Nonenzymatic kinetic resolution of racemic β-hydroxyalkanephosphonates with a chiral copper catalyst

Article abstract of DOI:10.1016/j.tetasy.2010.04.059

Kinetic resolution of β-hydroxyalkanephosphonates was efficiently performed by 2-fluorobenzoylation in the presence of copper(II) triflate and (R,R)-Ph-BOX as a catalyst with good s value of up to 21.

Full text of DOI:10.1016/j.tetasy.2010.04.059

Tetrahedron: Asymmetry 21 (2010) 810–824
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Nonenzymatic kinetic resolution of racemic b-hydroxyalkanephosphonates
with a chiral copper catalyst
*
Atsushi Moriyama, Shintaro Matsumura, Masami Kuriyama, Osamu Onomura
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Kinetic resolution of b-hydroxyalkanephosphonates was efficiently performed by 2-fluorobenzoylation in
the presence of copper(II) triflate and (R,R)-Ph-BOX as a catalyst with good s value of up to 21.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 10 March 2010
Accepted 26 April 2010
Available online 2 June 2010
1. Introduction
tions (entries 2–13). For instance, a combination of Zn(OTf)2 and
(R,R)-Ph-BOX promoted the benzoylation well, while the selectiv-
Optically active b-hydroxyalkanephosphonic acid derivatives
are important precursors for biologically active compounds.1
Although a multitude of enzymatic kinetic resolution methods
have been developed for the preparation of enantiomerically en-
riched b-hydroxyalkanephosphonic acid derivatives,2 to the best
of our knowledge, nonenzymatic methods have not been de-
scribed. We recently reported an efficient method for the kinetic
ity was somewhat low (entry 2). Combinations of other metal tri-
flates, copper dichloride, or palladium diacetate and (R,R)-Ph-BOX
did not promote any kinetic resolution (entries 3–11). (R,R)-Bn-
BOX and (S,S)-t-Bu-BOX were not applicable to the kinetic resolu-
tion (entries 12 and 13).
2.2. Effect of acylating agents
resolution of 1,2-diols,3 vic-amino alcohols,4 and
a- or b-hydrox-
yalkanamides5 with copper(II) ions associated with the chiral li-
gand (R,R)-Ph-BOX by acylation to obtain optically active alcohols
with excellent enantioselectivity.6 More recently, we have found
that this copper catalyst efficiently mediated the kinetic resolution
We then investigated the effect of the acylating agent to im-
prove the selectivity. Table 2 summarizes the effect of different
acylating agents on the kinetic resolution of rac-1a. Use of benzoic
anhydride and N-benzoylimidazole which have lower reactivity
compared with benzoyl chloride gave no benzoylated product
(S)-2a(Bz) (entries 1 and 2). On the other hand, the use of 2-meth-
ylbenzoyl chloride afforded (S)-2a(2-MeBz) with a moderate s va-
lue (entry 3), while the use of 2-methoxylbenzoyl chloride
afforded (S)-2a(2-MeOBz) with a low s value (entry 4).
Among the 2-halogenated benzoyl chlorides which gave im-
proved results (entries 5, 10, and 11), 2-fluorobenzoyl chloride
gave the best result. 3- or 4-fluorobenzoyl chloride was unfavor-
able when compared to 2-fluorobenzoyl chloride (entries 6–9).
On the other hand, 1- or 2-naphthoyl chloride gave moderate
selectivities (entries 12 and 13). Aliphatic acyl chlorides such as
acetyl, pivaloyl, and chloroacetyl chloride did not give good results
(entries 14–16). Interestingly, the reaction of rac-1a with phenyl
isocyanate gave the opposite stereoselectivity (entry 17). On the
other hand, p-TsCl and ClP(O)(OEt)2 did not react with rac-1a (en-
tries 18 and 19).
of a
-hydroxyalkanephosphonates.7 Herein, we apply our method-
ology to the kinetic resolution of b-hydroxyalkanephosphonates
1 to afford optically active b-acyloxyalkanephosphonates 2 in high
yields and enantioselectivities. This is based on molecular recogni-
tion by a Cu(II)–(R,R)-Ph-BOX complex to form the activated inter-
mediates A or A0 followed by benzoylation (Scheme 1).
2. Result and discussion
2.1. Effect of the chiral catalyst
We began by surveying the effect of chiral catalysts composed
of a metal salt and the chiral ligand to optimize their effect. The ki-
netic resolution of dimethyl (2-hydroxy-2-phenylethyl)phospho-
nate 1a with benzoyl chloride (0.5 equiv) in CH2Cl2 was carried
out in the presence of K2CO3 (1 equiv), metal salt (0.05 equiv),
and chiral ligand (0.05 equiv). The results are shown in Table 1.
The selectivity s value8 of a combination of Cu(OTf)2 and (R,R)-
Ph-BOX shown in entry 1 was higher than those of other combina-
2.3. Solvent effect
Table 3 summarizes the effect of solvents on the kinetic resolu-
tion of rac-1a. Alcohols as protic solvents did not work to acceler-
ate the 2-fluorobenzoylation (entries 1–4). Acetonitrile, acetone,
* Corresponding author. Tel.: +81 95 819 2429; fax: +81 95 819 2476.
E-mail address: onomura@nagasaki-u.ac.jp (O. Onomura).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.059

A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
811
L*
L*
O
O
O
Cu2+
Cu2+
OH
O
P
Cu2+
L*
RCOCl
OR1
OR1
-H+
H+
N
N
HO
R2
O
P
R
O
O
P
O
O
P
R2
OR1
OR1
OR1
OR1
OR1
OR1
Ph
K2CO3
-HCl
Ph
R2
R2
Cu2+ L*
-
L* (R,R)-Ph-BOX
1
A
A'
2
Scheme 1. Kinetic resolution of b-hydroxyalkanephosphonates with a chiral copper catalyst.
Table 1
Effect of the chiral catalyst on kinetic resolution of rac-1aa
BzCl (0.5 equiv)
MXn (0.05 equiv)
OH
O
P
chiral ligand (0.05 equiv)
OBz
O
P
OH
O
P
OMe
OMe
+
OMe
OMe
OMe
OMe
K2CO3 (1.0 equiv)
CH2Cl2
Ph
Ph
Ph
0 °C to rt, 20 h
(S)-2a(Bz)
(R)-1a
rac-1a
Entry
Metal salt
Chiral ligand
Product (S)-2a(Bz)
Recovered (R)-1a
s
Yield (%)
eeb (%)
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Cu(OTf)2
Zn(OTf)2
Mg(OTf)2
Sn(OTf)2
Sc (OTf)3
Sm(OTf)3
In(OTf)3
Yb(OTf)3
Hf(OTf)4
CuCl2
(R,R)-Ph-BOX
(R,R)-Ph-BOX
(R,R)-Ph-BOX
(R,R)-Ph-BOX
(R,R)-Ph-BOX
(R,R)-Ph-BOX
(R,R)-Ph-BOX
(R,R)-Ph-BOX
(R,R)-Ph-BOX
(R,R)-Ph-BOX
(R,R)-Ph-BOX
(R,R)-Bn-BOX
(S,S)-t-Bu-BOX
24
43
23
Trace
9
17
11
18
15
13
62
23
6
—
0
3
0
0
0
73
53
76
>99
90
71
85
77
84
83
>99
89
89
22
15
0
—
0
0
0
0
0
5
2
0
—
0
0
0
0
0
0
—
1
0
0
0
Pd(OAc)2
Cu(OTf)2
Cu(OTf)2
Trace
9
10
—
—
ꢀ6d
0
ꢀ12c
ꢀ4c
a
b
c
rac-1a (0.5 mmol), metal salt (0.025 mmol), chiral ligand (0.025 mmol), BzCl (0.25 mmol), K2CO3 (0.5 mmol) in CH2Cl2 (3.0 mL) at 0 °C to rt for 20 h.
Determined by HPLC.
(R)-2a(Bz) was obtained.
(S)-1a was recovered.
d
and AcOEt which might coordinate with Cu(II) gave (S)-2a(2-FBz)
with a low s value (entries 5, 8, and 9), while DMF and DMSO as
polar solvents did not work at all (entries 6 and 7). Use of ethers
or aromatic solvents improved the yields and enantioselectivities
(entries 10–15). Halogenated aliphatic solvents were suitable for
the kinetic resolution (entries 16–19), CH2Cl2 being the most suit-
able solvent for the kinetic resolution. On the other hand, fluoro-
benzene or chlorobenzene gave moderate selectivities (entries 20
and 21).
kinetic resolution of b-hydroxy-b-phenylethanephosphonates 1a–
d with benzoyl or 2-fluorobenzoyl chloride (0.5 equiv) in CH2Cl2
was carried out in the presence of K2CO3 (1 equiv), Cu(OTf)2
(0.05 equiv), and (R,R)-Ph-BOX (0.05 equiv). The results are shown
in Table 5. In the case of benzoylation of 1a–d, the s values for sub-
strates 1a and 1d substituted with a methyl or n-butyl ester were
slightly lower than those of 1b and 1c substituted with an ethyl or
isopropyl ester (entries 1–4). The s values of 2-fluorobenzoylation
for 1a–d were somewhat higher than those of benzoylation for 1a–
d (entries 1–8). Among 2-fluorobenzoylation for 1a–d, the s value
for substrate 1b was slightly better than those of 1a, 1c, and 1d
(entries 4–8).
2.4. Effect of base
Table 4 summarizes the effect of bases on the kinetic resolution of
rac-1a. Use of K2CO3, Na2CO3, or NaHCO3 as a base gave 2-fluor-
obenzoylated product (S)-2a(2-FBz) with good s values (entries 1–
3), while other carbonate salts such as Li2CO3, ZnCO3, BaCO3 CaCO3,
Cs2CO3, and (NH4)2CO3 did not effectively accelerate the kinetic res-
olution (entries 4–9). On the other hand, diisopropylethylamine (DI-
PEA) gave (S)-2a(2-FBz) with low yield and selectivity (entry 10).
However, these selectivities were relatively lower than those of
a
-hydroxyphosphonates (Scheme 2).7
To clarify the reason for the different selectivities, a compet-
itive reaction of b-hydroxyphosphonate rac-1b and
a-hydroxy-
phosphonate rac-3 with benzoyl chloride under the optimized
reaction condition was examined (Scheme 3). The reactivity of
b-isomer rac-1b was much lower than that of
a-isomer rac-3.
This result may imply that the formation of the activated inter-
mediates A or A0 composed of Cu(II)–(R,R)-Ph-BOX complex and
rac-1b (in Scheme 1) was slower than the formation of the
corresponding intermediate Cu(II)–(R,R)-Ph-BOX complex and
rac-3.
2.5. Effect of the ester substituents
Next, we surveyed the effect of the ester substituents of
b-hydroxyalkanephosphonates 1 to optimize their effect. The

812
A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
Table 2
Effect of acylating agent on the kinetic resolutiona
Acylating agent (0.5 equiv)
Cu(OTf)2 (0.05 equiv)
Acyl
Ph
OH
O
P
(R,R)-Ph-BOX (0.05 equiv)
O
O
P
OH
O
P
OMe
OMe
+
OMe
OMe
OMe
OMe
K2CO3 (1.0 equiv)
CH2Cl2
Ph
Ph
0 °C to rt, 20 h
(S)-2a(Acyl)
(R)-1a
rac-1a
Entry
Acylating agent
Product
Recovered (R)-1a
s
(S)-2a(Acyl)
Yield (%)
eeb (%)
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17c
18
19
Bz2O
(S)-2a(Bz)
(S)-2a(Bz)
(S)-2a(2-MeBz)
(S)-2a(2-MeOBz)
(S)-2a(2-FBz)
0
—
—
69
6
>99
96
69
66
66
53
60
63
70
70
85
78
63
59
>99
68
55
>99
>99
—
—
16
0
28
30
30
27
13
20
5
—
—
6
0
12
5
4
5
3
7
4
5
4
2
—
1
2
—
—
N-Bz-Imidazole
2-MeBzCl
2-MeOBzCl
2-FBzCl
3-FBzCl
4-FBzCl
2,6-F2BzCl
C6F5COCl
2-ClBzCl
2-BrBzCl
1-Naphthoyl-Cl
2-Naphthoyl-Cl
AcCl
t-BuCOCl
ClCH2COCl
PhNCO
Trace
23
31
32
19
27
22
23
30
15
20
30
36
Trace
20
45
0
80
59
52
56
47
72
61
64
55
16
—
(S)-2a(3-FBz)
(S)-2a(4-FBz)
(S)-2a(2,6-F2Bz)
(S)-2a(C6F5CO)
(S)-2a(2-ClBz)
(S)-2a(2-BrBz)
(S)-2a(1-Naphthoyl)
(S)-2a(2-Naphthoyl)
(S)-2a(Ac)
(S)-2a(t-BuCO)
(S)-2a(ClCH2CO)
(R)-2a(PhNHCO)
(S)-2a(p-Ts)
8
23
10
—
8
29
—
7
24d
—
p-TsCl
ClP(O)(OEt)2
(S)-2a(P(O)(OEt)2)
0
—
—
a
b
c
rac-1a (0.5 mmol), Cu(OTf)2 (0.025 mmol), (R,R)-Ph-BOX (0.025 mmol), acylating agent (0.25 mmol), K2CO3 (0.5 mmol) in CH2Cl2 (3.0 mL) at 0 °C to rt for 20 h.
Determined by HPLC.
Without K2CO3, at 40 °C, for 20 min.
(S)-1a was recovered.
d
2.6. Kinetic resolution of various b-hydroxyalkanephosph-
onates
with 2-fluorobenzoyl chloride was very slow (entry 1), while in
the presence of Cu(OTf)2, the yield of 2-fluorobenzoylated com-
pound 2a(2-FBz) was somewhat improved (entry 2). Further
Kinetic resolutions of various dimethyl or diethyl b-hydrox-
yalkanephosphonates rac-1e–r or rac-1s–v by 2-fluorobenzoyla-
tion under the optimized reaction conditions are summarized in
Table 6. First, substrates having a 2, 3, or 4-methylated phenyl
group 1e–g efficiently afforded the corresponding optically active
2-fluorobenzoylated compounds (S)-2e–g (entries 1–3). The
kinetic resolution of rac-1e gave the best s value of 21 among
dimethyl phosphonates rac-1e–r. On the other hand, 4-meth-
oxyphenylated alcohol rac-1i afforded somewhat better result than
2-methoxyphenylated alcohol rac-1h (entries 4 and 5). In case of
alcohols rac-1j–m, which contain electron-withdrawing substitu-
ents such as nitro or halogen group at the 4-position, the selectiv-
ities were moderate (entries 6–9). The kinetic resolution of 1- or
2-naphthylated alcohols rac-1n or 1o proceeded effectively (en-
tries 10 and 11). Also, this method was applicable to kinetic reso-
lution of aliphatic alcohols rac-1p–r to give moderate selectivities
(entries 12–14). The s value for 2-fluorobenzoylation of diethyl
phosphonate rac-1v improved compared to that of the correspond-
ing dimethyl ester rac-1p (entries 12 and 18), while the s values for
2-fluorobenzoylation of diethyl phosphonates rac-1s–u did not
improve relative to those of the corresponding dimethyl esters
rac-1e,i,n (entries 1 and 15, 5 and 16, 10 and 17).
improvement was accomplished by using a combination of
Cu(OTf)2 and (R,R)-Ph-BOX to afford 2a(2-FBz) in 32% yield (entry
3). These results suggest that rac-1a is recognized by the Cu(II)–
(R,R)-Ph-BOX complex in the same way as in the kinetic resolution
of a
-hydroxyphosphonates.7
2.8. Stereochemistry
A plausible stereochemical course is shown in Scheme 4. Firstly,
Cu(II)–(R,R)-Ph-BOX complex B might be formed.6b B can approach
(R)- or (S)-1 to generate the activated intermediates A0(R)-complex
or A0(S)-complex, respectively. Since A0(S)-complex has steric hin-
drance between phenyl group on oxazoline ring and R2 group on
(S)-1, A0(R)-complex might form more quickly than A0(S)-complex.
Reactive phenyl isocyanate quickly reacted with A’(R)-complex to
give (R)-2a(PhNHCO) (path a, entry 17 in Table 2). On the other
hand, although less reactive than phenyl isocyanate, 2-fluor-
obenzoyl chloride hardly closes the A0(R)-complex due to steric
hindrance (path b), whereas it easily closes the A0(S)-complex to
produce (S)-2 with good selectivity (path c).
3. Conclusion
2.7. Acceleration effect of the catalyst
In conclusion, we have demonstrated a new nonenzymatic
method for the kinetic resolution of b-hydroxyalkanephospho-
nates. Synthetic applications of this enantiomerically enriched 2-
fluorobenzoylation of racemic b-hydroxyalkanephosphonates are
underway.
Next, we investigated the 2-fluorobenzoylation of b-hydroxy-
phosphonate rac-1a to see whether it could be accelerated by a chi-
ral copper(II) complex or not. The results are shown in Table 7. In
the absence of Cu(OTf)2 and (R,R)-Ph-BOX the reaction of rac-1a

A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
813
Table 3
Effect of solvents on the kinetic resolutiona
F
2-FBzCl (0.5 equiv)
Cu(OTf)2 (0.05 equiv)
(R,R)-Ph-BOX (0.05 equiv)
OH
O
P
O
O
O
P
OH
O
P
OMe
OMe
+
OMe
OMe
OMe
OMe
K2CO3 (1.0 equiv)
solvent
Ph
Ph
Ph
0 °C to rt, 20 h
(S)-2a(2-FBz)
(R)-1a
rac-1a
Entry
Solvent
Product (S)-2a(2-FBz)
Recovered (R)-1a
s
Yield (%)
eeb (%)
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
MeOH
EtOH
i-PrOH
t-BuOH
MeCN
DMF
DMSO
Acetone
AcOEt
THF
0
0
—
—
—
—
32
—
>99
>99
>99
>99
68
>99
>99
71
77
79
56
56
75
70
75
66
57
77
57
72
—
—
—
—
17
—
—
—
—
—
2
—
—
2
1
3
5
9
5
3
5
12
8
5
8
3
7
Trace
Trace
24
0
0
—
—
14
17
11
25
26
22
30
12
32
25
20
31
25
13
19
15
48
59
71
59
34
61
80
72
60
69
38
68
13
10
19
35
40
24
24
22
28
22
23
41
21
24
Et2O
i-Pr2O
Benzene
Toluene
Mesitylene
CH2Cl2
CHCl3
CCl4
1,2-Dichloroethane
Fluorobenzene
Chlorobenzene
84
a
rac-1a (0.5 mmol), Cu(OTf)2 (0.025 mmol), (R,R)-Ph-BOX (0.025 mmol), 2-FBzCl (0.25 mmol), K2CO3 (0.5 mmol) in solvent (3.0 mL) at 0 °C to rt for 20 h.
Determined by HPLC.
b
Table 4
Effect of bases on the kinetic resolutiona
F
2-FBzCl (0.5 equiv)
Cu(OTf)2 (0.05 equiv)
(R,R)-Ph-BOX (0.05 equiv)
OH
Ph
O
P
O
O
O
P
OH
O
P
OMe
OMe
+
OMe
OMe
OMe
OMe
base (1.0 equiv)
CH2Cl2
Ph
Ph
0 °C to rt, 20 h
(S)-2a(2-FBz)
(R)-1a
rac-1a
Entry
Base
Product (S)-2a(2-FBz)
Recovered (R)-1a
s
Yield (%)
eeb (%)
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
K2CO3
32
30
30
13
25
8
9
13
0
80
70
53
1
20
31
9
16
—
26
66
58
61
77
68
74
78
77
28
49
42
0
12
17
1
1
—
0
12
9
5
0
2
2
1
1
—
0
Na2CO3
NaHCO3
Li2CO3
ZnCO3
BaCO3
CaCO3
Cs2CO3
(NH4)2CO3
DIPEA
>99
25
10
18
a
rac-1a (0.5 mmol), Cu(OTf)2 (0.025 mmol), (R,R)-Ph-BOX (0.025 mmol), 2-FBzCl (0.25 mmol), base (0.5 mmol) in solvent (3.0 mL) at 0 °C to rt for 20 h.
Determined by HPLC.
b
dard. IR spectra were obtained on a Shimadzu FTIR-8100A. Mass
spectra were obtained on a JEOL JMS-700N instrument. HPLC
analyses were achieved by using an LC-10AT VP and an SPD-
10A VP of Shimadzu Seisakusho, Inc. Specific rotations were
measured with JASCO DIP-1000. Melting points are uncor-
rected.
4. Experimental section
4.1. General
1H NMR and 13C NMR spectra were measured on a Varian
Gemini 300 or 400 spectrometer with TMS as an internal stan-

814
A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
Table 5
Effect of the ester substituents of rac-1a–da
BzCl or 2-FBzCl(0.5 equiv)
Cu(OTf)2 (0.05 equiv)
Acyl
OH
O
P
(R,R)-Ph-BOX (0.05 equiv)
O
O
P
OH
O
P
OR1
OR1
OR1
OR1
OR1
OR1
+
K2CO3 (1.0 equiv)
CH2Cl2
Ph
Ph
Ph
0 °C to rt, 20 h
(S)-2a-d(Bz or 2-FBz)
(R)-1a-d
rac-1a−d
Entry
Substrate
Product
Yield (%)
24
26
34
29
32
31
36
20
Recovered (R)-1a–d
s
eeb (%)
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
1a: R1 = Me
1b: R1 = Et
(S)-2a(Bz)
(S)-2b(Bz)
(S)-2c(Bz)
(S)-2d(Bz)
(S)-2a(2-FBz)
(S)-2b(2-FBz)
(S)-2c(2-FBz)
(S)-2d(2-FBz)
62
66
66
56
80
83
77
82
(R)-1a
73
55
51
60
66
53
57
71
22
41
36
20
28
36
29
28
5
7
7
4
(R)-1b
(R)-1c
(R)-1d
(R)-1a
(R)-1b
(R)-1c
(R)-1d
1c: R1 = i-Pr
1d: R1 = n-Bu
1a: R1 = Me
1b: R1 = Et
12
15
10
13
1c: R1 = i-Pr
1d: R1 = n-Bu
a
rac-1a–d (0.5 mmol), Cu(OTf)2 (0.025 mmol), (R,R)-Ph-BOX (0.025 mmol), BzCl or 2-FBzCl (0.25 mmol), K2CO3 (0.5 mmol) in CH2Cl2 (3.0 mL) at 0 °C to rt for 20 h.
Determined by HPLC.
b
BzCl (0.5 equiv)
OH
OBz
OH
Cu(OTf)2 (0.05 equiv)
(R,R)-Ph-BOX (0.05 equiv)
Ph
OEt
OEt
Ph
OEt
OEt
Ph
OEt
OEt
P
O
P
O
(R)-4
P
O
+
K2CO3 (1 equiv)
CH2Cl2
(S)-3
rac-3
0°C to rt, 12 h
48% yield
52% ee
39% yield
83% ee
s=18
Scheme 2. Kinetic resolution of a-hydroxyphosphonate.
BzCl (0.25 mmol)
Cu(OTf)2 (0.025 mmol)
OH
O
P
OH
Ph
(R,R)-Ph-BOX (0.025 mmol)
OEt
OEt
OEt
OEt
Ph
+
P
K2CO3 (0.5 mmol)
CH2Cl2 (5 mL)
0°C to rt, 20 h
O
rac-1b (0.5 mmol)
rac-3 (0.5 mmol)
OBz
O
P
OH
O
P
OBz
OH
OEt
OEt
OEt
OEt
Ph
+
OEt
OEt
Ph
OEt
OEt
+
+
Ph
Ph
P
O
P
O
(R)-4
(S)-3
(S)-2b(Bz)
(R)-1b
57% yield
44% ee
0% yield
28% yield
82% ee
94% yield
0% ee
Scheme 3. Competitive reaction of a- and b-hydroxyphosphonate.
All reagents and solvents were used as supplied without further
purification.
vent was removed under reduced pressure and water (25 mL) was
added to the residue. The organic portion was extracted with
CH2Cl2 (3 ꢁ 30 mL), dried over MgSO4, and the filtrate was concen-
trated under reduced pressure. The residue was subjected to silica
gel column chromatography (n-hexane/AcOEt = 1/4). Recrystalliza-
tion from Et2O and n-hexane afforded 1l (84% yield) as white
crystals.
4.2. Preparation of racemic b-hydroxyphosphonates 1a–o, q–u:
typical procedure9
Under an argon atmosphere n-butyl lithium (1.6 M, 15 mL,
24 mmol) was slowly added to a solution of dimethyl methyl-
phosphonate (2.14 mL, 20 mmol) in THF (40 mL) at ꢀ70 °C. After
stirring for 30 min, to the solution was added slowly a solution
of 4-chlorobenzaldehyde (3.37 g, 24 mmol) in THF (10 mL). After
stirring for 1 h, acetic acid (1.49 mL, 24 mmol) was added. The sol-
4.3. Preparation of racemic b-hydroxyphosphonates 1p, v
To a solution of dimethyl 2-oxopropylphosphonate (0.69 mL,
5 mmol) in methanol (10 mL) was added sodium borohydride

A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
815
2+
O
O
O
N
H
O
O
P
2OTf−
N
N
OMe
OMe
R2
Cu
R
Ph
Ph
B
(R)-1
(S)-1
O
path a
R2
O
N
O
N
Cu
O
O
O
N
N
P
Cu
OMe
O
O
OMe
P
R2
OMe
OMe
A'(S)-complex
A'(R)-complex
F
O
path b
path c
Cl
F
O
R2
Cl
O
O
O
O
N
O
N
N
Cu
N
Cu
O
O
O
P
P
OMe
OMe
OMe
OMe
R2
F
O
F
O
F
O
Cl
O
O
P
O
O
OMe
OMe
OMe
OMe
R2
P
R
R2
S
Scheme 4. A plausible stereochemical course.
(0.76 g, 20 mmol) at 0 °C. After stirring for 16 h at room tempera-
ture, 2 M aq HCl was added to the reaction mixture and the result-
ing mixture was concentrated under reduced pressure. To the
residue was added H2O (10 mL), and the organic portion was ex-
tracted with AcOEt (3 ꢁ 25 mL). The organic layer was then dried
over MgSO4, and the filtrate was concentrated under reduced pres-
sure. The residue was subjected to silica gel column chromatogra-
phy (AcOEt) to afford 1p (51% yield).
(n-hexane/AcOEt = 1:1) to afford (S)-2a(2-FBz) (32% yield, 80% ee)
as colorless oil and (R)-1a (66% yield, 28% ee) as white solid.
4.4.1. Dimethyl (R)-(2-hydroxy-2-phenylethyl)phosphonate 1a1b
White solid; mp 57.5–58.0 °C (Et2O); ½a D20
¼ ꢀ14:5 (c 1.3, ace-
ꢂ
tone, 49% ee); 1H NMR (300 MHz, CDCl3) d 2.15–2.34 (m, 2H),
3.66 (br s, 1H), 3.73 (d, J = 10.8 Hz, 3H), 3.78 (d, J = 11.1 Hz, 3H),
5.08–5.17 (m, 1H), 7.27–7.41 (m, 5H); HPLC chiralcel OB column
(4.6 ꢁ 250 mm),
n-hexane/2-propanol = 20:1,
254 nm, flow rate: 1.0 mL/min, retention time: 11.9 min,
15.9 min (enriched).
wavelength:
4.4. Kinetic resolution of racemic b-hydroxyphosphonate,
typical procedure
4.4.2. Dimethyl (S)-(2-benzoyloxy-2-phenylethyl)phosphonate
A typical kinetic resolution procedure of rac-1a: Under an aero-
bic atmosphere, a solution of Cu(OTf)2 (9.0 mg, 0.025 mmol) and
(R,R)-Ph-BOX (8.4 mg, 0.025 mmol) in CH2Cl2 (3 mL) was stirred
for 10 min. Into the solution were added rac-1a (115 mg,
0.5 mmol), K2CO3 (69 mg, 0.5 mmol), and 2-fluorobenzoyl chloride
2a(Bz)
Colorless oil; ½a D20
ꢂ
¼ ꢀ12:8 (c 0.53, acetone, 62% ee); IR(neat)
1H NMR (300 MHz,
2955, 1721, 1269, 1111, 1034, 714 cmꢀ1
;
CDCl3)
d 2.36–2.50 (m, 1H), 2.63–2.78 (m, 1H), 3.63 (d,
J = 10.8 Hz, 3H), 3.64 (d, J = 10.8 Hz, 3H), 6.27–6.35 (m, 1H), 7.28–
7.60 (m, 8H), 8.09 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 32.4 (d, J = 140 Hz), 52.0 (d, J = 6.6 Hz), 52.2 (d, J = 6.6 Hz),
71.1, 126.1 (2C), 128.1 (2C), 128.2, 128.3 (2C), 129.4 (2C), 129.6,
132.8, 139.5 (d, J = 10.7 Hz), 164.9; MS [HR-EI (M+)] calcd for
C17H19O5P 334.0970 found 334.0965; HPLC chiralcel OJ-H column
(4.6 mmu, 250 mm), n-hexane/2-propanol = 10:1, wavelength:
(30 lL, 0.25 mmol) at 0 °C. The resulting mixture was allowed to
stand until it warmed to room temperature and stirred for 20 h.
To the solution was poured water (20 mL) and extracted with
CH2Cl2 (3 ꢁ 20 mL). The combined organic layer was dried over
MgSO4 and the solvent was removed under reduced pressure.
The residue was purified by silica gel column chromatography

816
A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
Table 6
Kinetic resolution of various b-hydroxyalkanephosphonates rac-1e–va
F
2-FBzCl (0.5 equiv)
Cu(OTf)2 (0.05 equiv)
OH
O
P
(R,R)-Ph-BOX (0.05 equiv)
O
O
O
P
OH
O
P
OR1
OR1
OR1
OR1
OR1
OR1
+
R2
R2
R2
K2CO3 (1.0 equiv)
CH2Cl2
0 °C to rt, 20 h
rac-1e-r: R1=Me
rac-1s-v: R1=Et
(S)-2e-r: R1=Me
(S)-2s-v: R1=Et
(R)-1e-r: R1=Me
(R)-1s-v: R1=Et
Entry
Substrate
Product (S)-2e–r
Recovered (R)-1e–r
s
R1
R2
Yield (%)
eeb (%)
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
2-MePh
3-MePh
4-MePh
2-MeOPh
4-MeOPh
4-NO2Ph
4-FPh
(S)-2e
(S)-2f
(S)-2g
(S)-2h
(S)-2i
(S)-2j
(S)-2k
(S)-2l
(S)-2m
(S)-2n
(S)-2o
(S)-2p
(S)-2q
(S)-2r
(S)-2s
(S)-2t
(S)-2u
(S)-2v
27
29
31
30
20
37
26
31
35
22
33
20
35
39
36
33
36
39
87
83
75
74
84
57
72
66
60
79
72
57
58
47
78
77
61
56
(R)-1e
(R)-1f
(R)-1g
(R)-1h
(R)-1i
(R)-1j
(R)-1k
(R)-1l
(R)-1m
(R)-1n
(R)-1o
(R)-1p
(R)-1q
(R)-1r
(R)-1s
(R)-1t
(R)-1u
(R)-1v
61
57
57
54
58
56
46
56
53
37
50
68
46
55
58
47
55
43
38
31
38
38
29
29
41
37
49
43
47
10
38
50
60
59
47
49
21
15
10
10
15
5
9
7
6
13
10
4
5
4
15
14
6
4-ClPh
4-BrPh
1-Naphthyl
2-Naphthyl
Me
Ph-CH@CH
Ph-C„C
2-MePh
4-MeOPh
1-Naphthyl
Me
Et
Et
Et
1u
1v
6
a
rac-1e–v (0.5 mmol), Cu(OTf)2 (0.025 mmol), (R,R)-Ph-BOX (0.025 mmol), 2-FBzCl (0.25 mmol), K2CO3 (0.5 mmol) in CH2Cl2 (3.0 mL) at 0 °C to rt for 20 h.
Determined by HPLC.
b
Table 7
2-Fluorobenzoylation of rac-1a with or without a catalysta
2-FBzCl (0.5 equiv)
F
Cu(OTf)2 (X equiv)
(R,R)-Ph-BOX (Y equiv)
O
P
OH
O
O
O
P
OH
O
P
OMe
OMe
+
OMe
OMe
OMe
OMe
Ph
Ph
Ph
K2CO3 (1.0 equiv)
CH2Cl2
0 °C to rt, 20 h
DL-1a
(S)-2a(2-FBz)
(R)-1a
Entry
Amount (equiv)
2a(2-FBz)
1a
X: Cu(OTf)2
Y: (R,R)-Ph-BOX
Yield (%)
eeb (%)
Yield (%)
eeb (%)
1
2
3
0
0.05
0.05
0
0
0.05
0
20
32
—
0
80
>99
77
66
—
0
28
a
rac-3a (0.5 mmol), Cu(OTf)2 (X equiv), (R,R)-Ph-BOX (Y equiv), 2-FBzCl (0.25 mmol), K2CO3 (0.5 mmol) in CH2Cl2 (3.0 mL) at 0 °C to rt for 20 h.
Determined by HPLC.
b
254 nm, flow rate: 1.0 mL/min, retention time: 31.4 min (en-
riched), 36.6 min.
132.0, 139.9 (d, J = 10.7 Hz), 140.4, 165.8; MS [HR-EI (M+)] calcd
for C18H21O5P 348.1126 found 348.1134; HPLC chiralcel OJ-H col-
umn (4.6 mmu, 250 mm), n-hexane/2-propanol = 20:1, wave-
length: 254 nm, flow rate: 1.0 mL/min, retention time: 30.5 min
(enriched), 35.1 min.
4.4.3. Dimethyl (S)-[2-phenyl-2-(2-toluoyloxy)ethyl]phospho-
nate 2a(2-MeBz)
Colorless solid; mp 94.0–96.0 °C (Et2O); ½a D20
¼ þ3:7 (c 1.1, ace-
ꢂ
tone, 69% ee); IR(neat) 3463, 2955, 1725, 1458, 1267, 1082 cmꢀ1
;
4.4.4. Dimethyl (S)-[2-(2-methoxybenzoyloxy)-2-phenylethyl]-
1H NMR (300 MHz, CDCl3) d 2.33–2.49 (m, 1H), 2.57 (s, 3H),
2.61–2.74 (m, 1H), 3.63 (d, J = 11.4 Hz, 6H), 6.26–6.33 (m, 1H),
7.21–7.48 (m, 8H), 8.00–8.03 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 21.6, 32.7 (d, J = 140 Hz), 52.2 (d, J = 6.6 Hz), 52.4 (d, J = 6.6 Hz),
71.0, 125.6, 126.4 (2C), 128.4, 128.6 (2C), 129.1, 130.5, 131.6,
phosphonate 2a(2-MeOBz)
White solid; mp 109–110 °C (Et2O); ½a D20
¼ ꢀ0:15 (c 1.4, ace-
ꢂ
tone, 6% ee); IR(neat) 3456, 2955, 1738, 1495, 1266, 1082 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 2.34–2.49 (m, 1H), 2.61–2.74 (m,
1H), 3.62 (d, J = 11.1 Hz, 3H), 3.63 (d, J = 11.1 Hz, 3H), 3.88 (s,

A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
817
3H), 6.24–6.32 (m, 1H), 6.95–7.01 (m, 2H), 7.10–7.18 (m, 3H),
7.44–7.50 (m, 3H), 7.89–7.92 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 32.6 (d, J = 139 Hz), 52.1 (d, J = 6.6 Hz), 52.2 (d, J = 6.6 Hz), 55.7,
70.9, 111.8, 119.3, 119.9, 126.4 (2C), 128.1, 128.3 (2C), 131.6,
133.6, 139.8 (d, J = 9.9 Hz), 159.3, 164.2; MS [HR-EI (M+)] calcd
for C18H21O6P 364.1076 found 364.1090; HPLC chiralcel OJ-H col-
umn (4.6 mmu, 250 mm), n-hexane/ethanol = 5:1, wavelength:
254 nm, flow rate: 0.3 mL/min, retention time: 46.9 min (en-
riched), 50.5 min.
3.63 (d, J = 11.1 Hz, 3H), 6.29–6.37 (m, 1H), 6.94 (t, J = 8.4 Hz,
2H), 7.32–7.51 (m, 6H); 13C NMR (100 MHz, CDCl3) d 32.5 (d,
J = 140 Hz), 52.1 (d, J = 6.6 Hz), 52.3 (d, J = 6.6 Hz), 71.4, 110.5 (t,
J = 17.3 Hz), 111.8 (t, J = 2.5 Hz), 112.0 (t, J = 2.5 Hz), 126.5 (2C),
128.47 (2C), 128.51, 132.9 (t, J = 10.7 Hz), 138.9 (d, J = 9.9 Hz),
160.0, 160.6 (dd, J = 5.8, 256 Hz, 2C); MS [HR-EI (M+)] calcd for
C17H17F2O5P 370.0781 found 370.0780; HPLC chiralcel OD-H col-
umn (4.6 mmu, 250 mm), n-hexane/2-propanol = 10:1, wave-
length: 254 nm, flow rate: 1.0 mL/min, retention time: 16.0 min
(enriched), 20.4 min.
4.4.5. Dimethyl (S)-[2-(2-fluorobenzoyloxy)-2-phenylethyl]phos-
4.4.9. Dimethyl (S)-(2-pentafluorobenzoyloxy-2-phenylethyl)-
phonate 2a(2-FBz)
Colorless oil; ½a D20
ꢂ
¼ ꢀ6:5 (c 0.69, acetone, 80% ee); IR(neat)
1H NMR (300 MHz,
phosphonate 2a(C6F5CO)
Colorless oil; ½a D20
ꢂ
¼ þ3:4 (c 0.96, acetone, 47% ee); IR(neat)
3465, 2955, 1732, 1456, 1262, 1044 cmꢀ1
;
2957, 1742, 1653, 1497, 1221, 1026 cmꢀ1
;
1H NMR (300 MHz,
CDCl3)
d 2.35–2.49 (m, 1H), 2.62–2.76 (m, 1H), 3.62 (d,
CDCl3)
d 2.36–2.48 (m, 1H), 2.57–2.72 (m, 1H), 3.63 (d,
J = 11.1 Hz, 3H), 3.64 (d, J = 11.1 Hz, 3H), 6.29–6.37 (m, 1H), 7.10–
J = 10.8 Hz, 3H), 3.65 (d, J = 10.8 Hz, 3H), 6.31–6.39 (m, 1H), 7.33–
7.48 (m, 5H); 13C NMR (100 MHz, CDCl3) d 32.3 (d, J = 140 Hz),
52.1 (d, J = 6.6 Hz), 52.4 (d, J = 6.6 Hz), 73.3, 107.7 (dt, J = 4.1,
15.6 Hz), 126.6 (2C), 128.6 (2C), 128.8, 136.1–136.4 (m), 138.3 (d,
J = 9.1 Hz), 138.6–138.9 (m), 141.7–142.0 (m), 144.0–144.6 (m),
146.6–146.8 (m), 157.5; MS [HR-FAB (M+H)+] calcd for
C17H15F5O5P 425.0577 found 425.0592; HPLC chiralcel OD-H col-
umn (4.6 mmu, 250 mm), n-hexane/2-propanol = 10:1, wave-
length: 254 nm, flow rate: 1.0 mL/min, retention time: 15.5 min
(enriched), 17.9 min.
7.23 (m, 2H), 7.29–7.41 (m, 3H), 7.46–7.53 (m, 3H), 7.99 (td,
J = 1.5, 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 32.8 (d,
J = 140 Hz), 52.5 (d, J = 6.6 Hz), 52.6 (d, J = 6.6 Hz), 71.8, 117.1 (d,
J = 22.2 Hz), 118.6 (d, J = 9.9 Hz), 124.2 (d, J = 3.3 Hz), 126.7 (2C),
128.7, 128.8 (2C), 132.4, 134.9 (d, J = 9.1 Hz,), 139.7 (d,
J = 10.7 Hz), 162.1 (d, J = 259 Hz), 163.0 (d, J = 4.1 Hz); MS [HR-EI
(M+)] calcd for C17H18FO5P 352.0876 found 352.0872; HPLC chiral-
cel OD-H column (4.6 mmu, 250 mm) ꢁ 2, n-hexane/2-propa-
nol = 5:1, wavelength: 254 nm, flow rate: 1.0 mL/min, retention
time: 19.8 min (enriched), 25.6 min.
4.4.10. Dimethyl (S)-[2-(2-chlorobenzoyloxy)-2-phenylethyl]-
4.4.6. Dimethyl (S)-[2-(3-fluorobenzoyloxy)-2-phenylethyl]-
phosphonate 2a(2-ClBz)
phosphonate 2a(3-FBz)
Colorless solid; Mp 62.0–63.0 °C; ½a D20
ꢂ
¼ þ4:1 (c 1.3, acetone,
1H NMR
Colorless oil; ½a D20
ꢂ
¼ ꢀ7:9 (c 0.70, acetone, 59% ee); IR(neat)
72% ee); IR(neat) 2955, 1733, 1256, 1051, 772 cmꢀ1
;
2955, 1727, 1447, 1272, 1202, 1030 cmꢀ1
;
1H NMR (300 MHz,
(300 MHz, CDCl3) d 2.37–2.50 (m, 1H), 2.63–2.76 (m, 1H), 3.631
(d, J = 11.1 Hz, 3H), 3.634 (d, J = 11.1 Hz, 3H), 6.28–6.36 (m, 1H),
7.31–7.50 (m, 8H), 7.91–7.95 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 32.5 (d, J = 139 Hz), 52.2 (d, J = 6.6 Hz), 52.3 (d, J = 6.6 Hz), 71.9,
126.47, 126.53 (2C), 128.45, 128.50 (2C), 129.5, 130.9, 131.5,
132.5, 133.6, 139.2 (d, J = 9.9 Hz), 163.9; MS [HR-EI (M+)] calcd
for C17H18ClO5P 368.0580 found 368.0590; HPLC chiralcel OD-H
column (4.6 mmu, 250 mm) ꢁ 2, n-hexane/2-propanol = 5:1,
wavelength: 254 nm, flow rate: 1.0 mL/min, retention time:
21.2 min (enriched), 24.7 min.
CDCl3)
d 2.35–2.49 (m, 1H), 2.62–2.77 (m, 1H), 3.63 (d,
J = 11.1 Hz, 3H), 3.65 (d, J = 11.1 Hz, 3H), 6.26–6.35 (m, 1H), 7.22–
7.47 (m, 7H), 7.72–7.78 (m, 1H), 7.86–7.90 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 32.4 (d, J = 140 Hz), 52.1 (d, J = 6.6 Hz) 52.3
(d, J = 6.6 Hz), 71.6 (d, J = 1.7 Hz), 116.3 (d, J = 23.1 Hz), 120.0 (d,
J = 20.6 Hz), 125.3 (d, J = 3.3 Hz), 126.2 (2C), 128.4, 128.5 (2C),
129.9 (d, J = 7.4 Hz), 131.9 (d, J = 7.4 Hz), 139.3 (d, J = 10.7 Hz),
162.3 (d, J = 246 Hz), 163.9 (d, J = 2.5 Hz); MS [HR-EI (M+)] calcd
for C17H18FO5P 352.0876 found 352.0869; HPLC chiralcel OJ-H col-
umn (4.6 mmu, 250 mm), n-hexane/2-propanol = 10:1, wave-
length: 254 nm, flow rate: 1.0 mL/min, retention time: 28.4 min
(enriched), 34.7 min.
4.4.11. Dimethyl (S)-[2-(2-bromobenzoyloxy)-2-phenylethyl]-
phosphonate 2a(2-BrBz)
Colorless oil; ½a D20
ꢂ
¼ ꢀ6:2 (c 1.2, acetone, 61% ee); IR(neat) 2955,
1748, 1293, 1136, 772 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 2.38–
4.4.7. Dimethyl (S)-[2-(4-fluorobenzoyloxy)-2-phenylethyl]phos-
phonate 2a(4-FBz)
2.51 (m, 1H), 2.64–2.78 (m, 1H), 3.63 (d, J = 11.1 Hz, 3H), 3.64 (d,
J = 11.1 Hz, 3H), 6.28–6.36 (m, 1H), 7.29–7.42 (m, 5H), 7.48–7.51
(m, 2H), 7.65 (dd, J = 1.8, 7.8 Hz, 1H), 7.90 (dd, J = 2.1, 7.5 Hz,
1H); 13C NMR (100 MHz, CDCl3) d 32.4 (d, J = 139 Hz), 52.2 (d,
J = 6.6 Hz), 52.4 (d, J = 6.6 Hz), 72.0, 121.6, 126.6 (2C), 127.0,
128.5 (3C), 131.4, 131.5, 132.6, 134.2, 139.0 (d, J = 9.9 Hz), 164.4;
MS [HR-FAB (M+H)+] calcd for C17H1979BrO5P 413.0153 found
413.0155; HPLC chiralcel OD-H column (4.6 mmu, 250 mm) ꢁ 2,
n-hexane/2-propanol = 5:1, wavelength: 254 nm, flow rate:
1.0 mL/min, retention time: 22.4 min (enriched), 25.8 min.
Colorless oil; ½a D20
ꢂ
¼ ꢀ6:6 (c 1.1, acetone, 52% ee); IR(neat)
1H NMR (300 MHz, CDCl3) d
2955, 1725, 1605, 1273, 1034 cmꢀ1
2.35–2.47 (m, 1H), 2.62–2.76 (m, 1H), 3.63 (d, J = 10.8 Hz, 3H),
3.64 (d, J = 10.8 Hz, 3H), 6.25–6.33 (m, 1H), 7.11 (t, J = 9.0 Hz,
2H), 7.30–7.46 (m, 5H), 8.07–8.13 (m, 2H); 13C NMR (100 MHz,
;
CDCl3)
d 32.5 (d, J = 140 Hz), 52.1 (d, J = 6.6 Hz), 52.3 (d,
J = 6.6 Hz), 71.4 (d, J = 1.7 Hz), 115.3 (d, J = 21.4 Hz, 2C), 126.0,
126.2 (2C), 128.4, 128.5 (2C), 132.1 (d, J = 9.1 Hz, 2C), 139.5 (d,
J = 10.7 Hz), 164.0, 165.6 (d, J = 253 Hz); MS [HR-EI (M+)] calcd
for C17H18FO5P 352.0876 found 352.0869; HPLC chiralcel OJ-H
column (4.6 mmu, 250 mm), n-hexane/2-propanol = 10:1, wave-
length: 254 nm, flow rate: 1.0 mL/min, retention time: 33.2 min
(enriched), 43.7 min.
4.4.12. Dimethyl (S)-[2-(1-naphthoyloxy)-2-phenylethyl]phos-
phonate (2a(1-naphthoyl))
Colorless oil; ½a D20
ꢂ
¼ þ28:7 (c 0.40, acetone, 64% ee); IR(neat)
2953, 1717, 1242, 1196, 1132, 1030 cmꢀ1
;
1H NMR (300 MHz,
4.4.8. Dimethyl (S)-[2-(2,6-difluorobenzoyloxy)-2-phenylethyl]-
CDCl3)
d 2.40–2.54 (m, 1H), 2.68–2.82 (m, 1H), 3.646 (d,
phosphonate 2a(2,6-F2Bz)
J = 11.1 Hz, 3H), 3.655 (d, J = 11.1 Hz, 3H), 6.39–6.47 (m, 1H),
7.33–7.42 (m, 3H), 7.49–7.61 (m, 5H), 7.87 (dd, J = 1.8, 7.8 Hz,
1H), 8.03 (d, J = 8.1 Hz, 1H), 8.32 (dd, J = 1.2, 7.2 Hz, 1H), 8.87 (d,
J = 9.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 32.6 (d, J = 139 Hz),
Colorless oil; ½a D20
ꢂ
¼ þ7:1 (c 1.2, acetone, 56% ee); IR(neat) 2957,
1732, 1626, 1472, 1269, 1061 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
2.36–2.49 (m, 1H), 2.60–2.75 (m, 1H), 3.61 (d, J = 11.1 Hz, 3H),

818
A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
52.2 (d, J = 6.6 Hz), 52.3 (d, J = 6.6 Hz), 71.2 (d, J = 1.6 Hz), 124.3,
125.5, 126.0, 126.3 (2C), 126.4, 127.6, 128.29, 128.32, 128.5 (2C),
130.2, 131.2, 133.4, 133.5, 139.7 (d, J = 10.7 Hz), 165.7; MS [HR-EI
(M+)] calcd for C21H21O5P 384.1127 found 384.1108; HPLC chiralcel
OJ-H column (4.6 mmu, 250 mm), n-hexane/2-propanol = 10:1,
wavelength: 254 nm, flow rate: 1.0 mL/min, retention time:
31.9 min (enriched), 38.8 min.
flow rate: 1.0 mL/min, retention time: 42.3 min (enriched),
49.3 min.
4.4.17. Diethyl (R)-(2-hydroxy-2-phenylethyl)phosphonate 1b2b
Colorless oil; ½a D20
ꢂ
¼ ꢀ10:8 (c 1.1, acetone, 41% ee); 1H NMR
(300 MHz, CDCl3) d 1.30 (t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H),
2.17–2.25 (m, 2H), 3.87 (br s, 1H), 4.03–4.21 (m, 4H), 5.07–5.18
(m, 1H), 7.26–7.40 (m, 5H); HPLC chiralcel OD-H column
(4.6 ꢁ 250 mm),
n-hexane/2-propanol = 50:1,
254 nm, flow rate: 1.0 mL/min, retention time: 30.5 min (en-
riched), 35.1 min.
wavelength:
4.4.13. Dimethyl (S)-[2-(2-naphthoyloxy)-2-phenylethyl]phos-
phonate 2a(2-naphthoyl)
Colorless oil; ½a D20
ꢂ
¼ ꢀ37:3 (c 0.51, acetone, 55% ee); IR(neat)
2953, 1717, 1277, 1225, 1196, 1026 cmꢀ1
;
1H NMR (300 MHz,
4.4.18. Diethyl (S)-(2-benzoyloxy-2-phenylethyl)phosphonate
CDCl3)
d 2.41–2.54 (m, 1H), 2.69–2.83 (m, 1H), 3.64 (d,
2b(Bz)
J = 11.1 Hz, 3H), 3.65 (d, J = 11.1 Hz, 3H), 6.34–6.42 (m, 1H), 7.32–
7.42 (m, 3H), 7.50–7.62 (m, 4H), 7.88 (d, J = 8.7 Hz, 2H), 7.97 (d,
J = 7.5 Hz, 1H), 8.09 (dd, J = 1.8, 8.7 Hz, 1H), 8.66 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 32.8 (d, J = 140 Hz), 52.3 (d, J = 6.6 Hz), 52.5
(d, J = 6.6 Hz), 71.5 (d, J = 2.5 Hz), 125.2, 126.4 (2C), 126.6, 127.1,
127.7, 128.1, 128.3, 128.5, 128.7 (2C), 129.3, 131.2, 132.4, 135.5,
139.8 (d, J = 10.7 Hz), 165.3; MS [HR-EI (M+)] calcd for C21H21O5P
384.1127 found 384.1116; HPLC chiralcel OJ-H column
(4.6 mmu, 250 mm), n-hexane/2-propanol = 5:1, wavelength:
254 nm, flow rate: 1.0 mL/min, retention time: 30.6 min (en-
riched), 46.0 min.
Colorless oil; ½a D20
ꢂ
¼ ꢀ7:8 (c 1.0, acetone, 66% ee); IR(neat) 2984,
1H NMR (300 MHz, CDCl3) d
1725, 1275, 1111, 1080, 716 cmꢀ1
;
1.17–1.23 (m, 6H), 2.35–2.48 (m, 1H), 2.62–2.75 (m, 1H), 3.94–
4.07 (m, 4H), 6.28–6.35 (m, 1H), 7.30–7.48 (m, 7H), 7.53–7.58
(m, 1H), 8.07–8.11 (m, 2H); 13C NMR (100 MHz, CDCl3) d 16.4,
16.5, 33.9 (d, J = 140 Hz), 62.1 (d, J = 6.6 Hz), 62.3 (d, J = 6.6 Hz),
71.8, 126.7 (2C), 128.6 (2C), 128.7, 128.9 (2C), 130.0 (2C), 130.3,
133.3, 140.2 (d, J = 10.7 Hz), 165.5; MS [HR-EI (M+)] calcd for
C19H23O5P 362.1283 found 362.1288; HPLC chiralcel OJ-H column
(4.6 mmu, 250 mm), n-hexane/2-propanol = 30:1, wavelength:
254 nm, flow rate: 1.0 mL/min, retention time: 33.1 min (en-
riched), 45.6 min.
4.4.14. Dimethyl (S)-(2-acetoxy-2-phenylethyl)phosphonate
2a(Ac)
4.4.19. Diethyl (S)-[2-(2-fluorobenzoyloxy)-2-phenylethyl]phos-
Colorless oil; ½a D20
¼ þ2:6 (c 1.0, acetone, 16% ee); IR(neat) 2957,
ꢂ
phonate 2b(2-FBz)
1744, 1248, 1049, 820, 544 cmꢀ1; 1H NMR (300 MHz, CDCl3) d 2.08
(s, 3H), 2.22–2.37 (m, 1H), 2.46–2.60 (m, 1H), 3.65 (d, J = 11.1 Hz,
6H), 6.05–6.12 (m, 1H), 7.30–7.40 (m, 5H); 13C NMR (100 MHz,
CDCl3) d 21.0, 32.4 (d, J = 140 Hz), 52.3 (d, J = 6.6 Hz), 52.5 (d,
J = 6.6 Hz), 70.5, 126.5 (2C), 128.4, 128.6 (2C), 139.6 (d,
J = 10.7 Hz), 169.6; MS [HR-EI (M+)] calcd for C12H17O5P 272.0814
found 272.0802; HPLC chiralcel OD-H column (4.6 mmu,
250 mm), n-hexane/2-propanol = 10:1, wavelength: 254 nm, flow
rate: 1.0 mL/min, retention time: 14.8 min (enriched), 17.3 min.
Colorless oil; ½a D20
ꢂ
¼ þ2:0 (c 1.2, acetone, 83% ee); IR(neat) 2986,
1H NMR (300 MHz, CDCl3) d
1728, 1294, 1256, 1030, 758 cmꢀ1
;
1.18–1.23 (m, 6H), 2.35–2.48 (m, 1H), 2.61–2.75 (m, 1H), 3.94–
4.08 (m, 4H), 6.30–6.37 (m, 1H), 7.10–7.23 (m, 2H), 7.28–7.40
(m, 3H), 7.46–7.55 (m, 3H), 8.00 (td, J = 1.8, 7.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 15.96, 16.03, 33.4 (d, J = 140 Hz), 61.5 (d,
J = 6.6 Hz), 61.7 (d, J = 6.6 Hz), 71.7, 116.7 (d, J = 22.2 Hz), 118.3
(d, J = 9.1 Hz), 123.8 (d, J = 4.1 Hz), 126.4 (2C), 128.3, 128.4 (2C),
132.0, 134.5 (d, J = 9.1 Hz), 139.5 (d, J = 10.7 Hz), 161.8 (d,
J = 256 Hz), 162.6; MS [HR-FAB (M+H)+] calcd for C19H23FO5P
381.1267 found 381.1271; HPLC chiralcel OD-H column
(4.6 mmu, 250 mm), n-hexane/2-propanol = 30:1, wavelength:
254 nm, flow rate: 1.0 ml/min, retention time: 20.4 min (enriched),
30.8 min.
4.4.15. Dimethyl (S)-(2-chloroacetoxy-2-phenylethyl)phospho-
nate (S)-2a(ClCH2CO)
Colorless oil; ½a D20
ꢂ
¼ þ4:7 (c 0.93, acetone, 8% ee); IR(neat) 2957,
1761, 1268, 1173, 1046, 820 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
2.25–2.40 (m, 1H), 2.56–2.63 (m, 1H), 3.66 (d, J = 10.8 Hz, 3H),
3.67 (d, J = 10.8 Hz, 3H), 4.08 (d, J = 3.6 Hz, 2H), 6.13–6.21 (m,
1H), 7.30–7.43 (m, 5H); 13C NMR (100 MHz, CDCl3) d 32.2 (d,
J = 140 Hz), 40.9, 52.4 (d, J = 6.6 Hz), 52.6 (d, J = 6.6 Hz), 72.5,
126.6 (2C), 128.7 (2C), 128.9, 138.7 (d, J = 10.7 Hz), 166.0; MS
[HR-EI (M+)] calcd for C12H16ClO5P 306.0424 found 306.0400; HPLC
chiralcel OD-H column (4.6 mmu, 250 mm), n-hexane/2-propa-
nol = 10:1, wavelength: 254 nm, flow rate: 1.0 mL/min, retention
time: 16.0 min (enriched), 18.5 min.
4.4.20. Diisopropyl (R)-(2-hydroxy-2-phenylethyl)phosphonate
1c10
White solid; Mp 69.0–69.5 °C (Et2O); ½a D20
¼ ꢀ10:1 (c 1.4, ace-
ꢂ
tone, 36% ee); 1H NMR (300 MHz, CDCl3) d 1.28–1.38 (m, 12H),
2.12 (d, J = 6.3 Hz, 1H), 2.18 (d, J = 6.3 Hz, 1H), 4.13 (br s, 1H),
4.64–4.82 (m, 2H), 5.03–5.12 (m, 1H), 7.24–7.41 (m, 5H); HPLC chi-
ralcel OD-H column (4.6 mmu, 250 mm) ꢁ 2, n-hexane/2-propa-
nol = 50:1, wavelength: 254 nm, flow rate: 1.0 mL/min, retention
time: 32.7 min (enriched), 36.3 min.
4.4.16. Dimethyl (R)-(2-phenyl-2-
phenylaminocarbonyloxyethyl)phosphonate (R)-2a(PhNHCO
Colorless solid; mp 128–130 °C (AcOEt and n-hexane);
4.4.21. Diisopropyl (S)-(2-benzoyloxy-2-phenylethyl)phospho-
nate 2c(Bz)
½
a 2D0
ꢂ
¼ ꢀ6:7 (c 1.2, acetone, 29% ee); IR(neat) 2955, 1732, 1549,
Colorless oil; ½a D20
ꢂ
¼ ꢀ11:6 (c 1.4, acetone, 66% ee); IR(neat)
1233, 1049, 758 cmꢀ1 1H NMR (300 MHz, CDCl3) d 2.17–2.42 (m,
;
2980, 1725, 1275, 1111, 1017, 712 cmꢀ1 1H NMR (300 MHz,
;
1H), 2.52–2.66 (m, 1H), 3.64 (d, J = 10.8 Hz, 3H), 3.67 (d,
J = 10.8 Hz, 3H), 6.04–6.11 (m, 1H), 6.96 (br s, 1H), 7.04 (t,
J = 7.2 Hz, 1H), 7.25–7.39 (m, 9H); 13C NMR (100 MHz, CDCl3) d
32.6 (d, J = 139 Hz), 52.2 (d, J = 6.6 Hz), 52.5 (d, J = 6.6 Hz), 71.3,
118.5 (2C), 123.1, 126.2 (2C), 128.3, 128.5 (2C), 128.7 (2C), 137.9,
139.7 (d, J = 10.7 Hz), 152.2; MS [HR-EI (M+)] calcd for C17H20NO5P
349.1079 found 349.1065; HPLC chiralcel OD-H column (4.6 mmu,
250 mm) ꢁ 2, n-hexane/2-propanol = 15:1, wavelength: 254 nm,
CDCl3) d 1.18–1.25 (m, 12H), 2.29–2.43 (m, 1H), 2.57–2.71 (m,
1H), 4.60–4.71 (m, 2H), 6.26–6.34 (m, 1H), 7.29–7.47 (m, 7H),
7.53–7.58 (m, 1H), 8.09–8.12 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
23.70 (d, J = 3.3 Hz, 2C), 23.73 (d, J = 3.3 Hz), 23.77 (d,
J = 3.3 Hz), 34.8 (d, J = 141 Hz), 70.4 (d, J = 6.6 Hz), 70.6 (d,
J = 6.6 Hz), 71.6, 126.4 (2C), 128.1 (2C), 128.2, 128.4 (2C), 129.6
(2C), 130.0, 132.9, 140.1 (d, J = 10.7 Hz), 165.1; MS [HR-EI (M+)]
calcd for C21H27O5P 390.1596 found 390.1578; HPLC chiralcel

A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
819
OJ-H column (4.6 mmu, 250 mm), n-hexane/2-propanol = 30:1,
wavelength: 254 nm, flow rate: 0.5 mL/min, retention time:
24.1 min, 30.3 min (enriched).
254 nm, flow rate: 0.5 ml/min, retention time: 31.4 min (enriched),
43.5 min.
4.4.26. Dimethyl (R)-[2-hydroxy-2-(2-methylphenyl)ethyl]-
4.4.22. Diisopropyl (S)-[2-(2-fluorobenzoyloxy)-2-phenylethyl]-
phosphonate 1e
Colorless oil; ½a D20
ꢂ
¼ ꢀ21:0 (c 1.4, acetone, 38% ee); IR(neat)
1H NMR (300 MHz, CDCl3) d
phosphonate 2c(2-FBz)
Colorless oil; ½a D20
ꢂ
¼ þ2:9 (c 1.1, acetone, 77% ee); IR(neat) 2980,
3350, 2955, 1462, 1227, 1075 cmꢀ1
;
1736, 1456, 1264, 1019, 762 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
2.06–2.26 (m, 2H), 2.34 (s, 3H), 3.56 (br s, 1H), 3.76 (d,
J = 11.1 Hz, 3H), 3.80 (d, J = 11.1 Hz, 3H), 5.29–5.38 (m, 1H), 7.11–
7.27 (m, 3H), 7.54 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 18.6, 33.6 (d, J = 136 Hz), 52.1 (d, J = 7.4 Hz), 52.4 (d, J = 7.4 Hz),
64.9 (d, J = 4.1 Hz), 124.8, 126.1, 127.2, 130.1, 133.7, 141.7 (d,
J = 14.8 Hz); MS [HR-EI (M+)] calcd for C11H17O4P 244.0865 found
244.0861; The ee of the dimethyl (R)-[2-hydroxy-2-(2-methyl-
phenyl)ethyl]phosphonate 1e was determined by HPLC of the
corresponding dimethyl (S)-[2-(2-fluorobenzoyloxy)-2-(2-methyl-
phenyl)ethyl]phosphonate 2e.
1.18–1.25 (m, 12H), 2.29–2.43 (m, 1H), 2.56–2.70 (m, 1H), 4.59–
4.70 (m, 2H), 6.29–6.37 (m, 1H), 7.09–7.23 (m, 2H), 7.26–7.39
(m, 3H), 7.46–7.55 (m, 3H), 8.02 (td, J = 1.8, 7.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 23.55 (d, J = 3.3 Hz), 23.59 (d, J = 3.3 Hz),
23.62 (d, J = 3.3 Hz), 23.65 (d, J = 3.3 Hz), 34.7 (d, J = 141 Hz), 70.2
(d, J = 6.6 Hz), 70.3 (d, J = 6.6 Hz), 71.8, 116.6 (d, J = 22.2 Hz),
118.4 (d, J = 9.1 Hz), 123.7 (d, J = 4.1 Hz), 126.4 (2C), 128.1, 128.3
(2C), 132.0, 134.3 (d, J = 9.1 Hz), 139.7 (d, J = 10.7 Hz), 161.7 (d,
J = 259 Hz), 162.6 (d, J = 3.3 Hz); MS [HR-FAB (M+H)+] calcd for
C21H27FO5P 408.1580 found 408.1602; HPLC chiralcel OD-H col-
umn (4.6 mmu, 250 mm), n-hexane/2-propanol = 30:1, wave-
length: 254 nm, flow rate: 0.7 ml/min, retention time: 15.2 min
(enriched), 23.1 min.
4.4.27. Dimethyl (S)-[2-(2-fluorobenzoyloxy)-2-(2-methylphe-
nyl)ethyl]phosphonate 2e
Colorless oil; ½a D20
ꢂ
¼ ꢀ27:0 (c 0.83, acetone, 87% ee); IR(neat)
2955, 1728, 1300, 1262, 1040, 760 cmꢀ1
;
1H NMR (300 MHz,
4.4.23. Dibutyl (R)-(2-hydroxy-2-phenylethyl)phosphonate 1d
CDCl3) d 2.30–2.43 (m, 1H), 2.53 (s, 3H), 2.58–2.72 (m, 1H), 3.63
(d, J = 11.1 Hz, 3H), 3.64 (d, J = 11.1 Hz, 3H), 6.49–6.57 (m, 1H),
7.10–7.26 (m, 5H), 7.43–7.56 (m, 2H), 7.97–8.02 (m, 1H); 13C
NMR (100 MHz, CDCl3) d 18.9, 32.0 (d, J = 139 Hz), 52.2 (d,
J = 6.6 Hz), 52.3 (d, J = 6.6 Hz), 68.4, 116.8 (d, J = 22.2 Hz), 118.2
(d, J = 9.9 Hz), 123.9 (d, J = 3.3 Hz), 125.7, 126.3, 128.1, 130.5,
132.1, 134.5 (d, J = 9.1 Hz), 135.1, 138.1 (d, J = 10.7 Hz), 161.9 (d,
J = 259 Hz), 162.7 (d, J = 3.3 Hz); MS [HR-EI (M+)] calcd for
C18H20FO5P 366.1033 found 366.1021; HPLC chiralcel OJ-H column
(4.6 mmu, 250 mm), n-hexane/2-propanol = 5:1, wavelength:
254 nm, flow rate: 1.0 mL/min, retention time: 14.4 min (en-
riched), 18.3 min.
Colorless oil; ½a D20
ꢂ
¼ ꢀ11:7 (c 1.2, acetone, 20% ee); IR(neat)
3360, 2961, 1240, 1221, 1026 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
0.90–0.98 (m, 6H), 1.31–1.47 (m, 4H), 1.55–1.72 (m, 4H), 2.17–
2.25 (m, 2H), 3.92 (br s, 1H), 3.98–4.17 (m, 4H), 5.07–5.16 (m,
1H), 7.26–7.41 (m, 5H); 13C NMR (100 MHz, CDCl3) d 13.2 (2C),
18.3 (2C), 32.00, 32.05, 35.5 (d, J = 136 Hz), 65.0, 65.3, 68.3, 125.3
(2C), 127.1, 127.9 (2C), 143.7; MS [HR-EI (M+)] calcd for
C16H27O4P 314.1647 found 314.1651; HPLC chiralcel OD-H column
(4.6 mmu, 250 mm) ꢁ 2, n-hexane/2-propanol = 50:1, wavelength:
254 nm, flow rate: 1.0 mL/min, retention time: 39.6 min (en-
riched), 42.1 min.
4.4.24. Dibutyl (S)-(2-benzoyloxy-2-phenylethyl)phosphonate
4.4.28. Dimethyl (R)-[2-hydroxy-2-(3-methylphenyl)ethyl]-
2d(Bz)
Colorless oil; ½a D20
ꢂ
¼ ꢀ7:8 (c 1.1, acetone, 56% ee); IR(neat) 2961,
1H NMR (300 MHz, CDCl3) d
phosphonate 1f
Colorless oil; ½a D20
ꢂ
¼ ꢀ11:3 (c 1.2, acetone, 31% ee); IR(neat)
1H NMR (300 MHz, CDCl3) d
1725, 1273, 1109, 1026, 716 cmꢀ1
;
3370, 2956, 1489, 1248, 1082 cmꢀ1
;
0.82–0.88 (m, 6H), 1.23–1.35 (m, 4H), 1.46–1.57 (m, 4H), 2.36–
2.49 (m, 1H), 2.62–2.76 (m, 1H), 3.86–4.00 (m, 4H), 6.27–6.34
(m, 1H), 7.30–7.47 (m, 7H), 7.53–7.60 (m, 1H), 8.07–8.10 (m,
2H); 13C NMR (100 MHz, CDCl3) d 13.4 (2C), 18.5 (2C), 32.27,
32.33, 33.4 (d, J = 140 Hz), 65.5 (d, J = 6.6 Hz), 65.7 (d, J = 6.6 Hz),
71.5, 126.4 (2C), 128.2 (2C), 128.3, 128.5 (2C), 129.6 (2C), 129.8,
133.0, 139.9 (d, J = 9.9 Hz), 165.1; MS [HR-EI (M+)] calcd for
C23H31O5P 418.1910 found 418.1902; HPLC chiralcel OJ-H column
(4.6 mmu, 250 mm), n-hexane/ethanol = 30:1, wavelength:
254 nm, flow rate: 0.3 mL/min, retention time: 24.1 min (en-
riched), 27.5 min.
2.10–2.34 (m, 2H), 2.36 (s, 3H), 3.62 (br s, 1H), 3.74 (d,
J = 11.1 Hz, 3H), 3.78 (d, J = 11.1 Hz, 3H), 5.03–5.14 (m, 1H), 7.07–
7.28 (m, 4H); 13C NMR (100 MHz, CDCl3)
d 21.1, 34.8 (d,
J = 136 Hz), 52.0 (d, J = 6.6 Hz), 52.3 (d, J = 6.6 Hz), 68.3 (d,
J = 4.1 Hz), 122.3, 125.9, 128.1 (2C), 137.8, 143.7 (d, J = 15.6 Hz);
MS [HR-EI (M+)] calcd for C11H17O4P 244.0865 found 244.0859;
HPLC chiralcel OD-H column (4.6 mmu, 250 mm) ꢁ 2, n-hexane/
2-propanol = 10:1, wavelength: 254 nm, flow rate: 1.0 mL/min,
retention time: 23.1 min (enriched), 25.4 min.
4.4.29. Dimethyl (S)-[2-(2-fluorobenzoyloxy)-2-(3-methylphe-
nyl)ethyl]phosphonate 2f
4.4.25. Dibutyl (S)-[2-(2-fluorobenzoyloxy)-2-phenylethyl]-
Colorless oil; ½a D20
ꢂ
¼ þ9:2 (c 1.4, acetone, 83% ee); IR(neat) 2955,
phosphonate 2d(2-FBz)
Colorless oil; ½a D20
ꢂ
¼ ꢀ2:7 (c 1.1, acetone, 82% ee); IR(neat) 2960,
1732, 1615, 1456, 1264, 1048 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
1732, 1458, 1260, 1034, 760 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
2.33–2.46 (m, 1H), 2.36 (s, 3H), 2.61–2.75 (m, 1H), 3.63 (d,
J = 11.1 Hz, 3H), 3.65 (d, J = 11.1 Hz, 3H), 6.26–6.33 (m, 1H), 7.09–
7.30 (m, 6H), 7.47–7.55 (m, 1H), 7.97–8.02 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 21.2, 32.6 (d, J = 140 Hz), 52.1 (d, J = 6.6 Hz),
52.3 (d, J = 6.6 Hz), 71.5 (d, J = 2.5 Hz), 116.7 (d, J = 22.2 Hz), 118.3
(d, J = 9.9 Hz), 123.3, 123.8 (d, J = 4.1 Hz), 127.0, 128.4, 129.1,
132.1, 134.5 (d, J = 9.1 Hz), 138.1, 139.4 (d, J = 11.5 Hz), 161.8 (d,
J = 259 Hz), 162.7 (d, J = 4.1 Hz); MS [HR-EI (M+)] calcd for
C18H20FO5P 366.1032 found 366.1023; HPLC chiralcel OJ-H column
(4.6 mmu, 250 mm), n-hexane/2-propanol = 10:1, wavelength:
254 nm, flow rate: 1.0 mL/min, retention time: 24.4 min (en-
riched), 31.1 min.
0.83–0.89 (m, 6H), 1.23–1.36 (m, 4H), 1.46–1.57 (m, 4H), 2.35–
2.48 (m, 1H), 2.61–2.75 (m, 1H), 3.87–3.99 (m, 4H), 6.29–6.36
(m, 1H), 7.09–7.22 (m, 2H), 7.27–7.39 (m, 3H), 7.45–7.55 (m,
3H), 7.97–8.02 (m, 1H); 13C NMR (100 MHz, CDCl3) d 13.4 (2C),
18.5 (2C), 32.18, 32.25, 33.3 (d, J = 139 Hz), 65.3 (d, J = 6.6 Hz),
65.5 (d, J = 6.6 Hz), 71.8, 116.8 (d, J = 22.2 Hz), 118.4 (d,
J = 9.1 Hz), 123.8 (d, J = 4.1 Hz), 126.5 (2C), 128.3, 128.5 (2C),
132.1, 134.5 (d, J = 9.1 Hz), 139.6 (d, J = 9.9 Hz), 161.9 (d,
J = 256 Hz), 162.68; MS [HR-FAB (M+H)+] calcd for C23H31FO5P
437.1894 found 437.1941; HPLC chiralcel OJ-H column
(4.6 mmu, 250 mm), n-hexane/ethanol = 60:1, wavelength:

820
A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
4.4.30. Dimethyl (R)-[2-hydroxy-2-(4-methylphenyl)ethyl]phos-
4.4.34. Dimethyl (R)-[2-hydroxy-2-(4-methoxyphenyl)ethyl]ph-
phonate 1g
osphonate 1i
White solid; mp 57.0–57.5 °C (Et2O); ½a D20
ꢂ
¼ ꢀ12:5 (c 1.3, ace-
1H
Colorless oil; ½a D20
ꢂ
¼ ꢀ7:1 (c 3.8, acetone, 29% ee); IR(neat) 3350,
tone, 38% ee); IR(neat) 3380, 2955, 1242, 1051, 830 cmꢀ1
;
2955, 1514, 1254, 1048, 837 cmꢀ1 1H NMR (300 MHz, CDCl3) d
;
NMR (300 MHz, CDCl3) d 2.10–2.29 (m, 2H), 2.34 (s, 3H), 3.56 (br
s, 1H), 3.73 (d, J = 11.1 Hz, 3H), 3.75 (d, J = 11.1 Hz, 3H), 5.05–
5.14 (m, 1H), 7.16 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 9.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) d 21.9, 34.9 (d, J = 135 Hz), 52.2 (d,
J = 6.6 Hz), 52.4 (d, J = 135 Hz), 68.4 (d, J = 4.1 Hz), 125.3 (2C),
129.0 (2C), 137.2, 140.7 (d, J = 15.6 Hz); MS [HR-EI (M+)] calcd for
C11H17O4P 244.0864 found 244.0869; The ee of the dimethyl (R)-
[2-hydroxy-2-(4-methylphenyl)ethyl]phosphonate 1g was deter-
mined by HPLC of the corresponding dimethyl (S)-[2-(2-fluor-
obenzoyloxy)-2-(4-methylphenyl)ethyl]phosphonate 2g.
2.04–2.34 (m, 2H), 3.53 (br s, 1H), 3.74 (d, J = 10.8 Hz, 3H), 3.77
(d, J = 10.8 Hz, 3H), 3.81 (s, 3H), 5.02–5.13 (m, 1H), 6.89 (d,
J = 8.7 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 34.7 (d, J = 136 Hz), 51.9 (d, J = 5.8 Hz), 52.2 (d, J = 5.8 Hz), 54.8,
67.9, 113.4 (2C), 126.5 (2C), 135.9 (d, J = 14.0 Hz), 158.7; MS [HR-
EI (M+)] calcd for C11H17O5P 260.0814 found 260.0800; HPLC chi-
ralcel AY-H column (4.6 mmu, 250 mm), n-hexane/2-propa-
nol = 5:1, wavelength: 254 nm, flow rate: 1.0 mL/min, retention
time: 33.2 min (enriched), 41.4 min.
4.4.35. Dimethyl (S)-[2-(2-fluorobenzoyloxy)-2-(4-methoxyphe-
nyl)ethyl]phosphonate 2i
4.4.31. Dimethyl (S)-[2-(2-fluorobenzoyloxy)-2-(4-methylphe-
Colorless oil; ½a D20
ꢂ
¼ þ1:7 (c 1.4, acetone, 84% ee); IR(neat) 2955,
nyl)ethyl]phosphonate 2g
1728, 1613, 1516, 1248, 1030 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
Colorless oil; ½a D20
ꢂ
¼ þ2:8 (c 1.3, acetone, 75% ee); IR(neat) 2955,
2.34–2.48 (m, 1H), 2.66–2.76 (m, 1H), 3.62 (d, J = 11.1 Hz, 3H),
3.64 (d, J = 11.1 Hz, 3H), 3.80 (s, 3H), 6.25–6.33 (m, 1H), 6.90 (d,
J = 9.0 Hz, 2H), 7.09–7.22 (m, 2H), 7.42 (d, J = 9.0 Hz, 2H), 7.47–
7.54 (m, 1H), 7.94–8.00 (m, 1H); 13C NMR (100 MHz, CDCl3) d
32.3 (d, J = 139 Hz), 52.1 (d, J = 6.6 Hz), 52.2 (d, J = 6.6 Hz), 55.0,
71.2, 113.7 (2C), 116.7 (d, J = 22.2 Hz), 118.3 (d, J = 9.9 Hz), 123.7
(d, J = 4.1 Hz), 127.9 (2C), 131.4 (d, J = 9.9 Hz), 131.9, 134.4 (d,
J = 9.1 Hz), 159.5, 161.7 (d, J = 259 Hz), 162.7 (d, J = 3.3 Hz); MS
[HR-EI (M+)] calcd for C18H20FO6P 382.0982 found 382.0995; HPLC
chiralcel OD-H column (4.6 mmu, 250 mm) ꢁ 2, n-hexane/2-pro-
panol = 5:1, wavelength: 254 nm, flow rate: 1.0 mL/min, retention
time: 28.4 min (enriched), 35.0 min.
1738, 1615, 1456, 1266, 1084 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
2.31–2.48 (m, 1H), 2.34 (s, 3H), 2.62–2.76 (m, 1H), 3.63 (d,
J = 11.1 Hz, 3H), 3.65 (d, J = 11.1 Hz, 3H), 6.26–6.34 (m, 1H), 7.09–
7.22 (m, 4H), 7.37 (d, J = 8.1 Hz, 2H), 7.47–7.55 (m, 1H), 7.95–8.01
(m, 1H); 13C NMR (100 MHz, CDCl3) d 21.0, 32.4 (d, J = 139 Hz),
52.1 (d, J = 6.6 Hz), 52.3 (d, J = 6.6 Hz), 71.4, 116.7 (d, J = 22.2 Hz),
118.3 (d, J = 9.1 Hz), 123.8 (d, J = 4.1 Hz), 126.4 (2C), 129.1 (2C),
132.0, 134.4 (d, J = 9.1 Hz), 136.5 (d, J = 9.9 Hz), 138.2, 161.8 (d,
J = 259 Hz), 162.7 (d, J = 4.1 Hz); MS [HR-EI (M+)] calcd for
C18H20FO5P 366.1033 found 366.1021; HPLC chiralcel OD-H column
(4.6 mmu, 250 mm) ꢁ 2, n-hexane/2-propanol = 5:1, wavelength:
254 nm, flow rate: 1.0 mL/min, retention time: 17.9 min (enriched),
21.0 min.
4.4.36. Dimethyl (R)-[2-hydroxy-2-(4-nitrophenyl)ethyl]phos-
phonate 1j11
Pale yellow solid; mp 115–116 °C (Et2O); ½a D20
¼ ꢀ7:6 (c 1.0,
ꢂ
4.4.32. Dimethyl (R)-[2-hydroxy-2-(2-methoxyphenyl)ethyl]-
acetone, 29% ee); 1H NMR (300 MHz, CDCl3) d 2.16–2.24 (m, 2H),
3.75 (d, J = 10.8 Hz, 3H), 3.81 (d, J = 10.8 Hz, 3H), 4.29 (br s, 1H),
5.18–5.26 (m, 1H), 7.58 (d, J = 8.4 Hz, 2H), 8.22 (d, J = 8.7 Hz, 2H);
The ee of the dimethyl (R)-[2-hydroxy-2-(4-nitrophenyl)ethyl]-
phosphonate 1j was determined by HPLC of the corresponding
dimethyl (S)-[2-(2-fluorobenzoyloxy)-2-(4-nitrophenyl)ethyl]phos-
phonate 2j.
phosphonate 1h
White solid; mp 77.5–78.0 °C (Et2O); ½a D20
ꢂ
¼ ꢀ20:4 (c 3.5, ace-
1H
tone, 38% ee); IR(neat) 3380, 2957, 1491, 1250, 1078 cmꢀ1
;
NMR (300 MHz, CDCl3) d 2.16–2.43 (m, 2H), 3.70 (d, J = 11.1 Hz,
3H), 3.75 (br s, 1H), 3.78 (d, J = 11.1 Hz, 3H), 3.85 (s, 3H), 5.26–5.37
(m, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 7.24–7.29
(m, 1H), 7.49 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 32.6
(d, J = 134 Hz), 51.9 (d, J = 6.6 Hz), 52.1 (d, J = 6.6 Hz), 54.9, 64.0 (d,
J = 4.9 Hz), 109.8, 120.4, 125.9, 128.1, 131.5 (d, J = 14.8 Hz), 155.3;
MS [HR-EI (M+)] calcd for C11H17O5P 260.0814 found 260.0795;
HPLC chiralcel OJ-H column (4.6 mmu, 250 mm), n-hexane/2-pro-
panol = 10:1, wavelength: 254 nm, flow rate: 1.0 mL/min, retention
time: 12.4 min, 14.5 min (enriched).
4.4.37. Dimethyl (S)-[2-(2-fluorobenzoyloxy)-2-(4-nitrophenyl)-
ethyl]phosphonate 2j
Pale yellow oil; ½a D20
ꢂ
¼ ꢀ2:3 (c 1.3, acetone, 57% ee); IR(neat)
1H NMR (300 MHz,
2957, 1738, 1615, 1219, 1123, 772 cmꢀ1
;
CDCl3)
d 2.34–2.49 (m, 1H), 2.61–2.74 (m, 1H), 3.67 (d,
J = 11.1 Hz, 3H), 3.69 (d, J = 11.1 Hz, 3H), 6.34–6.32 (m, 1H), 7.13–
7.24 (m, 2H), 7.52–7.60 (m, 1H), 7.67 (d, J = 9.3 Hz, 2H), 7.96–
8.02 (m, 1H), 8.25 (d, J = 9.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 32.4 (d, J = 141 Hz), 52.4 (d, J = 5.8 Hz), 52.5 (d, J = 5.8 Hz), 70.7,
117.0 (d, J = 22.2 Hz), 117.7 (d, J = 9.1 Hz), 123.8 (2C), 124.1 (d,
J = 4.1 Hz), 127.4 (2C), 132.2, 135.1 (d, J = 9.1 Hz), 146.5 (d,
J = 9.9 Hz), 147.7, 161.9 (d, J = 259 Hz), 162.8 (d, J = 3.3 Hz); MS
[HR-EI (M+)] calcd for C17H17FNO7P 397.0726 found 397.0735;
HPLC chiralcel AS column (4.6 mmu, 250 mm) ꢁ 2, n-hexane/2-
propanol = 1:1, wavelength: 254 nm, flow rate: 1.0 mL/min, reten-
tion time: 34.9 min (enriched), 42.1 min.
4.4.33. Dimethyl (S)-[2-(2-fluorobenzoyloxy)-2-(2-methoxy-
phenyl)ethyl]phosphonate 2h
Colorless oil; ½a D20
ꢂ
¼ ꢀ17:4 (c 1.4, acetone, 74% ee); IR(neat)
2955, 1732, 1493, 1291, 1246, 1026 cmꢀ1
;
1H NMR (300 MHz,
CDCl3) d 2.54 (dd, J = 6.6, 16.2 Hz, 2H), 3.66 (d, J = 10.8 Hz, 3H),
3.68 (d, J = 10.8 Hz, 3H), 3.89 (s, 3H), 6.61–6.70 (m, 1H), 6.89–
6.98 (m, 2H), 7.11–7.29 (m, 3H), 7.41–7.45 (m, 1H), 7.48–7.57
(m, 1H), 8.03–8.09 (m, 1H); 13C NMR (100 MHz, CDCl3) d 30.6 (d,
J = 138 Hz), 52.0 (d, J = 5.8 Hz), 52.1 (d, J = 5.8 Hz), 55.2, 66.7 (d,
J = 4.1 Hz), 110.4, 116.6 (d, J = 22.2 Hz), 118.3 (d, J = 9.1 Hz),
120.4, 123.7 (d, J = 3.3 Hz), 126.0, 127.9 (d, J = 12.4 Hz), 129.0,
132.0, 134.3 (d, J = 8.2 Hz), 155.6, 161.7 (d, J = 259 Hz), 162.4 (d,
J = 3.3 Hz); MS [HR-EI (M+)] calcd for C18H20FO6P 382.0982 found
382.0995; HPLC chiralcel OD-H column (4.6 mmu, 250 mm), n-
hexane/2-propanol = 10:1, wavelength: 254 nm, flow rate:
1.0 mL/min, retention time: 21.9 min (enriched), 38.2 min.
4.4.38. Dimethyl (R)-[2-hydroxy-2-(4-fluorophenyl)ethyl]-
phosphonate 1k
Colorless oil; ½a D20
ꢂ
¼ ꢀ12:3 (c 1.0, acetone, 41% ee); IR(neat)
1H NMR (300 MHz,
3360, 2957, 1514, 1258, 1076, 845 cmꢀ1
;
CDCl3) d 2.09–2.30 (m, 2H), 3.71 (br s, 1H), 3.74 (d, J = 10.8 Hz,
3H), 3.78 (d, J = 10.8 Hz, 3H), 5.05–5.16 (m, 1H), 7.01–7.07 (m,

A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
821
2H), 7.34–7.19 (m, 2H); 13C NMR (100 MHz, CDCl3) d 34.8 (d,
J = 137 Hz), 51.9 (d, J = 6.6 Hz), 52.2 (d, J = 6.6 Hz), 67.7, 114.8 (d,
J = 21.4 Hz, 2C), 127.0 (d, J = 8.2 Hz, 2C), 139.7 (d, J = 14.0 Hz),
161.8 (d, J = 245 Hz); MS [HR-EI (M+)] calcd for C10H14FO4P
248.0614 found 248.0592; HPLC chiralcel AY-H column
(4.6 mmu, 250 mm), n-hexane/2-propanol = 20:1, wavelength:
254 nm, flow rate: 1.0 mL/min, retention time: 38.1 min (en-
riched), 41.5 min.
C
10H1479BrO4P 307.9814 found 307.9789; HPLC chiralcel AY-H col-
umn (4.6 mmu, 250 mm), n-hexane/2-propanol = 10:1, wave-
length: 254 nm, flow rate: 1.0 mL/min, retention time: 23.4 min
(enriched), 33.8 min.
4.4.43. Dimethyl (S)-[2-(4-bromophenyl)-2-(2-fluorobenzoyl-
oxy)ethyl]phosphonate 2m
Colorless oil; ½a D20
ꢂ
¼ ꢀ9:6 (c 1.3, acetone, 60% ee); IR(neat) 2955,
1732, 1489, 1258, 1036, 758 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
4.4.39. Dimethyl (S)-[2-(2-fluorobenzoyloxy)-2-(4-fluorophenyl)-
2.30–2.45 (m, 1H), 2.59–2.72 (m, 1H), 3.64 (d, J = 10.8 Hz, 3H),
3.66 (d, J = 10.8 Hz, 3H), 6.23–6.31 (m, 1H), 7.10–7.23 (m, 2H),
7.36 (d, J = 8.7 Hz, 2H), 7.49–7.57 (m, 3H), 7.94–8.00 (m, 1H); 13C
NMR (100 MHz, CDCl3) d 32.3 (d, J = 140 Hz), 52.2 (d, J = 6.6 Hz),
52.3 (d, J = 6.6 Hz), 70.9, 116.8 (d, J = 22.2 Hz), 117.9 (d,
J = 9.9 Hz), 122.29, 123.9 (d, J = 4.1 Hz), 128.1 (2C), 131.6 (2C),
132.0, 134.7 (d, J = 9.1 Hz), 138.4 (d, J = 9.9 Hz), 161.7 (d,
J = 259 Hz), 162.6 (d, J = 3.3 Hz); MS [HR-FAB (M+H)+] calcd for
C17H1879BrFO5P 431.0059 found 431.0085; HPLC chiralcel OD-H
column (4.6 mmu, 250 mm) ꢁ 2, n-hexane/2-propanol = 5:1,
wavelength: 254 nm, flow rate: 1.0 mL/min, retention time:
22.5 min (enriched), 26.2 min.
ethyl]phosphonate 2k
Colorless oil; ½a D20
ꢂ
¼ þ2:1 (c 2.4, acetone, 72% ee); IR(neat) 2957,
1732, 1615, 1514, 1264, 1080 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
2.32–2.47 (m, 1H), 2.61–2.74 (m, 1H), 3.63 (d, J = 10.8 Hz, 3H),
3.65 (d, J = 10.8 Hz, 3H), 6.27–6.34 (m, 1H), 7.04–7.23 (m, 4H),
7.43–7.56 (m, 3H), 7.94–8.00 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 32.4 (d, J = 140 Hz), 52.2 (d, J = 6.6 Hz), 52.3 (d, J = 6.6 Hz), 71.0,
115.4 (d, J = 21.4 Hz, 2C), 116.8 (d, J = 22.2 Hz), 118.1 (d,
J = 9.1 Hz), 123.9 (d, J = 4.1 Hz), 128.4 (d, J = 8.2 Hz, 2C), 132.1,
134.7 (d, J = 8.2 Hz), 135.3 (dd, J = 3.3, 9.9 Hz), 161.8 (d,
J = 259 Hz), 162.5 (d, J = 246 Hz), 162.8; MS [HR-EI (M+)] calcd for
C17H17F2O5P 370.0782 found 370.0756; HPLC chiralcel OD-H col-
umn (4.6 mmu, 250 mm) ꢁ 2, n-hexane/2-propanol = 5:1, wave-
length: 254 nm, flow rate: 1.0 mL/min, retention time: 21.5 min
(enriched), 24.2 min.
4.4.44. Dimethyl (R)-[2-hydroxy-2-(1-naphthyl)ethyl]phospho-
nate 1n
Colorless oil; ½a D20
ꢂ
¼ ꢀ27:6 (c 2.6, acetone, 43% ee); IR(neat)
1H NMR (300 MHz, CDCl3) d
3350, 2955, 1231, 1044, 781 cmꢀ1
;
4.4.40. Dimethyl (R)-[2-hydroxy-2-(4-chlorophenyl)ethyl]-
2.24–2.48 (m, 2H), 3.77 (d, J = 10.8 Hz, 3H), 3.84 (d, J = 10.8 Hz,
3H), 3.89 (br s, 1H), 5.86–5.94 (m, 1H), 7.47–7.57 (m, 3H), 7.78
(t, J = 8.7 Hz, 2H), 7.86–7.90 (m, 1H), 8.01 (d, J = 8.1 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 33.9 (d, J = 136 Hz), 51.7 (d, J = 6.6 Hz),
52.3 (d, J = 6.6 Hz), 65.1 (d, J = 4.9 Hz), 122.4 (2C), 125.07, 125.10,
125.8, 127.5, 128.5, 129.3, 133.3, 139.5 (d, J = 15.6 Hz); MS [HR-EI
(M+)] calcd for C14H17O4P 280.0865 found 280.0857; HPLC chiralcel
OJ-H column (4.6 mmu, 250 mm), n-hexane/2-propanol = 20:1,
wavelength: 254 nm, flow rate: 1.0 mL/min, retention time:
20.9 min, 23.4 min (enriched).
phosphonate 1l
White solid; mp 60.5–61.0 °C (Et2O and n-hexane); ½a D20
¼ ꢀ9:2
ꢂ
(c 1.8, acetone, 37% ee); IR(neat) 3350, 2955, 1242, 1051, 835,
546 cmꢀ1 1H NMR (300 MHz, CDCl3) d 2.10–2.26 (m, 2H), 3.73
;
(d, J = 11.1 Hz, 3H), 3.78 (d, J = 11.1 Hz, 3H), 3.82 (s, 1H), 5.05–
5.14 (m, 1H), 7.30–7.36 (m, 4H); 13C NMR (100 MHz, CDCl3) d 34.5
(d, J = 137 Hz), 51.7 (d, J = 5.8 Hz), 52.1 (d, J = 5.8 Hz), 67.5 (d,
J = 3.3 Hz), 126.7 (2C), 128.0 (2C), 132.6, 142.5 (d, J = 14.8 Hz); MS
[HR-EI (M+)] calcd for C10H14 ClO4P 264.0319 found 264.0303; HPLC
chiralcel AY-H column (4.6 mmu, 250 mm), n-hexane/2-propa-
nol = 10:1, wavelength: 254 nm, flow rate: 1.0 mL/min, retention
time: 22.6 min (enriched), 29.4 min.
4.4.45. Dimethyl (S)-[2-(2-fluorobenzoyloxy)-2-(1-naphthyl)-
ethyl]phosphonate 2n
Colorless oil; ½a D20
ꢂ
¼ ꢀ60:0 (c 2.2, acetone, 79% ee); IR(neat)
4.4.41. Dimethyl (S)-[2-(4-chlorophenyl)-2-(2-fluorobenzoyl-
2955, 1732, 1298, 1260, 1038, 758 cmꢀ1 1H NMR (300 MHz,
;
oxy)ethyl]phosphonate 2l
CDCl3) d 2.54–2.67 (m, 1H), 2.73–2.86 (m, 1H), 3.65 (d,
Colorless oil; ½a D20
ꢂ
¼ ꢀ9:0 (c 1.2, acetone, 66% ee); IR(neat) 2955,
J = 11.1 Hz, 3H), 3.67 (d, J = 11.1 Hz, 3H), 7.05–7.28 (m, 3H), 7.44–
7.63 (m, 4H), 7.69 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.88
(d, J = 8.1 Hz, 1H), 8.05 (dt, J = 1.8, 7.5 Hz, 1H), 8.26 (d, J = 8.4 Hz,
1H); 13C NMR (100 MHz, CDCl3) d 32.2 (d, J = 139 Hz), 52.3 (d,
J = 6.6 Hz), 52.4 (d, J = 6.6 Hz), 69.1, 116.9 (d, J = 22.2 Hz), 118.2
(d, J = 9.9 Hz), 122.9, 123.9, 124.0, 125.2, 125.8, 126.6, 128.91,
128.94, 129.6, 132.2, 133.8, 134.6 (d, J = 9.1 Hz), 135.5 (d,
J = 12.3 Hz), 161.9 (d, J = 259 Hz), 162.8 (d, J = 4.1 Hz); MS [HR-
FAB (M+H)+] calcd for C21H21FO5P 403.1110 found 403.1112; HPLC
chiralcel OD-H column (4.6 mmu, 250 mm), n-hexane/2-propa-
nol = 5:1, wavelength: 254 nm, flow rate: 1.0 mL/min, retention
time: 12.2 min (enriched), 20.0 min.
1732, 1294, 1260, 1040, 758 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
2.31–2.46 (m, 1H), 2.59–2.72 (m, 1H), 3.64 (d, J = 10.8 Hz, 3H),
3.66 (d, J = 10.8 Hz, 3H), 6.25–6.32 (m, 1H), 7.10–7.24 (m, 2H),
7.35 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.49–7.57 (m, 1H),
7.94–8.00 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 32.3 (d,
J = 140 Hz), 52.2 (d, J = 5.8 Hz), 52.3 (d, J = 5.8 Hz), 70.9, 116.8 (d,
J = 22.2 Hz), 118.0 (d, J = 9.9 Hz), 123.9 (d, J = 4.1 Hz), 127.9 (2C),
128.6 (2C), 132.0, 134.1, 134.6 (d, J = 9.1 Hz), 137.9 (d, J = 9.9 Hz),
161.8 (d, J = 259 Hz), 162.6 (d, J = 4.1 Hz); MS [HR-EI (M+)] calcd for
C17H17ClFO5P 386.0486 found 386.0500; HPLC chiralcel OD-H col-
umn (4.6 mmu, 250 mm) ꢁ 2, n-hexane/2-propanol = 5:1, wave-
length: 254 nm, flow rate: 1.0 mL/min, retention time: 21.2 min
(enriched), 24.4 min.
4.4.46. Dimethyl (R)-[2-hydroxy-2-(2-naphthyl)ethyl]phospho-
nate 1o
4.4.42. Dimethyl (R)-[2-hydroxy-2-(4-bromophenyl)ethyl]-
White solid; mp 57.0–57.5 °C (Et2O); ½a D20
ꢂ
¼ ꢀ14:3 (c 1.0, ace-
phosphonate 1m
tone, 47% ee); IR(neat) 3330, 2955, 1223, 1049, 857 cmꢀ1 1H
;
White solid; mp 91.0–92.0 °C (Et2O); ½a D20
ꢂ
¼ ꢀ11:5 (c 0.68, ace-
1H
NMR (300 MHz, CDCl3) d 2.21–2.41 (m, 2H), 3.73 (d, J = 10.8 Hz,
3H), 3.80 (d, J = 10.8 Hz, 3H), 3.82 (br s, 1H), 5.24–5.35 (m, 1H),
7.45–7.53 (m, 3H), 7.81–7.88 (m, 4H); 13C NMR (100 MHz, CDCl3)
d 34.9 (d, J = 136 Hz), 52.2 (d, J = 6.6 Hz), 52.6 (d, J = 6.6 Hz), 68.7
(d, J = 4.1 Hz), 123.5, 124.1, 125.8, 126.1, 127.5, 127.9, 128.2,
132.8, 133.1, 141.0 (d, J = 15.6 Hz); MS [HR-EI (M+)] calcd for
C14H17O4P 280.0865 found 280.0857; HPLC chiralcel OD-H column
tone, 49% ee); IR(neat) 3365, 2955, 1242, 1069, 828, 544 cmꢀ1
;
NMR (300 MHz, CDCl3) d 2.06–2.25 (m, 2H), 3.70–3.80 (m, 6H),
3.98 (br s, 1H), 5.01–5.13 (m, 1H), 7.25–7.29 (m, 2H), 7.44–7.51
(m, 2H); 13C NMR (100 MHz, CDCl3) d 34.7 (d, J = 137 Hz), 52.1
(d, J = 6.6 Hz), 52.4 (d, J = 6.6 Hz), 67.8 (d, J = 4.1 Hz), 121.1, 127.1
(2C), 131.3 (2C), 142.9 (d, J = 14.8 Hz); MS [HR-EI (M+)] calcd for

822
A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
(4.6 mmu, 250 mm), n-hexane/2-propanol = 5:1, wavelength:
254 nm, flow rate: 1.0 mL/min, retention time: 11.3 min,
16.2 min (enriched).
7.50–7.57 (m, 1H), 7.98–8.03 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 30.8 (d, J = 139 Hz), 52.3 (d, J = 6.6 Hz), 52.5 (d, J = 6.6 Hz), 70.4,
116.9 (d, J = 22.2 Hz), 118.5 (d, J = 9.9 Hz), 123.9 (d, J = 4.1 Hz),
126.1 (d, J = 9.1 Hz), 126.7 (2C), 128.1, 128.5 (2C), 132.1, 133.5,
134.6 (d, J = 9.1 Hz), 135.7, 161.9 (d, J = 259 Hz), 162.9 (d,
J = 4.1 Hz); MS [HR-EI (M+)] calcd for C19H20FO5P 378.1032 found
378.1028; HPLC chiralcel OJ-H column (4.6 mmu, 250 mm), n-hex-
ane/2-propanol = 10:1, wavelength: 254 nm, flow rate: 1.0 mL/
min, retention time: 42.0 min (enriched), 52.6 min.
4.4.47. Dimethyl (S)-[2-(2-fluorobenzoyloxy)-2-(2-naphthyl)-
ethyl]phosphonate 2o
Colorless oil; ½a D20
¼ ꢀ24:6 (c 1.2, acetone, 72% ee); IR(neat) 2955,
ꢂ
1728, 1613, 1256, 1040, 760 cmꢀ1; 1H NMR (300 MHz, CDCl3) d 2.44–
2.57 (m, 1H), 2.72–2.86 (m, 1H), 3.61 (d, J = 10.8 Hz, 3H), 3.65 (d,
J = 10.8 Hz, 3H), 6.47–6.55 (m, 1H), 7.10–7.24 (m, 2H), 7.47–7.60
(m, 4H), 7.80–7.88 (m, 3H), 7.94–8.04 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 32.4 (d, J = 139 Hz), 52.1 (d, J = 6.6 Hz), 52.2 (d, J = 6.6 Hz),
71.6, 116.7 (d, J = 22.2 Hz), 118.2 (d, J = 9.9 Hz), 123.6, 123.8 (d,
J = 4.1 Hz), 125.8, 126.16, 126.18, 127.4, 127.9, 128.4, 132.0, 132.8,
133.0, 134.5 (d, J = 9.1 Hz), 136.6 (d, J = 9.9 Hz), 161.7 (d, J = 259 Hz),
162.7 (d, J = 3.3 Hz); MS [HR-FAB (M+H)+] calcd for C21H21FO5P
403.1110 found 403.1112; HPLC chiralcel OD-H column (4.6 mmu,
250 mm) ꢁ 2, n-hexane/2-propanol = 5:1, wavelength: 254 nm, flow
rate: 1.0 mL/min, retention time: 36.8 min (enriched), 44.2 min.
4.4.52. Dimethyl (R)-(2-hydroxy-4-phenylbut-3-ynyl)phospho-
nate 1r
Colorless oil; ½a D20
ꢂ
¼ þ3:4 (c 0.99, acetone, 50% ee); IR(neat)
1H NMR (300 MHz,
3375, 2957, 2359, 1491, 1260, 1069 cmꢀ1
;
CDCl3) d 2.38 (dd, J = 5.7, 16.8 Hz, 2H), 3.67 (br s, 1H), 3.80 (d,
J = 11.1 Hz, 3H), 3.81 (d, J = 11.1 Hz, 3H), 4.94–5.07 (m, 1H), 7.30–
7.36 (m, 3H), 7.41–7.46 (m, 2H); 13C NMR (100 MHz, CDCl3) d
33.6 (d, J = 137 Hz), 52.1 (d, J = 6.6 Hz), 52.4 (d, J = 6.6 Hz), 57.0,
84.1, 89.2 (d, J = 15.6 Hz), 122.1, 127.9 (2C), 128.1, 131.2 (2C); MS
[HR-EI (M+)] calcd for C12H15O4P 254.0708 found 254.0700; HPLC
chiralcel OD-H column (4.6 mmu, 250 mm), n-hexane/2-propa-
nol = 10:1, wavelength: 254 nm, flow rate: 1.0 mL/min, retention
time: 14.9 min, 19.3 min (enriched).
4.4.48. Dimethyl (R)-(2-hydroxypropyl)phosphonate 1p2c
Colorless oil; ½a D20
ꢂ
¼ ꢀ1:4 (c 0.46, acetone, 10% ee); 1H NMR
(300 MHz, CDCl3) d 1.29 (dd, J = 2.4, 6.3 Hz, 3H), 1.91–1.99 (m,
2H), 3.29 (br s, 1H), 3.77 (d, J = 11.1 Hz, 3H), 3.78 (d, J = 11.1 Hz,
3H), 4.14–4.27 (m, 1H); The ee of the dimethyl (R)-(2-hydroxypro-
pyl)phosphonate 1p was determined by HPLC of the corresponding
dimethyl (S)-[2-(2-fluorobenzoyloxy)propyl]phosphonate 2p.
4.4.53. Dimethyl (S)-[2-(2-fluorobenzoyloxy)-4-phenylbut-3-
ynyl]phosphonate 2r
Colorless oil; ½a D20
ꢂ
¼ þ4:6 (c 0.59, acetone, 47% ee); IR(neat)
1H NMR (300 MHz,
2955, 1736, 1491, 1252, 1036, 758 cmꢀ1
;
4.4.49. Dimethyl (S)-[2-(2-fluorobenzoyloxy)propyl]phospho-
CDCl3) d 2.51–2.73 (m, 2H), 3.78 (d, J = 10.8 Hz, 6H), 6.09–6.17
(m, 1H), 7.12–7.34 (m, 5H), 7.44–7.48 (m, 2H), 7.51–7.59 (m,
1H), 8.01–8.06 (m, 1H); 13C NMR (100 MHz, CDCl3) d 31.4 (d,
J = 141 Hz), 52.5 (d, J = 5.8 Hz), 52.6 (d, J = 5.8 Hz), 60.1, 85.0 (d,
J = 12.4 Hz), 86.2, 116.9 (d, J = 22.2 Hz), 117.8 (d, J = 9.1 Hz),
121.6, 123.9 (d, J = 4.1 Hz), 128.1 (2C), 128.8, 131.7 (2C), 132.1,
134.8 (d, J = 9.1 Hz), 162.0 (d, J = 260 Hz), 162.4 (d, J = 4.1 Hz); MS
[HR-EI (M+)] calcd for C19H18FO5P 376.0876 found 376.0866; HPLC
chiralcel OJ-H column (4.6 mmu, 250 mm), n-hexane/2-propa-
nol = 10:1, wavelength: 254 nm, flow rate: 1.0 mL/min, retention
time: 42.6 min (enriched), 52.7 min.
nate 2p
Colorless oil; ½a D20
ꢂ
¼ þ15:2 (c 1.0, acetone, 57% ee); IR(neat)
1H NMR (300 MHz,
2957, 1728, 1456, 1264, 1063, 762 cmꢀ1
;
CDCl3) d 1.52 (d, J = 6.3 Hz, 3H), 2.08–2.22 (m, 1H), 2.32–2.44 (m,
1H), 3.74 (d, J = 10.8 Hz, 3H), 3.76 (d, J = 10.8 Hz, 3H), 5.40–5.51
(m, 1H), 7.11–7.23 (m, 2H), 7.50–7.57 (m, 1H), 7.92–7.99 (m,
1H); 13C NMR (100 MHz, CDCl3) d 21.1 (d, J = 7.4 Hz), 31.7 (d,
J = 139 Hz), 52.4 (d, J = 6.6 Hz, 2C), 67.1, 116.9 (d, J = 21.4 Hz),
118.7 (d, J = 9.1 Hz), 123.9 (d, J = 4.1 Hz), 132.0, 134.5 (d,
J = 8.2 Hz), 161.9 (d, J = 259 Hz), 163.3 (d, J = 3.3 Hz); MS [HR-EI
(M+)] calcd for C12H16FO5P 290.0719 found 290.0721; HPLC chiral-
cel OD-H column (4.6 mmu, 250 mm), n-hexane/2-propa-
nol = 10:1, wavelength: 254 nm, flow rate: 1.0 mL/min, retention
time: 13.4 min, 15.0 min (enriched).
4.4.54. Diethyl (R)-[2-hydroxy-2-(2-methylphenyl)ethyl]phos-
phonate 1s
White solid; mp 52.5–54.5 °C (n-hexane); ½a D20
¼ ꢀ25:8 (c 0.91,
ꢂ
acetone, 60% ee); IR(neat) 3360, 2984, 1221, 1030, 965, 768 cmꢀ1
;
4.4.50. Dimethyl (E)-(R)-(2-hydroxy-4-phenylbut-3-enyl)phos-
1H NMR (300 MHz, CDCl3) d 1.33 (t, J = 6.9 Hz, 3H), 1.37 (t,
J = 6.9 Hz, 3H), 2.10–2.18 (m, 2H), 2.34 (s, 3H), 3.80 (s, 1H), 4.07–
4.23 (m, 4H), 5.29–5.37 (m, 1H), 7.12–7.24 (m, 3H), 7.55 (d,
J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 15.58 (d, J = 2.0 Hz),
15.65 (d, J = 2.0 Hz), 18.2, 34.2 (d, J = 135 Hz), 60.9 (d, J = 6.6 Hz),
61.1 (d, J = 6.6 Hz), 64.4 (d, J = 4.1 Hz), 124.6, 125.5, 126.5, 129.5,
133.3, 141.7 (d, J = 14.0 Hz); MS [HR-EI (M+)] calcd for C13H21O4P
272.1177 found 272.1096; HPLC chiralcel OD-H column
(4.6 mmu, 250 mm), n-hexane/2-propanol = 30:1, wavelength:
254 nm, flow rate: 1.0 ml/min, retention time: 18.7 min (enriched),
24.1 min.
phonate 1q
Colorless oil; ½a D20
ꢂ
¼ þ3:0 (c 1.2, acetone, 38% ee); IR(neat) 3420,
1H NMR (300 MHz, CDCl3) d
2955, 1651, 1462, 1260, 1078 cmꢀ1
;
2.10–2.18 (m, 2H), 3.44 (br s, 1H), 3.77 (d, J = 10.8 Hz, 3H), 3.79
(d, J = 10.8 Hz, 3H), 4.67–4.80 (m, 1H), 6.24 (dd, J = 6.3, 15.9 Hz,
1H), 6.67 (d, J = 15.9 Hz, 1H), 7.23–7.41 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 32.9 (d, J = 137 Hz), 52.1 (d, J = 6.6 Hz), 52.3
(d, J = 6.6 Hz), 66.9 (d, J = 3.3 Hz), 126.2 (2C), 127.4, 128.3 (2C),
129.8, 131.2 (d, J = 14.0 Hz), 136.2; MS [HR-EI (M+)] calcd for
C12H17O4P 256.0865 found 256.0875; HPLC chiralcel OD-H column
(4.6 mmu, 250 mm), n-hexane/2-propanol = 10:1, wavelength:
254 nm, flow rate: 1.0 mL/min, retention time: 21.0 min, 32.4
min (enriched).
4.4.55. Diethyl (S)-[2-(2-fluorobenzoyloxy)-2-(2-methylphenyl)-
ethyl]phosphonate 2s
Colorless oil; ½a D20
ꢂ
¼ ꢀ24:1 (c 1.1, acetone, 78% ee); IR(neat)
4.4.51. Dimethyl (E)-(S)-[2-(2-fluorobenzoyloxy)-4-phenylbut-
2986, 1728, 1298, 1250, 1026, 770 cmꢀ1 1H NMR (300 MHz,
;
3-enyl]phosphonate 2q
CDCl3) d 1.20 (t, J = 6.9 Hz, 3H), 1.21 (t, J = 6.9 Hz, 3H), 2.29–2.42
(m, 1H), 2.53 (s, 3H), 2.56–2.70 (m, 1H), 3.92–4.08 (m, 4H), 6.50–
6.58 (m, 1H), 7.10–7.23 (m, 5H), 7.44–7.56 (m, 2H), 7.98–8.04
(m, 1H); 13C NMR (100 MHz, CDCl3) d 16.07, 16.14, 19.0, 33.0 (d,
J = 139 Hz), 61.6 (d, J = 6.6 Hz), 61.7 (d, J = 6.6 Hz), 68.6, 116.8 (d,
J = 21.4 Hz), 118.4 (d, J = 9.1 Hz), 123.8 (d, J = 4.1 Hz), 125.8,
Colorless oil; ½a D20
ꢂ
¼ ꢀ13:3 (c 0.80, acetone, 58% ee); IR(neat)
2955, 1728, 1293, 1252, 1032, 756 cmꢀ1
;
1H NMR (300 MHz,
CDCl3) d 2.29–2.59 (m, 2H), 3.72 (d, J = 11.1 Hz, 3H), 3.74 (d,
J = 11.1 Hz, 3H), 5.93–6.04 (m, 1H), 6.33 (dd, J = 7.5, 15.9 Hz, 1H),
6.81 (d, J = 15.9 Hz, 1H), 7.11–7.34 (m, 5H), 7.40–7.43 (m, 2H),

A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
823
126.3, 128.1, 130.4, 132.1, 134.5 (d, J = 8.2 Hz), 135.1, 138.3 (d,
J = 10.7 Hz), 161.9 (d, J = 259 Hz), 162.7 (d, J = 4.1 Hz); MS [HR-
FAB (M+H)+] calcd for C20H25FO5P 395.1424 found 395.1438; HPLC
chiralcel OD-H column (4.6 mmu, 250 mm), n-hexane/2-propa-
nol = 20:1, wavelength: 254 nm, flow rate: 0.7 ml/min, retention
time: 17.0 min (enriched), 22.9 min.
J = 139 Hz), 61.6 (d, J = 6.6 Hz), 61.7 (d, J = 6.6 Hz), 69.2, 116.8 (d,
J = 22.2 Hz), 118.2, 122.9, 123.85 (d, J = 3.3 Hz), 123.93, 125.1,
125.7, 126.4, 128.8 (2C), 129.7, 132.2, 133.7, 134.5 (d, J = 9.1 Hz),
135.7 (d, J = 10.7 Hz), 161.9 (d, J = 259 Hz), 162.7; MS [HR-FAB
(M+H)+] calcd for C23H25FO5P 431.1424 found 431.1454; HPLC chi-
ralcel OD-H column (4.6 mmu, 250 mm), n-hexane/2-propa-
nol = 30:1, wavelength: 254 nm, flow rate: 1.0 ml/min, retention
time: 38.4 min (enriched), 48.5 min.
4.4.56. Diethyl (R)-[2-hydroxy-2-(4-methoxyphenyl)ethyl]phos-
phonate 1t
Colorless oil; ½a D20
ꢂ
¼ ꢀ12:4 (c 1.6, acetone, 59% ee); IR(neat)
1H NMR (300 MHz,
4.4.60. Diethyl (R)-(2-hydroxypropyl)phosphonate 1v2b
3360, 2986, 1514, 1254, 1044, 835 cmꢀ1
;
Colorless oil; ½a D20
ꢂ
¼ ꢀ5:2 (c 0.87, acetone, 49% ee); 1H NMR
CDCl3) d 1.31 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 2.09–2.30
(m, 2H), 3.78 (s, 1H), 3.81 (s, 3H), 4.05–4.21 (m, 4H), 5.03–5.12
(m, 1H), 6.89 (d, J = 9.0 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 16.0 (d, J = 3.3 Hz), 16.1 (d, J = 3.3 Hz), 35.6
(d, J = 135 Hz), 54.9, 61.4 (d, J = 5.8 Hz), 61.6 (d, J = 5.8 Hz), 68.1
(d, J = 4.1 Hz), 113.5 (2C), 126.6 (2C), 135.8 (d, J = 14.8 Hz), 158.8;
MS [HR-EI (M+)] calcd for C13H21O5P 288.1127 found 288.1111;
The ee of the diethyl (R)-[2-hydroxy-2-(4-methoxyphenyl)ethyl]-
phosphonate 1t was determined by HPLC of the corresponding
diethyl (S)-[2-(2-fluorobenzoyloxy)-2-(4-methoxyphenyl)ethyl]-
phosphonate 2t.
(300 MHz, CDCl3) d 1.26–1.38 (m, 9H), 1.83–2.04 (m, 2H), 3.48
(br s, 1H), 4.07–4.23 (m, 5H); The ee of the diethyl (R)-(2-hydroxy-
propyl)phosphonate 1v was determined by HPLC of the corre-
sponding diethyl (S)-[2-(2-fluorobenzoyloxy)propyl]phosphonate
2v.
4.4.61. Diethyl (S)-[2-(2-fluorobenzoyloxy)propyl]phosphonate
2v
Colorless oil; ½a D20
ꢂ
¼ þ15:1 (c 1.0, acetone, 56% ee); IR(neat)
1H NMR (300 MHz,
2994, 1717, 1456, 1264, 1057, 772 cmꢀ1
;
CDCl3) d 1.28 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H), 1.52 (d,
J = 6.3 Hz, 3H), 2.04–2.21 (m, 1H), 2.31–2.44 (m, 1H), 4.06–4.17
(m, 4H), 5.40–5.50 (m, 1H), 7.10–7.23 (m, 2H), 7.48–7.55 (m,
1H), 7.93–7.99 (m, 1H); 13C NMR (100 MHz, CDCl3) d 16.1 (d,
J = 4.1 Hz), 16.2 (d, J = 4.1 Hz), 21.0 (d, J = 8.2 Hz), 32.6 (d,
J = 140 Hz), 61.7 (d, J = 6.6 Hz, 2C), 67.1, 116.7 (d, J = 22.2 Hz),
118.7 (d, J = 9.9 Hz), 123.7 (d, J = 4.1 Hz), 131.9, 134.3 (d,
J = 9.1 Hz), 161.8 (d, J = 259 Hz), 163.1; MS [HR-EI (M+)] calcd for
C14H20FO5P 318.1032 found 318.1033; HPLC chiralcel OD-H col-
umn (4.6 mmu, 250 mm), n-hexane/2-propanol = 30:1, wave-
length: 254 nm, flow rate: 0.7 ml/min, retention time: 29.2 min,
32.4 min (enriched).
4.4.57. Diethyl (S)-[2-(2-fluorobenzoyloxy)-2-(4-methoxyphe-
nyl)ethyl]phosphonate 2t
Colorless oil; ½a D20
ꢂ
¼ þ0:95 (c 0.96, acetone, 77% ee); IR(neat)
2986, 1728, 1615, 1516, 1254, 1034 cmꢀ1
;
1H NMR (300 MHz,
CDCl3) d 1.20 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H), 2.33–2.47
(m, 1H), 2.61–2.75 (m, 1H), 3.80 (s, 3H), 3.94–4.08 (m, 4H), 6.26–
6.33 (m, 1H), 6.89 (d, J = 8.7 Hz, 2H), 7.09–7.21 (m, 2H), 7.42 (d,
J = 8.7 Hz, 2H), 7.47–7.54 (m, 1H), 7.95–8.01 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 15.94, 16.00, 33.2 (d, J = 139 Hz), 55.0, 61.4
(d, J = 6.6 Hz), 61.5 (d, J = 6.6 Hz), 71.4, 113.7 (2C), 116.6 (d,
J = 22.2 Hz), 118.4 (d, J = 9.1 Hz), 123.7 (d, J = 3.3 Hz), 127.9 (2C),
131.5 (d, J = 9.9 Hz), 131.9, 134.3 (d, J = 8.2 Hz), 159.4, 161.7 (d,
J = 259 Hz), 162.6 (d, J = 3.3 Hz); MS [HR-FAB (M+H)+] calcd for
C20H25FO6P 411.1372 found 411.1376; HPLC chiralcel OD-H col-
umn (4.6 mmu, 250 mm), n-hexane/2-propanol = 10:1, wave-
length: 254 nm, flow rate: 0.5 ml/min, retention time: 24.9 min
(enriched), 30.7 min.
Acknowledgment
This work was supported by the president’s discretion fund of
Nagasaki University.
References
4.4.58. Diethyl (R)-[2-hydroxy-2-(1-naphthyl)ethyl]phospho-
nate 1u
1. (a) Hirschmann, R.; Smith, A. B.; Taylor, C. M.; Benkovic, P. A.; Taylor, S. D.;
Yanger, K. M.; Spregenler, P. A.; Benkovic, S. J. Science 1994, 265, 234; (b)
Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 2931; (c)
Meier, C.; Laux, W. H. G. Tetrahedron 1996, 52, 589; (d) Yamano, T.; Taya, N.;
Kawada, M.; Huang, T.; Imamoto, T. Tetrahedron Lett. 1999, 40, 2577; (e) Liu, P.;
Murakami, K.; Seki, T.; He, X.; Yeung, S.-M.; Kuzuyama, T.; Seto, H.; Liu, H.-w. J.
Am. Chem. Soc. 2001, 123, 4619; (f) Madec, J.; Pfister, X.; Phansavath, P.;
Ratovelomanana-Vidal, V.; Genêt, J.-P. Tetrahedron 2001, 57, 2563; (g) Vargas,
S.; Suárez, A.; Álvarez, E.; Pizzano, A. Chem. Eur. J. 2008, 14, 9856.
White solid; mp 44.0–46.0 °C (n-hexane); ½a D20
ꢂ
¼ ꢀ31:5 (c 0.76,
1H
acetone, 47% ee); IR(neat) 3350, 2986, 1221, 1026, 776 cmꢀ1
;
NMR (300 MHz, CDCl3) d 1.32 (t, J = 6.9 Hz, 3H), 1.42 (t, J = 6.9 Hz,
3H), 2.17–2.48 (m, 2H), 4.05–4.30 (m, 5H), 5.85–5.93 (m, 1H),
7.48–7.56 (m, 3H), 7.78 (t, J = 8.1 Hz, 2H), 7.88 (d, J = 8.7 Hz, 1H),
8.01 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 15.59 (d,
J = 3.3 Hz), 15.65 (d, J = 3.3 Hz), 34.7 (d, J = 136 Hz), 60.9 (d,
J = 6.6 Hz), 61.4 (d, J = 6.6 Hz), 65.0 (d, J = 4.1 Hz), 122.27, 122.31,
124.80, 124.87, 125.4, 127.2, 128.2, 129.2, 133.1, 139.5 (d,
J = 14.8 Hz); MS [HR-EI (M+)] calcd for C16H21O4P 308.1178 found
308.1165; HPLC chiralcel OD-H column (4.6 mmu, 250 mm), n-
hexane/2-propanol = 30:1, wavelength: 254 nm, flow rate: 1.0 ml/
min, retention time: 25.2 min (enriched), 32.5 min.
2. Recent literatures for kinetic resolution of b-hydroxyalkanephosphonates by
enzymatic methods: (a) Guanti, G.; Zannetti, M. T.; Banfi, L.; Riva, R. Adv. Synth.
_
´
Catal. 2001, 343, 682; (b) Zurawinski, R.; Nakamura, K.; Drabowicz, J.;
Kiełbasinski, P.; Mikołajczyk, M. Tetrahedron: Asymmetry 2001, 12, 3139; (c)
Zhang, Y.; Yuan, C.; Li, Z. Tetrahedron 2002, 58, 2973; (d) Mikołajczyk, M.;
Łuczak, J.; Kiełbasinski, P. J. Org. Chem. 2002, 67, 7872; (e) Pàmies, O.; Bäckvall,
J. E. J. Org. Chem. 2003, 68, 4815; Recent diastereomeric methods: (f) Ordóñez,
M.; González-Morales, A.; Ruíz, C.; De la Cruz-Cordero, R.; Fernández-Zertuche,
M. Tetrahedron: Asymmetry 2003, 14, 1775; (g) Rojas-Cabrera, H.; Fernández-
Zertuche, M.; García-Barradas, O.; Muñoz-Muñiz, O.; Ordóñez, M. Tetrahedron:
Asymmetry 2007, 18, 142.
4.4.59. Diethyl (S)-[2-(2-fluorobenzoyloxy)-2-(1-naphthyl)-
3. Mono-benzoylation: (a) Matsumura, Y.; Maki, T.; Murakami, S.; Onomura, O. J.
Am. Chem. Soc. 2003, 125, 2052; (b) Matsumura, Y.; Maki, T.; Tsurumaki, K.;
Onomura, O. Tetrahedron Lett. 2004, 45, 9131; Mono-carbamoylation: (c)
Matsumoto, K.; Mitsuda, M.; Ushijima, N.; Demizu, Y.; Onomura, O.;
Matsumura, Y. Tetrahedron Lett. 2006, 47, 8453; Mono-tosylation: (d)
Demizu, Y.; Matsumoto, K.; Onomura, O.; Matsumura, Y. Tetrahedron Lett.
2007, 48, 7605; (e) Mono-tosylation of 1,3-diols: Kuriyama, M.; Tanigawa, S.;
Kubo, Y.; Demizu, Y.; Onomura, O. Tetrahedron: Asymmetry, in press,
doi:10.1016/j.tetasy.2010.03.015.
ethyl]phosphonate 2u
Colorless oil; ½a D20
ꢂ
¼ ꢀ44:9 (c 1.0, acetone, 61% ee); IR(neat)
2984, 1732, 1296, 1250, 1024, 970 cmꢀ1
;
1H NMR (300 MHz,
CDCl3) d 1.19 (t, J = 6.9 Hz, 3H), 1.20 (t, J = 6.9 Hz, 3H), 2.53–2.66
(m, 1H), 2.71–2.85 (m, 1H), 3.96–4.09 (m, 4H), 7.06–7.24 (m,
3H), 7.44–7.62 (m, 4H), 7.69 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 8.4 Hz,
1H), 7.88 (d, J = 8.1 Hz, 1H), 8.06 (td, J = 1.8, 7.5 Hz, 1H), 8.28 (d,
J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 16.00, 16.06, 33.2 (d,
4. Mitsuda, M.; Tanaka, T.; Tanaka, T.; Demizu, Y.; Onomura, O.; Matsumura, Y.
Tetrahedron Lett. 2006, 47, 8073.

824
5. Tosylation of
A. Moriyama et al. / Tetrahedron: Asymmetry 21 (2010) 810–824
a
-hydroxyalkanamides: (a) Onomura, O.; Mitsuda, M.; Nguyen, T.
Y.; Onomura, O.; Demizu, Y. Yuki Gosei Kagaku Kyokaishi 2007, 65, 216; (e)
Onomura, O. Electrochemistry 2010, 78, 194.
T. M.; Demizu, Y. Tetrahedron Lett. 2007, 48, 9080; Benzoylation and tosylation
of b-hydroxyalkanamides: (b) Demizu, Y.; Kubo, Y.; Matsumura, Y.; Onomura,
O. Synlett 2008, 433.
7. Demizu, Y.; Moriyama, A.; Onomura, O. Tetrahedron Lett. 2009, 50, 5241.
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Nagasue, Y.; Demizu, Y.; Onomura, O. Tetrahedron 2008, 64, 6675; Asymmetric
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