Asymmetric hydrophosphonylation of aldehydes catalyzed by bifunctional chiral Al(III) complexes

Article abstract of DOI:10.1016/j.tet.2008.01.022

A new bifunctional chiral Al(III) complex of BINOL derivative, which contained tert-amine at 3,3′-position of the BINOL, has been developed for the effective enantioselective hydrophosphonylation of aldehydes. A variety of aromatic, heteroaromatic, conden

Full text of DOI:10.1016/j.tet.2008.01.022

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2864e2870
www.elsevier.com/locate/tet
Asymmetric hydrophosphonylation of aldehydes catalyzed
by bifunctional chiral Al(III) complexes
Shaohua Gou a, Xin Zhou a, Jun Wang a, Xiaohua Liu a, Xiaoming Feng a,b,
*
a Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China
b State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
Received 22 October 2007; received in revised form 4 January 2008; accepted 8 January 2008
Available online 11 January 2008
Abstract
A new bifunctional chiral Al(III) complex of BINOL derivative, which contained tert-amine at 3,30-position of the BINOL, has been developed
for the effective enantioselective hydrophosphonylation of aldehydes. Avariety of aromatic, heteroaromatic, condensed-ring, a,b-unsaturated, and
aliphatic aldehydes were found to be suitable substrates for the reaction, and the desired a-hydroxy phosphonate were obtained in good to excellent
yields (up to 99%) with moderate to good enantioselectivities (up to 87% ee) under mild conditions (at 0 ꢀC). A possible catalytic cycle based on the
experimental results was proposed.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Aldehydes; Asymmetric catalysis; BINOL; Hydrophosphonylation; Al(III)
1. Introduction
with high enantioselectivity and reactivity. Just recently, we de-
veloped a BINOL based titanium(IV) complex in asymmetric
cyano-ethoxycarbonylation of aldehydes, giving the desired
products with good yields and enantioselectivities.6 Enlight-
ened by this, herein, we wish to report the asymmetric hydro-
phosphonylation of aldehydes using chiral Al(III) complex of
BINOL derivative as the catalyst.
In recent years, chiral a-hydroxy phosphoryl compounds
(phosphonic acids and phosphonates) have attracted signifi-
cant attentions owing to their biological activities.1 To the
best of our knowledge, the asymmetric hydrophosphonylation
of aldehyde is probably the most effective methodology for
their synthesis. However, in contrast to the hydrophosphonyla-
tion of imine compounds in which considerable progress has
been made,2,3 the asymmetric hydrophosphonylation of alde-
hydes is still less developed.2a,4 Thus introduction of novel
catalytic system that could show wide applicability for hydro-
phosphonylation of aldehydes has been strongly required.
Bifunctional catalysts have been tremendously developed
for a broad range of asymmetric catalytic reactions.5 Such cata-
lysts could attach both electrophilic and nucleophilic substrates
to the chiral catalyst in the transition state complex, thus could
lead to a strong stereodiscrimination and catalyze the reaction
2. Results and discussion
2.1. Chiral ligand screening
In the preliminary studies, several BINOL derivatives were
complexed in situ with AlEt2Cl to catalyze the asymmetric
hydrophosphonylation of benzaldehyde in dry THF at 0 ꢀC.
As shown in Table 1, Al(III) complexes of BINOL and BINOL
derivatives, which contained phosphorus, quinoline or steri-
cally bulky b-naphthyl moieties only gave extremely poor
results for the reaction (Table 1, entries 1e4), while the chiral
aluminum species bearing two tert-amine moieties on the
BINOL showed high reactivities (Table 1, entries 6e10), and
the aluminum complex of (R,S)-1j gave the product with the
* Corresponding author. Fax: þ86 28 8541 8249.
E-mail address: xmfeng@scu.edu.cn (X. Feng).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.022

S. Gou et al. / Tetrahedron 64 (2008) 2864e2870
2865
Table 1
Ligand screening for the hydrophosphonylation of benzaldehyde
Table 2
Effect of solvent in the asymmetric hydrophosphonylation of benzaldehyde
OH
OH
O
O
O
P
OEt
O
P
OEt
*
*
10 mol% Et2AlCl, 10 mol% 1j
10 mol% Et2AlCl, 10 mol% 1
P(OEt)2
P(OEt)2
O
+
+
H
H
OEt
OEt
Solvent, 0 °C
THF, 0 °C
H
H
O
3
4a
2a
2a
3
4a
Entrya
Ligand (10 mol %)
Time (h)
Yieldb (%)
eec (%)
7 (S)
d
Entrya
Solvent
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
a
1a
1b
1c
1d
1e
1f
48
24
40
24
24
24
40
48
48
48
Trace
NDd
Trace
NR
<19
49
1
2
3
4
5
6
7
THF
48
48
24
24
30
15
15
85
51
76
68
26
66
88
70
71
61
60
12
2
CH2Cl2
Et2O
t-BuOCH3
d
0
Anisole
1,2-Dimethoxyethane
2-Methoxypropane
27 (R)
46 (S)
65 (S)
56 (S)
70 (S)
1g
1h
1i
71
81
43
a
The reactions were carried out under nitrogen, benzaldehyde (0.25 mmol),
and diethyl phosphite (0.325 mmol) in 0.5 mL solvent.
68
85
1j
b
Isolated yield.
Determined by HPLC on Chiral AS-H column analysis.
c
The reactions were carried out under nitrogen, benzaldehyde (0.25 mmol),
and diethyl phosphite (0.325 mmol) in 0.5 mL THF.
b
Isolated yield.
Determined by HPLC on Chiral AS-H column analysis, the absolute con-
Although CH2Cl2 gave a comparable enantioselectivity for the
reaction, it led to a dramatic loss of reactivity (Table 2, entry
2). Further solvent studies focusing on ethers did not give any
improvement for the reaction (Table 2, entries 3e7), especially
for the anisole and 1,2-dimethoxyethane, only poor ee were
obtained (Table 2, entries 5 and 6).
c
figuration of the major product was determined by the comparison with the
reported value of optical rotation (Ref. 4h).
d
Not determined.
best result (85% yield and 70% ee) (Table 1, entry 10). In con-
trast, ligand (S,S)-1f with an (S)-BINOL fragment displayed
low enantioselectivity and favored the chiral a-hydroxy phos-
phonate with an opposite configuration as that produced by
(R,S)-1j (Table 1, entry 6 vs entry 10). These results suggested
that the axial chirality of the BINOL moieties had more influ-
ence in determining the absolute configuration of the hydrophos-
phonylation product, and the matched stereogenic elements are
(R)-BINOL and (S)-1-phenylethanamine component (Fig. 1j).
2.3. Effect of Lewis acids, concentration of benzaldehyde, and
molecular sieves
The counterions of 1j-Al(III) complexes showed a crucial
effect on the enantioselectivity.7 Upon changing the alumi-
num(III) reagent from AlEt2Cl through AlEt3 to Al(OiPr)3, the
enantioselectivities of the reaction decreased from 70% to
25% (Table 3, entries 1e3). Furthermore, increasing the con-
centration of the reaction led to slightly decreased reactivity
and enantioselectivity (Table 3, entry 5), while only 53% yield
and 42% ee were obtained when lowering the concentration of
benzaldehyde from 0.5 M to 0.25 M (Table 3, entry 4), and
2.2. Effect of reaction solvent
Solvent survey revealed that THF provided the product with
the best reactivity and enantioselectivity (Table 2, entry 1).
Ph2
P
N
O
OH
OH
OH
OH
OH
OH
OH
OH
(R)
(R)
(R)
(R)
O
N
P
Ph2
1d
1c
1a
1b
(S)
N
R3
(S)
N
(s)
N
Bn
Bn
Ph
Ph
N
R2
Ph
Ph
Ph
OH
OH
OH
OH
OH
OH
(R)
OH
OH
(R)
(S)
(S)
R3
N
(S)
R2
N
N
(S)
1g : R2 = H
1h : R2 = CH3
1i : R3 = H
1j : R3 = CH3
1e
1f
Figure 1. Structures of the ligands evaluated in this study.

2866
S. Gou et al. / Tetrahedron 64 (2008) 2864e2870
Table 3
Effect of Lewis acid, concentration of benzaldehyde, and molecular sieves
Table 4
Asymmetric hydrophosphonylation of aldehydes catalyzed by 1jeAl(III)
complex
OH
O
O
P
OEt
*
10 mol% Al(III), 10 mol% 1j
OH
O
O
P
OEt
P(OEt)2
O
+
10 mol% Et2AlCl, 10 mol% 1j
H
*
OEt
Additives, THF, 0 °C
H
+
OEt
R
P(OEt)2
O
4a-o
R
H
H
10 mg 3 Å MS, THF, 0 °C
4a
3
2a
2a-o
Entrya Aldehyde
3
Entrya Metal
Concentration MS (mg)
(M)
Time Yieldb eec
Time Yieldb eec (%)
(h)
(%)
(%)
(h)
(%)
1
AlEt2Cl
0.5
d
d
d
d
d
40
15
15
40
30
85
87
98
53
83
88
33
51
71
76
70
25
52
42
67
75
37
36
57
46
1
Benzaldehyde (2a)
4-Methoxybenzaldehyde (2b)
3-Methoxybenzaldehyde (2c)
24
40
40
88
74
71
73
91
88
87
88
85
90
82
86
75
99
85
75 (S)
87 (S)
81
2
Al(OiPr)3 0.5
2
3
AlEt3
0.5
0.25
0.75
0.5
3
4
Benzo[d][1,3]dioxole-5-carbaldehyde (2d) 24
83d
4
AlEt2Cl
AlEt2Cl
AlEt2Cl
AlEt2Cl
AlEt2Cl
AlEt2Cl
AlEt2Cl
5
5
4-Methylbenzaldehyde (2e)
4-Chlorobenzaldehyde (2f)
4-Fluorobenzaldehyde (2g)
4-Nitrobenzaldehyde (2h)
Biphenyl-4-carbaldehyde (2i)
1-Naphthaldehyde (2j)
40
40
40
20
40
20
20
20
30
30
20
83 (S)
65 (S)
62
6d
7d
8d
9d
10d
a
3 A (10 mg) 24
˚
6
˚
0.5
0.5
4 A (10 mg) 24
7
˚
5 A (10 mg) 24
8
67
82
78 (S)e
74
˚
0.5
0.5
3 A (5 mg) 20
3 A (15 mg) 24
9
˚
10
11
12
13
14
15
a
2-Naphthaldehyde (2k)
(E)-Cinnamaldehyde (2l)
Thiophene-2-carbaldehyde (2m)
3-Phenylpropanal (2n)
The reactions were carried out under nitrogen, benzaldehyde (0.25 mmol),
63 (S)
45 (S)
75
77f
and diethyl phosphite (0.325 mmol) in THF.
b
Isolated yield.
Determined by HPLC on Chiral AS-H column analysis.
THF was dried over CaCl2, and used directly without distilling.
c
d
Pentanal (2o)
The reactions were carried out under nitrogen, aldehyde (0.25 mmol), and
diethyl phosphite (0.325 mmol) in 0.5 mL THF.
b
the concentration of benzaldehyde seemed to be appropriate at
0.5 M. To further improve the enantioselectivity of the reaction,
Isolated yield.
Unless indicated, the ee was determined by HPLC on Chiral AS-H column
c
˚
˚
molecular sieves were investigated. Compared with 4 A and 5 A
molecular sieves, which showed unsatisfied results for the reac-
analysis, the absolute configuration of the major product was S compared with
the reported value of optical rotation (Ref. 4h,i).
˚
tion (Table 3, entries 7 and 8 vs entry 1), the addition of 3 A
molecular sieves could improve the ee to 75% (Table 3, entry
6 vs entry 1). Further increasing or decreasing the amount of
d
Determined by Chiral OD-H column analysis.
Determined by Chiral AD-H column analysis.
e
f
Determined by HPLC analysis after conversion of the product into the
corresponding benzoate.
˚
3 A molecular sieves would dramatically decrease the enantio-
selectivity of the reaction (Table 3, entries 9 and 10 vs entry 6).
Hence, the optimized reaction conditions were as following:
benzaldehyde (0.25 mmol), diethyl phosphite (0.325 mmol),
of a,b-unsaturated aldehyde (cinnamaldehyde) showed a re-
duced enantioselectivity with good reactivity (Table 4, entry
12). For the heteroaromatic aldehyde (thiophene-2-carbalde-
hyde), a slightly higher ee was also obtained compared with
the previous report (Table 4, entry 13).4h The enantioselective
hydrophosphonylation of aliphatic aldehydes gave the corre-
sponding a-hydroxy phosphonate in good to excellent yields
with good ee values (Table 4, entries 14 and 15).
˚
10 mmol % lj, 10 mmol % Et2AlCl, and 10 mg 3 A molecular
sieves in 0.5 mL THF at 0 ꢀC.
2.4. Substrate generality
Under the optimized conditions, various aldehydes were
tested in the asymmetric hydrophosphonylation reaction, pro-
viding the corresponding products in good to excellent yield
with moderate to good ee value. As shown in Table 4, the sub-
stituents of aromatic aldehydes impacted both reactivities and
enantioselectivities of the reaction. In contrast to benzaldehyde,
the electron-donating groups on the aromatic aldehydes had
a beneficial effect on the enantioslectivities (Table 4, entries
1e5), and the aromatic aldehydes bearing electron-withdraw-
ing groups gave the products with only moderate ee values
(Table 4, entries 6e8). It was noteworthy that biphenyl-4-carb-
aldehyde, which was rarely studied previously, was also
examined in the asymmetric hydrophosphonylation reaction,
affording diethyl(4-phenyl)(hydroxy)methylphosphonate with
82% ee (Table 4, entry 9). While the condensed-ring aldehydes
(1-naphthaldehyde and 2-naphthaldehyde) reacted smoothly
with diethyl phosphite, giving the products with 78% and
74% ee, respectively (Table 4, entries 10 and 11), the reaction
2.5. Catalytic cycle considerations
The phosphonateephosphite tautomerism is common. The
nonnucleophilic phosphonate form will shift to the reactive
nucleophilic phosphite in the presence of a base or a Lewis
acid.3,4,8 And, it has been proved that the hydrophosphonylation
could proceed smoothly using tertiary amines or aluminum(III)
as the catalyst.2e4 As to our catalytic system, the asymmetric
hydrophosphonylation of aldehyde showed high reactivity in
the presence of chiral Al(III) complex of BINOL derivative
(AlEt2Cl as the aluminum(III) source), which contains two
tert-amine moieties (Table 1, entries 8 and 10). However, using
BINOLeAlEt2Cl complex as the catalyst, only trace amount of
product was afforded (Table 1, entry 1). Thus, we considered
that the tert-amine moiety of the BINOL derivative played a cru-
cial role in the reaction. Indeed, the addition of a competing ex-
ternal base Et3N (10 mol %) decreased the enantioselectivity of

S. Gou et al. / Tetrahedron 64 (2008) 2864e2870
2867
Table 5
Control experiments in the asymmetric hydrophosphonylation of
benzaldehyde
been proposed. As shown in Scheme 2, the Al(III) center of cata-
lyst acted as a Lewis acid and activated the aldehyde to give the
species II. The aldehyde was fixed on the catalyst and activated
by two kinds of interactions: the strong one involving the coor-
dination between Al(III) and the oxygen of the carbonyl group,
and the weak one was the hydrogen bond effect between proton
of aldehyde and chlorine atom.9b,10 In addition, considering the
steric effect of the bulk tertiary amine moiety as well as the di-
ethyl phosphite, we envisage that the aldehyde seems to be not
possible to approach the Al(III) center of catalyst along a vector
trans to the coordinated nitrogen. In contrast, the carbonyl pre-
ferred to approach the catalyst along a vector trans to oxygen
(the less hindered way, as shown in Scheme 2, species II), and
led to a distorted square pyramidal configuration of alumi-
num(III) species. On the other hand, the tertiary amine moiety
of the catalyst functioned as a Lewis base to activate the diethyl
phosphite. The subsequent nucleophilic addition of phosphite to
the aldehyde produced the chiral a-hydroxy phosphonate and
regenerated the catalyst I.
OH
O
O
P
OEt
*
10 mol% Et2AlCl, 10 mol% 1
P(OEt)2
O
+
H
OEt
THF, 0 °C
H
3
4a
2a
Entrya
Ligand (10 mol %)
Time (h)
Yieldb (%)
eec (%)
1d
2
3d
4d
5e
6f
1j
48
48
48
48
48
48
>93
Trace
Trace
73
51
7
1a
d
1a
1a
1a
d
0
27
61
4
0
a
The reactions were carried out under nitrogen, benzaldehyde (0.25 mmol),
and diethyl phosphite (0.325 mmol) in 0.5 mL THF.
b
Isolated yield.
The ee was determined by HPLC on Chiral AS-H column analysis.
Et3N (10 mol %) was added.
Al(OiPr)3 was used as the aluminum source.
AlEt3 was used as the aluminum source.
c
d
e
f
NR2R3
OH
O
S
∗
O
O
the reaction while the reactivity was improved (Table 5, entry 1).
Furthermore, it was the tert-amine moiety and not the Lewis acid
Al(III) center of the catalyst (1jeAlEt2Cl) that shifted the phos-
phonateephosphite equilibrium toward the phosphate form to
undergo nucleophilic addition (Scheme 1). Based on the previ-
ous reports,9 it is proposed that the complex 1jeAlEt2Cl acted as
a bifunctional catalyst for the reaction, which was also proved by
the control experiments. While the BINOLeAlEt2Cl and Et3N
could not catalyze the reaction, respectively, the hydrophospho-
nylation of aldehyde proceed smoothly in the presence of
BINOLeAlEt2Cl and Et3N (Table 5, entries 2 and 3 vs entry 4).
P(OEt)2
O
R
R
H
Al Cl
NR2R3
I
H
N
NR2R3
O
P
R2R3
OEt
O
O
O
O
OEt
H
Cl
Al
Cl
Al
H
O
O
R
R
NR2R3
NR2R3
II
IV
H
O
OEt
OEt
N
R2R3
P
O
O
Cl
Al
H
R2 = CH3
O
O
P
OEt
OEt
P
O
R
P
OEt
OEt
H
OEt
EtO
NR2R3
H
OH
R3
=
Phosphonate form
nonnucleophilic species
Phosphite form
nucleophilic species
III
Si Favoured
Scheme 2. The proposed catalytic cycle for the asymmetric hydrophosponyl-
ation of aldehyde.
Scheme 1. The equilibrium of phosphonateephosphite.
3. Conclusions
Furthermore, the counterions of 1jeAl(III) complexes
played an important role for the asymmetric hydrophosponyla-
tion reaction (Table 3, entries 1e3). These disparate results
were probably caused by the steric and electronic differences
of the counterions (Cl, Et, and OiPr), which showed a different
action in the catalytic cycles. In fact, using BINOL as the chi-
ral ligand, AlEt3 and Al(OiPr)3 provided the racemate products
with 27% and 61% yield, respectively, while the reaction did
not proceed using AlEt2Cl as the aluminum(III) source (Table
5, entries 5 and 6 vs entry 2). Thus, we suspected that the
Lewis acid Al(III) moiety of the AlEt3e1j and Al(OiPr)3e1j
complexes may catalyze the reaction independently, and con-
sequently the complex with AlEt3 and Al(OiPr)3 shows high
reactivity and low enantioselectivity in the reaction.
In summary, a new bifunctional chiral Al(III) complex of
BINOL derivative 1j has been developed for the asymmetric
hydrophosphonylation of aldehyde, and showed a broad sub-
strate generality. Based on previous reports and the experimen-
tal phenomena, a possible catalytic cycle has been proposed.
The applications of the catalyst system in other asymmetric
catalytic reactions are currently underway.
4. Experimental section
4.1. General
On the basis of the previous reports,3,4,9,10 our experimental
investigations and the absolute configuration of the products,
a possible catalytic cycle containing the transition state has
1H NMR spectra were recorded on commercial instruments
(400 MHz). Chemical shifts were reported in parts per million
from tetramethylsilane with the solvent resonance as the

2868
S. Gou et al. / Tetrahedron 64 (2008) 2864e2870
internal standard (CDCl3, d¼7.26). Spectra are reported as
follows: chemical shift (d, ppm), multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet), coupling con-
stants (J, Hz), integration, and assignment. 13C NMR spectra
were collected on commercial instruments (100 MHz) with
complete proton decoupling. Chemical shifts are reported in
parts per million from tetramethylsilane with the solvent reso-
nance as internal standard (CDCl3, d¼77.0). The enantiomeric
excesses were determined by HPLC analysis on chiral DAICEL
CHIRALCEL AS-H, AD-H, OD-H, and AD column at 254 nm
unless specially indicated. Optical rotations were measured on
a commercial polarimeter and reported as follows: [a]DT (c g/
100 mL, solvent). Reagents obtained from commercial sources
were used without further purification. Unless specially indi-
cated, CH2Cl2 and THF were distilled over CaH2 and Na,
respectively, before use.
1H), 5.03 (d, J¼10.8 Hz, 1H), 3.99e4.16 (m, 4H), 3.84 (s,
3H), 1.24e1.39 (dt, J¼20.0, 6.8 Hz, 6H) ppm.
4.2.4. Diethyl benzo[d][1,3]dioxol-5-yl(hydroxy)methyl-
phosphonate (4d)
Colorless oil, yield 73%. [a]2D0 þ19.20 (c 0.5 in CHCl3) (83%
ee). HPLC (OD-H, 2-hexane/iPrOH, 90/10, flow 1.0 mL/min,
detection at 254 nm). tR (minor)¼8.2 min, tR (major)¼9.6 min.
1H NMR (400 MHz, CDCl3): d¼6.94 (s, 1H), 6.84(d, J¼8.0 Hz,
1H), 6.70 (d, J¼8.0 Hz, 1H), 5.88 (s, 2H), 4.83 (d, J¼10.0 Hz,
1H), 3.88e4.05 (m, 4H), 1.18 (dt, J¼18.4, 7.2 Hz, 6H) ppm.
4.2.5. (S)-Diethyl hydroxy(4-methylphenyl)methyl-
phosphonate (4e)
Colorless oil, yield 91%. [a]2D0 ꢁ37.96 (c 0.6 in CHCl3)
(83% ee) [lit.4h [a]D20 ꢁ20.0 (c 1.0, CHCl3) for S enantiomer
in 58% ee]. HPLC (AS-H column, 2-propanol/hexane 20/80,
flow 1.0 mL/min, detection at 254 nm). tR (minor)¼8.7 min,
4.2. Typical procedure for the enantioselective
hydrophosphonylation of aldehydes
1
tR (major)¼11.5 min. H NMR (400 MHz, CDCl3): d¼7.37
(dd, J¼2.0, 8.0 Hz, 2H), 7.18 (d, J¼8.0 Hz, 2H), 4.98 (dd,
J¼6.0, 10.4 Hz, 1H), 3.93e4.10 (m, 4H), 2.35 (d, J¼1.6 Hz,
3H), 1.25 (dt, J¼23.2, 7.2 Hz, 6H) ppm.
AlEt2Cl (25%, w/w, 16 mL, 0.025 mmol) was added to a
solution of 1j (14.5 mg, 0.025 mmol) in 0.5 mL THF, and the
mixture was stirred at 25 ꢀC for 0.5 h under N2 atmosphere,
followed by the addition of the corresponding aldehyde
(0.25 mmol) and diethyl phosphonate (40 mL, 0.325 mmol) at
0 ꢀC. The contents were stirred for the indicated time as shown
in Table 5, and the residue was purified by silica gel column
chromatography (acetone/petroleum oil, 3:7e7:3 v/v) to afford
the corresponding a-hydroxy phosphonate.
4.2.6. (S)-Diethyl (4-chlorophenyl)(hydroxy)methyl-
phosphonate (4f)
White solid, yield 88%. [a]2D0 ꢁ31.51 (c 0.6 in CHCl3)
(65% ee) [lit.4i [a]D20 þ24.3 (c 1.0, CHCl3) for R enantiomer
in 52% ee]. HPLC (AS-H, 2-hexane/iPrOH, 80/20, flow
1.0 mL/min, detection at 254 nm). tR (minor)¼7.1 min, tR
(major)¼9.1 min. 1H NMR (400 MHz, CDCl3): d¼7.33e
7.44 (m, 4H), 5.00 (dd, J¼4.8, 10.8 Hz, 1H), 3.99e4.17 (m,
4H), 1.22e1.30 (dt, J¼6.8, 12.8 Hz, 6H) ppm.
4.2.1. (S)-Diethyl hydroxy(phenyl)methylphosphonate (4a)
White solid, yield 88%. [a]2D5 ꢁ20.5 (c 2.0 in CHCl3) (75%
ee) [lit.4h [a]D20 ꢁ6.6 (c 1.0, CHCl3) for S enantiomer in 20%
ee]. HPLC (AS-H column, 2-propanol/hexane 15/85, flow
1.0 mL/min, detection at 254 nm). tR (minor)¼8.6 min, tR (ma-
jor)¼10.8 min. 1H NMR (300 MHz, CDCl3): d¼7.46e7.49 (m,
2H), 7.25e7.37 (m, 3H), 5.00 (d, J¼11.0 Hz, 1H), 3.94e4.08
(m, 4H), 1.14e1.27 (m, 6H) ppm.
4.2.7. Diethyl (4-fluorophenyl)(hydroxy)methylphosphonate
(4g)
White solid, yield 87%. [a]2D0 ꢁ16.85 (c 0.2 in CHCl3) (62%
ee). HPLC (AS-H, 2-hexane/iPrOH, 80/20, flow 1.0 mL/min,
detection at 254 nm). tR (minor)¼6.5 min, tR (major)¼7.9 min.
1H NMR (400 MHz, CDCl3): d¼6.95e6.98 (m, 2H), 6.56 (t,
J¼8.4 Hz, 2H), 4.50 (d, J¼10.4 Hz, 1H), 3.47e3.61 (m, 4H),
0.72e0.79 (m, 6H) ppm. 13C NMR (100 MHz, CDCl3):
d¼162.5 (d, J¼245 Hz), 132.6, 128.8, 115.1 (d, J¼22 Hz),
70.1 (d, J¼158 Hz), 63.4 (d, J¼7 Hz), 63.0 (d, J¼7 Hz), 16.4
(d, J¼6 Hz) ppm. ESIeHRMS calcd for (C11H16FO4PþHþ)
263.0843, found: 263.0844.
4.2.2. (S)-Diethyl hydroxy(4-methoxyphenyl)methyl-
phosphonate (4b)
White solid, yield 74%. [a]2D0 ꢁ34.7 (c 0.9 in CHCl3) (87%
ee) [lit.4h [a]D20 ꢁ31.1 (c 1.0, CHCl3) for S enantiomer in 82%
ee]. HPLC (AS-H column, 2-propanol/hexane 20/80, flow
1.0 mL/min, detection at 254 nm). tR (minor)¼10.5 min, tR
1
(major)¼14.7 min. H NMR (400 MHz, CDCl3): d¼7.43 (d,
J¼6.8 Hz, 2H), 6.93 (t, J¼8.8 Hz, 2H), 4.98 (d, J¼9.6 Hz,
1H), 3.94e4.14 (m, 4H), 3.83 (s, 3H), 1.27 (dt, J¼23.2,
7.2 Hz, 6H) ppm.
4.2.8. Diethyl hydroxy(4-nitrophenyl)methylphosphonate
(4h)
White solid, yield 88%. [a]2D0 ꢁ31.2 (c 2.0 in CHCl3) (67%
ee). HPLC (AS-H, 2-hexane/iPrOH, 80/20, flow 1.0 mL/min,
detection at 254 nm). tR (minor)¼9.9 min, tR (major)¼12.8 min.
1H NMR (400 MHz, CDCl3): d¼8.23 (d, J¼8.4 Hz, 2H), 7.67
(dd, J¼2.0, 8.8 Hz, 2H), 5.17 (d, J¼12.0 Hz, 1H), 4.05e4.24
(m, 4H), 1.25e1.31 (m, 6H) ppm. 13C NMR (100 MHz,
CDCl3): d¼147.52, 144.45, 127.7 (d, J¼5 Hz), 123.3, 70.1 (d,
J¼158 Hz), 64.0 (d, J¼8 Hz), 63.3 (d, J¼8 Hz) 16.4 ppm.
4.2.3. Diethyl hydroxy(3-methoxyphenyl)methyl-
phosphonate (4c)
Colorless oil, yield 71%. [a]2D0 ꢁ18.14 (c 0.6 in CHCl3) (81%
ee). HPLC (AS-H column, 2-propanol/hexane 20/80, flow
1.0 mL/min, detection at 254 nm). tR(minor)¼10.0 min, tR
1
(major)¼15.8 min. H NMR (400 MHz, CDCl3): d¼7.30 (t,
J¼7.6 Hz, 1H), 7.08 (d, J¼8.0 Hz, 2H), 6.88 (d, J¼8.4 Hz,

S. Gou et al. / Tetrahedron 64 (2008) 2864e2870
2869
ESIeHRMS calcd for (C11H16NO6PþHþ) 290.0788, found:
7.19 (t, J¼7.2 Hz, 1H), 7.01 (dd, J¼4.0, 5.2 Hz, 1H), 5.24 (d,
J¼10.8 Hz, 1H), 4.04e4.30 (m, 4H), 1.29 (dt, J¼6.8, 20.0 Hz,
6H) ppm.
290.0785.
4.2.9. Diethyl (4-phenyl)(hydroxy)methylphosphonate (4i)
White solid, yield 85%. [a]2D0 ꢁ34.95 (c 2.0 in CHCl3) (82%
ee). HPLC (AS-H, 2-hexane/iPrOH, 80/20, flow 1.0 mL/min,
detection at 254 nm). tR (minor)¼8.9 min, tR (major)¼12.9 min.
1H NMR (400 MHz, CDCl3): d¼7.54e7.63 (m, 4H), 7.44 (t,
J¼7.6 Hz, 2H), 7.35 (t, J¼7.6 Hz, 2H), 7.26 (s, 1H), 5.07 (d,
J¼10.8 Hz, 1H), 3.99e4.13 (m, 4H), 1.27 (dt, J¼6.8, 16.8 Hz,
6H) ppm. 13C NMR (100 MHz, CDCl3): d¼140.8, 140.6,
135.7, 128.8, 127.5 (d, J¼6 Hz), 127.4, 127.1, 126.9, 70.1 (d,
J¼158 Hz), 63.4 (d, J¼7 Hz), 63.1 (d, J¼7 Hz), 16.4 ppm.
ESIeHRMS calcd for (C17H21O4PþNaþ) 343.1070, found:
343.1065.
4.2.14. Diethyl 1-hydroxy-3-phenylpropylphosphonate (4n)
Colorless oil, yield 99%. [a]2D0 þ14.65 (c 0.3 in CHCl3) (75%
ee). HPLC (AS-H, 2-hexane/iPrOH, 90/10, flow 1.0 mL/min,
detection at 254 nm). tR (minor)¼6.1 min, tR (major)¼10.7 min.
1H NMR (400 MHz, CDCl3): d¼7.17e7.31 (m, 5H), 4.11e4.21
(m, 4H), 3.82e3.87 (m, 1H), 2.92e2.99 (m, 1H), 2.70e2.78 (m,
1H), 1.99e2.08 (m, 2H), 1.29e1.35 (m, 6H) ppm.
4.2.15. Diethyl 1-hydroxypentylphosphonate (4o)
Colorless oil, yield 85%. 1H NMR (400 MHz, CDCl3):
d¼4.13e4.21 (m, 4H), 3.85 (dt, J¼5.6, 15.6 Hz, 1H), 1.58e
1.80 (m, 3H), 1.32e1.41 (m, 9H), 0.82 (t, J¼7.2 Hz, 3H) ppm.
The product of 4o: diethyl 1-(phenylperoxy)pentylphosphonate:
colorless oil, yield 89%. [a]2D0 þ14.67 (c 2.0 in CHCl3)(77% ee).
HPLC (AS-H, 2-hexane/iPrOH, 90/10, flow 1.0 mL/min, detec-
tion at 254 nm). tR (minor)¼8.7 min, tR (major)¼14.9 min. 1H
NMR (400 MHz, CDCl3): d¼8.07e8.10 (m, 2H), 7.60 (t,
J¼7.6 Hz, 1H), 7.47 (t, J¼8.0 Hz 2H), 5.53 (dt, J¼4.8,
12.4 Hz, 1H), 4.13e4.21 (m, 4H), 1.96e2.18 (m, 2H), 1.28e
1.44 (m, 10H), 0.89 (t, J¼7.2 Hz 3H) ppm. 13C NMR
(100 MHz, CDCl3): d¼165.6 (d, J¼5 Hz), 133.3, 129.8,
129.5, 128.5, 68.4 (d, J¼166 Hz), 62.8 (d, J¼7 Hz), 62.6 (d,
J¼6 Hz), 29.2, 27.8, 22.2, 16.5 (d, J¼5 Hz), 16.4 (d, J¼6 Hz),
13.8 ppm. ESIeHRMS calcd for (C16H25O5PþHþ) 329.1512,
found: 329.1515.
4.2.10. (S)-Diethyl hydroxy(naphthalen-1-yl)methyl-
phosphonate (4j)
White solid, yield 90%. [a]2D0 ꢁ100.5 (c 0.6 in CHCl3) (78%
ee)[lit.4h [a]D20 þ19.4(c1.0,CHCl3)forRenantiomerin35%ee].
HPLC (AD-H, 2-hexane/iPrOH, 90/10, flow 1.0 mL/min, detec-
tion at 254 nm). tR (major)¼10.8 min, tR (minor)¼12.0 min. 1H
NMR (400 MHz, CDCl3): d¼8.10 (d, J¼8.4 Hz, 1H), 7.82e7.88
(m, 3H), 7.47e7.56 (m, 3H), 5.86 (d, J¼11.6 Hz, 1H), 3.92e
4.12 (m, 3H), 3.72e3.83 (m, 1H), 3.37 (s, 1H), 1.25 (t,
J¼7.2 Hz, 3H), 1.06 (t, J¼7.2 Hz, 3H) ppm.
4.2.11. Diethyl hydroxy(naphthalen-2-yl)methyl-
phosphonate (4k)
White solid, yield 82%. [a]2D0 ꢁ26.97 (c 0.5 in CHCl3) (74%
ee). HPLC (AS-H, 2-hexane/iPrOH, 80/20, flow 1.0 mL/min,
detection at 254 nm). tR (minor)¼8.8 min, tR (major)¼11.2 min.
1H NMR (400 MHz, CDCl3): d¼7.96 (s, 1H), 7.81e7.85 (m,
3H), 7.60 (d, J¼8.8 Hz, 1H), 7.46e7.51 (m, 2H), 5.20 (d, J¼
11.2 Hz, 1H), 3.95e4.10 (m, 4H), 1.24 (dt, J¼7.2, 21.2 Hz,
6H) ppm. 13C NMR (100 MHz, CDCl3): d¼134.2, 133.1 (d, J¼
2 Hz), 128.1 (d, J¼1 Hz), 127.9, 127.7, 126.1 (d, J¼7 Hz),
125.0, 71.0 (d, J¼158 Hz), 63.4 (d, J¼7 Hz), 63.1 (d, J¼
7 Hz), 16.4 ppm; ESIeHRMS calcd for (C15H19O4PþHþ)
295.1094, found: 295.1091.
Acknowledgements
The authors thank the National Natural Science Foundation
of China (No. 20732003) and Sichuan University for financial
support. We also thank Sichuan University Analytical &
Testing Center for NMR analysis and the State Key Labora-
tory of Biotherapy for HRMS analysis.
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