford 1t (4.1 g, 75.2%) as a light yellow oil:
1H NMR (400 MHz, CDCl3) δ 3.76 (d, J = 11.0 Hz, 3H), 3.74 (d, J =
11.0 Hz, 3H), 3.30−3.11 (m, 1H), 2.31 (s, 3H), 1.45−1.32 (m, 3H);
13C NMR (101 MHz, CDCl3) δ 203.5, 53.2, 47.3, 30.2, 10.7.
Dimethyl (1-Ethylacetonyl)phosphonate (1u). The crude
material was purified by column chromatography on silica gel (eluting
with ethyl acetate/petroleum ether 2:1) to give 1u (4.5 g, 68.2%) as a
Dimethyl 2-Hydroxy-2-phenylethylphosphonate (2a).25 The
crude material was purified by column chromatography on silica gel
(eluting with ethyl acetate/petroleum ether 2:1) to give 2a (226.0 mg,
98.3%) as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 7.29−7.11
(m, 5H), 4.97 (t, J = 9.7 Hz, 1H), 4.57 (d, J = 3.6 Hz, 1H), 3.56 (s,
3H), 3.50 (s, 3H), 2.22−1.97 (m, 2H); 13C NMR (101 MHz, CDCl3)
δ 144.0, 128.2, 127.3, 125.4, 68.4, 52.3, 35.5; HPLC (Chiralcel OB-H
column, hexane/i-PrOH 96/4, 1.0 mL min−1, 220 nm): t1 = 17.9 min
(major), t2 = 26.9 min (minor).
Diethyl 2-Hydroxy-2-phenylethylphosphonate (2b).26 The
crude material was purified by column chromatography on silica gel
(eluting with ethyl acetate/petroleum ether 3:1) to give 2b (250.0 mg,
97.0%) as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J
= 7.5 Hz, 2H), 7.13 (d, J = 7.5 Hz, 2H), 7.05 (dd, J = 10.3, 4.2 Hz,
1H), 4.92−4.84 (m, 1H), 4.75 (d, J = 3.4 Hz, 1H), 3.85−3.70 (m,
4H), 2.13−1.87 (m, 2H), 1.04 (t, J = 7.1 Hz, 6H); 13C NMR (101
MHz, CDCl3) δ 143.9, 127.8, 126.9, 125.3, 68.2, 61.3, 36.2, 15.8;
HPLC (Chiralcel AS-H column, hexane/i-PrOH 90/10, 0.6 mL min−1,
220 nm) t1 = 12.3 min (major), t2 = 13.9 min (minor).
1
light yellow oil: H NMR (400 MHz, CDCl3) δ 3.75 (d, J = 11.0 Hz,
3H), 3.72 (d, J = 11.0 Hz, 3H), 3.21−3.06 (m, 1H), 2.29 (s, 3H),
1.42−1.35 (m, 2H), 1.34−1.22 (m, 3H); 13C NMR (101 MHz,
CDCl3) δ 203.5, 53.0, 47.3, 30.0, 20.2, 10.7; HRMS (collected on an
UPLC and Q-TOF MS spectrometer) calcd for C7H15O4P (M + H)+
195.0786, found 195.0786.
Diisopropyl 2-Hydroxy-2-phenylethylphosphonate (2c).3h
The crude material was purified by column chromatography on silica
gel (eluting with ethyl acetate/petroleum ether 3:1) to give 2c (280.0
1
mg, 98.0%) as a colorless oil: H NMR (400 MHz, CDCl3) δ 7.40−
7.24 (m, 5H), 5.07 (ddd, J = 12.8, 6.3, 2.3 Hz, 1H), 4.80−4.64 (m,
2H), 4.23−4.19 (m, 1H), 2.17−2.10 (m, 2H), 1.32 (ddd, J = 23.7,
11.9, 5.1 Hz, 12H); 13C NMR (101 MHz, CDCl3) δ 143.5, 128.4,
127.5, 125.4, 70.8, 70.7, 70.6, 68.7, 37.7, 36.4, 24.0; HPLC (Chiralcel
AD-H column, hexane/i-PrOH 97/3, 0.4 mL min−1, 220 nm) t1 = 50.3
min (minor), t2 = 54.9 min (major).
Diethyl (1-Methylacetonyl)phosphonate (1v).25 The crude
material was purified by column chromatography on silica gel (eluting
with ethyl acetate/petroleum ether 1:1) to give 1v (3.5 g, 65.2%) as a
1
light yellow oil: H NMR (400 MHz, CDCl3) δ 4.09−4.02 (m, 4H),
3.20−3.07 (m, 1H), 2.27 (d, J = 4.3 Hz, 3H), 1.31−1.23 (m, 9H); 13C
NMR (101 MHz, CDCl3) δ 203.6, 62.4, 47.9, 46.6, 30.2, 16.2, 10.6.
Dimethyl 1-Bromo-2-oxopropylphosphonate (1w).4a A 500
mL, three-necked, round-bottomed flask equipped with a Teflon-
coated stirring bar, two pressure-equalizing dropping funnels was
charged with dimethyl 2-oxopropylphosphonate (1m) (20.0 g, 0.12
mol) and THF (350 mL). The funnels were filled with 30% aqueous
hydrogen peroxide (13.7 mL, 0.12 mol) and 40% aqueous hydrogen
bromide (12.3 mL, 0.12 mol). The two solutions were then added to
the THF solution of 1m at 25 °C during 4 h. After the mixture was
stirred at 25 °C for another 2 h, the solvent was evaporated under
reduced pressure. The resulting residue was partitioned between ether
(80 mL) and water (50 mL). The organic layer was extracted with four
portions of water (50 mL). The combined aqueous layer were washed
with ether (80 mL) and then partially saturated with sodium chloride
(ca. 10.0 g). After being successively washed with hexane (80 mL) and
a 1:1 hexane−ether mixture (80 mL) and then saturated with sodium
chloride (ca. 10.0 g), the aqueous layer was extracted with five 50-mL
portions of ether. Drying of the combined organic layers over
anhydrous sodium sulfate and evaporation of the solvent afforded a
yellow oil. Distillation (95−100 °C/0.01 mmHg) gave 1w (17.5 g,
59.3%) as a light yellow oil: 1H NMR (400 MHz, CDCl3) δ 4.36 (d, J
= 15.1 Hz, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 2.33 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 196.5, 54.7, 54.5, 44.0, 27.5, 13.8.
Dimethyl [2-Hydroxy-2-(2-methoxyphenyl)ethyl]-
phosphonate (2d).27 The crude material was purified by column
chromatography on silica gel (eluting with ethyl acetate/petroleum
ether 3:1) to give 2d (256.0 mg, 98.5%) as a light yellow oil: 1H NMR
(400 MHz, CDCl3) δ 7.47 (dd, J = 7.6, 1.4 Hz, 1H), 7.23 (ddd, J = 9.5,
6.8, 2.8 Hz, 1H), 6.96 (td, J = 7.5, 0.8 Hz, 1H), 6.84 (d, J = 8.2 Hz,
1H), 5.36−5.26 (m, 1H), 3.82 (s, 3H), 3.74 (s, 3H), 3.71 (s, 3H),
2.39−2.13 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 143.5, 128.4,
127.5, 125.4, 70.8, 70.7, 68.7, 37.7, 36.4, 24.0; HPLC (Chiralcel AD-H
column, hexane/i-PrOH 97/3, 0.4 mL min−1, 220 nm) t1 = 27.7 min
(minor), t2 = 35.2 min (major).
Dimethyl [2-Hydroxy-2-(2-methylphenyl)ethyl]-
phosphonate (2e).3h The crude material was purified by column
chromatography on silica gel (eluting with ethyl acetate/petroleum
ether 2:1) to give 2e (240.0 mg, 98.4%) as a light yellow oil: 1H NMR
(400 MHz, CDCl3) δ 7.43 (d, J = 7.6 Hz, 1H), 7.14−6.97 (m, 3H),
5.24−5.15 (m, 1H), 4.40 (d, J = 3.5 Hz, 1H), 3.59 (s, 3H), 3.54 (s,
3H), 2.23 (s, 3H), 2.12−1.90 (m, 2H); 13C NMR (101 MHz, CDCl3)
δ 142.3, 134.0, 130.4, 127.4, 126.4, 125.3, 65.2, 52.7, 34.7, 19.0; HPLC
(Chiralcel OB-H column, hexane/i-PrOH 90/10, 1.0 mL min−1, 220
nm) t1 = 7.5 min (major), t2 = 23.5 min (minor).
Dimethyl [2-Hydroxy-2-(3-methylphenyl)ethyl]-
phosphonate (2f).3h The crude material was purified by column
chromatography on silica gel (eluting with ethyl acetate/petroleum
ether 3:1) to give 2f (238.0 mg, 97.5%) as a light yellow oil: 1H NMR
(400 MHz, CDCl3) δ 6.91 (ddd, J = 18.9, 14.1, 7.7 Hz, 4H), 4.80 (dd,
J = 44.1, 7.6 Hz, 2H), 3.46−3.18 (m, 6H), 2.04 (d, J = 14.6 Hz, 4H),
1.88−1.71 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 141.0, 140.9,
136.1, 128.1, 124.9, 67.5, 51.6, 35.1, 20.2; HPLC (Chiralcel OB-H
column, hexane/i-PrOH 98/2, 0.4 mL min−1, 220 nm) t1 = 65.4 min
(major), t2 = 76.2 min (minor).
Dimethyl [2-Hydroxy-2-(4-methylphenyl)ethyl]-
phosphonate (2g).3h The crude material was purified by column
chromatography on silica gel (eluting with ethyl acetate/petroleum
ether 2:1) to give 2g (240.0 mg, 98.5%) as a light yellow oil: 1H NMR
(400 MHz, CDCl3) δ 7.10−7.01 (m, 2H), 6.92 (d, J = 6.5 Hz, 2H),
4.91−4.69 (m, 2H), 3.45−3.36 (m, 6H), 2.12 (d, J = 2.1 Hz, 3H),
2.09−1.83 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 141.0, 136.3,
Typical Procedure for the Asymmetric Hydrogenation. To a
20 mL Schlenk tube were added [RuCl2(benzene)]2 (5.0 mg, 0.01
mmol) and (S)-SunPhos (15.0 mg, 0.02 mmol). The tube was
vacuumed and purged with nitrogen three times before addition of
freshly distilled and freeze−thaw−degassed EtOH/CH2Cl2 (2 mL/2
mL). The resulting mixture was heated at 50 °C for 1.5 h and then
cooled to room temperature. The solvent was removed under reduced
pressure to give the catalyst as a yellow solid. The catalyst was
dissolved in degassed MeOH (8 mL), and then the solution was
equally divided into four vials. The β-ketophosphonates (1.00 mmol)
were added to these vials, respectively, and were transferred to an
autoclave. The autoclave was purged five times with H2 and the
required pressure of H2 was set. The autoclave was stirred under
specified reaction conditions. After being cooled to ambient
temperature and careful release of the hydrogen, the autoclave was
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128.4, 125.0, 67.7, 51.9, 35.2, 20.4; HPLC (Chiralcel OB-H column,
hexane/i-PrOH 98/2, 0.4 mL min−1, 220 nm) t1 = 66.8 min (major), t2
= 77.6 min (minor).
3.74 (m, 6H), 3.26 (d, J = 3.0 Hz, 1H), 1.99−1.80 (m, 3H), 1.73 (dd, J
= 12.9, 6.6 Hz, 1H), 0.92 (dd, J = 6.7, 5.8 Hz, 6H); 13C NMR (101
MHz, CDCl3) δ 70.8, 52.4, 34.2, 29.9, 17.9, 17.3.
Dimethyl [2-Hydroxy-2-(4-methoxyphenyl)ethyl]-
phosphonate (2h).3h The crude material was purified by column
chromatography on silica gel (eluting with ethyl acetate/petroleum
ether 3:1) to give 2h (258.0 mg, 99.2%) as a light yellow oil: 1H NMR
(400 MHz, CDCl3) δ 7.33−7.27 (m, 2H), 6.90−6.84 (m, 2H), 5.07 (t,
J = 10.2 Hz, 1H), 3.79 (d, J = 1.1 Hz, 3H), 3.76−3.70 (m, 6H), 2.30−
2.10 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 158.5, 135.9, 126.4,
113.2, 67.7, 54.7, 52.0, 35.3; HPLC (Chiralcel OB-H column, hexane/
i-PrOH 96/4, 0.3 mL min−1, 220 nm) t1 = 63.5 min (major), t2 = 75.1
min (minor).
Dimethyl [2-hydroxy-2-(4-fluorophenyl)ethyl]phosphonate
(2i).3h The crude material was purified by column chromatography
on silica gel (eluting with ethyl acetate/petroleum ether 2:1) to give 2i
(240.0 mg, 96.8%) as a light yellow oil: 1H NMR (400 MHz, CDCl3)
δ 7.33−7.27 (m, 2H), 6.96 (td, J = 8.7, 1.6 Hz, 2H), 5.02 (dd, J = 11.6,
8.0 Hz, 1H), 4.46 (s, 1H), 3.66−3.61 (m, 6H), 2.25−2.02 (m, 2H);
13C NMR (101 MHz, CDCl3) δ 163.4, 160.9, 139.7, 139.6, 127.5,
Dimethyl (2-Hydroxyheptyl)phosphonate (2p).4a The crude
material was purified by column chromatography on silica gel (eluting
with ethyl acetate/petroleum ether 3:1) to give 2p (220.0 mg, 98.2%)
1
as a light yellow oil: H NMR (400 MHz, CDCl3) δ 4.10−3.90 (m,
1H), 3.78−3.74 (m, 6H), 3.26 (d, J = 3.2 Hz, 1H), 2.02−1.96 (m,
2H), 1.60−1.54 (m, 1H), 1.45 (dd, J = 9.5, 3.9 Hz, 2H), 1.36−1.28
(m, 6H), 0.90 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
66.2, 52.2, 38.2, 33.1, 31.5, 24.9, 22.4, 13.8.
Dimethyl (2-Hydroxytridecyl)phosphonate (2q).22 The crude
material was purified by column chromatography on silica gel (eluting
with ethyl acetate/petroleum ether 3:1) to give 2q (304.0 mg, 98.7%)
1
as a light yellow oil: H NMR (400 MHz, CDCl3) δ 3.99 (s, 1H),
3.77−3.74 (m, 6H), 3.29 (s, 1H), 1.99−1.84 (m, 2H), 1.66−1.38 (m,
4H), 1.25 (s, 19H), 0.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
66.5, 52.4, 38.3, 38.1, 33.1, 31.8, 29.6, 29.5, 29.4, 29.3, 25.3, 22.6, 14.0.
Dimethyl (2-Hydroxycyclohexyl)phosphonate (2r).22 The
crude material was purified by column chromatography on silica gel
(eluting with ethyl acetate/petroleum ether 3:1) to give 2r (230.0 mg,
127.3, 115.3, 115.1, 68.1, 68.0, 52.6, 35.8; HPLC (Chiralcel OB-H
column, hexane/i-PrOH 96/4, 1.0 mL min−1, 220 nm) t1 = 19.8 min
(major), t2 = 32.6 min (minor).
1
97.5%) as a light yellow oil: H NMR (400 MHz, CDCl3) δ 3.78 (s,
3H), 3.75 (s, 3H), 3.21 (d, J = 3.1 Hz, 1H), 2.02−1.88 (m, 2H), 1.87−
1.73 (m, 4H), 1.44−1.35 (m, 1H), 1.26−0.98 (m, 6H); 13C NMR
(101 MHz, CDCl3) δ 69.8, 52.0, 51.9, 51.8, 51.7, 44.0, 43.8, 29.9, 28.2,
27.3, 26.0, 25.7, 25.6.
Dimethyl 2-Hydroxy-3-(N-tert-butoxycarbonylamino)-
phosphonate (2s).6b The crude material was purified by column
chromatography on silica gel (eluting with ethyl acetate/petroleum
ether 3:1) to give 2s (280.0 mg, 98.9%) as a light yellow oil: 1H NMR
(400 MHz, CDCl3) δ 5.26 (s, 1H), 4.09−4.04 (m, 1H), 3.74−3.69 (m,
6H), 3.30 (s, 1H), 3.11 (dd, J = 13.4, 6.4 Hz, 1H), 2.01−1.88 (m, 3H),
1.40 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 156.5, 79.4, 66.0, 52.5,
46.7, 30.4, 29.0, 28.2.
Dimethyl [2-Hydroxy-2-(4-chlorophenyl)ethyl]phosphonate
(2j).3h The crude material was purified by column chromatography on
silica gel (eluting with ethyl acetate/petroleum ether 3:1) to give 2j
(260.0 mg, 98.5%) as a light yellow oil: 1H NMR (400 MHz, CDCl3)
δ 7.17 (dd, J = 5.6, 2.9 Hz, 4H), 4.92 (d, J = 3.4 Hz, 1H), 4.79 (s, 1H),
3.61−3.43 (m, 6H), 2.19−1.88 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 142.6, 132.9, 128.2, 126.8, 67.7, 52.4, 35.4; HPLC (Chiralcel
OB-H column, hexane/i-PrOH 96/4, 1.0 mL min−1, 220 nm) t1 = 19.5
min (major), t2 = 25.7 min (minor).
Dimethyl [2-Hydroxy-2-(4-bromophenyl)ethyl]phosphonate
(2k).3h The crude material was purified by column chromatography on
silica gel (eluting with ethyl acetate/petroleum ether 3:1) to give 2k
(306.0 mg, 99.5%) as a light yellow oil: 1H NMR (400 MHz, CDCl3)
δ 7.26−7.21 (m, 2H), 7.06 (d, J = 8.4 Hz, 2H), 4.99 (s, 1H), 4.82 (t, J
= 9.2 Hz, 1H), 3.45−3.38 (m, 6H), 2.09−1.84 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ 143.2, 131.0, 127.1, 120.8, 67.5, 52.4, 35.2;
HPLC (Chiralcel OB-H column, hexane/i-PrOH 97/3, 1.0 mL min−1,
220 nm) t1 = 28.8 min (major), t2 = 37.4 min (minor).
Dimethyl (3-Hydroxybut-2-yl)phosphonate (2t). The crude
material was purified by column chromatography on silica gel (eluting
with ethyl acetate/petroleum ether 4:1) to give 2t (178.0 mg, 97.8%)
1
as a light yellow oil: H NMR (400 MHz, CDCl3) δ 3.93 (ddd, J =
10.6, 8.1, 4.5 Hz, 1H), 3.90−3.74 (m, 6H), 2.05−1.88 (m, 1H), 1.80
(s, 1H), 1.24 (dd, J = 9.1, 3.1 Hz, 3H), 1.15−1.09 (m, 3H); 13C NMR
(101 MHz, CDCl3) δ 67.7, 66.0, 52.9, 21.1, 11.0; HRMS (collected on
an UPLC and Q-TOF MS spectrometer) calcd for C6H15O4P (M +
Na)+ 205.0606, found 205.0606.
Dimethyl [2-Hydroxy-2-(4- trifuoromethylphenyl)ethyl]-
phosphonate (2l). The crude material was purified by column
chromatography on silica gel (eluting with ethyl acetate/petroleum
ether 5:1) to give 2l (290.0 mg, 97.3%) as a light yellow oil: 1H NMR
(400 MHz, CDCl3) δ 7.60 (d, J = 8.2 Hz, 2H), 7.52−7.46 (m, 2H),
5.17 (dt, J = 14.4, 3.4 Hz, 1H), 4.35−4.29 (m, 1H), 3.76−3.69 (m,
6H), 2.26−2.09 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 147.7,
130.2, 129.9, 129.5, 125.9, 125.7, 125.6, 68.3, 52.9, 35.7; HRMS
(collected on an UPLC and Q-TOF MS spectrometer): calcd for
C11H14F3O4P (M + Na)+ 321.0479, found 321.0480; HPLC (Chiralcel
OD-H column, hexane/i-PrOH 90/10, 0.8 mL min−1, 220 nm) t1 =
19.8 min (minor), t2 = 24.5 min (major).
Dimethyl (2-Hydroxypentan-3-yl)phosphonate (2u). The
crude material was purified by column chromatography on silica gel
(eluting with ethyl acetate/petroleum ether 4:1) to give 2u (185.0 mg,
1
94.4%) as a light yellow oil: H NMR (400 MHz, CDCl3) δ 4.20 (s,
1H), 4.00−3.88 (m, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 1.24 (dd, J = 8.8,
3.2 Hz, 3H), 1.18 (d, J = 18.6 Hz, 3H), 1.13−1.06 (m, 3H); 13C NMR
(101 MHz, CDCl3) δ 67.4, 65.8, 52.4, 39.2, 29.6, 10.7.; HRMS
(collected on an UPLC and Q-TOF MS spectrometer) calcd for
C7H17O4P (M + Na)+ 219.0762, found 219.0762.
Diethyl 3-Hydroxybut-2-ylphosphonate (2v).29 The crude
material was purified by column chromatography on silica gel (eluting
with ethyl acetate/petroleum ether 3:1) to give 2v (206.0 mg, 98.1%)
Dimethyl (2-Hydroxypropyl)phosphonate (2m).4a The crude
material was purified by column chromatography on silica gel (eluting
with ethyl acetate/petroleum ether 2:1) to give 2m (160.0 mg, 95.3%)
1
as a light yellow oil: H NMR (400 MHz, CDCl3) δ 4.13−4.05 (m,
1
as a light yellow oil: H NMR (400 MHz, CDCl3) δ 4.20 (s, 1H),
4H), 3.90 (d, J = 4.7 Hz, 1H), 2.42 (s, 1H), 1.95−1.77 (m, 1H), 1.33−
1.26 (m, 6H), 1.19 (dd, J = 9.7, 6.0 Hz, 3H), 1.12−1.02 (m, 3H); 13C
NMR (101 MHz, CDCl3) δ 67.2, 61.8, 38.2, 20.6, 16.3, 7.0.
3.82−3.69 (m, 6H), 3.36 (s, 1H), 1.99−1.89 (m, 2H), 1.32−1.25 (m,
3H); 13C NMR (101 MHz, CDCl3) δ 62.0, 51.9, 34.4, 23.9.
Dimethyl (2-Hydroxybutyl)phosphonate (2n).28 The crude
material was purified by column chromatography on silica gel (eluting
with ethyl acetate/petroleum ether 2:1) to give 2n (178.0 mg, 97.8%)
as a light yellow oil: 1H NMR (400 MHz, CDCl3) δ 3.80 (s, 2H), 3.65
(s, 3H), 3.62 (s, 3H), 1.88−1.76 (m, 2H), 1.48−1.38 (m, 2H), 0.82
(dd, J = 12.3, 4.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 67.3, 52.0,
32.5, 30.9, 30.7, 9.4.
Dimethyl 1-Bromo-2-hydroxypropylphosphonate (2w).4a
The crude material was purified by column chromatography on silica
gel (eluting with ethyl acetate/petroleum ether 3:1) to give 2w (210.0
1
mg, 85.0%) as a light yellow oil: H NMR (400 MHz, CDCl3) δ 4.16
(dt, J = 11.9, 6.2 Hz, 1H), 3.74 (t, J = 1.8 Hz, 1H), 3.73−3.70 (m, 6H),
1.25 (dd, J = 6.2, 2.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 62.1,
51.9, 34.7, 24.0.
Typical Procedure for the Preparation 3m−u. A 25 mL round
flask was charged with 2m (168.0 mg, 1.0 mmol), triethylamine (303.2
mg, 3.00 mmol), 4-nitrobenzoyl chloride (185.6 mg, 1.50 mmol),
DMAP (24.4 mg, 0.20 mmol), and CH2Cl2 (10 mL). The mixture was
Dimethyl (2-Hydroxy-3-methylbutyl)phosphonate (2o).4a
The crude material was purified by column chromatography on silica
gel (eluting with ethyl acetate/petroleum ether 3:1) to give 2o (190.0
mg, 97.0%) as a light yellow oil: 1H NMR (400 MHz, CDCl3) δ 3.78−
8406
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stirred at 26−30 °C for 8 h, saturated aqueous NaHCO3 solution (6
mL) was added, and the organic layer was separated. The organic layer
was washed with water and brine, dried over Na2SO4, filtered, and
evaporated in vacuo. The residue was purified by column
chromatography with petroleum ether and ethyl acetate to give
compound 1-(dimethoxyphosphoryl)propan-2-yl 4-nitrobenzoate
1.90−1.80 (m, 4H), 1.36−1.34 (m, 1H), 1.06 (ddd, J = 22.5, 12.3, 3.2
Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 163.8, 159.5, 150.3, 135.6,
130.7, 123.4, 73.7, 70.3, 52.4, 44.2, 42.1, 30.1, 28.7, 28.6, 28.5, 27.8,
27.7, 27.6, 26.3, 26.0, 25.9, 25.7; HRMS (collected on an UPLC and
Q-TOF MS spectrometer) calcd for C17H24NO7P (M + H)+ 386.1369,
found 386.1369; HPLC (Chiralcel AD-H column, hexane/i-PrOH 90/
10, 0.6 mL min−1, 254 nm) t1 = 29.6 min (minor), t2 = 32.8 min
(major).
1-[(tert-Butoxycarbonyl)amino]-3-(dimethoxyphosphoryl)-
propan-2-yl 4-Nitrobenzoate (3s). The crude material was purified
by column chromatography on silica gel (eluting with ethyl acetate/
petroleum ether 1:6) to give 3s (320.0 mg, 75.8%) as a light yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.21 (dd, J = 9.7, 7.5 Hz, 4H), 5.39
(dd, J = 10.4, 5.4 Hz, 1H), 5.09 (s, 1H), 3.72−3.64 (m, 6H), 3.61 (dd,
J = 9.3, 5.3 Hz, 1H), 3.51 (dd, J = 13.7, 7.3 Hz, 1H), 2.37−2.20 (m,
2H), 1.36 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 163.8, 155.8,
150.5, 135.1, 130.8, 123.4, 79.6, 70.1, 52.5, 43.5, 28.1, 26.5; HRMS
(collected on an UPLC and Q-TOF MS spectrometer): calcd for
C17H25N2O9P (M + H)+ 433.1376, found 433.1389; HPLC (Chiralcel
AD-H column, hexane/i-PrOH 85/15, 0.5 mL min−1, 254 nm) t1 =
36.9 min (minor), t2 = 40.8 min (major).
3-(Dimethoxyphosphoryl)butan-2-yl 4-Nitrobenzoate (3t).
The crude material was purified by column chromatography on silica
gel (eluting with ethyl acetate/petroleum ether 1:8) to give 3t (310.0
mg, 93.8%) as a light yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.28−
8.24 (m, 2H), 8.21 (dd, J = 9.0, 2.0 Hz, 2H), 5.45 (ddd, J = 9.2, 6.5, 4.8
Hz, 1H), 3.91 (dd, J = 12.8, 5.8 Hz, 1H), 3.78 (d, J = 11.0 Hz, 3H),
3.76 (d, J = 11.0 Hz, 3H), 2.45 (ddd, J = 22.4, 7.4, 4.8 Hz, 1H), 1.27
(s, 3H), 1.15 (d, J = 10.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
163.9, 150.4, 135.6, 130.7, 123.5, 71.9, 52.5, 28.8, 17.9, 9.3; HRMS
(collected on an UPLC and Q-TOF MS spectrometer) calcd for
C13H18NO7P (M + H)+ 332.0899, found 332.0899; HPLC (Chiralcel
IC-3 column, hexane/i-PrOH 85/15, 1.0 mL min−1, 254 nm): t1 =
11.8 min (minor), t2 = 12.9 min (minor), t3 = 16.7 min (major), t4 =
22.4 min (minor).
1
(3m, 254.0 mg, 80.1%) as a light yellow oil: H NMR (400 MHz,
CDCl3) δ 8.29−8.24 (m, 2H), 8.23−8.16 (m, 2H), 5.45−5.42 (m,
1H), 3.73−3.68 (m, 6H), 2.36−2.10 (m, 2H), 1.52 (dd, J = 6.3, 0.9
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.7, 150.4, 135.5, 130.7,
123.4, 67.8, 52.5, 32.4, 31.0, 21.1; HRMS (collected on an UPLC and
Q-TOF MS spectrometer) calcd for C12H16NO7P (M + H)+ 318.0743,
found 318.0743; HPLC (Chiralcel AD-H column, hexane/i-PrOH 85/
15, 1.0 mL min−1, 254 nm) t1 = 14.6 min (major), t2 = 16.1 min
(minor).
1-(Dimethoxyphosphoryl)butan-2-yl 4-Nitrobenzoate (3n).
The crude material was purified by column chromatography on silica
gel (eluting with ethyl acetate/petroleum ether 1:8) to give 3n (258.0
mg, 77.9%) as a light yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.30−
8.26 (m, 2H), 8.22 (d, J = 9.0 Hz, 2H), 5.42−5.31 (m, 1H), 3.73−3.67
(m, 6H), 2.35−2.13 (m, 2H), 1.88 (dd, J = 14.4, 7.2 Hz, 2H), 0.98 (t, J
= 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.9, 150.4, 135.6,
130.7, 123.5, 115.8, 52.5, 30.2, 28.8, 28.0, 9.3; HRMS (collected on an
UPLC and Q-TOF MS spectrometer): calcd for C13H18NO7P (M +
Na)+ 354.0719, found 354.0719; HPLC (Chiralcel AD-H column,
hexane/i-PrOH 90/10, 1.0 mL min−1, 254 nm) t1 = 20.0 min (major),
t2 = 25.5 min (minor).
1-(Dimethoxyphosphoryl)-3-methylbutan-2-yl 4-Nitroben-
zoate (3o). The crude material was purified by column chromatog-
raphy on silica gel (eluting with ethyl acetate/petroleum ether 1:8) to
1
give 3o (260.0 mg, 74.7%) as a light yellow oil: H NMR (400 MHz,
CDCl3) δ 8.30−8.23 (m, 2H), 8.23−8.17 (m, 2H), 5.33−5.30 (m,
1H), 3.73−3.57 (m, 6H), 2.29−2.05 (m, 3H), 0.97 (td, J = 7.9, 2.8 Hz,
6H); 13C NMR (101 MHz, CDCl3) δ 163.8, 150.1, 135.6, 130.6,
123.4, 74.2, 52.5, 32.2, 32.1, 27.6, 26.2, 18.1, 17.0; HRMS (collected
on an UPLC and Q-TOF MS spectrometer): calcd for C14H20NO7P
(M + H)+ 346.1056, found 346.1056; HPLC (Chiralcel AD-H column,
hexane/i-PrOH 85/15, 1.0 mL min−1, 254 nm) t1 = 12.3 min (major),
t2 = 13.9 min (minor).
3-(Dimethoxyphosphoryl)pentan-2-yl 4-Nitrobenzoate (3u).
The crude material was purified by column chromatography on silica
gel (eluting with ethyl acetate/petroleum ether 1:6) to give 3u (312.0
1
mg, 90.1%) as a light yellow oil: H NMR (400 MHz, CDCl3) δ 8.28
(d, J = 9.0 Hz, 2H), 8.22 (d, J = 9.0 Hz, 2H), 5.35 (dd, J = 11.5, 5.6
Hz, 1H), 3.76 (d, J = 7.6 Hz, 1H), 3.70 (s, 3H), 3.68 (s, 3H), 1.88 (d, J
= 7.2 Hz, 3H), 1.33−1.00 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 163.9, 150.5, 135.6, 130.7, 123.5, 71.9, 52.6,
30.2, 28.8, 17.4, 9.4; HRMS (collected on an UPLC and Q-TOF MS
spectrometer) calcd for C14H20NO7P (M + H)+ 346.1056, found
346.1056; HPLC (Chiralcel IC-3 column, hexane/i-PrOH 85/15, 1.0
mL min−1, 254 nm) t1 = 20.6 min (minor), t2 = 23.1 min (minor), t3 =
33.9 min (minor), t4 = 40.8 min (major).
3-[(Diethoxyphosphoryl)butyl]-2-nitrobenzoate (3v). The
crude material was purified by column chromatography on silica gel
(eluting with ethyl acetate/petroleum ether 1:8) to give 3v (301.0 mg,
83.8%) as a light yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J
= 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 4.11 (s, 1H), 3.92−3.79 (m,
6H), 1.12 (s, 6H), 1.04 (s, 3H), 0.97 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 163.2, 150.1, 135.4, 130.3, 123.0, 66.5, 61.3, 39.1, 20.0, 16.0,
9.5; HRMS (collected on an UPLC and Q-TOF MS spectrometer)
calcd for C15H22NO7P (M + H)+ 360.1212, found 360.1220; HPLC
(Chiralcel AD-H column, hexane/i-PrOH 95/5, 1.0 mL min−1, 254
nm) t1 = 20.0 min (minor), t2 = 25.4 min (minor), t3 = 26.7 min
(major), t4 = 39.8 min (minor).
Bromo 1-[(Dimethoxyphosphoryl)propan-2-yl]-4-nitroben-
zoate (3w). The crude material was purified by column
chromatography on silica gel (eluting with ethyl acetate/petroleum
ether 1:8) to give 3w (321.0 mg, 81.5%) as a light yellow oil: 1H NMR
(400 MHz, CDCl3) δ 8.25−8.20 (m, 2H), 8.18−8.12 (m, 2H), 5.44−
5.42 (m, 1H), 3.72−3.68 (m, 6H), 2.40−2.30 (m, 1H), 2.17−2.10 (m,
1H), 1.50 (dd, J = 6.3, 0.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
163.7, 150.4, 135.5, 130.7, 123.4, 67.8, 52.5, 32.4, 31.0, 21.1; HRMS
(collected on an UPLC and Q-TOF MS spectrometer): calcd for
C12H15BrNO7P (M + H)+ 395.9848, found 395.9870; HPLC
1-(Dimethoxyphosphoryl)heptan-2-yl 4-Nitrobenzoate (3p).
The crude material was purified by column chromatography on silica
gel (eluting with ethyl acetate/petroleum ether 1:8) to give 3p (250.0
1
mg, 67.0%) as a light yellow oil: H NMR (400 MHz, CDCl3) δ 8.25
(d, J = 9.0 Hz, 2H), 8.19 (d, J = 9.0 Hz, 2H), 5.43−5.33 (m, 1H),
3.70−3.64 (m, 6H), 2.26−2.16 (m, 2H), 1.87−1.74 (m, 2H), 1.40−
1.24 (m, 6H), 0.86−0.80 (m, 3H); 13C NMR (101 MHz, CDCl3) δ
163.9, 150.3, 135.5, 130.6, 123.4, 70.7, 52.4, 52.3, 34.9, 31.2, 30.5, 29.1,
24.6, 22.3, 13.8; HRMS (collected on an UPLC and Q-TOF MS
spectrometer) calcd for C16H24NO7P (M + H)+ 374.1369, found
374.1369; HPLC (Chiralcel AD-H column, hexane/i-PrOH 90/10, 0.6
mL min−1, 254 nm) t1 = 29.6 min (major), t2 = 33.6 min (minor).
1-(Dimethoxyphosphoryl)tridecan-2-yl 4-Nitrobenzoate
(3q). The crude material was purified by column chromatography
on silica gel (eluting with ethyl acetate/petroleum ether 1:6) to give
1
3q (289.0 mg, 63.2%) as a light yellow oil: H NMR (400 MHz,
CDCl3) δ 8.29−8.26 (m, 2H), 8.21 (d, J = 8.9 Hz, 2H), 5.40 (dt, J =
12.2, 6.2 Hz, 1H), 3.72−3.67 (m, 6H), 2.33−2.23 (m, 2H), 1.87−1.79
(m, 2H), 1.25 (d, J = 18.6 Hz, 18H), 0.85 (t, J = 6.9 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 163.9, 150.5, 135.6, 130.7, 127.3, 123.5,
70.9, 52.5, 35.0, 34.9, 31.8, 30.6, 29.5, 29.4, 29.3, 29.2, 29.1, 25.0, 22.6,
14.0; HRMS (collected on an UPLC and Q-TOF MS spectrometer)
calcd for C22H36NO7P (M + H)+ 458.2308, found 458.2308; HPLC
(Chiralcel AD-H column, hexane/i-PrOH 90/10, 0.6 mL min−1, 254
nm) t1 = 17.6 min (major), t2 = 20.2 min (minor).
1-Cyclohexyl-2-(dimethoxyphosphoryl)ethyl 4-Nitroben-
zoate (3r). The crude material was purified by column chromatog-
raphy on silica gel (eluting with ethyl acetate/petroleum ether 1:6) to
1
give 3r (301.0 mg, 78.2%) as a light yellow oil: H NMR (400 MHz,
CDCl3) δ 8.26 (d, J = 9.0 Hz, 2H), 8.19 (d, J = 9.0 Hz, 2H), 5.31 (ddd,
J = 8.5, 6.5, 3.9 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 2.20 (s, 2H),
8407
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(Chiralcel AD-H column, hexane/i-PrOH 80/20, 0.4 mL min−1, 254
nm) t1 = 18.0 min (minor), t2 = 20.3 min (major), t3 = 22.5 min
(minor), t4 = 27.6 min (minor).
(6) (a) Vargas, S.; Suar
́
ez, A.; Alvarez, E.; Pizzano, A. Chem.Eur. J.
́
́
2008, 14, 9856−9859. (b) Chav
́
ez, M. A.; Vargas, S.; Suar
́
ez, A.;
́
Alvarez, E.; Pizzano, A. Adv. Synth. Catal. 2011, 353, 2775−2794.
(7) (a) You, J.; Drexler, H.-J.; Zhang, S.; Fischer, C.; Heller, D.
Angew. Chem., Int. Ed. 2003, 42, 913−916. (b) Hu, X.-P.; Zheng, Z.
Org. Lett. 2005, 7, 419−422. (c) Zhu, G.; Chen, Z.; Zhang, X. J. Org.
Chem. 1999, 64, 6907−6910.
ASSOCIATED CONTENT
* Supporting Information
NMR and/or HPLC data of compounds 1−3. This material is
■
S
(8) Rubio, M.; Suarez, A.; Alvarez, E.; Pizzano, A. Chem. Commun.
2005, 628−630.
available free of charge via the Internet at http://pubs.acs.org.
(9) (a) Sun, Y.; Wan, X.; Guo, M.; Wang, D.; Dong, X.; Pan, Y.;
Zhang, Z. Tetrahedron: Asymmetry 2004, 15, 2185−2188. (b) Wan, X.;
Sun, Y.; Luo, Y.; Li, D.; Zhang, Z. J. Org. Chem. 2005, 70, 1070−1072.
(c) Sun, Y.; Wan, X.; Wang, J.; Meng, Q.; Zhang, H.; Jiang, L.; Zhang,
Z. Org. Lett. 2005, 7, 5425−5427. (d) Wan, X.; Meng, Q.; Zhang, H.;
Sun, Y.; Fan, W.; Zhang, Z. Org. Lett. 2007, 9, 5613−5616. (e) Sun, X.;
Zhou, L.; Li, W.; Zhang, X. J. Org. Chem. 2008, 73, 1143−1146.
AUTHOR INFORMATION
Corresponding Author
*E-mail: zhaoguo@sjtu.edu.cn.
Notes
■
The authors declare no competing financial interest.
̂
(f) Meng, Q.; Sun, Y.; Ratovelomanana-Vidal, V.; Genet, J. P.; Zhang,
Z. J. Org. Chem. 2008, 73, 3842−3847. (g) Meng, Q.; Zhu, L.; Zhang,
Z. J. Org. Chem. 2008, 73, 7209−7212. (h) Zhu, L.; Meng, Q.; Fan,
W.; Xie, X.; Zhang, Z. J. Org. Chem. 2010, 75, 6027−6030. (i) Yao, Y.;
Fan, W.; Li, W.; Ma, X.; Zhu, L.; Xie, X.; Zhang, Z. J. Org. Chem. 2011,
76, 2807−2813. (j) Fan, W.; Li, W.; Ma, X.; Tao, X.; Li, X.; Yao, Y.;
Xie, X.; Zhang, Z. J. Org. Chem. 2011, 76, 9444−9451. (k) Tao, X.; Li,
W.; Ma, X.; Li, X.; Fan, W.; Xie, X.; Ayad, T.; Ratovelomanana-Vidal,
V.; Zhang, Z. J. Org. Chem. 2012, 77, 612−616. (l) Fan, W.; Li, W.;
Ma, X.; Tao, X.; Li, X.; Yao, Y.; Xie, X.; Zhang, Z. Chem. Commun.
2012, 48, 4247−4249. (m) Ma, X.; Li, W.; Li, X.; Tao, X.; Fan, W.;
Xie, X.; Ayad, T.; Ratovelomanana-Vidal, V.; Zhang, Z. Chem.
Commun. 2012, 48, 5352−5354. (n) Li, W.; Ma, X.; Fan, W.; Tao,
X.; Li, X.; Xie, X.; Zhang, Z. Org. Lett. 2011, 13, 3876−3879.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China,
the Science and Technology Commission of Shanghai
Municipality, and the Education Commission of Shanghai
Municipality for financial support.
REFERENCES
■
(1) (a) Wynberg, H.; Smaardijk, A. A. Tetrahedron Lett. 1983, 24,
5899−5900. (b) Huber, R.; Knierzinger, A.; Obrecht, J.-P.; Vasella, A.
Helv. Chim. Acta 1985, 68, 1730−1747. (c) Seebach, D.; Charczuk, R.;
Gerber, C.; Renaud, P.; Berner, H.; Schneider, H. Helv. Chim. Acta
1989, 72, 401−425. (d) Sawamura, M.; Ito, Y.; Hayashi, T.
Tetrahedron Lett. 1989, 30, 2247−2250. (e) Groth, U.; Richter, L.;
(10) (a) Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem.
2000, 65, 6223−6226. (b) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi,
T.; Sayo, N.; Miura, T.; Kumobayashi, H. Adv. Synth. Catal. 2001, 343,
264−267. (c) Wu, S.; Wang, W.; Tang, W.; Lin, M.; Zhang, X. Org.
Lett. 2002, 4, 4495−4497. (d) de Paule, S. D.; Jeulin, S.;
Schollkopf, U. Tetrahedron 1992, 48, 117−122. (f) Yokomatsu, T.;
̈
Yamagishi, T.; Shibuya, S. Tetrahedron: Asymmetry 1993, 4, 1783−
1784. (g) Li, Y.-F.; Hammerschmidt, F. Tetrahedron: Asymmetry 1993,
4, 109−120. (h) Yager, K. M.; Taylor, C. M.; Smith, A. B. J. Am. Chem.
Soc. 1994, 116, 9377−9378.
̂
Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.; Dellis, P.
Eur. J. Org. Chem. 2003, 2003, 1931−1941. (e) Kakei, H.; Nemoto, T.;
Ohshima, T.; Shibasaki, M. Angew. Chem., Int. Ed. 2004, 43, 317−320.
(11) Tsutsumi, K.; Katayama, T.; Utsumi, N.; Murata, K.; Arai, N.;
Kurono, N.; Ohkuma, T. Org. Process Res. Dev. 2009, 13, 625−628.
(12) Casy, A. F.; Drake, A. F.; Ganellin, C. R.; Mercer, A. D.; Upton,
C. Chirality 1992, 4, 356−366.
́
(2) (a) Wroblewski, A. E.; Halajewska-Wosik, A. Tetrahedron:
Asymmetry 2004, 15, 3201−3205. (b) Dellaria, J. F.; Maki, R. G.;
Stein, H. H.; Cohen, J.; Whittern, D.; Marsh, K.; Hoffman, D. J.;
Plattner, J. J.; Perun, T. J. J. Med. Chem. 1990, 33, 534−542. (c) Cui,
P.; Tomsig, J. L.; McCalmont, W. F.; Lee, S.; Becker, C. J.; Lynch, K.
R.; Macdonald, T. L. Bioorg. Med. Chem. Lett. 2007, 17, 1634−1640.
(d) Hashimoto, M.; Hemmi, K.; Takeno, H.; Kamiya, T. Tetrahedron
Lett. 1980, 21, 99−102. (e) Dellaria, J. F., Jr; Maki, R. G. Tetrahedron
Lett. 1986, 27, 2337−2340. (f) Sampson, N. S.; Bartlett, P. A. J. Org.
Chem. 1988, 53, 4500−4503. (g) Wu, G.; Wong, Y.; Chen, X.; Ding,
Z. J. Org. Chem. 1999, 64, 3714−3718.
(13) The absolute configuration of 2t was assigned as (1R,2S) on the
̇
́
basis of its optical rotation and NMR; see: Zymanczyk-Duda, E.;
Lejczak, B.; Kafarski, P.; Grimaud, J.; Fischer, P. Tetrahedron 1995, 51,
11809−11814.
(14) Giordano, C.; Castaldi, G. J. Org. Chem. 1989, 54, 1470−1473.
(15) Maloney, K. M.; Chung, J. Y. L. J. Org. Chem. 2009, 74, 7574−
7576.
(3) (a) Guanti, G.; Zannetti, M. T.; Banfi, L.; Riva, R. Adv. Synth.
̇
Catal. 2001, 343, 682−691. (b) Zurawin
ski, R.; Nakamura, K.;
̀
(16) Kramer, S. r.; Dooleweerdt, K.; Lindhardt, A. T.; RottlaInder,
́
Drabowicz, J.; Kiełbasinski, P.; Mikołajczyk, M. Tetrahedron:
M.; Skrydstrup, T. Org. Lett. 2009, 11, 4208−4211.
(17) Wei, W.; Ji, J.-X. Angew. Chem., Int. Ed. 2011, 50, 9097−9099.
(18) Milburn, R. R.; McRae, K.; Chan, J.; Tedrow, J.; Larsen, R.; Faul,
M. Tetrahedron Lett. 2009, 50, 870−872.
(19) Friedrich, M.; Waechtler, A.; Meijere, A. d. Synlett. 2002, 4,
619−621.
(20) Grieco, P. A.; Pogonowski, C. S. J. Am. Chem. Soc. 1973, 95,
3071−3072.
Asymmetry 2001, 12, 3139−3145. (c) Zhang, Y.; Yuan, C.; Li, Z.
Tetrahedron 2002, 58, 2973−2978. (d) Mikołajczyk, M.; Łuczak, J.;
Kiełbasinski, P. J. Org. Chem. 2002, 67, 7872−7875. (e) Pam
̀
ies, O.;
́
ez, M.;
̃
Backvall, J.-E. J. Org. Chem. 2003, 68, 4815−4818. (f) Ordon
̈
Gonzal
Zertuche, M. Tetrahedron: Asymmetry 2003, 14, 1775−1779.
(g) Rojas-Cabrera, H.; Fernandez-Zertuche, M.; García-Barradas, O.;
Munoz-Muniz, O.; Ordonez, M. Tetrahedron: Asymmetry 2007, 18,
́ ́
ez-Morales, A.; Ruíz, C.; Cruz-Cordero, R. D. l.; Fernandez-
́
́
̃
̃
̃
(21) Gasteiger, J.; Herzig, C. Tetrahedron Lett. 1980, 21, 2687−2688.
(22) Balreddy, K.; Dong, L.; M. Simpson, D.; Titmas, R. Tetrahedron
Lett. 1993, 34, 3037−3040.
142−148. (h) Moriyama, A.; Matsumura, S.; Kuriyama, M.; Onomura,
O. Tetrahedron: Asymmetry 2010, 21, 810−824. (i) Meier, C.; Laux, W.
H. G. Tetrahedron 1996, 52, 589−598. (j) Nesterov, V. V.;
Kolodiazhnyi, O. I. Tetrahedron 2007, 63, 6720−6731.
(23) Chakravarty, P. K.; Combs, P.; Roth, A.; Greenlee, W. J.
Tetrahedron Lett. 1987, 28, 611−612.
(4) (a) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc.
1995, 117, 2931−2932. (b) Kitamura, M.; Tokunaga, M.; Pham, T.;
Lubell, W. D.; Noyori, R. Tetrahedron Lett. 1995, 36, 5769−5772.
(5) (a) Gautier, I.; Ratovelomanana-Vidal, V.; Savignac, P.; Genet
P. Tetrahedron Lett. 1996, 37, 7721−7724. (b) Madec, J.; Pfister, X.;
Phansavath, P.; Ratovelomanana-Vidal, V.; Genet, J.-P. Tetrahedron
2001, 57, 2563−2568.
(24) Delarue-Cochin, S.; Panc, J.-J.; Dauteloup, A.; Hendra, F.; Pan,
J.-J.; Angoh, R. G.; Joseph, D.; Stephens, P. J.; Cave,
Asymmetry 2007, 18, 685−691.
́
C. Tetrahedron:
̂
, J.-
(25) Genov, D. G.; Tebby, J. C. J. Org. Chem. 1996, 61, 2454−2459.
(26) Wang, Z.; Wroblewski, A. E.; Verkade, J. G. J. Org. Chem. 1999,
64, 8021−8023.
̂
8408
dx.doi.org/10.1021/jo301532t | J. Org. Chem. 2012, 77, 8401−8409

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(27) Zhang, Y.; Li, Z.; Yuan, C. Tetrahedron Lett. 2002, 43, 3247−
3249.
(28) Pamies, O.; Backvall, J.-E. J. Org. Chem. 2003, 68, 4815−4818.
́
̈
̇
(29) Zyman
́
czyk-Duda, E.; Lejczak, B.; Kafarski, P.; Grimaud, J.;
Fischer, P. Tetrahedron 1995, 51, 11809−11814.
8409
dx.doi.org/10.1021/jo301532t | J. Org. Chem. 2012, 77, 8401−8409