Enzymatic synthesis of optically active α-chloro-δ-hydroxy- β-ketoalkanephosphonates and reactions thereof

Article abstract of DOI:10.1016/j.tet.2004.02.073

A novel and enzymatic approach to α-chloro-δ-hydroxy-β- ketoalkanephosphonates was developed via enantioselective CALB-catalyzed acetylation and CRL-catalyzed hydrolysis. The resultant optically active compounds provide, via Horner-Wadsworth-Emmons (HWE)

Full text of DOI:10.1016/j.tet.2004.02.073

Tetrahedron 60 (2004) 3883–3892
Enzymatic synthesis of optically active
a-chloro-d-hydroxy-b-ketoalkanephosphonates
and reactions thereofq
*
Chengfu Xu and Chengye Yuan
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 354 Fenglin Lu, Shanghai 200032, China.
Received 5 December 2003; revised 25 February 2004; accepted 26 February 2004
Abstract—A novel and enzymatic approach to a-chloro-d-hydroxy-b-ketoalkanephosphonates was developed via enantioselective CALB-
catalyzed acetylation and CRL-catalyzed hydrolysis. The resultant optically active compounds provide, via Horner–Wadsworth–Emmons
(HWE) reaction, chiral a,b-unsaturated ketones that are building block with potential application in organic synthesis.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
chiral compounds.8 As an extension of our studies on
enzymatic reactions of hydroxyphosphonates, we, herein,
report a convenient synthesis of optically active a-chloro-d-
hydroxy-b-ketoalkanephosphonates via CALB and crude
CRL catalyzed kinetic resolutions.
Enzymes represent some of the most sophisticated and
elegant machinery known for carrying out selective and
highly specific chemical reactions. They have been
extensively utilized in the synthesis of chiral pharma-
ceutics.2
2. Results and discussion
The most common synthetic application of phosphonates is
their use in the Horner–Wadsworth–Emmons (HWE)
reaction for preparing a,b-unsaturated carbonyl com-
pounds.3 We are interested in using enzymes, especially
lipase to synthesize potential biological active b-keto-
alkanephosphonates since such chirons could lead directly
to chiral a,b-unsaturated ketones. The existing practical
routes to chiral b-ketophosphonates are mainly focused on
the Michaelis–Arbuzov synthesis4 and the acylation of
alkylphosphonates.5 Another interesting approach to chiral
g-hydroxy-b-ketophosphonates is based on chiral allene
oxide starting from trimethylsilyl-1-alkye.6 Our group has
also exploited the Baker’s yeast-mediated enantioreduction
of ketones to prepare some optically active g-hydroxy-b-
ketophosphonates and d-hydroxy-b-ketophosphonates.7 We
also used Candia Antartic lipase B (CALB) and crude
Candia Rugosa lipase (CRL) to resolve hydroxyphopho-
nates and aminophosphonates to obtain the corresponding
The racemic a-chloro-d-hydroxy-b-ketoalkanephospho-
nates were easily prepared by reacting the carbanion ion
derived from a-chloro-b-ketopropanephosphonate with
aldehydes9 (Scheme 1 and Table 1).
It is well known that the utility of lipases to resolve alcohols
and related compounds is of great importance, and we wish
to exploit such hydrolases to prepare some interesting and
valuable molecules. CALB, a kind of hydrolases, could
efficiently resolve a lot of secondary alcohols bearing
medium groups which were less than the propyl moiety
(Fig. 2).10 Recently, we described CALB catalyzed enantio-
selective acetylation of a- or b-hydroxyalkanephosphonates
and d-hydroxy-b-ketoalkanephosphonates bearing methyl,
ethyl or vinyl group. Meanwhile all of those substrates gave
excellent results.8 It was therefore interest to examine the
structural effect on the enantioselectivity of CALB-
catalyzed acetylation of d-hydroxy-b-ketoalkanephospho-
nates containing a bulky chlorine atom at a-position.
However, our study indicated that there is no significant
steric hindrance of chlorine atom on enantioselectivity.
q Studies on organophosphorus compounds 130. For part 129, see Ref. 1.
Keywords: Horner–Wadsworth–Emmons (HWE) reaction; a-Chloro-d-
hydroxy-b-ketoalkanephosphonates; Candia Antartic lipase B (CALB);
Crude Candia Rugosa lipase (CRL); Acetylation; Hydrolysis; a,b-
Unsaturated ketones.
For example, the racemic 1a-c was subjected to CALB-
catalyzed acetylation in benzene using vinyl acetate as an
acetylating reagent to provide unreacted 2a-c in 42–45%
*
Corresponding author. Fax: þ86-2164166128;
e-mail address: yuancy@mail.sioc.ac.cn
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.073

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C. Xu, C. Yuan / Tetrahedron 60 (2004) 3883–3892
Scheme 1.
Table 1. Preparation of a-chloro-d-hydroxy-b-ketoalkanephosphonates 1
Entry
R
Yield (%)
Entry
R
Yield (%)
Entry
R
Yield (%)
1a
1b
1c
Me
Et
Vinyl
86
90
88
1d
1e
1f
C6H5
4-MeOC6H4
4-FC6H4
75
80
81
1g
1h
2,4-Cl2C6H3
2-Furyl
83
85
1
Figure 1. H NMR spectrum of E and Z isomers 5b and 6b.
yields and acetylated products 3a-c in 45–50% yields. Since
the enantiomers were not resolved under HPLC conditions
using a column with chiral stationary phase, the enantio-
meric excess of the products 2 and 3 were not obtained
directly. To solve this problem, derivatization of com-
pounds 2 and 3 were conducted. The conversion of
compounds 2 into a,b-unsaturated ketones through HWE
reaction was reported using a DBU/LiBr system.11 How-
ever, it took a long reaction time and provided low yields,
and even racemization of the chiral alcohols 2a-c. We then
treated compounds 2 with PhCHO, THF, H2O and KCO3,
which gave a mixture of chiral a,b-unsaturated ketones 5a-c
and 6a-c in good yields. The E and Z isomers were separated
by careful TLC and determined through steric hindrance and
1H NMR spectrum (Fig. 1). The enantiomeric excess of
compounds 5 and 6 that were determined readily by chiral
HPLC analysis were higher than 98%. Similar procedure
was applied to determine the ee values of products 3 after
the acetyl group was removed. Enzymatic hydrolysis was
necessary since chemical hydrolysis caused unavoidable
elimination to form olefins. In order to increase the yields of
hydrolysis, a system of diisopropyl ether saturated with H2O
was used. As this enzymatic process may enhance the ee
values of the hydrolyzed products 3a-c, the ee values of
their products 7a-c and 8a-c were also excellent as shown in
Scheme 2 and Table 2.
The results obtained indicated that (4R)-1 and (4R)-3 were
preferentially acetylated to esters or hydrolysis to alcohols
catalyzed by CALB, and that is in accordance with the
general rule13 predicted for CALB catalyzed resolutions
(Fig. 2).
It is noteworthy to state our unsuccessful trials to resolve
a-chloro-d-hydroxy-d-aryl-b-ketoalkanephosphonates
(1d-h) by use of CALB-catalyzed acetylation. It may be
rationalized by the large size of aryl group that is
unsuitable as medium group as shown in Figure 2 in

C. Xu, C. Yuan / Tetrahedron 60 (2004) 3883–3892
3885
Scheme 2.
Table 2. CALB-catalyzed enantioselective acetylation of 2a-c and subsequent derivatization
Entry
R
Yield (%)
5 (%)
Yield
6 (%)
Yield
7 (%)
Yield
8 (%)
Yield
Ea
2
3
4
eeb
eeb
eeb
eeb
a
b
c
Me
Et
Vinyl
42
43
45
44
45
46
85
87
90
15
18
20
99
99
99
75
77
74
99
99
99
14
16
19
99
99
99
71
73
70
99
99
99
.200
.200
.200
a
The enantiomeric ratio, E¼ln[(12c)(12ees)]/ln[(12c)(1þees)]¼ln[12c(1þeep)]/ln[12c(12eep)]; c¼ees/(eesþeep).12
The ee values were determined by the chiral HPLC (CHIRALPAK OD, n-hexane/isopropyl alcohol¼8/2–9/1.
b
this enzyme system. In contrast with crude CRL
dropped below 50%, as well as ee values of the products
were below 50%. The reasons maybe as follows (Scheme 3).
In order to solve this problem, the equal PhCHO and H2O
were used as solvents. And the reaction was completed in
1.5 h and the yields were over 80%. Also because of the
presence of a-chlorine atom, the HWE products have E and
Z isomers that could be isolated by careful TLC and
determined by steric hindrance and 1H NMR spectrum
(Scheme 4 and Table 3).
enantioselective hydrolysis the butyrylation products of
b-hydroxy-b-arylethanephosphonates and d-hydroxy-d-
aryl-b-ketoalkanephosphonates in diisopropyl ether pre-
equilibrated with 1.2 M aqueous MgCl2 to prepare
optically active b-hydroxy-b-arylethanephosphonates and
d-hydroxy-d-aryl-b-ketoalkanephosphonates.8a,c
Intrigued by the satisfactory results obtained, and taking
into the structure similarity, we wish to resolve those a-
chloro-d-hydroxy-d-aryl-b-ketoalkanephosphonates via
CRL-catalyzed hydrolysis in diisopropyl ether. Direct
butyrylation of 1d-h using DCC/butyric acid system
afforded the butyryl derivatives (9d-h) in 75–80% yields.
They could be enantioselectively hydrolyzed to correspond-
ing (R)-alcohols in diisopropyl ether preequilibrated with
1.2 M aqueous MgCl2. Based on the same reason, the (R)
alcohols 11d-h were converted to the corresponding HWE
products. When the HWE reaction were done, a problem
appeared, if equal substrates and PhCHO was used in THF,
the reaction time was extended over 10 h and the yields
The absolute configuration of compounds 10d-h and 11d-h
were determined through the corresponding d-hydroxy-b-
ketoalkanephosphonates.8a
It is a pity that the (S)-substrates 10d-h could not be
directly applied to HWE reactions due to the unstability.
Because those compounds converted into their g,d-
unsaturated ketones reaction in the base condition
(Scheme 4). And we are now being engaged in enzymatic
hydrolysis of those butyryl derivatives 10d-h to correspond-
ing alcohols.
3. Conclusion
In summary, a number of a-chloro-d-hydroxy-b-keto-
alkanephosphonates was successfully resolved by a CALB-
catalyzed acetylation and a CRL-catalyzed hydrolysis. The
high optically active a-chloro-d-hydroxy-b-ketoalkane-
phosphonates exhibits potential biological and synthetic
application.
Figure 2. Configuration of the preferential enantiomer of hydroxy-
alkanephosphonate acetylation catalyzed by CALB.

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C. Xu, C. Yuan / Tetrahedron 60 (2004) 3883–3892
4.1. General procedure for the preparation of a-chloro-
d-hydroxy-b-ketoalkanephosphonates (1a-h)
To a suspension of sodium hydride (80%, 0.54 g, 18 mmol)
in dry THF (8 mL) was added diethyl 1-chloro-2-oxo-
propylphophonate14 (3.43 g, 15 mmo) under nitrogen. After
30 min at rt, butyllithium (11.3 mL, in hexane 1.6 M,
18 mmol) was added at 245 to 230 8C. The mixture was
Scheme 3.
Scheme 4.
Table 3. CRL-Catalyzed enantioselective hydrolysis of 9d-h
Entry
Ar
Yield (%)
12 (%)
13 (%)
Ea
9
10
11
Yield
eeb
Yield
eeb
d
e
f
g
h
C6H5
4-MeOC6H4
4-FC6H4
2,4-Cl2C6H4
2-C4H3O
84
82
79
80
85
43
44
46
42
45
40
39
41
41
41
23
22
19
21
19
96
98
.99
99
66
67
70
65
71
96
.99
.99
99
.100
.100
.100
.100
.90
92
91
a
E, the enantiomeric ratio, were roughly calculated based on the yields of 10d-h and the ee values of 12d-h.
The ee values were determined by the chiral HPLC (CHIRALPAK OD and AD, n-hexane/isopropyl alcohol¼8/2–9/1).
b
4. Experiment
kept at this temperature for 1 h, then cooled to 278 8C, and
aldehydes (18 mmol) was added at 278 8C. After the
mixture was stirred for 1 h at low temperature, saturated
NH4Cl (30 mL) was added and the aqueous layer was
extracted with ethyl acetate (3£30 mL). The combined
extracts was dried and evaporated in vacuum. The residue
was subjected to flash chromatography to furnish the
racemic a-chloro-d-hydroxy-b-ketoalkanephosphonates
1a-h. The yields are listed in Table 1.
IR spectra were recorded on a Shimadzu IR-440 spec-
trometer. EI mass spectra (MS) were run on a HP-5989A
mass spectrometer. H NMR spectra were recorded on a
Bruker AMX-330 (300 MHz) spectrometer in CDCl3 and
chemical shifts were reported in ppm downfield relative to
TMS (internal standard); 31P NMR spectra were taken on
the same spectrometer using 80% phosphorus acid as
external standard.
1
4.2. General procedure for CALB-catalyzed acetylation
of racemic a-chloro-d-hydroxy-b-ketoalkane-
phosphonates (1a-c)
CALB (Novozym 435) is a gift from Novo Norvodisk Co.
CRL (901units/mg) was purchased from Sigma Chemical
Co.
To a stirred solution of hydroxyalkanephosphonate
(1 mmol) in benzene (10 mL) was added vinyl acetate
(2 mL). The reaction was started by addition of CALB
(100 mg). The mixture was maintained at 30 8C. When the
reaction proceeded to certain conversion (within 50 h), the
enzyme was filtered, and washed with ethyl acetate
(15 mL). The solvent was removed under reduced pressure
and the residue was subjected to flash chromatography to
The chiral liquid chromatography system: Waters 515
HPLC pump; UV Waters 2487 Dual l Absorbance
Detector, 254 nm; Penelson Network chromatography
interface NCI 900, Turbohrom Navigator data station
software; CHIRALPAK AD, OD, AS column and dimen-
sions: 0.46 cm£25 cm; the flow rate: 0.7 mL/min; eluent:
hexane:isopropanol¼9:1—8:2 (v/v).

C. Xu, C. Yuan / Tetrahedron 60 (2004) 3883–3892
3887
furnish hydroxyalkanephosphonates and their acetates. The
yields are listed in Table 2.
(EI) 284 (1, Mþ), 249 (19), 228 (15), 203 (22), 193 (52), 186
(100), 159 (67), 130 (69), 109 (37), 81 (58), 65 (43), 57 (48),
43 (80%); HRMS (EI): Mþ, found: 284.0613. C10H18ClO5P
requires 284.0580.
4.2.1. (4S) Diethyl 1-chloro-2-oxo-4-hydroxypentyl-
phosphonate (2a). Colorless oil; [a]2D0¼þ22.4 (c 1.1,
CHCl3). nmax (liquid film) 3420, 2982, 2934, 1729, 1256,
978 cm21; dH (300 MHz, CDCl3) 4.64 (1H, dd, J¼9.6,
17.7 Hz, ClCHP(O)), 4.32–4.20 (4H, m, OCH2CH3), 4.18–
4.09 (1H, m, HOCHCH2), 3.04–2.85 (2H, m, CHCH2CO),
1.41–1.34 (6H, m, OCH2CH3), 1.26–1.23 (3H, m,
4.2.6. (4S) Diethyl 1-chloro-2-oxo-4-acetyloxyhexenyl-
phosphonate (3c). Colorless oil; [a]2D0¼22.6 (c 1.0,
CHCl3). nmax (liquid film) 2988, 2939, 1743, 1240, 1023,
983 cm21; dH (300 MHz, CDCl3) 5.92–5.79 (1H, m,
CHvCH2), 5.73–5.65 (1H, m, OCHCH2CO), 5.37–5.21
(CHvCH2), 4.54 (1H, d, J¼17.7 Hz, ClCHP(O)), 4.29–
4.23 (4H, m, OCH2CH3), 3.40–3.06 (2H, m, CHCH2CO),
2.05 (3H, d, J¼2.4 Hz, COCH3), 1.41–1.26 (6H, m,
31
CHCH3); d P (120 MHz, CDCl3) 12.90, 12.80; m/z (EI)
272 (1, Mþ), 237 (2), 193(29), 186 (100), 165 (83), 159 (71),
137 (24), 130 (45), 109 (29), 81 (14), 43 (12%); HRMS (EI):
Mþ, found: 272.0563. C9H18ClO5P requires 272.0580.
31
OCH2CH3); d P (120 MHz, CDCl3) 15.16, 15.04; m/z
(EI) 291 (3, Mþ2Cl), 249 (9), 231 (16), 203 (28), 186 (34),
175 (36), 159(31), 130 (18), 109 (15), 81 (100), 65 (22), 43
(73%); HRMS (EI): Mþ2Cl, found: 291.1024. C12H20O6P
requires 291.0998.
4.2.2. (4R) Diethyl 1-chloro-2-oxo-4-acetyloxypentyl-
phosphonate (3a). Colorless oil; [a]2D0¼þ6.7 (c 1.5,
CHCl3). [Found: C, 41.98; H, 6.34. C11H20ClO6P requires
C, 41.98; H, 6.41]. nmax (liquid film) 2987, 2937, 1741,
1247, 1023, 979 cm21; dH (300 MHz, CDCl3) 5.35–5.27
(1H, m, OCHCH2CO), 4.54 (1H, d, J¼17.7 Hz, ClCHP(O)),
4.30–4.19 (4H, m, OCH2CH3), 3.30–2.89 (2H, m, CHCH2-
CO), 2.01 (3H, d, J¼2.7 Hz, COCH3), 1.43–1.33 (6H, m,
4.3. General procedure for CALB-catalyzed hydrolysis
of 1-chloro-2-oxo-4-acetyloxy-phosphonates (3a-c)
To a stirred diisopropyl ether presaturated with water
(4 mL) was added a mixture of the acetylated phosphonates
3a-c and 100 mg CALB. The solution was stirred at room
temperature until the starting material nearly disappeared
(24–48 h or so). After filtration and washing with 15 mL
ethyl acetate, the solvent was removed under reduced
pressure and the residue was subjected to flash chromato-
graphy to furnish the hydrolyzed products of which yields
are listed in Table 2.
31
OCH2CH3), 1.31–1.23 (3H, m, CHCH3); d P (120 MHz,
CDCl3) 15.31, 15.15; m/z (EI) 315 (1, Mþþ1), 254 (10), 219
(8), 186 (38), 159 (21), 130 (13), 81 (17), 69 (91), 65 (22),
43 (100%).
4.2.3. (4S) Diethyl 1-chloro-2-oxo-4-hydroxyhexyl-
phosphonate (2b). Colorless oil; [a]2D0¼þ19.4 (c 1.6,
CHCl3). [Found: C, 41.90; H, 7.03. C10H20ClO5P requires
C, 41.73; H, 7.14]. nmax (liquid film) 3422, 2979, 2936,
1729, 1257, 1024, 980 cm21; dH (300 MHz, CDCl3) 4.64
(1H, dd, J¼9.9, 17.7 Hz, ClCHP(O)), 4.31–4.20 (4H, m,
OCH2CH3), 4.05–3.99 (1H, m, HOCHCH2), 3.04–2.86
(2H, m, CHCH2CO), 2.81 (1H, s, OH), 1.58–1.49 (2H, m,
CHCH2CH3), 1.41–1.26 (6H, m, OCH2CH3), 0.97 (3H, t,
4.3.1. (4R) Diethyl 1-chloro-2-oxo-4-hydroxypentyl-
phosphonate (4a). Colorless oil; [a]2D0¼223.0 (c 1.0,
CHCl3). 4a is the enantiomer of 2a, its spectroscopic data
are identical to 2a as expected. nmax (liquid film) 3419,
2982, 2935, 1728, 1254, 1025, 979 cm21; dH (300 MHz,
CDCl3) 4.63 (1H, dd, J¼9.3, 17.4 Hz, ClCHP(O)), 4.32–
4.20 (4H, m, OCH2CH3), 4.19–4.10 (1H, m, HOCHCH2),
3.05–2.85 (2H, m, CHCH2CO), 1.43–1.35 (6H, m,
31
J¼7.5 Hz, CHCH2CH3); d P (120 MHz, CDCl3) 12.93,
12.84; m/z (EI) 286 (1, Mþ), 257 (23), 193 (26), 186 (100),
173 (12), 159 (62), 130 (28), 123 (7), 109 (7), 81 (6%).
31
OCH2CH3), 1.28–1.23 (3H, m, CHCH3); d P (120 MHz,
4.2.4. (4R) Diethyl 1-chloro-2-oxo-4-acetyloxypentyl-
phosphonate (3b). Colorless oil; [a]2D0¼þ10.3 (c 1.7,
CHCl3). [Found: C, 43.90; H, 6.87. C12H22ClO6P requires
C, 43.85; H, 6.75]. nmax (liquid film) 2977, 2938, 1741,
1373, 1244, 1023, 978 cm21; dH (300 MHz, CDCl3) 5.26–
5.16 (1H, m, OCHCH2CO), 4.57 (1H, dd, J¼9.3, 17.7 Hz,
ClCHP(O)), 4.30–4.19 (4H, m, OCH2CH3), 3.17–2.94 (2H,
m, CHCH2CO), 2.03 (3H, d, J¼2.4 Hz, COCH3), 1.68–1.61
(2H, m, CHCH2CH3), 1.40–1.25 (6H, m, OCH2CH3),
1.31–1.23 (3H, m, CHCH3) 0.92 (3H, t, J¼7.5 Hz,
CDCl3) 13.37, 13.25; m/z (EI) 272 (2, Mþ), 193(22), 186
(82), 165 (100), 159 (55), 137 (31), 130 (38), 109 (40), 81
(20), 69 (28%).
4.3.2. (4S) Diethyl 1-chloro-2-oxo-4-hydroxyhexyl-
phosphonate (4b). Colorless oil; [a]2D0¼219.2 (c 1.3,
CHCl3). 4b is the enantiomer of 2b, its spectroscopic data
are identical to 2b as expected. nmax (liquid film) 3420,
2979, 2936, 1729, 1255, 1024, 981 cm21; dH (300 MHz,
CDCl3) 4.63 (1H, dd, J¼9.9, 17.7 Hz, ClCHP(O)), 4.30–
4.20 (4H, m, OCH2CH3), 4.04–3.99 (1H, m, HOCHCH2),
3.04–2.83 (2H, m, CHCH2CO), 2.80 (1H, s, OH), 1.57–
1.50 (2H, m, CHCH2CH3), 1.41–1.33 (6H, m, OCH2CH3),
31
CHCH2CH3); d P (120 MHz, CDCl3) 12.85, 12.70; m/z
(EI) 328 (1, Mþþ1), 268 (15), 233 (22), 213 (12), 186 (100),
177 (11), 159(53), 130 (24), 83 (24), 43 (20%).
31
0.97 (3H, t, J¼7.2 Hz, CHCH2CH3); d P (120 MHz,
4.2.5. (4R) Diethyl 1-chloro-2-oxo-4-hydroxy-5-hexenyl-
phosphonate (2c). Colorless oil; [a]2D0¼þ11.0 (c 1.0,
CHCl3). nmax (liquid film) 3362, 2985, 1721, 1248, 1049,
1024, 977 cm21; dH (300 MHz, CDCl3) 5.89–5.83 (1H, m,
CHvCH2), 5.36–5.13 (1H, m, CHvCH2), 4.71–4.60 (2H,
m, ClCHP(O), HOCHCH2), 4.31–4.20 (4H, m, OCH2CH3),
3.16–2.93 (2H, m, CHCH2CO), 1.40–1.34 (6H, m,
CDCl3) 13.40, 13.21; m/z (EI) 286 (1, Mþ), 257 (26), 229
(9), 193 (25), 186 (100), 173 (12), 159 (66), 130 (37), 123
(10), 109 (10), 83 (15%).
4.3.3. (4R) Diethyl 1-chloro-2-oxo-4-hydroxy-5-hexenyl-
phosphonate (4c). Colorless oil; [a]2D0¼211.2 (c 1.2,
CHCl3). 4c is the enantiomer of 2c, its spectroscopic data
are identical to 2c as expected. nmax (liquid film) 3362,
31
OCH2CH3); d P (120 MHz, CDCl3) 12.77, 12.73; m/z

3888
C. Xu, C. Yuan / Tetrahedron 60 (2004) 3883–3892
2985, 1721, 1248, 1049, 1024, 977 cm21; dH (300 MHz,
CDCl3) 5.94–5.83 (1H, m, CHvCH2), 5.33 (1H, d,
J¼16.8 Hz, CHvCH2), 5.15 (1H, d, J¼10.5 Hz,
CHvCH2), 4.71–4.60 (2H, m, ClCHP(O), HOCHCH2),
4.31–4.20 (4H, m, OCH2CH3), 3.16–2.93 (2H, m, CHCH2-
1684, 1597, 1164, 757, 691 cm21; dH (300 MHz, CDCl3)
7.88–7.85 (2H, m, C6H5), 7.79 (1H, s, PhCHvC), 7.45–
7.43 (3H, m, C6H5), 4.37–4.33 (1H, m, HOCHCH2), 3.12–
2.93 (3H, m, CHCH2CO, OH), 1.30 (3H, d, J¼7.5 Hz,
HOCHCH3); m/z (EI) 224 (21, Mþ), 206 (34), 189 (22), 165
(38), 145 (33), 137 (34), 131 (74), 115 (39), 102 (88), 75
(32), 43 (100) 41 (72%).
31
CO), 1.40–1.34 (6H, m, OCH2CH3); d P (120 MHz,
CDCl3) 13.23, 13.17; m/z (EI) 284 (1, Mþ), 242 (22), 231
(23), 203 (22), 199 (84), 186 (100), 179 (39), 171 (35), 159
(66), 143 (56), 130 (55), 109 (21), 81 (56), 43 (34%).
4.4.5. (5S,1E) 1-Phenyl-2-chloro-1-hepten-3-one (5b).
Colorless oil; [a]2D0¼þ46.0 (c 0.6, CHCl3). [Found: C,
65.69; H, 6.53. C13H15ClO2 requires C, 65.41; H, 6.33].
nmax (liquid film) 3426, 2966, 2929, 1700, 1079, 979,
696 cm21; dH (300 MHz, CDCl3) 7.37–7.26 (5H, m, C6H5),
7.19 (1H, s, PhCHvC), 3.99–3.94 (1H, m, HOCHCH2),
2.82–2.60 (2H, m, CHCH2CO), 1.50–1.33 (2H, m,
CHCH2CH3), 0.87 (3H, t, J¼6.9 Hz, CHCH2CH3); m/z
(EI) 238 (14, Mþ), 203 (30), 179 (18), 165 (100), 145 (53),
137 (43), 131 (73), 115 (28), 102 (60), 77 (11), 57(21%).
4.4. General procedure for HWE reactions of the chiral
a-chloro-d-hydroxy-b-ketoalkanephosphonates (3a-c)
with benzaldehyde
Substrates 3a-c (50 mg), K2CO3 (200 mg), H2O (1 mL),
THF (1 mL) and benzaldehyde (0.2 mL) was added in a
flask, after the mixture was stirred 2 h, ethyl acetate (5 mL)
and brine (5 mL) was added. The aqueous layer was
extracted with ethyl acetate (3£5 mL). Dried with
anhydrous sodium sulfate, the solvent was removed under
reduced pressure and the residue was subjected to flash
chromatography to furnish the products. The eluting
solvents were ethyl acetate and n-hexane (1:10–1:8) and
the yields are listed in Table 2.
4.4.6. (5S,1Z) 1-Phenyl-2-chloro-1-hepten-3-one (6b).
Colorless oil; [a]2D0¼þ35.3 (c 1.0, CHCl3). [Found: C,
65.63; H, 6.58. C13H15ClO2 requires C, 65.41; H, 6.33].
nmax (liquid film) 3426, 2966, 2929, 1700, 1079, 979,
696 cm21; dH (300 MHz, CDCl3) 7.88–7.85 (2H, m, C6H5),
7.80 (1H, s, PhCHvC), 7.46–7.42 (3H, m, C6H5), 4.16–
4.04 (1H, m, HOCHCH2), 3.12–2.92 (2H, m, CHCH2CO),
1.67–1.55 (2H, m, CHCH2CH3), 1.01 (3H, t, J¼7.5 Hz,
CHCH2CH3); m/z (EI) 238 (15, Mþ), 203 (31), 179 (16),
165 (100), 145 (54), 137 (40), 131 (63), 115 (23), 102 (50),
77 (9), 57 (22%).
4.4.1. (5S,1E) 1-Phenyl-2-chloro-1-hexen-3-one (5a).
Colorless oil; [a]D20¼þ36.0 (c 0.6, CHCl3). nmax (liquid
film) 3420, 2966, 2928, 2855, 1699, 1376, 1080, 1052, 959,
749, 696 cm21; dH (300 MHz, CDCl3) 7.37–7.26 (5H, m,
C6H5), 7.18 (1H, s, PhCHvC), 4.25–4.19 (1H, m,
HOCHCH2), 2.84–2.64 (2H, m, CHCH2CO), 1.14 (3H, d,
J¼6.3 Hz, HOCHCH3); m/z (EI) 224 (18, Mþ), 189 (23),
179 (18), 165 (45), 145 (42), 137 (41), 131 (100), 115 (37),
109 (73%); HRMS (EI): Mþ, found: 224.0592. C12H13ClO2
requires 224.0604.
4.4.7. (5R,1E) 1-Phenyl-2-chloro-1-hepten-3-one (7b).
Colorless oil; [a]2D0¼245.5 (c 0.4, CHCl3). 7b is the
enantiomer of 5b, its spectroscopic data are identical to 5b
as expected. nmax (liquid film) 3447, 2966, 2934, 1681,
1596, 1158, 979, 757, 691 cm21; dH (300 MHz, CDCl3)
7.39–7.27 (5H, m, C6H5), 7.19 (1H, s, PhCHvC), 3.97–
3.94 (1H, m, HOCHCH2), 2.81–2.60 (3H, m, CHCH2CO,
OH), 1.47–1.28 (2H, m, CHCH2CH3), 0.86 (3H, t,
J¼7.5 Hz, CHCH2CH3); m/z (EI) 238 (16, Mþ), 220 (39),
203 (29), 179 (14), 165 (100), 145 (50), 137 (41), 131 (65),
115 (22), 102 (61), 83 (48), 77 (16), 57(32%).
4.4.2. (5S,1Z) 1-Phenyl-2-chloro-1-hexen-3-one (6a).
Colorless oil; [a]2D0¼þ22.2 (c 1.0, CHCl3). [Found: C,
64.40; H, 6.10. C12H13ClO2 requires C, 64.15; H, 5.83].
nmax (liquid film) 3441, 2966, 2931, 2879, 1683, 1596,
1158, 757, 691 cm21; dH (300 MHz, CDCl3) 7.88–7.85
(2H, m, C6H5), 7.80 (1H, s, PhCHvC), 7.45–7.43 (3H, m,
C6H5), 4.38–4.32 (1H, m, HOCHCH2), 3.12–2.93 (2H, m,
CHCH2CO), 1.30 (3H, d, J¼6.0 Hz, HOCHCH3); m/z (EI)
224 (20, Mþ), 189 (19), 165 (32), 145 (32), 137 (25), 131
(69), 115 (30), 102 (59), 77 (20), 43 (100%).
4.4.8. (5R,1Z) 1-Phenyl-2-chloro-1-hepten-3-one (8b).
Colorless oil; [a]2D0¼236.1 (c 0.7, CHCl3). 8b is the
enantiomer of 6b, its spectroscopic data are identical to 6b
as expected. nmax (liquid film) 3450, 2966, 2935, 1684,
1596, 1159, 979, 757, 691 cm21; dH (300 MHz, CDCl3)
7.88–7.85 (2H, m, C6H5), 7.80 (1H, s, PhCHvC), 7.46–
7.41 (3H, m, C6H5), 4.18–4.09 (1H, m, HOCHCH2), 3.12–
2.92 (3H, m, CHCH2CO, OH), 1.65–1.53 (2H, m, CHCH2-
CH3), 1.01 (3H, t, J¼7.5 Hz, CHCH2CH3); m/z (EI) 238
(13, Mþ), 220 (86), 205 (28), 185 (34), 165 (92), 145 (43),
137 (40), 131 (56), 115 (29), 102 (79), 83 (100), 77 (20), 55
(34%).
4.4.3. (5R,1E) 1-Phenyl-2-chloro-1-hexen-3-one (7a).
Colorless oil; [a]2D0¼235.8 (c 0.8, CHCl3). 7a is the
enantiomer of 5a, its spectroscopic data are identical to 5a
as expected. nmax (liquid film) 3407, 2966, 2923, 2852,
1684, 1596, 1448, 1164, 1080, 757, 690 cm21; dH
(300 MHz, CDCl3) 7.38–7.27 (5H, m, C6H5), 7.18 (1H, s,
PhCHvC), 4.25–4.19 (1H, m, HOCHCH2), 2.81–2.64
(2H, m, CHCH2CO), 1.14 (3H, d, J¼6.9 Hz, HOCHCH3);
m/z (EI) 224 (29, Mþ), 206 (62), 205 (61), 189 (28), 179
(20), 165 (51), 145 (37), 137 (38), 131 (88), 115 (30), 102
(74), 77 (22), 69 (100%).
4.4.9. (5R,1E) 1-Phenyl-2-chloro-1-1,6-heptadien-3-one
(5c). Colorless oil; [a]D20¼þ19.0 (c 0.4, CHCl3). [Found: C,
65.85; H, 5.84. C13H13ClO2 requires C, 65.97; H, 5.54].
nmax (liquid film) 3424, 3027, 2926, 1698, 929, 751,
696 cm21; dH (300 MHz, CDCl3) 7.45–7.26 (5H, m, C6H5),
7.20 (1H, s, PhCHvC), 5.85–5.74 (1H, m, CHvCH2),
5.28–5.10 (2H, m, CHvCH2), 4.72–4.58 (1H, m,
4.4.4. (5R,1Z) 1-Phenyl-2-chloro-1-hexen-3-one (8a).
Colorless oil; [a]2D0¼221.8 (c 1.0, CHCl3). 8a is the
enantiomer of 6a, its spectroscopic data are identical to 6a
as expected. nmax (liquid film) 3421, 2971, 2930, 2879,

C. Xu, C. Yuan / Tetrahedron 60 (2004) 3883–3892
3889
HOCHCH2), 2.87–2.80 (2H, m, CHCH2CO), 2.71 (1H, s,
OH); m/z (EI) 236 (3, Mþ), 201 (17), 179 (19), 165 (38), 145
(67), 137 (39), 131 (77), 115 (48), 102 (100), 77 (31), 57
(82%).
(5 mL). The mixture was stirred 48 h at 30 8C, and filtered
off the CRL that could be reused and washed with ethyl
acetate (15 mL). The combined solvent was removed under
reduced pressure and the residue was subjected to flash
chromatography to afford unreacted esters 10d-h and the
hydrolyzed alcohols 11d-h. The yields are listed in Table 3.
4.4.10. (5R,1Z) 1-Phenyl-2-chloro-1-1,6-heptadien-3-one
(6c). Colorless oil; [a]D20¼þ15.5 (c 0.7, CHCl3). [Found: C,
65.84; H, 5.80. C13H13ClO2 requires C, 65.97; H, 5.54].
4.6.1. (4S) Diethyl 1-chloro-2-oxo-4-butyryloxy-4-
n
max (liquid film) 3448, 3027, 2925, 1683, 1596, 1156, 928,
phenylbutylphosphonate
(10d).
Colorless
oil;
758, 691 cm21; dH (300 MHz, CDCl3) 7.89–7.86 (2H, m,
C6H5), 7.81 (1H, s, PhCHvC), 7.47–7.43 (3H, m, C6H5),
6.01–5.91 (1H, m, CHvCH2), 5.41–5.18 (2H, m,
CHvCH2), 4.81–4.70 (1H, m, HOCHCH2), 3.19–3.08
(2H, m, CHCH2CO), 3.08 (1H, s, OH); m/z (EI) 236 (9,
Mþ), 201 (37), 179 (30), 165 (66), 145 (100), 137 (49), 131
(88), 115 (44), 102 (76), 77 (14), 57 (16%).
[a]2D0¼23.1 (c 1.2, CHCl3). [Found: C, 53.54; H, 6.54.
C18H26ClO6P requires C, 53.41; H, 6.47]. nmax (liquid film)
3036, 2970, 2936, 2877, 1739, 1262, 1023, 981 cm21; dH
(300 MHz, CDCl3) 7.48–7.27 (5H, m, C6H5), 6.24–6.18
(1H, m, PhCHCH2), 4.51 (1H, dd, J¼17.4 Hz, ClCHP(O)),
4.30–4.10 (4H, m, OCH2CH3), 3.59–3.17 (2H, m, CHCH2-
CO), 2.33–2.25 (2H, m, COCH2CH2CH3), 1.68–1.59 (2H,
m, COCH2CH2CH3), 1.43–1.26 (6H, m, OCH2CH3), 0.90
31
4.4.11. (5S,1E) 1-Phenyl-2-chloro-1-1,6-heptadien-3-one
(7c). Colorless oil; [a]2D0¼219.0 (c 0.4, CHCl3). 7c is the
enantiomer of 5c, its spectroscopic data are identical to 5c as
expected. nmax (liquid film) 3420, 3025, 2932, 1699, 1088,
929, 753, 695 cm21; dH (300 MHz, CDCl3) 7.38–7.28 (5H,
m, C6H5), 7.21 (1H, s, PhCHvC), 5.86–5.75 (1H, m,
CHvCH2), 5.25 (1H, d, J¼16.8 Hz, CHvCH2), 5.12 (1H,
d, J¼10.5 Hz, CHvCH2), 4.71–4.58 (1H, m, HOCHCH2),
2.84–2.74 (3H, m, CHCH2CO, OH); m/z (EI) 236 (8, Mþ),
201 (31), 179 (25), 165 (62), 145 (93), 137 (52), 131 (96),
115 (51), 102 (100), 77 (25), 57 (42%).
(3H, t, J¼7.5 Hz, COCH2CH2CH3); d P (120 MHz, CDCl3)
12.14; m/z (EI) 316 (1, Mþ2nPrCOOH), 290 (23), 205 (7),
187 (26), 174 (100), 152 (23), 131 (34), 125 (42), 108 (16),
97 (22), 80 (17%).
4.6.2. (4R) Diethyl 1-chloro-2-oxo-4-hydroxy-4-phenyl-
butylphosphonate (11d). Colorless oil; [a]2D0¼þ38.0 (c
1.4, CHCl3). [Found: C, 49.98; H, 6.25. C14H20ClO5P
requires C, 50.23, H, 6.02]. nmax (liquid film) 3403, 2986,
2914, 1729, 1255, 1023, 981 cm21; dH (300 MHz, CDCl3)
7.41–7.27 (5H, m, C6H5), 5.25–5.17 (1H, m, HOCHCH2),
4.63 (1H, dd, J¼17.7 Hz, ClCHP(O)), 4.28–4.11 (4H, m,
OCH2CH3), 3.39–3.07 (3H, m, OH, CHCH2CO), 1.44–
4.4.12. (5S,1Z) 1-Phenyl-2-chloro-1-1,6-heptadien-3-one
(8c). Colorless oil; [a]2D0¼215.5 (c 0.5, CHCl3). 8c is the
enantiomer of 6c, its spectroscopic data are identical to 6c as
expected. nmax (liquid film) 3456, 3057, 2926, 1684, 1596,
1448, 1156, 928, 758, 691 cm21; dH (300 MHz, CDCl3)
7.89–7.86 (2H, m, C6H5), 7.81 (1H, s, PhCHvC), 7.47–
7.42 (3H, m, C6H5), 6.01–5.90 (1H, m, CHvCH2), 5.36
(1H, d, J¼15.3 Hz, CHvCH2), 5.20 (1H, d, J¼10.2 Hz,
CHvCH2), 4.80–4.71 (1H, m, HOCHCH2), 3.15–3.07
(3H, m, CHCH2CO, OH), 3.08 (1H, s, OH); m/z (EI) 236 (9,
Mþ), 201 (34), 180 (25), 165 (65), 145 (100), 137 (53), 131
(98), 115 (47), 102 (97), 91 (21), 77 (28), 57 (59%).
31
1.24 (6H, m, OCH2CH3); d P (120 MHz, CDCl3) 12.29; m/z
(EI) 317 (1, Mþ2OH), 299 (44), 228 (25), 193 (85), 186
(46), 159 (49), 131 (64), 105 (100), 77 (57), 65 (100%).
4.6.3. (4S) Diethyl 1-chloro-2-oxo-4-butyryloxy-4-(4-
methoxyphenyl) butylphosphonate (10e). Colorless oil;
[a]2D0¼215.9 (c 0.9, CHCl3). [Found: C, 52.24; H, 6.51.
C19H28ClO7P requires C, 52.48; H, 6.49]. nmax (liquid film)
2970, 2937, 2914, 2841, 1738, 1595, 1513, 1257, 1020,
981 cm21; dH (300 MHz, CDCl3) 7.31 (2H, d, J¼8.7 Hz,
C6H4), 6.93 (2H, d, J¼8.4 Hz, C6H4), 6.20–6.10 (1H, m,
ArCHCH2), 4.58 (1H, dd, J¼18.0 Hz, ClCHP(O)), 4.29–
4.09 (4H, m, OCH2CH3), 3.86 (3H, s, OCH3), 3.65–3.19
(2H, m, CHCH2CO), 2.32–2.22 (2H, m, COCH2CH2CH3),
1.68–1.58 (2H, m, COCH2CH2CH3), 1.44–1.26 (6H, m,
4.5. General procedure for the preparation of diethyl
1-chloro-2-oxo-4-butyryloxy-4-arybutylphosphonates
(9d-h)
31
OCH2CH3), 0.94 (3H, t, J¼7.5 Hz, COCH2CH2CH3) d P
In a 25 mL flask was added substrates 1d-h (1 mmol),
n-butyric acid (0.11 mL, 1.2 mmol), DCC (248 mg,
1.2 mmol) and CH2Cl2 (10 mL). The mixture was cooled
(120 MHz, CDCl3) 13.57; m/z (EI) 346 (8, Mþ2nPrCOOH),
329 (10), 311 (9), 255 (6), 208 (6), 190 (12), 161 (100), 135
(62), 109 (7%).
8
to 210 C using ice-salt bath and DMAP (5 mg) was
introduced. After the starting material was almost consumed
at 210,0 8C (about 1–2 h), diethyl ether (10 mL) was
added and the precipitate was filtered off. The solvent
was removed under reduced pressure and the residue was
subjected to flash chromatography to furnish the corre-
sponding butyryl derivatives of which yields are listed in
Table 3.
4.6.4. (4R) Diethyl 1-chloro-2-oxo-4-hydroxy-4-(4-
methoxyphenyl) butylphosphonate (11e). Colorless oil;
[a]2D0¼þ37.1 (c 0.9, CHCl3). [Found: C, 49.42; H, 6.17.
C15H22ClO6P requires C, 49.39; H, 6.08]. nmax (liquid film)
3404, 2986, 2913, 1730, 1613, 1515, 1247, 1095 981 cm21
;
dH (300 MHz, CDCl3) 7.31 (2H, d, J¼8.4 Hz, C6H4), 6.89
(2H, d, J¼8.4 Hz, C6H4), 5.21–5.13 (1H, m, HOCHCH2),
4.62 (1H, dd, J¼18.3 Hz, ClCHP(O)), 4.29–4.11 (4H, m,
OCH2CH3), 3.81 (3H, s, OCH3), 3.40–3.08 (2H, m,
4.6. General procedure of CRL-catalyzed enantio-
selective hydrolysis of (9d-h)
31
CHCH2CO), 1.41–1.24 (6H, m, OCH2CH3); d P
(120 MHz, CDCl3) 12.29; m/z (EI) 346 (1, Mþ2H2O),
329 (12), 228 (9), 193 (33), 161 (29), 135 (100), 109 (18), 77
(16), 65 (10%).
Substrates 9d-h (100 mg) and CRL (30 mg) were added in
diisopropyl ether pre-saturated with 1.2 M aqueous MgCl2

3890
C. Xu, C. Yuan / Tetrahedron 60 (2004) 3883–3892
4.6.5. (4S) Diethyl 1-chloro-2-oxo-4-butyryloxy-4-(4-
flurophenyl) butylphosphonate (10f). Colorless oil;
[a]2D0¼215.9 (c 0.9, CHCl3). nmax (liquid film) 2970,
2938, 2878, 1739, 1512, 1234, 1024, 983 cm21; dH
(300 MHz, CDCl3) 7.37 (2H, t, J¼7.2 Hz, C6H4), 7.02
(2H, t, J¼8.4 Hz, C6H4), 6.22–6.18 (1H, m, ArCHCH2),
4.54 (1H, dd, J¼18.0 Hz, ClCHP(O)), 4.30–4.11 (4H, m,
OCH2CH3), 3.66–3.19 (2H, m, CHCH2CO), 2.36–2.23
(2H, m, COCH2CH2CH3), 1.71–1.60 (2H, m, COCH2CH2-
CH3), 1.40–1.24 (6H, m, OCH2CH3), 0.98 (3H, t,
2970, 2937, 1733, 1607, 1264, 1021, 977 cm21; dH
(300 MHz, CDCl3) 7.38 (1H, s, C4H3O), 6.34–6.33 (3H,
m, C4H3O, ArCHCH2), 4.59 (1H, dd, J¼18.0 Hz,
ClCHP(O)), 4.30–4.22 (4H, m, OCH2CH3), 3.77–3.31
(2H, m, CHCH2CO), 2.36–2.25 (2H, m, COCH2CH2CH3),
1.68–1.61 (2H, m, COCH2CH2CH3), 1.41–1.34 (6H, m,
31
OCH2CH3), 0.95 (3H, t, J¼7.5 Hz, COCH2CH2CH3) d P
(120 MHz, CDCl3) 12.28, 12.14; m/z (EI) 359 (1, Mþ2Cl),
323 (13), 306 (9), 289 (17), 271 (16), 218 (15), 179 (20), 121
(100), 94 (60), 81 (26), 65 (57%).
31
J¼7.5 Hz, COCH2CH2CH3) d P (120 MHz, CDCl3)
12.62, 12.48; m/z (EI) 422 (1, Mþ), 351 (24), 334 (14),
317 (37), 299 (26), 286 (24), 243 (22), 179 (34), 149 (69),
123 (100), 71 (73), 43 (87%); HRMS (EI): Mþ, found:
422.1084. C18H25ClO6FP requires 422.1061.
4.6.10. (4R) Diethyl 1-chloro-2-oxo-4-hydroxy-4-(2-
furyl) butylphosphonate (11h). Colorless oil; [a]2D0¼
þ27.2 (c 1.3, CHCl3). [Found: C, 44.35; H, 5.59.
C12H18ClO6P requires C, 44.39; H, 5.59]. nmax (liquid
film) 3337, 2991, 2906, 1733, 1243, 1043, 1019, 740 cm21
;
4.6.6. (4R) Diethyl 1-chloro-2-oxo-4-hydroxy-4-(4-
fluorophenyl) butylphosphonate (11f). Colorless oil;
[a]2D0¼þ28.7 (c 1.0, CHCl3). nmax (liquid film) 3394,
2987, 2914, 1730, 1511, 1255, 1224, 1023, 981 cm21; dH
(300 MHz, CDCl3) 7.36 (2H, t, J¼7.8 Hz, C6H4), 7.04 (2H,
d, J¼7.8 Hz, C6H4), 5.22–5.16 (1H, m, HOCHCH2), 4.62
(1H, dd, J¼18.0 Hz, ClCHP(O)), 4.29–4.17 (4H, m,
OCH2CH3), 3.66–3.05 (2H, m, CHCH2CO), 1.44–1.26
dH (300 MHz, CDCl3) 7.36 (1H, s, C4H3O), 6.33–6.28 (2H,
m, C4H3O), 5.24–5.18 (1H, m, HOCHCH2), 4.64 (1H, dd,
J¼18.0 Hz, ClCHP(O)), 4.28–4.10 (4H, m, OCH2CH3),
3.49–3.16 (2H, m, CHCH2CO), 1.39–1.33 (6H, m,
31
OCH2CH3); d P (120 MHz, CDCl3) 12.25, 12.10; m/z
(EI) 307 (8, Mþ2OH), 290 (61), 272 (17), 261 (12), 218
(22), 193 (36), 186 (55), 179 (87), 159 (63), 149 (83), 130
(66), 121 (100), 109 (45), 98 (88), 65 (38%).
31
(6H, m, OCH2CH3); d P (120 MHz, CDCl3) 12.27; m/z (EI)
352 (1, Mþ), 329 (12), 317 (38), 243 (6), 228 (19), 193 (66),
186 (32), 179 (38), 159 (33), 123 (100), 109 (24), 97 (42), 65
(10%); HRMS (EI): Mþ, found: 352.0602. C14H19ClFO5P
requires 352.0643.
4.7. General procedure for HWE reactions of the chiral
a-chloro-d-hydroxy-b-ketoalkanephosphonates
(11d-h) with benzaldehyde
Substrates 11d-h (50 mg), K2CO3 (200 mg), H2O (0.5 mL)
and benzaldehyde (0.5 mL) were added in a flask, after the
mixture was stirred 2 h, ethyl acetate (5 mL) and brine
(5 mL) was added. The aqueous layer was extracted with
ethyl acetate (3£5 mL). Dried with anhydrous sodium
sulfate, the solvent was removed under reduced pressure and
the residue was subjected to flash chromatography to furnish
the products. The eluting solvents were ethyl acetate and
n-hexane (1:10–1:8) and the yields are listed in Table 3.
4.6.7. (4S) Diethyl 1-chloro-2-oxo-4-butyryloxy-4-(2,4-
dichlorophenyl) butylphosphonate (10g). Colorless oil;
[a]2D0¼23.5 (c 1.5, CHCl3). [Found: C, 45.47; H, 4.84.
C18H24Cl3O6P requires C, 45.64; H, 5.11]. nmax (liquid film)
2971, 2937, 2877, 1743, 1264, 1023, 980 cm21; dH
(300 MHz, CDCl3) 7.38–7.23 (3H, m, C6H3), 6.48–6.44
(1H, m, ArCHCH2), 4.53 (1H, d, J¼18.0 Hz, ClCHP(O)),
4.27–4.18 (4H, m, OCH2CH3), 3.58–3.26 (2H, m, CHCH2-
CO), 2.34–2.28 (2H, m, COCH2CH2CH3), 1.71–1.60 (2H,
m, COCH2CH2CH3), 1.40–1.26 (6H, m, OCH2CH3), 0.92
4.7.1. (5R,1E) 1-Chloro-1,5-diphenyl-5-hydroxy-1-pen-
ten-3-one (12d). Colorless oil; [a]2D0¼þ51.8 (c 0.6, CHCl3).
nmax (liquid film) 3506, 3031, 2910, 1684, 1596, 1448,
1152, 759, 692 cm21; dH (300 MHz, CDCl3) 7.37–7.26
(10H, m, Ar-H), 7.18 (1H, s, PhCHvC), 5.17 (1H, dd,
J¼8.4 Hz, HOCHCH2), 3.10–2.95 (3H, m, OH, CHCH2-
CO); m/z (EI) 286 (1, Mþ), 268 (7), 251 (14), 205 (12), 179
(26), 145 (33), 131 (34), 105 (100), 77 (52), 43 (26%);
HRMS (EI): Mþ, found: 286.0769. C17H15ClO2 requires
286.0761.
31
(3H, t, J¼7.5 Hz, COCH2CH2CH3) d P (120 MHz, CDCl3)
12.97, 12.94; m/z (EI) 472 (1, Mþ), 401 (42), 367 (68), 349
(48), 321 (22), 293 (27), 199 (100), 186 (49), 173 (56), 159
(36), 71 (82), 43 (62%).
4.6.8. (4R) Diethyl 1-chloro-2-oxo-4-hydroxy-4-(2,4-
dichlorophenyl) butylphosphonate (11g). Colorless oil;
[a]2D0¼þ38.4 (c 0.5, CHCl3). [Found: C, 41.81; H, 4.61.
C14H18Cl3O5P requires C, 41.66; H, 4.49]. nmax (liquid film)
3308, 2985, 2900, 1735, 1245, 1023, 967 cm21; dH
(300 MHz, CDCl3) 7.60 (1H, d, J¼8.4 Hz, C6H3), 7.36–
7.28 (2H, m, C6H3), 5.52–5.49 (1H, m, HOCHCH2), 4.63
(1H, dd, J¼18.0 Hz, ClCHP(O)), 4.30–4.11 (4H, m,
OCH2CH3), 3.29–3.06 (2H, m, CHCH2CO), 1.43–1.24
4.7.2. (5R,1Z) 1-Chloro-1,5-diphenyl-5-hydroxy-1-pen-
ten-3-one (13d). Colorless oil; [a]2D0¼þ51.3 (c 0.9,
CHCl3). [Found: C, 71.13; H, 5.56. C17H15ClO2 requires
C, 71.21; H, 5.27]. nmax (liquid film) 3501, 3036, 2911,
1683, 1604, 1152, 1124, 759, 699 cm21; dH (300 MHz,
CDCl3) 7.86–7.83 (2H, m, C6H5), 7.78 (1H, s, PhCHvC),
7.44–7.30 (8H, m, 2C6H5), 5.27 (1H, dd, J¼8.4 Hz,
HOCHCH2), 3.40 (1H, s, OH), 3.31–3.27 (2H, m, CHCH2-
CO); m/z (EI) 286 (4, Mþ), 251 (20), 180 (8), 165 (12), 145
(27), 131 (25), 115 (21), 105 (100), 77 (54), 51 (22%).
31
(6H, m, OCH2CH3); d P (120 MHz, CDCl3) 12.74, 12.69;
m/z (EI) 384 (1, Mþ2H2O), 367 (16), 228 (37), 193 (100),
186 (45), 175 (43), 159 (39), 123 (100), 130 (32), 111 (34),
81 (19), 65 (17%).
4.6.9. (4S) Diethyl 1-chloro-2-oxo-4-butyryloxy-4-(2-
furyl)
butylphosphonate
(10h).
Colorless
oil;
[a]2D0¼238.7 (c 1.8, CHCl3). [Found: C, 48.38; H, 6.31.
4.7.3. (5R,1E) 1-Chloro-1-phenyl-5-hydroxy-5-(4-
methoxyphenyl)-1-penten-3-one (12e). Colorless oil;
C16H24Cl3O7P requires C, 48.68; H, 6.13. nmax (liquid film)

C. Xu, C. Yuan / Tetrahedron 60 (2004) 3883–3892
3891
[a]2D0¼þ47.0 (c 0.4, CHCl3). nmax (liquid film) 3497, 2910,
2838, 1686, 1599, 1513, 1251, 1174, 1033, 832, 758,
692 cm21; dH (300 MHz, CDCl3) 7.37–7.28 (5H, m, C6H5),
7.27 (1H, s, PhCHvC), 7.20 (2H, d, J¼8.7 Hz, C6H4), 6.85
(2H, d, J¼8.4 Hz, C6H4), 5.12 (1H, dd, J¼8.4 Hz,
HOCHCH2), 3.80 (3H, s, OCH3), 3.04–2.98 (2H, m,
CHCH2CO); m/z (EI) 316 (3, Mþ), 298 (4), 281 (5), 179
(26), 145 (25), 135 (100), 109 (10), 102 (20), 77 (25), 43
(13%); HRMS (EI): Mþ2H2O, found: 298.0740.
C18H15ClO2 requires 298.0761.
C17H13Cl3O2 requires C, 57.41; H, 3.68]. nmax (liquid film)
3493, 3028, 2926, 2855, 1735, 1684, 1593, 1153, 1124, 757,
690 cm21; dH (300 MHz, CDCl3) 7.88–7.84 (2H, m, C6H5),
7.81 (1H, s, PhCHvC), 7.64 (1H, d, J¼7.8 Hz, C6H3),
7.45–7.43 (3H, m, C6H5), 7.37–7.26 (2H, m, C6H3), 5.57
(1H, d, J¼9.3 Hz, HOCHCH2), 3.66 (1H, d, J¼3.6 Hz, OH),
3.42–3.03 (2H, m, CHCH2CO); m/z (EI) 354 (10, Mþ), 319
(26), 283 (19), 248 (10), 175 (93), 174 (100), 145 (64), 131
(22), 111 (38), 102 (35), 75 (17%).
4.7.9. (5R,1E) 1-Chloro-1-phenyl-5-hydroxy-5-(2-furyl)-
1-penten-3-one (13h). Colorless oil; [a]2D0¼þ37.1 (c 0.8,
CHCl3). [Found: C, 65.33; H, 5.04. C15H13ClO3 requires C,
65.11; H, 4.74]. nmax (liquid film) 3483, 2922, 1687, 1607,
1154, 1128, 757, 691 cm21; dH (300 MHz, CDCl3) 7.35–
7.26 (6H, m, C6H5, C4H3O), 7.20 (1H, s, PhCHvC), 6.32–
6.21 (2H, m, C4H3O), 5.20 (1H, t, J¼4.2 Hz, HOCHCH2),
3.29–3.01 (2H, m, CHCH2CO), 2.98 (1H, d, J¼3.9 Hz,
OH); m/z (EI) 276 (18, Mþ), 258 (8), 241 (48), 170 (34), 165
(22), 145 (34), 131 (60), 110 (100), 102 (51), 97 (69), 95
(50), 65 (12), 41 (24%).
4.7.4. (5R,1Z) 1-Chloro-1-phenyl-5-hydroxy-5-(4-
methoxyphenyl)-1-penten-3-one (13e). Colorless oil;
[a]2D0¼þ39.5 (c 0.7, CHCl3). [Found: C, 68.00; H, 5.45.
C18H17ClO3 requires C, 68.25; H, 5.41]. nmax (liquid film)
3485, 3060, 2910, 2837, 1687, 1611, 1514, 1249, 1176,
1034, 833 cm21; dH (300 MHz, CDCl3) 7.87–7.83 (2H, m,
C6H5), 7.78 (1H, s, PhCHvC), 7.45–7.37 (3H, m, C6H5),
7.33 (2H, d, J¼9.0 Hz, C6H4), 6.91 (2H, d, J¼9.0 Hz,
C6H4), 5.23 (1H, dd, J¼8.7 Hz, HOCHCH2), 3.80 (3H, s,
OCH3), 3.31–3.26 (2H, m, CHCH2CO); m/z (EI) 316 (3,
Mþ), 298 (33), 263 (26), 179 (48), 161 (49), 145 (29), 135
(100), 115 (13), 102 (28), 77 (20%).
4.7.10. (5R,1Z) 1-Chloro-1-phenyl-5-hydroxy-5-(2-
furyl)-1-penten-3-one (13h). Colorless oil; [a]2D0¼þ30.5
(c 1.1, CHCl3). nmax (liquid film) 3482, 3028, 2922, 1689,
1607,1575, 1156, 1129, 757, 691 cm21; dH (300 MHz,
CDCl3) 7.88–7.85 (2H, m, C6H5), 7.82 (1H, s, PhCHvC),
7.45–7.39 (4H, m, C6H5, C4H3O), 6.37–6.33 (2H, m,
C4H3O), 5.30 (1H, d, J¼8.7 Hz, HOCHCH2), 3.57–3.33
(3H, m, CHCH2CO, OH); m/z (EI) 276 (18, Mþ), 258 (11),
241 (49), 170 (34), 145 (34), 131 (61), 110 (100), 102 (53),
97 (22), 95 (54), 77 (15), 41 (31%); HRMS (EI): Mþ, found:
276.0555. C15H13ClO3 requires 276.0553.
4.7.5. (5R,1E) 1-Chloro-1-phenyl-5-hydroxy-5-(4-fluoro-
phenyl)-1-penten-3-one (12f). Colorless oil; [a]2D0¼þ60.1
(c 0.3, CHCl3). nmax (liquid film) 3484, 2909, 1685, 1604,
1510, 1156, 1126, 758, 691 cm21; dH (300 MHz, CDCl3)
7.45–7.23 (9H, m, Ar-H), 7.19 (1H, s, PhCHvC), 5.16 (1H,
dd, J¼8.1 Hz, HOCHCH2), 3.10–2.94 (2H, m, CHCH2CO);
m/z (EI) 304 (3, Mþ), 286 (27), 268 (29), 251 (30), 205 (18),
179 (100), 145 (85), 123 (24), 102 (16), 77 (10%); HRMS
(EI): Mþ, found: 304.0670. C17H14ClO2F requires
304.0666.
4.7.6. (5R,1Z) 1-Chloro-1-phenyl-5-hydroxy-5-(4-fluoro-
phenyl)-1-penten-3-one (13f). Colorless oil; [a]2D0¼þ66.0
(c 0.6, CHCl3). [Found: C, 67.00; H, 4.63. C17H14ClO2F
requires C, 67.00; H, 4.63]. nmax (liquid film) 3481, 3062,
Acknowledgements
This project was supported by the National Natural Science
Foundations of China (Grant No. 20272075 and 20372076).
2924, 1683, 1604, 1511, 1224, 1155, 1124, 758, 691 cm21
;
dH (300 MHz, CDCl3) 7.86–7.83 (2H, m, C6H5), 7.78 (1H,
s, PhCHvC), 7.44–7.30 (5H, m, C6H4, C6H5), 7.05 (2H, d,
J¼8.7 Hz, C6H4), 5.25 (1H, dd, J¼7.8 Hz, HOCHCH2),
3.44 (1H, s, OH), 3.31–3.24 (2H, m, CHCH2CO); m/z (EI)
304 (4, Mþ), 286 (8), 269 (17), 251 (13), 179 (13), 145 (48),
131 (35), 123 (100), 115 (77), 97 (28), 77 (47%).
References and notes
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3069, 2924, 1685, 1593, 1382, 1153, 1124, 823, 777, 756,
690 cm21; dH (300 MHz, CDCl3) 7.64 (1H, d, J¼7.8 Hz,
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(72), 131 (35), 111 (55), 102 (50), 77 (23), 43 (42%); HRMS
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