Candida Rugosa lipase-catalyzed kinetic resolution of β-hydroxy- β-arylpropionates and δ-hydroxy-δ-aryl-β-oxo-pentanoates

Article abstract of DOI:10.1016/j.tet.2004.12.059

A simple and convenient method was reported for the preparation of optically active β-hydroxy-β-arylpropionates, δ-hydroxy-δ- aryl-β-oxo-pentanoates and their butyryl derivatives via CRL-catalyzed hydrolysis. The optically active products are potential precursors of some chiral pharmaceuticals and natural products.

Full text of DOI:10.1016/j.tet.2004.12.059

Tetrahedron 61 (2005) 2169–2186
Candida Rugosa lipase-catalyzed kinetic resolution of
b-hydroxy-b-arylpropionates and
d-hydroxy-d-aryl-b-oxo-pentanoates
*
Chengfu Xu and Chengye Yuan
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai, 200032, People’s Republic of China
Received 19 October 2004; revised 15 December 2004; accepted 16 December 2004
Available online 21 January 2005
Abstract—A simple and convenient method was reported for the preparation of optically active b-hydroxy-b-arylpropionates, d-hydroxy-d-
aryl-b-oxo-pentanoates and their butyryl derivatives via CRL-catalyzed hydrolysis. The optically active products are potential precursors of
some chiral pharmaceuticals and natural products.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
many natural products, such as compactin and mevinolin,3
manoalide,4 compaction and (C)-dihydrocompaction,5
(K)-pestalotin,6 bryostatin,7 and so on.
Optically active b-hydroxy-b-arylpropionates and the
derivatives thereafter are synthetically important and highly
functionalized chiral synthons, of which the chiral b-
hydroxy-b-arylpropionates are precursors of enantiopure
pharmaceuticals including enantiomers of tomoxetine
hydrochloride (I) and fluoxetine hydrochloride (II). The
racemic I and II are pharmaceuticals for treatment of
psychiatric disorders (depression, anxiety, alcoholism)
and metabolic problems (obesity, bulimia).1 Meanwhile,
(R)-tomoxetine (I) is the first norepinephrine reuptake-
inhibiting anti-depressant which does not possess strong
affinity for either a- or b-adrenergic receptors.1a,2
Since optically active b-hydroxy-b-arylpropionates and
d-hydroxy-d-aryl-b-oxo-pentanoates have practical and
potential uses in organic reactions and chiral pharma-
ceuticals, synthetic study of these molecules has therefore
attracted considerable interest. The preparation of chiral
b-hydroxy-b-arylpropionates was mainly focused on cata-
lytic asymmetric8 and biological reduction9 of correspond-
ing b-keto carboxylates. As examples for preparation of
optically active d-hydroxy-d-aryl-b-oxo-pentanoates,
1,3-bis(trimethylsiloxy)-1-methoxybuta-1,3-diene was
reacted with chiral acetals through a distereselective
addition10 or with aldehydes via an asymmetric aldol
condensation catalyzed by Ti(IV)/BINOL complex.11
Another method used an enantioselective reaction of
diketene with aldehydes through a chiral Schiff’s base–
titanium alkoxide complex.12
The drawbacks of above synthetic routes include harsh
reaction conditions, expensive reagents, poor chemical
yields and low optical purity.8–12 An alternative way to
synthesize these chiral molecules is based on biocatalytic
kinetic resolution, which has attracted the interest of
synthetic chemists because of the high-, regio- and
stereoselectivity.13 Our group has exploited baker’s yeast-
mediated enantioreduction for preparation of some optically
active g-hydroxy-b-ketophosphonates and d-hydroxy-b-
ketophosphonates.14 In addition we also used Candia
Antartic lipase B (CALB) and crude Candia Rugosa lipase
On other hand, optically active d-hydroxy-d-aryl-b-oxo-
pentanoates can be converted to 6-substituted-4-hydroxy
lactones and also reacted with an equivalent of aldehydes
via a tandem Knovenenagel reaction in the presence of
BF3$Et2O to give single diasetereomers of highly substi-
tuted tetrahydropyran-4-ones, which are key precursors of
Keywords: b-Hydroxy-b-arylpropionates; d-Hydroxy-d-aryl-b-oxo-pen-
tanoates; Candia Rugosa lipase (CRL); Enantioselectivity; Hydrolysis.
* Corresponding author. Fax: C86 21 64166128;
e-mail: yuancy@mail.sioc.ac.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.059

2170
C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
(CRL) to resolve hydroxyphophonates and aminophos-
phonates to obtain chiral compounds.15
In this paper, we wish to report our experimental results on
CRL-catalyzed enantioselective hydrolysis and alcoholysis
for the preparation of chiral hydroxycarboxylates bearing
aryl groups.
2. Results and discussion
First, the racemic b-hydroxy-b-arylpropionates and
d-hydroxy-d-aryl-b-oxo-pentanoates were synthesized via
a convenient and simple method with high yields (Schemes
1 and 2)
Scheme 4.
Comparing the data in Table 1 with that of corresponding
b-hydroxy-b-arylethylphosphonates,15a,f we found that the
overall yields of CRL-catalyzed reaction were dramatically
increased and reaction time was significantly shortened.
However, the enantioselectivity of CRL decreased a little
bit. Efforts to improve it by changing the bulky degree of the
ester groups were unsuccessful.
Similar results were obtained and shown on Table 2. The
enantioselectivity of CRL were very good in comparison
to that for corresponding d-hydroxy-d-aryl-b-oxo-
butylphosphonates.15c
Scheme 1.
In our previous work,15a,c,f we successfully resolved
b-hydroxy-b-arylethylphosphonates and d-hydroxy-d-aryl-
b-oxo-butylphosphonates by crude CRL in diisopropyl
ether. Because of the similarity of phosphonates and
carboxylates, this strategy was successfully applied to
resolve compounds 1a–m and 2a–n.
Due to the similarity of the substrates 3a–m and 6a–n, the
enantioselectivity of the resolution reaction catalyzed by
CRL are identical. Consequently, if the absolute configu-
ration of one of the products 4a–m and 5a–m or 7a–n and
8a–n was determined, the stereochemistry of the other
molecules could be deduced. Subsequently, the absolute
configuration of hydrolyzed the ethyl b-hydroxy-b-phenyl-
propionate (4c) and methyl d-hydroxy-d-phenyl-b-oxo-
pentanoate (7a) was determined by optical rotation. The
optical rotation of 4c is [a]2D0ZC48.7 (c 1.4, CHCl3)
{literature9a (S)-1c: [a]D20ZK50.8 (c 1.0, CHCl3) and
literature17 (R)-1c: [a]D22ZC40.0 (c 2.8, CHCl3)} and 7a
is [a]2D0ZC58.1 (cZ1.0, CHCl3) {literature11a (R)-2a:
Direct butyrylation of 1a–m and 2a–n using DCC/butyric
acid system afforded the butyryl derivatives in above 90%
yields. The resulted products could be enantioselectively
hydrolyzed to corresponding (R)-alcohols and (S)-esters by
crude CRL in diisopropyl ether pre-equilibrated with
1.2 mol/L aqueous MgCl2. (Schemes 3 and 4, Tables 1
and 2)
Scheme 2.
Scheme 3.

C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
Table 1. CRL catalyzed enantioselective hydrolysis of 3a–m
2171
Entry
R
Ar
Yield of 3 (%)
4
5
Ea
Yield (%)
eeb (%)
Yield (%)
eeb (%)
a
b
c
d
e
f
g
h
i
Me
Me
Et
Et
Et
Et
Et
Et
Et
C6H5
4-MeOC6H4
C6H5
4-MeC6H4
4-MeOC6H4
2-Furyl
2-ClC6H4
4-FC6H4
2,4-Cl2C6H3
4-O2NC6H4
C6H5
94
93
95
93
95
91
92
94
90
96
93
92
95
48
44
43
42
47
51
46
41
46
43
44
45
42
86.9
O99
O99
94.5
85.9
75.1
95.4
93.7
93.7
91.6
93.6
75.7
93.0
44
47
48
44
44
40
41
49
42
43
48
46
47
92.0
92.0
91.9
95.3
90.6
90.2
98.6
86.8
O99
99.6
81.9
76.7
86.8
O68
O150
O150
O100
O60
O45
O150
O100
O150
O150
O50
j
k
l
Et
i-Pr
i-Pr
n-Bu
4-MeOC6H4
C6H5
O20
O50
m
a The enantiomeric ratio, EZln[(1Kc)(1Kees)]/ln[(1Kc)(1Cees)]Zln[1Kc(1Ceep)]/ln[1Kc(1Keep)]; cZees/(eesCeep).16
b The ee values were determined by the chiral HPLC (CHIRALPAK AD, OD, AS).
Table 2. CRL catalyzed enantioselective hydrolysis of 6a–n
Entry
R
Ar
Yield of 6 (%)
7
8
Ea
Yield (%)
eeb (%)
Yield (%)
eeb (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
C6H5
92
91
93
94
91
96
94
93
94
91
92
94
93
93
46
46
45
54c
47
48
46
46
47
47
45
46
45
45
97.0
98.6
99.9
52.0
99.8
97.7
98.1
99.9d
99.7
98.6
97.2
89.6
99.1
99.8
47
47
46
39c
47
46
47
48
47
46
47
48
49
45
99.9
99.9
96.0
98.1
97.5
97.2
94.9
91.9
99.7
99.9
99.6
84.9
99.9
O200
O200
O200
O80
4-MeC6H4
4-MeOC6H4
2-Furyl
2-BrC6H4
4-FC6H4
2,4-Cl2C6H3
4-O2NC6H4
C6H5
4-MeC6H4
4-MeOC6H4
2-Furyl
O200
O200
O200
O200
O200
O200
O200
O100
O200
/
2,4-Cl2C6H3
4-O2NC6H4
e
Et
/
a The enantiomeric ratio, EZln[(1Kc)(1Kees)]/ln[(1Kc)(1Cees)]Zln[1Kc(1Ceep)]/ln[1Kc(1Keep)]; cZees/(eesC eep).16
b The ee values were determined by the chiral HPLC (CHIRALPAK AD, OD, AS).
c The reaction time was too long.
d The ee values of 7h was determined by 8h.
e 8n can not be determined by chiral HPLC.
Figure 1. The preferential configuration of CRL-catalyzed hydrolysis.
Scheme 5.

2172
C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
Figure 2. 19F NMR spectrum of 9Cquinine and 11Cquinine.
[a]D25ZC57.1 (cZ1.0, CHCl3) and literature11b (S)-2a
[a]2D5ZK46.0 (cZ1.0, CHCl3)}.
These trifluoromethyl analog are the precursors of novel
fluorinated pharmaceuticals, such as the antidepressant
beloxatone,18 chiral ethyl 3-hydroxy-4,4,4-trifluorobutyrate
was synthesized. (Scheme 5 and Fig. 2)
Based on the optical rotation data, the absolute configu-
ration of products 4a–m and 5a–m or 7a–n and 8a–n was
thus determined. So, the enantioselectivity of CRL-
catalyzed hydrolysis of substrates 3a–m and 6a–n was
consequently deduced (Fig. 1).
The absolute configuration of product 11 was also
determined by optical rotation with an [a]2D0ZC20.8 (c
0.7, CHCl3) {literature18c (S)-9: [a]2D0ZK18.4 (c 2.85,
CHCl3); literature18b (R)-9: [a]D20ZC21.8 (c 1.25, CHCl3);
literature19 (R)-9: [a]D25ZC20.1 (c 1.2, CHCl3)}. Based on
the above data, the enantioselectivity of CRL-
catalyzed hydrolysis was also deduced as shown in
Figure 1.
It was found that the enantioselectivity of CRL-catalyzed
hydrolysis was kept almost identical. When the aryl group
of b-hydroxy-b-arylethylphosphonates was replaced by a
trifluoromethyl moiety,15b similar outcomes were observed.
Scheme 6.
Figure 3. The curve between the transformation and reaction time of CRL-catalyzed hydrolysis of substrate 6a (transformation was determined by 1H NMR
spectrum, because of big difference of chemical shift of d-H between the product 7a (dH: w5.20 ppm) and 8a (dH: w6.20 ppm)).
Scheme 7.

C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
2173
Scheme 8.
Due to the slow reaction rate of CRL-catalyzed hydrolysis
of hydroxycarboxylates bearing aryl groups, we were able to
investigate the kinetics of the transformation at 30 8C.
(Scheme 6 and Fig. 3)
as Et3N, NH3$H2O, K2CO3 etc.,20 and such treatment also
good for our substrates. The chloroacetyl esters formed by
conventional method (DCC/chloroacetic acid) gave corre-
sponding alcohols upon treatment with aqueous NH3 in
MeOH with excellent yield. (Scheme 8)
Although good results of CRL-catalyzed hydrolysis of
d-hydroxy-d-aryl-b-oxo-pentanoates were achieved, we
still met difficulty of transforming the chiral butyryl esters
into corresponding optically active alcohols. Chemical
hydrolysis only provided elimination products. It is
necessary to point out that our trials to furnish this
transformation by enzyme-catalyzed hydrolysis including
CALB, IM, PS-30, PPL, GM as well as AY failed.
(Scheme 7)
Since this method solved the problem of elimination of
butyryl esters, and if the chloroacetyl esters could be
resolved, the enantiomers of d-hydroxy-d-aryl-b-oxo-pen-
tanoates were obtained.
Based on above idea, we first enantioselectively hydrolyzed
the chloroacetyl esters catalyzed by crude CRL in
diisopropyl ether preequilibrated with 1.2 M MgCl2 solu-
tion. Although this enantioselective hydrolysis reaction
successfully proceeded, the enantioselectivity was worse
than their butyryl counterparts. (Scheme 9).
Some chloroacetyl esters were reported to transform into
corresponding alcohols under weak basic conditions, such
Scheme 9.
Scheme 10.
Table 3. CRL catalyzed enantioselective alcoholysis of 13a,c,g,i,k,m
Entry
R
Ar
Yield of 14
(%)
7
15
Ea
Yield (%)
eeb (%)
Yield (%)
eeb (%)
a
c
g
i
k
m
Me
Me
Me
Et
Et
Et
C6H5
48
49
46
49
49
44
45
46
43
44
45
42
78.6
86.5
92.0
95.4
96.7
O99
76
78
70
82
79
71
88.7
94.9
90.6
O99
O99
97.3
O80
4-MeOC6H4
2,4-Cl2C6H3
C6H5
4-MeOC6H4
2,4-Cl2C6H3
O100
O100
O100
O100
O100
a The enantiomeric ratio, EZln[(1Kc)(1Kees)]/ln[(1Kc)(1Cees)]Zln[1Kc(1Ceep)]/ln[1Kc(1Keep)]; cZees/(eesCeep).16
b The ee values were determined by the chiral HPLC (CHIRALPAK AD, OD, AS).

2174
C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
Scheme 11.
Another alternative method to improve enantioselectivity
was alcoholysis, and our group has prepared optically active
1- or 2-hydroxyalkanephosphonates through butyl alco-
holysis reaction of corresponding chloroacetyl esters
catalyzed by CALB and IM.21 Fortunately, this method is
successfully used in our substrates catalyzed by crude CRL.
(Scheme 10 and Table 3).
extremely useful chiral pharmaceuticals tomoxetine hydro-
chloride (I) and fluoxetine hydrochloride (II). We therefore
selected one couple of the highest enantiomeric excess (4c
and 5c) to prepare them. We also transformed several chiral
products (7a, 7i, 15a and 15i) into optically active
precursors of natural products, such as chiral 4-hydroxy-6-
phenyll-5,6-dihydro-2-pyones (16 and 17) and methyl
4-oxo-2,6-diphenyl-tetrahydro-pyran-3-carboxylatete (18).
(Schemes 11 and 12).
After successful completion of the CRL-catalyzed
hydrolysis/alcoholysis of substrates 3a–m, 6a–n and
13a–m, we utilized the optically active products to
synthesize some chiral pharmaceuticals and precursors of
natural products. In the introduction, we stated the
3. Conclusion
In summary, b-hydroxy-b-arylpropionates and d-hydroxy-
d-aryl-b-oxo-pentanoates were successfully resolved by
CRL-catalyzed hydrolysis to furnish optically active
b-hydroxy-b-arylpropionates, d-hydroxy-d-aryl-b-oxo-pen-
tanoates and their butyryl derivatives, which are useful
precursors of chiral pharmaceuticals, such as tomoxetine
hydrochloride (I) and fluoxetine hydrochloride (II).
4. Experimental
IR spectra were recorded on a Shimadzu IR-440 spectro-
meter. EI mass spectra (MS) were run on a HP-5989A mass
spectrometer. 1H NMR and 13C 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); 19F NMR spectra were taken on
the same spectrometer using CF3COOH as external
standard.
Scheme 12.

C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
2175
CRL (901 units/mg) was purchased from Sigma Chemical
Co.
diisopropyl ether pre-saturated with 1.2 M aqueous MgCl2
(5 mL). The mixture was stirred 24 h at 30 8C, and filtered
off the CRL that could be reuse 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 the hydrolyzed alcohols 4a–m
and unreacted esters 5a–m. The yields are listed in Table 1.
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; column
dimensions: 0.46 cm!25 cm; the flow rate: 0.7 mL/min;
eluent: hexane–isopropanolZ9:1–8:2 (v/v).
4.4.1. (3R) Methyl b-hydroxy-b-phenyl propionate
(4a).8i,22 Colorless oil; [a]D20ZC46.9 (c 1.2, CHCl3).
nmax(liquid film) 3464, 3032, 2955, 1737, 1439, 1201,
1062, 1026, 763, 701 cmK1; dH (300 MHz, CDCl3) 7.40–
7.27 (5H, m, C6H5), 5.14 (1H, dd, JZ7.5, 8.7 Hz,
PhCHCH2), 3.73 (3H, s, OCH3), 2.83–2.69 (2H, m,
PhCHCH2CO); m/z (EI) 180 (41, MC), 120 (12), 107
(100), 105 (29), 79 (68), 77 (44), 51 (15), 43 (13%).
4.1. General procedure for the preparation of
b-hydroxy-b-arylpropionates 1a–m
To a solution of diisopropyl amine (1.82 g, 18 mmol) in dry
THF (20 mL) was added butyllithium (in hexane 1.6 M,
11.3 mL, 18 mmol) at K78 8C under nitrogen. The mixture
was kept at this temperature for 1 h, then a mixture of
acetate (15 mmol) and dry THF (10 mL) was added at low
temperature. After it stirred for 1 h at K78 8C, a mixture of
aldehyde (18 mmol) and dry THF (10 mL) was added. After
the mixture was stirred for another 1 h, saturated NH4Cl
solution was added and the aqueous layer was extracted
with ethyl acetate (3!30 mL), the combined extracts were
dried and evaporated in vacuum. The residue was subjected
to flash chromatography to furnish the racemic b-hydroxy-
b-arylpropionates 1a–m.
4.4.2. (3S) Methyl b-butyryloxy-b-phenyl propionate
(5a). Colorless oil; [a]2D0ZK45.9 (c 0.9, CHCl3). nmax
(liquid film) 3036, 2967, 2878, 1745, 1170, 1004, 700 cmK1
;
dH (300 MHz, CDCl3) 7.38–7.26 (5H, m, C6H5), 6.18 (1H,
dd, JZ4.8, 9.0 Hz, PhCHCH2), 3.67 (3H, s, OCH3), 2.97
(1H, dd, JZ9.0, 15.6 Hz, PhCHCH2CO), 2.76 (1H, dd, JZ
5.4, 15.6 Hz, PhCHCH2CO), 2.29 (2H, t, JZ8.1 Hz,
COCH2CH2CH3), 1.69–1.57 (2H, m, COCH2CH2CH3),
0.91 (3H, t, JZ8.1 Hz, COCH2CH2CH3); m/z (EI) 250 (1,
MC), 179 (100), 147 (20), 131 (14), 121 (37), 105 (62), 77
(16), 71 (47), 43 (33%). Found: C, 66.99; H, 7.31. C14H18O4
requires C, 67.18; H, 7.25.
4.2. General procedure for preparation of d-hydroxy-d-
aryl-b-oxo-pentanoates (2a–n)
To a suspension of sodium hydride (80%, 0.54 g, 18 mmol)
in dry THF (8 mL) was added acetoacetate (15 mmol) under
nitrogen, after 30 min at rt, butyllithium (in hexane 1.6 M,
11.3 mL, 18 mmol) was added at K15–10 8C (ice-salt bath).
The mixture was kept this temperature for 30 min, then
aldehydes (18 mmol) was added at this temperature. After
the mixture was stirred for 1–2 h at low temperature,
saturated NH4Cl (30 mL) was added and the aqueous was
extracted with ethyl acetate (3!30 mL). The combined
extracts was dried and evaporated in vacuum. The residues
were subjected to flash chromatography to furnish the
d-hydroxy-d-aryl-b-oxo-pentanoates (2a–n).
4.4.3. (3R) Methyl b-hydroxy-b-(p-methoxyphenyl) pro-
pionate (4b).23 Colorless oil; [a]D20ZC36.4 (c 1.0, CHCl3).
nmax (liquid film) 3482, 3003, 2955, 2839, 1738, 1614, 1515,
1249, 1033, 834 cmK1; dH (300 MHz, CDCl3) 7.24 (2H, d,
JZ6.9 Hz, C6H4), 6.82 (2H, d, JZ6.6 Hz, C6H4), 5.02
(1H, dd, JZ4.5, 9.3 Hz, ArCHCH2), 3.74 (3H, s, CO2CH3),
3.65 (3H, s, OCH3), 2.76–2.58 (2H, m, ArCHCH2CO);
d
13C(75.5 MHz, CDCl3) 173.07, 159.54, 135.31, 127.36,
114.28, 70.33, 55.64, 52.23, 43.70; m/z (EI) 210 (15, MC),
179 (3), 137 (100), 135 (12), 109 (23), 94 (13), 77 (14), 65
(4%).
4.4.4. (3S) Methyl b-butyryloxy-b-(p-methoxyphenyl)
propionate (5b). Colorless oil; [a]2D0ZK60.7(c 1.3,
CHCl3). nmax (liquid film) 2965, 2939, 2878, 1744, 1517,
1173, 832 cmK1; dH (300 MHz, CDCl3) 7.30 (2H, d, JZ
7.2 Hz, C6H4), 6.87 (2H, d, JZ7.5 Hz, C6H4), 6.13 (1H,
dd, JZ5.4, 9.3 Hz, ArCHCH2), 3.80 (3H, s, CO2CH3), 3.66
(3H, s, OCH3), 2.98 (1H, dd, JZ6.9, 15.6 Hz, ArCHCH2CO),
2.74 (1H, dd, JZ5.4, 15.9 Hz, ArCHCH2CO), 2.26 (2H,
t, JZ7.2 Hz, COCH2CH2CH3), 1.65–1.58 (2H, m,
COCH2CH2CH3), 0.90 (3H, t, JZ7.5 Hz, COCH2CH2CH3);
m/z (EI) 280 (15, MC), 209 (100), 193 (14), 151 (59), 137
(62), 135 (88), 119 (11), 77 (11), 71 (41%). Found: C, 64.15;
H, 7.41. C15H20O5 requires C, 64.27; H, 7.19.
4.3. General procedure for the preparation of
b-butyryloxy-b-arylpropionates (3a–m), d-butyryloxy-
d-aryl-b-oxo-pentanoates (6a–n) and d-chloroacetyloxy-
d-aryl-b-oxo-pentanoates (15a,c,g,i,k,m)
In a 25 mL bottle were added substrates 1a–m (or 2a–n)
(1 mmol), n-butyric acid (or chloroacetic acid) (1.2 mmol),
DCC (248 mg, 1.2 mmol), DMAP (5 mg) and CH2Cl2
(10 mL). After the starting material was almost consumed at
rt (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 corresponding butyryl
derivatives of which yields are listed in Tables 1 and 2.
4.4.5. (3R) Ethyl b-hydroxy-b-phenyl propionate (4c).8i,24
Colorless oil; [a]D20ZC43.7 (c 1.4, CHCl3). nmax(liquid
film) 3461, 2984, 2938, 1734, 1197, 1162, 1028, 761,
701 cmK1; dH (300 MHz, CDCl3) 7.39–7.26 (5H, m, C6H5),
5.13 (1H, dd, JZ4.5, 8.1 Hz, PhCHCH2), 4.18 (2H, q, JZ
6.9 Hz, OCH2CH3), 3.11 (1H, s, OH), 2.81–2.67 (2H, m,
PhCHCH2CO), 1.26 (3H, t, JZ6.9 Hz, OCH2CH3); m/z (EI)
4.4. General procedure of CRL-catalyzed enantio-
selective hydrolysis of b-butyryloxy-b-arylpropionates
(3a–m)
Substrates 3a–m (100 mg) and CRL (30 mg) were added in

2176
C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
194 (100, MC), 165 (6), 147 (13), 120 (19), 107 (97), 105
(65), 79 (49), 77 (38), 60 (11%).
9.3, 15.3 Hz, ArCHCH2CO), 2.73 (1H, dd, JZ4.8, 15.3 Hz,
ArCHCH2CO), 2.26 (2H, t, JZ7.8 Hz, COCH2CH2CH3),
1.65–1.55 (2H, m, COCH2CH2CH3), 1.21 (3H, t, JZ7.2 Hz,
OCH2CH3), 0.88 (3H, t, JZ7.5 Hz, COCH2CH2CH3); m/z
(EI) 294 (12, MC), 223 (96), 207 (14), 177 (8), 161 (21),
150 (16), 137 (47), 135 (100), 119 (11), 71 (25%). Found: C,
65.26; H, 7.47. C16H22O5 requires C, 65.29; H, 7.53.
4.4.6. (3S) Ethyl b-butyryloxy-b-phenyl propionate (5c).
Colorless oil; [a]D20ZK27.5(c 0.9, CHCl3). nmax (liquid
film) 3037, 2969, 2877, 1742, 1457, 1255, 1172, 1028,
763, 700 cmK1; dH (300 MHz, CDCl3) 7.38–7.26 (5H, m,
C6H5), 6.18 (1H, dd, JZ5.1, 9.0 Hz, PhCHCH2), 4.10
(2H, q, JZ6.9 Hz, OCH2CH3), 2.95 (1H, dd, JZ9.0,
15.3 Hz, PhCHCH2CO), 2.74 (1H, dd, JZ5.1, 15.9 Hz,
PhCHCH2CO), 2.30 (2H, t, JZ7.8 Hz, COCH2CH2CH3),
1.69–1.57 (2H, m, COCH2CH2CH3), 1.22 (3H, t, JZ7.5 Hz,
OCH2CH3), 0.91 (3H, t, JZ7.5 Hz, COCH2CH2CH3);
4.4.11. (3R) Ethyl b-hydroxy-b-furan-2-yl propionate
(4f).27 Colorless oil; [a]D20ZC15.0 (c 0.9, CHCl3). nmax
(liquid film) 3455, 2985, 2938, 1734, 1374, 1210, 1164,
1014, 742 cmK1; dH (300 MHz, CDCl3) 7.38–7.36 (1H, m,
C4H3O), 6.34–6.32 (1H, m, C4H3O), 6.28–6.26 (1H, m,
C4H3O), 5.13 (1H, dd, JZ4.8, 8.1 Hz, ArCHCH2), 4.18
(2H, q, JZ7.5 Hz, OCH2CH3), 3.43 (1H, s, OH), 2.94–2.78
(2H, m, ArCHCH2CO), 1.27 (3H, t, JZ7.2 Hz, OCH2CH3);
d
13C(75.5 MHz, CDCl3) 172.7, 170.1, 139.9, 129.0, 128.7,
126.95, 72.3, 61.1, 42.0, 36.6, 18.8, 14.5, 14.0; m/z (EI) 264
(1, MC), 193 (100), 147 (28), 131 (17), 121 (37), 105 (76),
77 (15), 71 (42), 43 (28%). Found: C, 68.18; H, 7.63.
C15H20O4 requires C, 68.16; H, 7.63.
d
13C(75.5 MHz, CDCl3) 172.13, 155.39, 142.47, 110.58,
106.55, 64.45, 61.24, 40.42, 14.44; m/z (EI) 184 (20, MC),
155 (4), 137 (14), 110 (16), 97 (100), 95 (46), 88 (4), 69 (7),
60 (6%).
4.4.7. (3R) Ethyl b-hydroxy-b-(p-methylphenyl) propio-
nate (4d).8i,25 Colorless oil; [a]D20ZC42.5 (c 1.2, CHCl3).
nmax (liquid film) 3464, 2983, 2927, 1735, 1373, 1160, 1041,
819 cmK1; dH (300 MHz, CDCl3) 7.26 (2H, d, JZ8.4 Hz,
C6H4), 7.16 (2H, d, JZ7.8 Hz, C6H4), 5.09 (1H, dd, JZ4.2,
9.0 Hz, ArCHCH2), 4.17 (2H, q, JZ7.5 Hz, OCH2CH3),
3.14 (1H, s, OH), 2.79–2.63 (2H, m, ArCHCH2CO), 2.34
(3H, s, ArCH3), 1.26 (3H, t, JZ6.9 Hz, OCH2CH3); m/z (EI)
208 (31, MC), 193 (14), 134 (7), 121 (100), 119 (42), 105
(9), 93 (38), 91 (34), 77 (17%).
4.4.12. (3S) Ethyl b-butyryloxy-b-furan-2-yl propionate
(5f). Colorless oil; [a]2D0ZK94.2 (c 1.3, CHCl3). nmax
(liquid film) 2970, 2939, 2879, 1744, 1376, 1287, 1172,
1014, 746 cmK1; dH (300 MHz, CDCl3) 7.39–7.37 (1H, m,
C4H3O), 6.38–6.26 (3H, m, C4H3O, ArCHCH2), 4.13 (2H,
q, JZ7.2 Hz, OCH2CH3), 3.09 (1H, dd, JZ8.4, 15.6 Hz,
ArCHCH2CO), 2.91 (1H, dd, JZ5.7, 15.6 Hz, ArCHCH2-
CO), 2.27 (2H, t, JZ7.2 Hz, COCH2CH2CH3), 1.69–1.57
(2H, m, COCH2CH2CH3), 1.23 (3H, t, JZ7.2 Hz,
OCH2CH3), 0.91 (3H, t, JZ7.2 Hz, COCH2CH2CH3);
4.4.8. (3S) Ethyl b-butyryloxy-b-(p-methylphenyl) pro-
pionate (5d). Colorless oil; [a]2D0ZK46.5 (c 0.9, CHCl3).
d
13C(75.5 MHz, CDCl3) 172.71, 169.81, 151.76, 143.04,
nmax (liquid film) 2969, 2877, 1743, 1174, 1027, 817 cmK1
;
110.72, 109.18, 65.01, 61.18, 38.13, 36.44, 18.72, 14.46,
13.84; m/z (EI) 254 (4, MC), 183 (100), 167 (11), 137 (50),
121 (21), 115 (23), 110 (19), 95 (46), 71 (33), 43 (22%).
Found: C, 61.43; H, 7.36. C13H18O5 requires C, 61.41; H,
7.13.
dH (300 MHz, CDCl3) 7.26 (2H, d, JZ8.1 Hz, C6H4), 7.15
(2H, d, JZ7.8 Hz, C6H4), 6.15 (1H, dd, JZ5.7, 9.0 Hz,
ArCHCH2), 4.12 (2H, q, JZ7.2 Hz, OCH2CH3), 2.95 (1H,
dd, JZ7.2, 14.4 Hz, ArCHCH2CO), 2.73 (1H, dd, JZ5.1,
15.6 Hz, ArCHCH2CO), 2.33 (3H, s, ArCH3), 2.27 (2H, t,
JZ7.8 Hz, COCH2CH2CH3), 1.66–1.58 (2H, m, COCH2-
CH2CH3), 1.22 (3H, t, JZ7.2 Hz, OCH2CH3), 0.90 (3H, t,
JZ7.2 Hz, COCH2CH2CH3); m/z (EI) 278 (2, MC), 207
(86), 191 (52), 149 (25), 145 (17), 119 (100), 177 (20), 91
(21), 71 (30), 43 (42%). Found: C, 69.07; H, 7.90. C16H22O4
requires C, 69.04; H, 7.97.
4.4.13. (3R) Ethyl b-hydroxy-b-(o-chlorophenyl) propio-
nate (4g).28 Colorless oil; [a]D20ZC80.3 (c 0.8, CHCl3).
nmax (liquid film) 3481, 2984, 2938, 1735, 1441, 1193, 1033,
758 cmK1; dH (300 MHz, CDCl3) 7.63 (1H, d, JZ6.6 Hz,
C6H4), 7.35–7.22 (3H, m, C6H4), 5.49 (1H, d, JZ9.6 Hz,
ArCHCH2), 4.20 (2H, q, JZ7.5 Hz, OCH2CH3), 3.63 (1H,
s, OH), 2.86 (1H, dd, JZ2.7, 16.8 Hz, ArCHCH2CO), 2.58
(1H, dd, JZ9.6, 16.5 Hz, ArCHCH2CO), 1.28 (3H, t, JZ
6.9 Hz, OCH2CH3); m/z (EI) 228 (6, MC), 193 (65), 147
(10), 143 (29), 141 (100), 139 (41), 113 (15), 105 (15), 88
(25), 77 (50), 60 (17%).
4.4.9. (3R) Ethyl b-hydroxy-b-(p-methoxylphenyl) pro-
pionate (4e).8i,26 Colorless oil; [a]2D0ZC26.5 (c 1.5,
CHCl3). nmax (liquid film) 3461, 2981, 2908, 1732, 1613,
1515, 1249, 1176, 1035, 834 cmK1; dH (300 MHz, CDCl3)
7.28 (2H, d, JZ7.5 Hz, C6H4), 6.88 (2H, d, JZ6.9 Hz,
C6H4), 5.08 (1H, dd, JZ4.2, 9.0 Hz, ArCHCH2), 4.18 (2H,
q, JZ6.9 Hz, OCH2CH3), 3.80 (3H, s, OCH3), 2.80–2.63
(2H, m, ArCHCH2CO), 1.26 (3H, t, JZ6.9 Hz, OCH2CH3);
m/z (EI) 224 (12, MC), 179 (4), 138 (9), 137 (100), 135 (18),
109 (18), 94 (8), 77 (10), 65 (3%).
4.4.14. (3S) Ethyl b-butyryloxy-b-(p-methoxylphenyl)
propionate (5g). Colorless oil; [a]2D0ZK5.6 (c 1.4,
CHCl3). nmax (liquid film) 2970, 2938, 2878, 1751, 1375,
1172, 1019, 759 cmK1; dH (300 MHz, CDCl3) 7.41–7.34
(2H, m, C6H4), 7.28–7.22 (2H, m, C6H4), 6.51 (1H, dd,
JZ5.1, 8.7 Hz, ArCHCH2), 4.15 (2H, q, JZ6.9 Hz,
OCH2CH3), 2.86–2.81 (2H, m, ArCHCH2CO), 2.34 (2H,
t, JZ7.2 Hz, COCH2CH2CH3), 1.70–1.62 (2H, m, COCH2-
CH2CH3), 1.24 (3H, t, JZ7.5 Hz, OCH2CH3), 0.93 (3H, t,
JZ7.2 Hz, COCH2CH2CH3); m/z (EI) 299 (21, MCC1),
263 (74), 227 (36), 211 (63), 193 (14), 175 (58), 169 (63),
165 (30), 139 (70), 71 (86), 43 (100%). Found: C, 60.21; H,
6.34. C15H19O4Cl requires C, 60.30; H, 6.41.
4.4.10. (3S) Ethyl b-butyryloxy-b-(p-methoxylphenyl)
propionate (5e). Colorless oil; [a]2D0ZK54.2 (c 1.3,
CHCl3). nmax (liquid film) 2968, 2938, 2877, 1741, 1517,
1251, 1174, 1034, 833 cmK1; dH (300 MHz, CDCl3) 7.30
(2H, d, JZ6.9 Hz, C6H4), 6.86 (2H, d, JZ6.6 Hz, C6H4),
6.13 (1H, dd, JZ5.7, 9.0 Hz, ArCHCH2), 4.11 (2H, q, JZ
6.9 Hz, OCH2CH3), 3.79 (3H, s, OCH3), 2.96 (1H, dd, JZ

C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
2177
4.4.15. (3R) Ethyl b-hydroxy-b-(p-fluorophenyl) propio-
nate (4h).25 Colorless oil; [a]D20ZC38.8 (c 1.2, CHCl3).
nmax (liquid film) 3455, 2985, 2908, 1733, 1606, 1512, 1223,
1158, 838 cmK1; dH (300 MHz, CDCl3) 7.34 (2H, dd, JZ
3.3, 9.0 Hz, C6H4), 7.03 (2H, t, JZ6.6 Hz, C6H4), 5.10 (1H,
dd, JZ4.5, 8.1 Hz, ArCHCH2), 4.18 (2H, q, JZ7.5 Hz,
OCH2CH3), 3.22 (1H, s, OH), 2.78–2.63 (2H, m, ArCHCH2-
CO), 1.26 (3H, t, JZ7.2 Hz, OCH2CH3); m/z (EI) 212 (22,
MC), 195 (38), 165 (6), 153 (22), 138 (9), 125 (100), 123
(74), 97 (69), 88 (36), 77 (27), 60 (27%).
(3H, t, JZ6.9 Hz, OCH2CH3); m/z (EI) 239 (30, MC), 210
(17), 192 (34), 165 (29), 152 (75), 150 (100), 134 (10), 105
(21), 88 (46), 77 (34), 43 (22%).
4.4.20. (3S) Ethyl b-butyryloxy-b-(p-nitrophenyl) pro-
pionate (5j). Colorless oil; [a]2D0ZK36.6 (c 1.5, CHCl3).
nmax (liquid film) 2970, 2939, 2878, 1743, 1608, 1526, 1349,
1169, 857 cmK1; dH (300 MHz, CDCl3) 8.22 (2H, d, JZ
6.9 Hz, C6H4), 7.55 (2H, d, JZ7.5 Hz, C6H4), 6.22 (1H, dd,
JZ5.4, 8.1 Hz, ArCHCH2), 4.14 (2H, q, JZ6.9 Hz,
OCH2CH3), 2.97 (1H, dd, JZ8.7, 15.9 Hz, ArCHCH2CO),
2.78 (1H, dd, JZ5.7, 15.9 Hz, ArCHCH2CO), 2.34 (2H, t,
JZ7.5 Hz, COCH2CH2CH3), 1.71–1.58 (2H, m, COCH2-
CH2CH3), 1.24 (3H, t, JZ7.5 Hz, OCH2CH3), 0.92 (3H, t,
JZ7.2 Hz, COCH2CH2CH3); m/z (EI) 309 (1, MC), 264
(4), 238 (50), 222 (100), 192 (25), 176 (48), 150 (54), 134
(51), 103 (9), 71 (91), 43 (45%). Found: C, 58.42; H, 6.17;
N, 4.74. C15H19NO6 requires C, 58.25; H, 6.19; N, 4.53.
4.4.16. (3S) Ethyl b-butyryloxy-b-(p-fluorophenyl) pro-
pionate (5h). Colorless oil; [a]2D0ZK37.7 (c 1.0, CHCl3).
nmax (liquid film) 2970, 2939, 2879, 1743, 1514, 1175, 1160,
838 cmK1; dH (300 MHz, CDCl3) 7.36 (2H, dd, JZ5.4,
8.7 Hz, C6H4), 7.04 (2H, t, JZ8.7 Hz, C6H4), 6.15 (1H, dd,
JZ5.4, 9.0 Hz, ArCHCH2), 4.12 (2H, q, JZ7.5 Hz,
OCH2CH3), 2.96 (1H, dd, JZ9.0, 15.9 Hz, ArCHCH2CO),
2.73 (1H, dd, JZ5.7, 15.9 Hz, ArCHCH2CO), 2.28 (2H, t,
JZ7.2 Hz, COCH2CH2CH3), 1.70–1.57 (2H, m, COCH2-
CH2CH3), 1.23 (3H, t, JZ7.2 Hz, OCH2CH3), 0.90 (3H, t,
JZ7.2 Hz, COCH2CH2CH3); m/z (EI) 282 (10, MC), 211
(96), 165 (31), 149 (20), 138 (7), 123 (100), 119 (8), 95 (10),
71 (77), 43 (87%). Found: C, 63.93; H, 6.96. C15H19O4F
requires C, 63.82; H, 6.78.
4.4.21. (3R) Isopropyl b-hydroxy-b-phenyl propionate
(4k).8i,31 Colorless oil; [a]D20ZC39.4 (c 1.1, CHCl3). nmax
(liquid film) 3462, 3033, 2983, 2937, 1731, 1455, 1375,
1198, 1109, 761, 701 cmK1; dH (300 MHz, CDCl3) 7.40–
7.25 (5H, m, C6H5), 5.14–5.01 (2H, m, PhCHCH2,
OCH(CH3)2), 3.31 (1H, s, OH), 2.80–2.62 (2H, m,
PhCHCH2CO), 1.22 (6H, d, JZ6.3 Hz, OCH(CH3)2); m/z
(EI) 208 (15, MC), 165 (41), 149 (11), 147 (19), 137 (7),
120 (7), 107 (100), 79 (50), 43 (23%).
4.4.17. (3R) Ethyl b-hydroxy-b-(o,p-dichlorophenyl)
propionate (4i).29 Colorless oil; [a]2D0ZC58.1 (c 0.9,
CHCl3). nmax (liquid film) 3473, 2984, 2908, 1720, 1591,
1471, 1375, 1192, 868, 823 cmK1; dH (300 MHz, CDCl3)
7.57 (1H, d, JZ8.7 Hz, C6H3), 7.35–7.26 (2H, m, C6H3),
5.42 (1H, dd, JZ2.1, 9.6 Hz, ArCHCH2), 4.17 (2H, q, JZ
7.5 Hz, OCH2CH3), 2.82 (1H, dd, JZ3.0, 16.5 Hz,
ArCHCH2CO), 2.53 (1H, dd, JZ9.6, 16.5 Hz, ArCHCH2-
CO), 1.28 (3H, t, JZ7.2 Hz, OCH2CH3); d13C(75.5 MHz,
CDCl3) 172.62, 139.13, 134.13, 132.29, 129.42, 128.54,
127.88, 67.01, 61.50, 60.85, 41.77, 14.51; m/z (EI) 263 (1,
MC), 227 (36), 177 (55), 175 (100), 173 (39), 139 (14), 111
(40), 88 (50), 75 (19), 43 (19%).
4.4.22. (3S) Isopropyl b-butyryloxy-b-phenyl propionate
(5k). Colorless oil; [a]2D0ZK41.8(c 1.4, CHCl3). nmax
(liquid film) 3067, 2980, 2938, 1740, 1376, 1274, 1172,
1109, 1007, 763, 700 cmK1; dH (300 MHz, CDCl3) 7.39–
7.26 (5H, m, C6H5), 6.18 (1H, dd, JZ5.4, 9.0 Hz,
PhCHCH2), 5.04–4.95 (1H, m, OCH(CH3)2), 2.93 (1H,
dd, JZ9.0, 15.3 Hz, PhCHCH2CO), 2.72 (1H, dd, JZ5.1,
15.3 Hz, PhCHCH2CO), 2.90 (2H, t, JZ7.5 Hz, COCH2-
CH2CH3), 1.69–1.57 (2H, m, COCH2CH2CH3), 1.20 (6H, t,
JZ7.5 Hz, OCH(CH3)2), 0.90 (3H, t, JZ7.2 Hz, COCH2-
CH2CH3); m/z (EI) 278 (1, MC), 207 (66), 165 (100), 147
(41), 131 (28), 120 (12), 105 (57), 71 (69), 43 (50%). Found:
C, 69.06; H, 7.84. C16H22O4 requires C, 69.04; H, 7.97.
4.4.18. (3S) Ethyl b-butyryloxy-b-(o,p-dichlorophenyl)
propionate (5i). Colorless oil; [a]2D0ZK12.3 (c 1.4,
CHCl3). nmax (liquid film) 2970, 2938, 2878, 1708, 1475,
1376, 1168, 1022, 824 cmK1; dH (300 MHz, CDCl3) 7.39–
7.23 (3H, m, C6H3), 6.44 (1H, dd, JZ5.4, 8.1 Hz,
ArCHCH2), 4.15 (2H, q, JZ6.9 Hz, OCH2CH3), 2.82–
2.79 (2H, m, ArCHCH2CO), 2.33 (2H, t, JZ7.8 Hz,
COCH2CH2CH3), 1.70–1.61 (2H, m, COCH2CH2CH3),
1.25 (3H, t, JZ7.2 Hz, OCH2CH3), 0.93 (3H, t, JZ
6.9 Hz, COCH2CH2CH3); d13C(75.5 MHz, CDCl3) 172.4,
169.7, 136.4, 134.8, 133.2, 130.0, 128.4, 127.9, 67.0, 61.3,
40.3, 36.4, 18.7, 14.5, 14.0; m/z (EI) 332 (1, MC), 297 (7),
263 (26), 261 (39), 215 (10), 209 (9), 199 (10), 175 (32), 173
(43), 71 (100), 43 (60%). Found: C, 54.37; H, 5.65.
C15H18O4Cl2 requires C, 54.07; H, 5.44.
4.4.23. (3R) Isopropyl b-hydroxy-b-(p-methoxylphenyl)
propionate (4l). Colorless oil; [a]2D0ZC32.1 (c 1.3,
CHCl3). nmax (liquid film) 3482, 2982, 2938, 2838, 1729,
1614, 1515, 1249, 1109, 1035, 834 cmK1; dH (300 MHz,
CDCl3) 7.29 (2H, d, JZ9.3 Hz, C6H4), 6.88 (2H, d, JZ
9.3 Hz, C6H4), 5.15–5.01 (2H, m, ArCHCH2, OCH(CH3)2),
3.80 (3H, s, OCH3), 2.73 (1H, dd, JZ8.7, 16.2 Hz,
ArCHCH2CO), 2.64 (1H, dd, JZ3.9, 16.5 Hz, ArCHCH2-
CO), 1.23 (6H, d, JZ6.0 Hz, OCH(CH3)2); d13C(75.5 MHz,
CDCl3) 172.3, 159.5, 135.3, 127.4, 114.2, 70.4, 68.7, 55.6,
44.1, 22.1; m/z (EI) 238 (12, MC), 195 (10), 179 (7), 137
(100), 135 (49), 109 (20), 94 (9), 77 (12), 43 (9%). Found:
C, 65.31; H, 7.54. C13H18O4 requires C, 65.53; H, 7.61.
4.4.19. (3R) Ethyl b-hydroxy-b-(p-nitrophenyl) propio-
nate (4j).30 Colorless oil; [a]D20ZC23.1 (c 1.0, CHCl3).
nmax (liquid film) 3480, 2985, 1732, 1522, 1349, 1195,
856 cmK1; dH (300 MHz, CDCl3) 8.22 (2H, d, JZ6.9 Hz,
C6H4), 7.57 (2H, d, JZ9.0 Hz, C6H4), 5.24 (1H, dd, JZ5.1,
7.5 Hz, ArCHCH2), 4.20 (2H, q, JZ6.9 Hz, OCH2CH3),
3.79 (1H, s, OH), 2.81–2.64 (2H, m, ArCHCH2CO), 1.28
4.4.24. (3S) Isopropyl b-butyryloxy-b-(p-methoxyl-
phenyl) propionate (5l). Colorless oil; [a]2D0ZK46.3 (c
1.2, CHCl3). nmax (liquid film) 2979, 2938, 2878, 1740,
1614, 1517, 1376, 1303, 1174, 1110, 833 cmK1; dH
(300 MHz, CDCl3) 7.30 (2H, d, JZ6.6 Hz, C6H4), 6.86
(2H, d, JZ6.6 Hz, C6H4), 6.13 (1H, dd, JZ5.4, 9.3 Hz,

2178
C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
ArCHCH2), 5.05–4.93 (1H, m, OCH(CH3)2), 3.79 (3H, s,
OCH3), 2.93 (1H, dd, JZ9.0, 15.9 Hz, ArCHCH2CO), 2.70
(1H, dd, JZ5.7, 15.0 Hz, ArCHCH2CO), 2.26 (2H, t, JZ
7.5 Hz, COCH2CH2CH3), 1.65–1.58 (2H, m, COCH2CH2-
CH3), 1.19 (6H, t, JZ6.6 Hz, OCH(CH3)2), 0.90 (3H, t, JZ
6.9 Hz, COCH2CH2CH3); d13C(75.5 MHz, CDCl3) 172.8,
169.7, 159.9, 131.9, 128.4, 114.3, 72.1, 68.5, 55.6, 42.1,
36.7, 22.1, 18.8, 14.0; m/z (EI) 308 (11, MC), 237 (60), 195
(78), 177 (9), 161 (30), 150 (19), 137 (47), 135 (100), 119
(8), 71 (44), 43 (59%). Found: C, 66.21; H, 7.78. C17H24O5
requires C, 66.21; H, 7.84.
3.05–2.86 (3H, m, OH, COCH2CHOH); m/z (EI) 222 (4,
MC), 204 (43), 149 (24), 144 (25), 131 (36), 116 (77), 107
(98), 105 (71), 79 (100), 77 (75), 43 (24%).
4.5.2. (5S) Methyl d-butyryloxy-d-phenyl-b-oxo-pen-
tanoates (8a). Colorless oil; [a]2D0ZK36.5 (c 1.5,
CHCl3). nmax (liquid film) 3066, 2967, 2878, 1741, 1324,
1552, 1174, 753, 703 cmK1; dH (300 MHz, CDCl3) 7.36–
7.26 (5H, m, C6H5), 6.20 (1H, dd, JZ4.8, 8.7 Hz, COCH2-
CHOCO), 3.72 (3H, s, OCH3), 3.46 (2H, s, COCH2CO2),
3.22 (1H, dd, JZ8.7, 16.8 Hz, COCH2CHOCO), 2.97 (1H,
dd, JZ4.8, 16.8 Hz, COCH2CHOCO), 2.28 (2H, t, JZ
7.5 Hz, COCH2CH2CH3), 1.68–1.58 (2H, m, COCH2CH2-
CH3), 0.90 (3H, t, JZ7.5 Hz, COCH2CH2CH3); m/z (EI)
274 (4, MCKH2O), 221 (39), 189 (52), 144 (15), 131 (27),
108 (88), 101 (27), 77 (22), 71 (100), 43 (81%). Found: C,
65.67; H, 7.02. C16H20O5 requires C, 65.74; H, 6.90.
4.4.25. (3R) n-Butyl b-hydroxy-b-phenyl propionate
(4m).8i,32 Colorless oil; [a]D20ZC28.3 (c 1.5, CHCl3).
nmax (liquid film) 3464, 2962, 2935, 1733, 1271, 1195, 1165,
1061, 761, 700 cmK1; dH (300 MHz, CDCl3) 7.39–7.26
(5H, m, C6H5), 5.12 (1H, dd, JZ4.5, 8.4 Hz, PhCHCH2),
4.12 (2H, t, JZ6.6 Hz, OCH2CH2CH2CH3), 3.22 (1H, s,
OH), 2.77 (1H, dd, JZ8.1, 15.9 Hz, PhCHCH2CO), 2.69
(1H, dd, JZ4.5, 16.5 Hz, PhCHCH2CO), 1.63–1.56 (2H, m,
OCH2CH2CH2CH3), 1.39–1.31 (2H, m, OCH2CH2CH2-
CH3), 0.92 (3H, t, JZ7.2 Hz, OCH2CH2CH2CH3);
4.5.3. (5R) Methyl d-hydroxy-d-(p-methylphenyl)-b-oxo-
pentanoates (7b). Colorless oil; [a]2D0ZC58.0 (c 1.0,
CHCl3). nmax (liquid film) 3496, 3025, 2955, 1747, 1715,
1516, 1438, 1325, 821 cmK1; dH (300 MHz, CDCl3) 7.24
(2H, d, JZ8.1 Hz, C6H4), 7.16 (2H, d, JZ7.8 Hz, C6H4),
5.14 (1H, dd, JZ3.3, 9.0 Hz, COCH2CHOH), 3.73 (3H, s,
OCH3), 3.50 (2H, s, COCH2CO2), 2.99 (1H, dd, JZ9.3,
17.1 Hz, COCH2CHOH), 2.87 (1H, dd, JZ3.6, 17.1 Hz,
COCH2CHOH), 2.34 (3H, s, ArCH3); m/z (EI) 236 (4, MC),
218 (33), 163 (16), 159 (10), 145 (23), 121 (100), 119 (40),
117 (14), 93 (52), 91 (47), 77 (25%). Found: C, 66.06; H,
7.03. C13H16O4 requires C, 66.09, H, 6.83.
d
13C(75.5 MHz, CDCl3) 172.8, 143.1, 128.9, 128.1, 126.1,
70.7, 65.1, 43.8, 31.0, 19.5, 14.1; m/z (EI) 272 (48, MC),
165 (14), 147 (27), 120 (18), 107 (100), 105 (85), 79 (50), 77
(34), 56 (19%).
4.4.26. (3S) n-Butyl b-butyryloxy-b-phenyl propionate
(5m). Colorless oil; [a]2D0ZK32.9(c 1.2, CHCl3). nmax
(liquid film) 2964, 2927, 2876, 1743, 1274, 1170, 1028, 763,
699 cmK1; dH (300 MHz, CDCl3) 7.39–7.27 (5H, m, C6H5),
6.17 (1H, dd, JZ4.8, 9.3 Hz, PhCHCH2), 4.08 (2H, t, JZ
6.3 Hz, OCH2CH2CH2CH3), 2.97 (1H, dd, JZ9.0, 15.6 Hz,
PhCHCH2CO), 2.75 (1H, dd, JZ5.1, 15.3 Hz, PhCHCH2-
CO), 2.29 (2H, t, JZ7.5 Hz, COCH2CH2CH3), 1.71–1.52
(4H, m, COCH2CH2CH3, OCH2CH2CH2CH3), 1.40–1.28
(2H, m, OCH2CH2CH2CH3), 0.94–0.88 (6H, m, COCH2-
CH2CH3, OCH2CH2CH2CH3); d13C(75.5 MHz, CDCl3)
172.7, 170.3, 139.9, 129.0, 128.7, 126.9, 72.4, 65.0, 42.0,
36.6, 31.0, 19.4, 18.89, 14.1, 14.0; m/z (EI) 293 (19, MC),
221 (38), 205 (100), 163 (46), 147 (13), 105 (35), 77 (12), 71
(24), 57 (39%). Found: C, 69.67; H, 8.11. C17H24O4 requires
C, 69.84; H, 8.27.
4.5.4. (5S) Methyl d-butyryloxy-d-(p-methylphenyl)-b-
oxo-pentanoates (8b). Colorless oil; [a]2D0ZK46.4 (c 0.8,
CHCl3). nmax (liquid film) 2964, 2876, 1738, 1516, 1174,
1085, 817 cmK1; dH (300 MHz, CDCl3) 7.24 (2H, d, JZ
7.8 Hz, C6H4), 7.15 (2H, d, JZ8.4 Hz, C6H4), 6.16 (1H, dd,
JZ5.1, 8.7 Hz, COCH2CHOCO), 3.72 (3H, s, OCH3), 3.45
(2H, s, COCH2CO2), 3.21 (1H, dd, JZ8.7, 17.1 Hz,
COCH2CHOCO), 2.95 (1H, dd, JZ4.8, 17.1 Hz, COCH2-
CHOCO), 2.33 (3H, s, ArCH3), 2.28 (2H, t, JZ7.2 Hz,
COCH2CH2CH3), 1.71–1.58 (2H, m, COCH2CH2CH3),
0.89 (3H, t, JZ7.2 Hz, COCH2CH2CH3); m/z (EI) 288 (2,
MCKH2O), 235 (35), 218 (9), 203 (43), 159 (7), 145 (27),
119 (100), 101 (17), 71 (60), 43 (37%). Found: C, 66.76; H,
7.20. C17H22O5 requires C, 66.65; H, 7.24.
4.5. General procedure of CRL-catalyzed enantio-
selective hydrolysis of d-butyryloxy-d-aryl-b-oxo-
pentanoates (6a–n)
4.5.5. (5R) Methyl d-hydroxy-d-(p-methoxylphenyl)-b-
oxo-pentanoates (7c).11a Colorless oil; [a]2D0ZC54.8 (c
0.8, CHCl3). nmax (liquid film) 3496, 3003, 2957, 2840,
1746, 1715, 1615, 1515, 1250, 1033, 836 cmK1; dH
(300 MHz, CDCl3) 7.27 (2H, d, JZ9.0 Hz, C6H4), 6.87
(2H, d, JZ8.4 Hz, C6H4), 5.12 (1H, dd, JZ3.3, 9.3 Hz,
COCH2CHOH), 3.79 (3H, s, ArOCH3), 3.73 (3H, s,
CO2CH3), 3.50 (2H, s, COCH2CO2), 2.99 (1H, dd, JZ9.0,
17.4 Hz, COCH2CHOH), 2.85 (1H, dd, JZ3.0, 17.4 Hz,
COCH2CHOH); m/z (EI) 252 (3, MC), 234 (6), 179 (4), 161
(8), 137 (100), 135 (19), 109 (19), 94 (10), 77 (12), 65 (4%).
Substrates 6a–n (150 mg) and CRL (30 mg) were added in
diisopropyl ether pre-saturated with 1.2 M aqueous MgCl2
(5 mL). The mixture was stirred 24 h at 30 8C, and filtered
off the CRL that could be reuse 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 the hydrolyzed alcohols 7a–n and
unreacted esters 8a–n. The yields are listed in Table 2.
4.5.1. (5R) Methyl d-hydroxy-d-phenyl-b-oxo-pentano-
ates (7a).33 Colorless oil; [a]D20ZC58.1 (c 1.0, CHCl3).
nmax (liquid film) 3497, 3064, 3033, 2956, 1745, 1714, 1439,
1327, 1156, 753, 702 cmK1; dH (300 MHz, CDCl3) 7.37–
7.26 (5H, m, C6H5), 5.18 (1H, dd, JZ5.7, 9.0 Hz, COCH2-
CHOH), 3.73 (3H, s, OCH3), 3.51 (2H, s, COCH2CO2),
4.5.6. (5S) Methyl d-butyryloxy-d-(p-methoxylphenyl)-
b-oxo-pentanoates (8c). Colorless oil; [a]2D0ZK48.6 (c
0.9, CHCl3). nmax (liquid film) 2966, 2939, 2878, 1739,
1614, 1516, 1251, 1174, 1033, 834 cmK1; dH (300 MHz,
CDCl3) 7.29 (2H, d, JZ8.7 Hz, C6H4), 6.87 (2H, d, JZ6.6 Hz,

C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
2179
C6H4), 6.15 (1H, dd, JZ4.8, 9.0 Hz, COCH2CHOCO), 3.79
(3H, s, ArOCH3), 3.72 (3H, s, CO2CH3), 3.45 (2H, s,
COCH2CO2), 3.22 (1H, dd, JZ9.0, 17.1 Hz, COCH2-
CHOCO), 2.96 (1H, dd, JZ5.1, 17.1 Hz, COCH2CHOCO),
2.25 (2H, t, JZ7.8 Hz, COCH2CH2CH3), 1.63–1.56 (2H, m,
COCH2CH2CH3), 0.89 (3H, t, JZ7.2 Hz, COCH2CH2-
CH3); m/z (EI) 322 (5, MC), 251 (27), 234 (15), 219 (25),
207 (9), 161 (52), 137 (67), 135 (100), 101 (16), 71 (36%).
Found: C, 63.11; H, 7.13. C17H22O6 requires C, 63.34; H,
6.88.
291 (20), 269 (11), 209 (10), 203 (100), 183 (31), 101 (37),
71 (77), 59 (17), 43 (43%). Found: C, 51.98; H, 5.20.
C16H19BrO5 requires C, 51.77; H, 5.16.
4.5.11. (5R) Methyl d-hydroxy-d-(p-fluorophenyl)-b-
oxo-pentanoates (7f). Colorless oil; [a]2D0ZC52.6 (c 1.4,
CHCl3). nmax (liquid film) 3503, 2957, 1747, 1716, 1606,
1512, 1223, 840 cmK1; dH (300 MHz, CDCl3) 7.35–7.28
(2H, m, C6H4), 7.03 (2H, t, JZ6.9 Hz, C6H4), 5.15 (1H, dd,
JZ2.7, 9.0 Hz, COCH2CHOH), 3.72 (3H, s, OCH3), 3.50
(2H, s, COCH2CO2), 2.97 (1H, dd, JZ9.0, 17.4 Hz,
COCH2CHOH), 2.87 (1H, dd, JZ3.6, 17.4 Hz, COCH2-
CHOH); m/z (EI) 240 (2, MC), 222 (27), 180 (9), 167 (21),
162 (15), 149 (32), 125 (100), 123 (65), 116 (64), 97 (77), 85
(25%). Found: C, 60.09; H, 5.63. C12H13FO4 requires C,
60.00; H, 5.45.
4.5.7. (5R) Methyl d-hydroxy-d-furan-2-yl-b-oxo-pen-
tanoates (7d).34 Colorless oil; [a]2D0ZC23.2 (c 1.0,
CHCl3). nmax (liquid film) 3482, 3124, 2957, 1745, 1716,
1439, 1327, 1151, 1012, 747 cmK1; dH (300 MHz, CDCl3)
7.37–7.36 (1H, m, C4H3O), 6.34–6.32 (1H, m, C4H3O), 6.28
(1H, d, JZ3.6 Hz, C4H3O), 5.20 (1H, dd, JZ3.6, 8.7 Hz,
COCH2CHOH), 3.74 (3H, s, OCH3), 3.53 (2H, s, COCH2-
CO2), 3.17 (1H, dd, JZ9.0, 17.4 Hz, COCH2CHOH), 3.03
(1H, dd, JZ3.6, 17.4 Hz, COCH2CHOH); m/z (EI) 212 (20,
MC), 180 (17), 152 (10), 139 (20), 121 (26), 116 (25), 110
(29), 97 (100), 95 (20), 69 (16%).
4.5.12. (5S) Methyl d-butyryloxy-d-(p-fluorophenyl)-b-
oxo-pentanoates (8f). Colorless oil; [a]2D0ZK31.7 (c 1.1,
CHCl3). nmax (liquid film) 2967, 2939, 2879, 1741, 1513,
1228, 1177, 1085, 839 cmK1; dH (300 MHz, CDCl3) 7.36–
7.31 (2H, m, C6H4), 7.03 (2H, t, JZ6.9 Hz, C6H4), 6.17
(1H, dd, JZ5.1, 8.7 Hz, COCH2CHOCO), 3.72 (3H, s,
OCH3), 3.45 (2H, s, COCH2CO2), 3.22 (1H, dd, JZ8.7,
16.8 Hz, COCH2CHOCO), 2.97 (1H, dd, JZ5.4, 17.1 Hz,
COCH2CHOCO), 2.27 (2H, t, JZ7.2 Hz, COCH2CH2CH3),
1.70–1.57 (2H, m, COCH2CH2CH3), 0.90 (3H, t, JZ7.2 Hz,
COCH2CH2CH3); m/z (EI) 292 (3, MCKH2O), 239 (69),
222 (16), 207 (100), 162 (14), 149 (36), 123 (90), 122 (38),
101 (41), 71 (83%). Found: C, 62.05; H, 6.30. C16H19O5F
requires C, 61.93; H, 6.17.
4.5.8. (5S) Methyl d-butyryloxy-d-furan-2-yl-b-oxo-pen-
tanoates (8d). Colorless oil; [a]2D0ZK95.1 (c 1.0, CHCl3).
nmax (liquid film) 2968, 2879, 1737, 1438, 1326, 1174,
1014, 749 cmK1; dH (300 MHz, CDCl3) 7.39–7.36 (1H, m,
C4H3O), 6.38–6.27 (3H, m, C4H3O, COCH2CHOCO), 3.74
(3H, s, OCH3), 3.49 (2H, s, COCH2CO2), 3.32 (1H, dd, JZ
8.4, 17.4 Hz, COCH2CHOCO), 3.16 (1H, dd, JZ5.4,
17.4 Hz, COCH2CHOCO), 2.25 (2H, t, JZ7.5 Hz, COCH2-
CH2CH3), 1.69–1.54 (2H, m, COCH2CH2CH3), 0.89 (3H, t,
JZ7.5 Hz, COCH2CH2CH3); m/z (EI) 282 (1, MC), 211
(52), 179 (100), 162 (9), 137 (41), 121 (36), 101 (33), 94
(36), 71 (68), 43 (51%). Found: C, 59.59; H, 6.44. C14H18O6
requires C, 59.57; H, 6.43.
4.5.13. (5R) Methyl d-hydroxy-d-(o,p-dichlorophenyl)-b-
oxo-pentanoates (7g). Colorless oil; [a]2D0ZC79.3 (c 1.2,
CHCl3). nmax (liquid film) 3524, 2982, 2951, 1737, 1695,
1442, 1336, 1087, 1006, 824 cmK1; dH (300 MHz, CDCl3)
7.57 (1H, d, JZ8.1 Hz, C6H3), 7.36–7.27 (2H, m, C6H3),
5.49 (1H, dd, JZ2.4, 9.6 Hz, COCH2CHOH), 3.75 (3H, s,
OCH3), 3.53 (2H, s, COCH2CO2), 3.06 (1H, dd, JZ2.7,
17.7 Hz, COCH2CHOH), 2.77 (1H, dd, JZ9.9, 17.7 Hz,
COCH2CHOH); d13C(75.5 MHz, CDCl3) 202.9, 167.7,
139.1, 134.1, 132.1, 129.4, 128.5, 128.0, 66.5, 52.9, 49.9,
49.8; m/z (EI) 274 (15, MCKH2O), 272 (23, MCKH2O),
237 (17), 177 (53), 175 (100), 173 (39), 147 (17), 116 (96),
111 (52), 84 (29), 74 (35%). Found: C, 49.60; H, 4.36.
C12H12Cl2O4 requires C, 49.51; H, 4.15.
4.5.9. (5R) Methyl d-hydroxy-d-(o-bromophenyl)-b-oxo-
pentanoates (7e). Colorless oil; [a]2D0ZC79.5 (c 0.9,
CHCl3). nmax (liquid film) 3522, 2981, 2947, 2920, 1735,
1698, 1440, 1331, 1196, 1144, 1006, 749 cmK1; dH
(300 MHz, CDCl3) 7.62 (1H, d, JZ6.6 Hz, C6H4), 7.51
(1H, d, JZ7.8 Hz, C6H4), 7.35 (1H, t, JZ7.5 Hz, C6H4),
7.13 (1H, t, JZ7.2 Hz, C6H4), 5.49 (1H, dd, JZ1.8, 9.6 Hz,
COCH2CHOH), 3.79 (3H, s, OCH3), 3.54 (2H, s, COCH2-
CO2), 3.09 (1H, dd, JZ2.4, 17.7 Hz, COCH2CHOH), 2.78
(1H, dd, JZ9.6, 17.7 Hz, COCH2CHOH); m/z (EI) 284 (14,
MCKH2O), 282 (14, MCKH2O), 221 (11), 203 (54), 187
(48), 185 (69), 157 (20), 116 (100), 105 (20), 84 (26), 77
(78), 59 (19%). Found: C, 47.88; H, 4.56. C12H13BrO4
requires C, 47.86; H, 4.35.
4.5.14. (5S) Methyl d-butyryloxy-d-(o,p-dichlorophenyl)-
b-oxo-pentanoates (8g). Colorless oil; [a]2D0ZK15.2 (c
1.6, CHCl3). nmax (liquid film) 3095, 2967, 2878, 1745,
1592, 1774, 1247, 1172, 1103, 824 cmK1; dH (300 MHz,
CDCl3) 7.39–7.24 (3H, m, C6H3), 6.45 (1H, dd, JZ3.9,
8.4 Hz, COCH2CHOCO), 3.74 (3H, s, OCH3), 3.51 (2H, s,
COCH2CO2), 3.18–3.03 (2H, m, COCH2CHOCO), 2.32
(2H, t, JZ7.5 Hz, COCH2CH2CH3), 1.69–1.60 (2H, m,
COCH2CH2CH3), 0.92 (3H, t, JZ7.2 Hz, COCH2CH2-
CH3); d13C(75.5 MHz, CDCl3) 198.6, 173.4, 172.5, 136.4,
134.8, 132.9, 130.0, 128.3, 127.9, 68.1, 52.9, 51.7, 49.5,
47.7, 36.4, 18.7, 14.0; m/z (EI) 325 (3, MCKCl), 291 (15),
289 (23), 257 (32), 237 (29), 215 (9), 199 (12), 173 (46), 101
(39), 71 (100), 43 (55%). Found: C, 53.38; H, 5.07.
C16H18Cl2O5 requires C, 53.20; H, 5.02.
4.5.10. (5S) Methyl d-butyryloxy-d-(o-bromophenyl)-b-
oxo-pentanoates (8e). Colorless oil; [a]2D0ZK0.92 (c 1.2,
CHCl3). nmax (liquid film) 3066, 2967, 2937, 2877, 1743,
1438, 1250, 1174, 1086, 757 cmK1; dH (300 MHz, CDCl3)
7.54 (1H, d, JZ8.1 Hz, C6H4), 7.37–7.28 (2H, m, C6H4),
7.15 (1H, dt, JZ2.1, 8.1 Hz, C6H4), 6.47 (1H, t, JZ6.3 Hz,
COCH2CHOCO), 3.73 (3H, s, OCH3), 3.53 (2H, s,
COCH2CO2), 3.50 (2H, d, JZ6.3 Hz, COCH2CHOCO),
2.33 (2H, t, JZ7.5 Hz, COCH2CH2CH3), 1.71–1.59 (2H, m,
COCH2CH2CH3), 0.93 (3H, t, JZ7.2 Hz, COCH2CH2-
CH3); m/z (EI) 301 (5, MCKnPrCO), 299 (5, MCKnPrCO),

2180
C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
4.5.15. (5R) Methyl d-hydroxy-d-(p-nitrophenyl)-b-oxo-
pentanoates (7h).11 Colorless oil; [a]2D0ZC49.8 (c 1.0,
CHCl3). nmax(liquid film) 3535, 2959, 2893, 1735, 1707,
1514, 1347, 1190, 100, 856 cmK1; dH (300 MHz, CDCl3)
8.21 (2H, d, JZ9.0 Hz, C6H4), 7.55 (2H, d, JZ8.7 Hz,
C6H4), 5.32 (1H, t, JZ6.0 Hz, COCH2CHOH), 3.75 (3H, s,
OCH3), 3.54 (2H, s, COCH2CO2), 2.99 (2H, d, JZ6.0 Hz,
COCH2CHOH); m/z (EI) 250 (13, MCKOH), 235 (44), 218
(21), 207 (14), 194 (14), 176 (27), 165 (20), 152 (75), 151
(90), 116 (100), 101 (32), 74 (64%).
(20), 145 (33), 130 (46), 121 (100), 119 (58), 93 (59), 91
(55), 77 (29%). Found: C, 67.04; H, 7.36. C14H18O4 requires
C, 67.18; H, 7.25.
4.5.20. (5S) Ethyl d-butyryloxy-d-(p-methylphenyl)-b-
oxo-pentanoates (8j). Colorless oil; [a]2D0ZK38.8 (c 1.0,
CHCl3). nmax (liquid film) 2969, 2937, 2877, 1740, 1319,
1251, 1176, 1087, 817 cmK1; dH (300 MHz, CDCl3) 7.25
(2H, d, JZ8.1 Hz, C6H4), 7.15 (2H, d, JZ7.8 Hz, C6H4),
6.17 (1H, dd, JZ4.8, 8.4 Hz, COCH2CHOCO), 4.18 (2H, q,
JZ7.2 Hz, OCH2CH3), 3.43 (2H, s, COCH2CO2), 3.22 (1H,
dd, JZ8.4, 16.8 Hz, COCH2CHOCO), 2.96 (1H, dd, JZ
4.8, 16.8 Hz, COCH2CHOCO), 2.33 (3H, s, ArCH3), 2.27
(2H, t, JZ7.5 Hz, COCH2CH2CH3), 1.70–1.56 (2H, m,
COCH2CH2CH3), 1.26 (3H, t, JZ7.2 Hz, OCH2CH3), 0.90
(3H, t, JZ7.5 Hz, COCH2CH2CH3); m/z (EI) 302 (4, MCK
H2O), 249 (34), 232 (9), 203 (50), 159 (9), 145 (25), 119
(100), 91 (16), 71 (53), 43 (39%). Found: C, 67.30; H, 7.76.
C18H24O5 requires C, 67.48; H, 7.55.
4.5.16. (5S) Methyl d-butyryloxy-d-(p-nitrophenyl)-b-
oxo-pentanoates (8h). Colorless oil; [a]2D0ZK27.8 (c 0.9,
CHCl3). nmax (liquid film) 2968, 2878, 1744, 1524, 1349,
1172, 1087, 856 cmK1; dH (300 MHz, CDCl3) 8.20 (2H, d,
JZ6.9 Hz, C6H4), 7.54 (2H, d, JZ6.6 Hz, C6H4), 6.26 (1H,
dd, JZ5.1, 8.1 Hz, COCH2CHOCO), 3.73 (3H, s, OCH3),
3.48 (2H, s, COCH2CO2), 3.27 (1H, dd, JZ8.1, 17.4 Hz,
COCH2CHOCO), 3.03 (1H, dd, JZ5.1, 17.4 Hz, COCH2-
CHOCO), 2.32 (2H, t, JZ7.5 Hz, COCH2CH2CH3), 1.78–
1.58 (2H, m, COCH2CH2CH3), 0.91 (3H, t, JZ7.5 Hz,
COCH2CH2CH3); m/z (EI) 319 (2, MCKH2O), 266 (29),
250 (29), 234 (53), 218 (63), 176 (55), 150 (43), 101 (40),
101 (16), 71 (100), 43 (56%). Found: C, 56.88; H, 5.84; N,
3.92. C16H19NO7 requires C, 56.97; H, 5.68; N, 4.15.
4.5.21. (5R) Ethyl d-hydroxy-d-(p-methoxylphenyl)-b-
oxo-pentanoates (7k).36 Colorless oil; [a]2D0ZC42.9 (c
1.1, CHCl3). nmax (liquid film) 3502, 2983, 2839, 1741,
1515, 1249, 1033, 835 cmK1; dH (300 MHz, CDCl3) 7.28
(2H, d, JZ6.9 Hz, C6H4), 6.88 (2H, d, JZ6.6 Hz, C6H4),
5.13 (1H, dd, JZ3.6, 9.0 Hz, COCH2CHOH), 4.19 (2H, q,
JZ7.5 Hz, OCH2CH3), 3.81 (3H, s, OCH3), 3.48 (2H, s,
COCH2CO2), 3.00 (1H, dd, JZ9.0, 17.4 Hz, COCH2-
CHOH), 2.88 (1H, dd, JZ3.6, 17.4 Hz, COCH2CHOH),
1.28 (3H, t, JZ6.9 Hz, OCH2CH3); m/z (EI) 266 (2, MC),
248 (7), 179 (4), 161 (10), 137 (100), 135 (22), 109 (19), 94
(10), 77 (13%).
4.5.17. (5R) Ethyl d-hydroxy-d-phenyl-b-oxo-pentano-
ates (7i).35 Colorless oil; [a]D20ZC50.8 (c 1.0, CHCl3). nmax
(liquid film) 3489, 3033, 2984, 2908, 1741, 1715, 1321,
1193, 1030, 702 cmK1; dH (300 MHz, CDCl3) 7.37–7.26
(5H, m, C6H5), 5.17 (1H, dd, JZ3.6, 5.7 Hz, COCH2-
CHOH), 4.18 (2H, q, JZ7.2 Hz, OCH2CH3), 3.47 (2H, s,
COCH2CO2), 2.99 (1H, dd, JZ9.0, 17.1 Hz, COCH2-
CHOH), 2.88 (1H, dd, JZ3.6, 17.1 Hz, COCH2CHOH),
1.26 (3H, t, JZ6.9 Hz, OCH2CH3); m/z (EI) 236 (4, MC),
218 (37), 189 (8), 162 (17), 144 (30), 131 (54), 130 (75), 107
(99), 105 (100), 84 (44), 79 (99), 77 (83%).
4.5.22. (5S) Ethyl d-butyryloxy-d-(p-methoxylphenyl)-b-
oxo-pentanoates (8k). Colorless oil; [a]2D0ZK47.0 (c 1.0,
CHCl3). nmax (liquid film) 2968, 2938, 2877, 2840, 1739,
1614, 1516, 1251, 1175, 1034, 834 cmK1; dH (300 MHz,
CDCl3) 7.29 (2H, d, JZ6.6 Hz, C6H4), 6.86 (2H, d, JZ
6.6 Hz, C6H4), 6.16 (1H, dd, JZ5.1, 8.4 Hz, COCH2-
CHOCO), 4.18 (2H, q, JZ7.2 Hz, OCH2CH3), 3.79 (3H, s,
OCH3), 3.43 (2H, s, COCH2CO2), 3.23 (1H, dd, JZ8.4,
16.8 Hz, COCH2CHOCO), 2.96 (1H, dd, JZ4.8, 16.8 Hz,
COCH2CHOCO), 2.50 (2H, t, JZ7.2 Hz, COCH2CH2CH3),
1.65–1.56 (2H, m, COCH2CH2CH3), 1.28 (3H, t, JZ7.2 Hz,
OCH2CH3), 0.89 (3H, t, JZ7.5 Hz, COCH2CH2CH3); m/z
(EI) 336 (3, MC), 265 (32), 248 (15), 219 (39), 207 (10),
161 (43), 137 (57), 135 (100), 71 (79), 43 (24%). Found: C,
64.18; H, 7.28. C18H24O6 requires C, 64.27; H, 7.19.
4.5.18. (5S) Ethyl d-butyryloxy-d-phenyl-b-oxo-pentano-
ates (8i). Colorless oil; [a]2D0ZK35.8 (c 1.1, CHCl3). nmax
(liquid film) 3066, 2969, 2877, 1741, 1369, 1252, 1175,
1091, 701 cmK1; dH (300 MHz, CDCl3) 7.36–7.26 (5H, m,
C6H5), 6.21 (1H, dd, JZ4.5, 8.7 Hz, COCH2CHOCO), 4.18
(2H, q, JZ6.9 Hz, OCH2CH3), 3.44 (2H, s, COCH2CO2),
3.23 (1H, dd, JZ9.0, 17.1 Hz, COCH2CHOCO), 2.98 (1H,
dd, JZ4.5, 17.1 Hz, COCH2CHOCO), 2.28 (2H, t, JZ
8.1 Hz, COCH2CH2CH3), 1.71–1.58 (2H, m, COCH2CH2-
CH3), 1.27 (3H, t, JZ7.5 Hz, OCH2CH3), 0.89 (3H, t, JZ
7.2 Hz, COCH2CH2CH3); m/z (EI) 306 (5, MC), 251 (27),
234 (15), 219 (25), 207 (9), 161 (52), 137 (67), 135 (100),
101 (16), 71 (36%). Found: C, 66.34; H, 7.21. C17H22O5
requires C, 66.65; H, 7.24.
4.5.23. (5R) Ethyl d-hydroxy-d-furan-2-yl-b-oxo-pen-
tanoates (7l). Colorless oil; [a]2D0ZC32.2 (c 1.1, CHCl3).
nmax (liquid film) 3484, 2985, 1741, 1716, 1370, 1321, 1151,
745 cmK1; dH (300 MHz, CDCl3) 7.39–7.36 (1H, m,
C4H3O), 6.35–6.28 (2H, m, C4H3O), 5.21 (1H, dd, JZ3.6,
8.4 Hz, COCH2CHOH), 4.21 (2H, q, JZ6.9 Hz,
OCH2CH3), 3.51 (2H, s, COCH2CO2), 3.18 (1H, dd, JZ
8.7, 17.7 Hz, COCH2CHOH), 3.05 (1H, dd, JZ3.6,
17.7 Hz, COCH2CHOH), 1.29 (3H, t, JZ6.9 Hz,
OCH2CH3); m/z (EI) 226 (22, MC), 180 (24), 152 (140),
139 (21), 130 (24), 121 (34), 110 (41), 97 (100), 95 (26), 84
(16%). Found: C, 58.20; H, 6.39. C11H14O5 requires C,
58.40; H, 6.24.
4.5.19. (5R) Ethyl d-hydroxy-d-(p-methylphenyl)-b-oxo-
pentanoates (7j). Colorless oil; [a]2D0ZC47.9 (c 1.3,
CHCl3). nmax (liquid film) 3491, 2984, 1743, 1714, 1320,
1033, 821 cmK1; dH (300 MHz, CDCl3) 7.24 (2H, d, JZ
8.1 Hz, C6H4), 7.15 (2H, d, JZ8.4 Hz, C6H4), 5.24 (1H, dd,
JZ3.0, 9.0 Hz, COCH2CHOH), 4.18 (2H, q, JZ6.6 Hz,
OCH2CH3), 3.47 (2H, s, COCH2CO2), 2.99 (1H, dd, JZ9.0,
17.1 Hz, COCH2CHOH), 2.87 (1H, dd, JZ3.3, 17.1 Hz,
COCH2CHOH), 2.33 (3H, s, ArCH3), 1.28 (3H, t, JZ
6.9 Hz, OCH2CH3); m/z (EI) 250 (5, MC), 232 (36), 163

C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
2181
4.5.24. (5S) Ethyl d-butyryloxy-d-furan-2-yl-b-oxo-pen-
tanoates (8l). Colorless oil; [a]2D0ZK94.5 (c 1.3, CHCl3).
nmax (liquid film) 2970, 2939, 2878, 1743, 1251, 1174, 1093,
1015, 748 cmK1; dH (300 MHz, CDCl3) 7.40–7.28 (1H, m,
C4H3O), 6.38–6.28 (3H, m, C4H3O, COCH2CHOCO), 4.20
(2H, q, JZ7.2 Hz, OCH2CH3), 3.47 (2H, s, COCH2CO2),
3.33 (1H, dd, JZ8.1, 17.1 Hz, COCH2CHOCO), 3.16 (1H,
dd, JZ4.8, 17.1 Hz, COCH2CHOCO), 2.25 (2H, t, JZ
7.5 Hz, COCH2CH2CH3), 1.68–1.58 (2H, m, COCH2CH2-
CH3), 1.28 (3H, t, JZ6.9 Hz, OCH2CH3), 0.90 (3H, t, JZ
7.2 Hz, COCH2CH2CH3); m/z (EI) 296 (1, MC), 225 (48),
219 (7), 203 (50), 179 (100), 137 (40), 121 (24), 95 (19), 71
(34), 43 (30%). Found: C, 60.82; H, 6.95. C15H20O6 requires
C, 60.80; H, 6.80.
CHCl3). nmax (liquid film) 2970, 2939, 2878, 1743, 1524,
1349, 1172, 856 cmK1; dH (300 MHz, CDCl3) 8.21 (2H, d,
JZ8.1 Hz, C6H4), 7.53 (2H, d, JZ8.7 Hz, C6H4), 6.26 (1H,
dd, JZ5.1, 8.4 Hz, COCH2CHOCO), 4.18 (2H, q, JZ
7.2 Hz, OCH2CH3), 3.45 (2H, s, COCH2CO2), 3.26 (1H, dd,
JZ8.4, 17.7 Hz, COCH2CHOCO), 3.00 (1H, dd, JZ5.4,
17.7 Hz, COCH2CHOCO), 2.31 (2H, t, JZ7.2 Hz, COCH2-
CH2CH3), 1.69–1.59 (2H, m, COCH2CH2CH3), 1.25 (3H, t,
JZ7.2 Hz, OCH2CH3), 0.90 (3H, t, JZ7.2 Hz, COCH2-
CH2CH3); m/z (EI) 333 (3, MCKH2O), 280 (26), 264 (25),
234 (56), 218 (64), 190 (23), 176 (59), 150 (40), 134 (25), 71
(100), 43 (75%). Found: C, 58.34; H, 5.82; N, 4.11.
C17H21NO7 requires C, 58.11; H, 6.02; N, 3.99.
4.6. General procedure of CRL-catalyzed enantio-
selective alcoholysis of d-chloroacetyloxy-d-aryl-b-oxo-
pentanoates (13a,c,g,i,k,m) and chemical hydrolysis of
chiral d-chloroacetyloxy-d-aryl-b-oxo-pentanoates
(14a,c,g,i,k,m)
4.5.25. (5R) Ethyl d-butyryloxy-d-(o,p-dichlorophenyl)-
b-oxo-pentanoates (7m). Colorless oil; [a]2D0ZC75.3 (c
1.0, CHCl3). nmax (liquid film) 3320, 2979, 2938, 1747,
1712, 1473, 1407, 1135, 1030, 821 cmK1; dH (300 MHz,
CDCl3) 7.58 (1H, d, JZ9.0 Hz, C6H3), 7.57–7.28 (2H, m,
C6H3), 5.50 (1H, dd, JZ2.1, 9.3 Hz, COCH2CHOH), 4.22
(2H, q, JZ7.2 Hz, OCH2CH3), 3.52 (2H, s, COCH2CO2),
3.42 (1H, d, JZ5.2 Hz, COCH2CHOH), 3.08 (1H, d, JZ
16.2 Hz, COCH2CHOH), 1.30 (3H, t, JZ7.8 Hz,
OCH2CH3); d13C(75.5 MHz, CDCl3) 203.0, 167.2, 139.1,
134.1, 132.1, 129.4, 128.6, 127.9, 66.5, 62.1, 50.1, 49.9,
14.5; m/z (EI) 288 (15, MCKH2O), 286 (22, MCKH2O),
251 (16), 212 (17), 199 (19), 175 (100), 147 (15), 130 (89),
111 (50), 88 (35), 75 (20%). Found: C, 51.26; H, 4.59;
C13H14Cl2O4 requires C, 51.17; H, 4.62.
Substrates 13a,c,g,i,k,m (0.5 mmol), butyl alcohol (23 mg,
0.31 mmol) and CRL (30 mg) were added anhydrous
benzene (3 mL). The mixture was stirred 12 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 the hydrolyzed
alcohols 7a–m and unreacted esters 14a,c,g,i,k,m. The
yields are listed in Table 3.
Chiral
d-chloroacetyloxy-d-aryl-b-oxo-pentanoates
(14a,c,g,i,k,m) (0.1 mmol), methyl alcohol (3 mL) and
ammonium hydroxide (5 drops) were stirred at 0 8C for 2 h,
then ethyl acetate (5 mL) and brine (3 mL) were added, and
water phase was washed with ethyl acetate (5 mL) again.
The combined organic phase was dried and solvent was
removed in vacuum, and the residue was subjected to flash
chromatography to afford optical active 15a,c,g,i,k,m. The
yields are listed in Table 3.
4.5.26. (5S) Ethyl d-butyryloxy-d-(o,p-dichlorophenyl)-
b-oxo-pentanoates (8m). Colorless oil; [a]2D0ZK16.8 (c
1.1, CHCl3). nmax (liquid film) 2970, 2937, 2878, 1745,
1475, 1369, 1244, 1173, 824 cmK1; dH (300 MHz, CDCl3)
7.39–7.23 (3H, m, C6H3), 6.45 (1H, dd, JZ5.2, 8.4 Hz,
COCH2CHOCO), 4.20 (2H, q, JZ7.2 Hz, OCH2CH3), 3.48
(2H, s, COCH2CO2), 3.09–2.98 (2H, m, COCH2CHOCO),
2.32 (2H, t, JZ7.5 Hz, COCH2CH2CH3), 1.69–1.60 (2H, m,
COCH2CH2CH3), 1.30 (3H, t, JZ7.2 Hz, OCH2CH3), 0.93
(3H, t, JZ7.5 Hz, COCH2CH2CH3); d13C(75.5 MHz,
CDCl3) 198.75, 172.45, 167.10, 136.45, 134.76, 132.93,
129.99, 128.31, 127.92, 68.12, 61.95, 49.78, 47.63, 36.46,
18.72, 14.54, 13.98; m/z (EI) 358 (1, MCKH2O), 356 (3,
MCKH2O), 305 (19), 303 (29), 259 (34), 257 (51), 251
(37), 215 (16), 199 (17), 175 (36), 71 (100), 43 (56%). Found:
C, 54.56; H, 5.39; C17H20Cl2O5 requires C, 54.41; H, 5.37.
4.6.1. (5R) Methyl d-hydroxy-d-phenyl-b-oxo-pentano-
ates (7a).33 Colorless oil; [a]D20ZC56.7 (c 1.0, CHCl3).
4.6.2. (5S) Methyl d-chloroacetyloxy-d-phenyl-b-oxo-
pentanoates (14a). Colorless oil; [a]2D0ZK38.1 (c 1.0,
CHCl3). nmax (liquid film) 3036, 2957, 1749, 1722, 1322,
1170, 993, 701 cmK1; dH (300 MHz, CDCl3) 7.40–7.26
(5H, m, C6H5), 6.27 (1H, dd, JZ4.5, 8.4 Hz, COCH2-
CHOCO), 4.06 (2H, s, ClCH2CO), 3.72 (3H, s, OCH3), 3.53
(2H, s, COCH2CO2), 3.31 (1H, dd, JZ9.0, 17.4 Hz,
COCH2CHOCO), 3.02 (1H, dd, JZ4.5, 17.4 Hz, COCH2-
CHOCO),; m/z (EI) 280 (13, MCKH2O), 221 (39), 204
(40), 189 (50), 144 (28), 131 (100), 105 (98), 101 (32), 77
(59), 59 (22%). Found: C, 56.55; H, 5.32. C14H15ClO5
requires C, 56.29; H, 5.06.
4.5.27. (5R) Ethyl d-hydroxy-d-(p-nitrophenyl)-b-oxo-
pentanoates (7n). Colorless oil; [a]2D0ZC37.8 (c 1.2,
CHCl3). nmax (liquid film) 3364, 3086, 2981, 1741, 1517,
1349, 1136, 1023, 856 cmK1; dH (300 MHz, CDCl3) 8.21
(2H, d, JZ8.7 Hz, C6H4), 7.56 (2H, d, JZ8.7 Hz, C6H4),
5.32 (1H, dd, JZ3.0, 9.6 Hz, COCH2CHOH), 4.22 (2H, q,
JZ6.9 Hz, OCH2CH3), 3.52 (2H, s, COCH2CO2), 2.99 (2H,
d, JZ6.3 Hz, COCH2CHOH), 1.28 (3H, t, JZ6.9 Hz,
OCH2CH3); m/z (EI) 263 (3, MCKH2O), 235 (66), 221
(33), 192 (13), 176 (32), 165 (24), 152 (78), 151 (93), 150
(100), 130 (91), 77 (42%). Found: C, 55.52; H, 5.39; N,
4.89. C13H15NO6 requires C, 55.51; H, 5.38; N, 4. 98.
4.6.3. (5S) Methyl d-hydroxy-d-phenyl-b-oxo-pentano-
ates (15a).33 Colorless oil; [a]D20ZK54.3 (c 1.2, CHCl3).
All of its spectrums were identical with its enantiomer.
4.6.4. (5R) Methyl d-hydroxy-d-(p-methoxylphenyl)-b-
oxo-pentanoates (7c).11a Colorless oil; [a]2D0ZC51.9 (c
1.0, CHCl3).
4.5.28. (5S) Ethyl d-butyryloxy-d-(p-nitrophenyl)-b-oxo-
pentanoates (8n). Colorless oil; [a]2D0ZK30.0 (c 1.0,

2182
C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
4.6.5. (5S) Methyl d-chloroacetyloxy-d-(p-methoxyl-
phenyl)-b-oxo-pentanoates (14c). Colorless oil; [a]2D0Z
K49.7 (c 2.0, CHCl3). nmax (liquid film) 3007, 2958, 2841,
1749, 1722, 1517, 1252, 1175, 1031, 835 cmK1; dH
(300 MHz, CDCl3) 7.32 (2H, d, JZ9.3 Hz, C6H4), 6.88
(2H, d, JZ9.3 Hz, C6H4), 6.23 (1H, dd, JZ4.8, 8.7 Hz,
COCH2CHOCO), 4.03 (2H, s, ClCH2CO), 3.80 (3H, s,
ArOCH3), 3.72 (3H, s, CO2CH3), 3.47 (2H, s, COCH2CO2),
3.31 (1H, dd, JZ8.7, 17.4 Hz, COCH2CHOCO), 3.01 (1H,
dd, JZ4.5, 17.4 Hz, COCH2CHOCO); m/z (EI) 328 (3,
MC), 234 (22), 175 (18), 161 (100), 137 (61), 135 (46), 101
(15), 77 (20), 59 (12%). Found: C, 55.02; H, 5.51.
C15H17ClO6 requires C, 54.80; H, 5.21.
4.6.13. (5R) Ethyl d-hydroxy-d-(p-methoxylphenyl)-b-
oxo-pentanoates (7k).36 Colorless oil; [a]2D0ZC40.5
(c 2.0, CHCl3).
4.6.14. (5S) Ethyl d-chloroacetyloxy-d-(p-methoxylphe-
nyl)-b-oxo-pentanoates (14k). Colorless oil; [a]2D0Z
K62.7 (c 1.0, CHCl3). nmax (liquid film) 2940, 2911,
2841, 1737, 1613, 1516, 1250, 1178, 1031, 835 cmK1; dH
(300 MHz, CDCl3) 7.31 (2H, d, JZ6.9 Hz, C6H4), 6.88
(2H, d, JZ7.2 Hz, C6H4), 6.23 (1H, dd, JZ4.5, 8.4 Hz,
COCH2CHOCO), 4.18 (2H, q, JZ7.2 Hz, OCH2CH3), 4.03
(2H, s, ClCH2CO), 3.80 (3H, s, OCH3), 3.47 (2H, s,
COCH2CO2), 3.32 (1H, dd, JZ9.0, 17.7 Hz, COCH2
CHOCO), 3.02 (1H, dd, JZ8.1, 17.1 Hz, COCH2CHOCO),
1.28 (3H, t, JZ7.5 Hz, OCH2CH3); m/z (EI) 342 (2, MC),
265 (4), 248 (14), 219 (20), 175 (16), 161 (100), 137 (96),
135 (92), 119 (12), 77 (29%). Found: C, 55.97; H, 5.60.
C16H19ClO6 requires C, 56.06; H, 5.59.
4.6.6. (5S) Methyl d-hydroxy-d-(p-methoxylphenyl)-b-
oxo-pentanoates (15c).11a Colorless oil; [a]2D0ZK50.5 (c
2.0, CHCl3). All of its spectrums were identical with its
enantiomer.
4.6.7. (5R) Methyl d-hydroxy-d-(o,p-dichlorophenyl)-b-
oxo-pentanoates (7g). Colorless oil; [a]2D0ZC73.3 (c 2.4,
CHCl3).
4.6.15. (5S) Ethyl d-hydroxy-d-(p-methoxylphenyl)-b-
oxo-pentanoates (15k).36 Colorless oil; [a]2D0ZK38.7 (c
1.0, CHCl3). All of its spectrums were identical with its
enantiomer.
4.6.8. (5S) Methyl d-chloroacetyloxy-d-(o,p-dichloro-
phenyl)-b-oxo-pentanoates (14g). Colorless oil;
[a]2D0ZK13.7 (c 1.9, CHCl3). nmax (liquid film) 3007,
2972, 2858, 1753, 1712, 1411, 1327, 1317, 1197, 1001, 865,
798 cmK1; dH (300 MHz, CDCl3) 7.40–7.26 (3H, m, C6H3),
6.53 (1H, dd, JZ3.9, 9.0 Hz, COCH2CHOCO), 4.11 (2H, s,
ClCH2CO), 3.75 (3H, s, OCH3), 3.51 (2H, s, COCH2CO2),
3.19 (1H, dd, JZ9.0, 18.0 Hz, COCH2CHOCO), 3.07 (1H,
dd, JZ3.6, 17.7 Hz, COCH2CHOCO); d13C (75.5 MHz,
CDCl3) 198.4, 167.4, 166.2, 135.3, 135.3, 133.0, 130.1,
128.4, 128.1, 69.9, 52.9, 49.5, 47.3, 41.0; m/z (EI) 348 (9,
MCKH2O), 257 (19), 237 (100), 199 (37), 175 (77), 137
(21), 101 (71), 77 (51), 59 (40%). Found: C, 46.02; H, 3.80.
C14H13Cl3O5 requires C, 45.74; H, 3.56.
4.6.16. (5R) Ethyl d-chloroacetyloxy-d-(o,p-dichloro-
phenyl)-b-oxo-pentanoates (7m). Colorless oil; [a]2D0Z
C65.9 (c 1.0, CHCl3).
4.6.17. (5S) Ethyl d-chloroacetyloxy-d-(o,p-dichloro-
phenyl)-b-oxo-pentanoates (14m). Colorless oil;
[a]2D0ZK6.8 (c 1.0, CHCl3). nmax (liquid film) 31.05,
2980, 2939, 1763, 1741, 1710, 1413, 1314, 1186, 1089,
1029, 825 cmK1; dH (300 MHz, CDCl3) 7.41–7.25 (3H, m,
C6H3), 6.53 (1H, dd, JZ3.6, 9.0 Hz, COCH2CHOCO), 4.20
(2H, q, JZ7.2 Hz, OCH2CH3), 4.08 (2H, s, ClCH2CO), 3.49
(2H, s, COCH2CO2), 3.19 (1H, dd, JZ9.0, 17.7 Hz,
COCH2CHOCO), 3.02 (1H, dd, JZ3.9, 17.7 Hz, COCH2-
CHOCO), 1.30 (3H, t, JZ6.9 Hz, COCH2CH2CH3); d13
C
4.6.9. (5S) Methyl d-hydroxy-d-(o,p-dichlorophenyl)-b-
oxo-pentanoates (15g). Colorless oil; [a]2D0ZK73.0 (c 1.0,
CHCl3). All of its spectrums were identical with its
enantiomer.
(75.5 MHz, CDCl3) 198.4, 167.0, 166.2, 135.3, 135.3,
133.0, 130.2, 128.4, 128.1, 67.0, 62.1, 49.8, 47.3, 41.0, 14.5;
m/z (EI) 362 (10, MCKH2O), 259 (19), 251 (100), 215 (13),
199 (40), 175 (72), 137 (19), 115 (30), 102 (15), 77 (55), 69
(18%). Found: C, 47.41; H, 4.19; C15H15Cl3O5 requires C,
47.21; H, 3.96.
4.6.10. (5R) Ethyl d-hydroxy-d-phenyl-b-oxo-pentano-
ates (7i).35 Colorless oil; [a]D20ZC47.6 (c 1.3, CHCl3).
4.6.18. (5S) Ethyl d-chloroacetyloxy-d-(o,p-dichloro-
phenyl)-b-oxo-pentanoates (15m). Colorless oil; [a]2D0Z
K65.4 (c 1.0, CHCl3). All of its spectrums were identical
with its enantiomer.
4.6.11. (5S) Ethyl d-chloroacetyloxy-d-phenyl-b-oxo-
pentanoates (14i). Colorless oil; [a]2D0ZK40.6 (c 2.0,
CHCl3). nmax (liquid film) 3067, 3036, 2985, 2910, 1745,
1721, 1411, 1370, 1171, 1030, 701 cmK1; dH (300 MHz,
CDCl3) 7.38–7.27 (5H, m, C6H5), 6.28 (1H, dd, JZ4.5,
8.4 Hz, COCH2CHOCO), 4.18 (2H, q, JZ7.2 Hz,
OCH2CH3), 4.06 (2H, s, ClCH2CO), 3.43 (2H, s, COCH2-
CO2), 3.32 (1H, dd, JZ9.0, 17.4 Hz, COCH2CHOCO), 3.03
(1H, dd, JZ4.2, 17.4 Hz, COCH2CHOCO), 1.28 (3H, t, JZ
7.2 Hz, OCH2CH3); m/z (EI) 294 (9, MCKH2O), 259 (12),
218 (21), 189 (69), 145 (19), 131 (78), 107 (59), 105 (100),
77 (60), 51 (15%). Found: C, 57.50; H, 5.64. C15H17ClO5
requires C, 57.61; H, 5.48.
4.7. CRL-catalyzed enantioselective hydrolysis ethyl
3-butyryloxy-4,4,4-trifluorobutyrate (10)
4.7.1. Preparation of ethyl 3-hydroxy-4,4,4-trifluoro-
butyrate (9). Sodium (3.45 g, 0.15 mol) was dissolved in
absolute ethanol (15 mL), and to this mixture was added
CH3CO2Et (8.8 g, 0.10 mol) and CF3CO2Et (14.2 g,
0.10 mol). The mixture was heated under refluxed for
48 h, then cooled to rt and hydrolyzed with minimum of
10 N H2SO4, yielding a mixture of ester and its hydrate, bp
100–130 8C/760 mm Hg. Reduction of this mixture with
NaBH4 gave ethyl 3-hydroxy-4,4,4-trifluorobutyrate 15.4 g
(83%).
4.6.12. (5S) Ethyl d-hydroxy-d-phenyl-b-oxo-pentano-
ates (15i).35 Colorless oil; [a]D20ZK46.6 (c 1.0, CHCl3). All
of its spectrums were identical with its enantiomer.

C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
2183
4.7.2. Preparation of diethyl ethyl 3-butyryloxy-4,4,4-
trifluorobutyrate (10). In a 25 mL bottle were added
substrate 9 (0.186 g, 1 mmol), n-butyric acid (0.11 mL,
1.2 mmol), DCC (248 mg, 1.2 mmol), DMAP (5 mg) and
CH2Cl2 (10 mL). After the starting material was almost
consumed at rt (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 give ethyl 3-butyr-
yloxy-4,4,4-trifluorobutyrate 2.43 g (95%).
(1R) 1-Phenylpropane-1,3-diol.9g,37 Colorless oil;
[a]2D0ZC57.4 (c 1.65, CHCl3). nmax (liquid film) 3349,
3032, 2974, 1494, 1454, 1050, 726, 701 cmK1; dH
(300 MHz, CDCl3) 7.35–7.21 (5H, m, C6H5), 4.84 (1H,
dd, JZ4.2, 8.4 Hz, PhCHCH2), 4.00 (1H, s, OH), 3.76–3.66
(2H, m, CHCH2CH2OH), 3.58 (1H, s, OH), 1.94–1.79 (2H,
m, PhCHCH2CH2); m/z (EI) 152 (MC, 19), 133 (11), 107
(100), 105 (32), 79 (72), 77 (49), 51 (13), 43 (7%).
(1S) 1-Phenylpropane-1,3-diol. Colorless oil; [a]2D0Z
K57.4 (c 1.20, CHCl3). All of its spectrums were identical
with its enantiomer.
4.7.3. CRL-catalyzed enantioselective hydrolysis ethyl
3-butyryloxy-4,4,4-trifluorobutyrate (10). Substrate 10
(100 mg) and CRL (30 mg) were added in diisopropyl ether
pre-saturated with 1.2 M aqueous MgCl2 (5 mL). The
mixture was stirred 24 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 the hydrolyzed alcohols 11 (41%) and unreacted
esters 12 (45%).
4.8.2. Preparation of (3R) 3-phenyl-3-hydroxypropyl
methanesulfonate and (3S) 3-phenyl-3-hydroxypropyl
methanesulfonate. In a 25 mL flask were added (1R) 1-
phenylpropane-1,3-diol (or (1S) 1-phenylpropane-1,3-diol)
(0.30 g, 2 mmol), Et3N (0.13 g, 3.6 mmol) and anhydrous
Et2O (10 mL), and at ice-salt bath the mixture of
methanesulfonyl chloride (0.26 g, 2.3 mmol) and 5 mL
Et2O were added. After the mixture was stirred at this low
temperature for 1 h, then at ice-water bath for another 2 h.
The reaction was terminated through adding 10 mL
saturated NH4Cl. The water phase was extracted with
EtOAc (3!5 mL), the combine extracts were dried and
evaporated in vacuum. The residue was subjected to flash
chromatography to obtain (3R) 3-phenyl-3-hydroxypropyl
methanesulfonate (or (3S) 3-phenyl-3-hydroxypropyl
methanesulfonate) 0.39 g, yield: 85%.
4.7.3.1. (3R) Ethyl 3-hydroxy-4,4,4-trifluorobutanozte
(11).19 Colorless oil; [a]D20ZC20.8 (c 0.7, CHCl3). nmax
(liquid film) 3463, 2990, 2945, 1725, 1305, 1171, 1021, 880,
662 cmK1; dH (300 MHz, CDCl3) 4.48–4.42 (1H, m,
CF3CHCH2), 4.22 (2H,q, JZ7.5 Hz, OCH2CH3), 3.60
(1H, s, OH), 2.78–2.63 (2H, m, CF3CHCH2), 1.30 (3H,
t, JZ7.2 Hz, OCH2CH3); d19F (120 MHz, CDCl3) K80.21,
K80.23; m/z (EI) 186 (2, MC), 159 (24), 141 (100), 117
(27), 113 (16), 99 (10), 77 (8), 71 (28), 69 (14), 43 (51%).
(3R) 3-Phenyl-3-hydroxypropyl methanesulfonate.9g,37 Col-
orless oil; [a]2D0ZC21.5 (c 2.00, CHCl3). nmax (liquid film)
3532, 3031, 2939, 1352, 1174, 975, 927, 703 cmK1; dH
(300 MHz, CDCl3) 7.39–7.26 (5H, m, C6H5), 4.84 (1H, dt,
JZ2.4, 6.6 Hz, PhCHCH2), 4.48–4.40 (1H, m, CHCH2-
CH2O), 4.28–4.21 (1H, m, CHCH2CH2O), 2.97 (3H, s,
CH2OSO2CH3), 2.62 (1H, s OH), 2.10 (2H, dd, JZ6.6,
12.3 Hz, PhCHCH2CH2); m/z (EI) 230 (MC, 2), 133 (47),
107 (100), 105 (66), 79 (71), 77 (43), 51 (9), 43 (3%).
4.7.3.2. (3S) Ethyl 3-butyryloxy-4,4,4-trifluorobuta-
nozte (12). Colorless oil; [a]2D0ZC6.3 (c 0.8, CHCl3). nmax
(liquid film) 2976, 2943, 1882. 1768, 1747, 1183, 1139,
1049, 1027, 659 cmK1; dH (300 MHz, CDCl3) 5.84–5.77
(1H, m, CF3CHCH2), 4.18 (2H, q, JZ6.9 Hz, OCH2CH3),
2.84–2.71 (2H, m, CF3CHCH2), 2.37 (2H, t, JZ7.2 Hz,
COCH2CH2CH3), 1.74–1.62 (2H, m, COCH2CH2CH3),
1.26 (3H, t, JZ6.6 Hz, OCH2CH3), 0.94 (3H, t, JZ
7.5 Hz, COCH2CH2CH3); d19F (120 MHz, CDCl3) K78.0,
K78.0; m/z (EI) 256 (1, MC), 228 (14), 211 (6), 187 (4),
141 (8), 123 (11), 71 (100), 70 (16), 43 (35%); HRMS (EI):
MC found: 256.0918. C10H15O4F3 requires 256.0922.
(3S) 3-Phenyl-3-hydroxypropyl methanesulfonate. Color-
less oil; [a]2D0ZK19.3 (c 1.65, CHCl3). All of its spectrums
were identical with its enantiomer.
4.8.3. Preparation of (1R) 3-(methylamino)-1-phenyl-1-
propanol and (1S) 3-(methylamino)-1-phenyl-1-propa-
nol. A solution of (3R) 3-phenyl-3-hydroxypropyl methane-
sulfonate (or (3S) 3-phenyl-3-hydroxypropyl methane-
sulfonate) (0.23 g, 1 mmol) and methylamine (6 mL, 25%
solution in water) in THF (6 mL) was heated at 60–65 8C in
a pressure tube for 4 h. After cooling, the solvent was
evaporated in vacuum. And the residue was dissolved in
8 mL aqueous HCl, then was extracted with EtOAc (1!
10 mL). The water phase was neutralized with Na2CO3 to
alkaline (pHO10), and extracted with ether (3!10 mL).
The combined extracts was dried and evaporated under
reduced pressure to get (1R) 3-(methylamino)-1-phenyl-1-
propanol (or (1S) 3-(methylamino)-1-phenyl-1-propanol)
0.133 g, yield: 80% (0.136 g, yield: 82%).
4.8. Preparation of chiral tomoxetine hydrochloride (I)
and fluoxetine hydrochloride (II)
4.8.1. Preparation of (1R) 1-phenylpropane-1,3-diol and
(1S) 1-phenylpropane-1,3-diol. In a 50 mL flask were
added (3R) ethyl b-hydroxy-b-phenyl propionate (4c)
(0.39 g, 2 mmol) (or (3S) ethyl b-butyryloxy-b-phenyl
propionate (5c) (0.53 g, 2 mmol)), THF (15 mL) and
LiAlH4 (0.11 g, 3 mmol) (or 0.18 g, 5 mmol). After the
mixture was stirred at room temperature for 1 h, 5 mL
aqueous HCl was added and THF was removed under
reduced pressure. Then the solution was extracted with
EtOAc (3!5 mL), the combine extracts were dried and
evaporated in vacuum. The residue was subjected to flash
chromatography to obtain (1R) 1-phenylpropane-1,3-diol
0.28 g, yield: 92%. (or (1S) 1-phenylpropane-1,3-diol
0.29 g, yield: 95%).
(1R) 3-(Methylamino)-1-phenyl-1-propanol.9g,37 Colorless
oil; [a]2D0ZC29.3 (c 1.05, CHCl3). nmax (liquid film) 3402,
3032, 2825, 1469, 1194, 1045, 774, 704 cmK1; dH

2184
C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
(300 MHz, CDCl3) 7.41–7.21 (5H, m, C6H5), 4.93 (1H, dd,
JZ3.0, 9.0 Hz, PhCHCH2), 2.92–2.81 (2H, m, CHCH2-
CH2NH), 2.44 (3H, d, JZ4.2 Hz, CH2NHCH3), 1.90–1.72
(2H, m, PhCHCH2CH2); m/z (EI) 165 (MC, 9), 133 (7), 107
(3), 104 (12), 79 (9), 77 (17), 58 (11), 51 (7), 44 (100%).
(S) Fluoxetine hydrochloride ((S)-II). White solid; mp 140–
141 8C; [a]D20ZC8.5 (c 1.00, CHCl3); [a]D20ZC9.0
(c 1.00, H2O). Found: C, 59.09; H, 5.49; N, 4.73.
C17H19ClF3NO requires C, 59.05; H, 5.54; N, 4.05. All of
its other spectrums were identical with its enantiomer.
(1S) 3-(Methylamino)-1-phenyl-1-propanol. Colorless oil;
[a]2D0ZK23.0 (c 1.55, CHCl3). All of its spectrums were
identical with its enantiomer.
4.8.6. Preparation of (3S) 3-phenyl-3-(2-methylphenoxy)-
propyl methanesulfonate and (3R) 3-phenyl-3-(2-methyl-
phenoxy)propyl methanesulfonate. To a solution of PPh3
(0.39 g, 1.5 mmol), o-cresol (0.22 g, 2 mmol) and anhydrous
ether (8 mL) was added DEAD (40% solution in toluene,
0.66 g, 1.5 mmol) at ice-salt bath. After reacted at this
temperature for 30 min, (3R) 3-phenyl-3-hydroxypropyl
methanesulfonate (or (3S) 3-phenyl-3-hydroxypropyl
methanesulfonate)(0.23 g,1 mmol)wasadded to thisreaction
mixture. The mixture was kept this temperature for another
1 h, then at ice-water bath for 1.5 h. The reaction mixture was
concentrated under reduced pressure, and the residue was
subjected to flash chromatography to obtain (3S) 3-phenyl-3-
(2-methylphenoxy)propyl methanesulfonate (or (3R) 3-phe-
nyl-3-(2-methylphenoxy)propyl methanesulfonate) 0.26 g,
yield: 80% (or 0.25 g, 78%).
4.8.4. Preparation of (R) fluoxetine and (S) fluoxetine. To
a solution of (1R) 3-(methylamino)-1-phenyl-1-propanol (or
(1S) 3-(methylamino)-1-phenyl-1-propanol) (83 mg,
0.5 mmol) in dry DMSO (3 mL) was added 80% NaH
(30 mg, 1 mmol). The mixture was reacted at 55 8C for
30 min. Then trifluoromethyl-p-chlorobenzene (135 mg,
0.75 mmol) in 1 mL dry DMSO was added, the mixture
was stirred at 90–100 8C for 1.5 h. After cooling dilution
with ether, the mixture was washed with brine, dried and
concentrated under vacuum. The residue was subjected to
flash chromatography to obtain (R) fluoxetine (or (S)
fluoxetine) 130 mg, yield: 84% (or 130 mg, yield: 84%).
(R) Fluoxetine.9g,35 Colorless oil; [a]2D0ZC1.2 (c 1.00,
CHCl3). nmax (liquid film) 3314, 3034, 2948, 2800, 1616,
1518, 1330, 1252, 1112, 1069 cmK1; dH (300 MHz, CDCl3)
7.42 (2H, d, JZ8.4 Hz, C6H4), 7.34–7.25 (5H, m, C6H5),
6.90 (2H, d, JZ8.7 Hz, C6H4), 5.31 (1H, dd, JZ4.8, 8.4 Hz,
PhCHCH2), 2.75 (2H, t, JZ6.9 Hz, CHCH2CH2NH), 2.44
(3H, s, CH2NHCH3), 2.25–2.17 (1H, m, PhCHCH2CH2),
2.08–1.99 (1H, m, PhCHCH2CH2), 1.86 (1H, s, NH); m/z
(EI) 309 (MC, 18), 251 (3), 183 (4), 104 (12), 164 (5), 148
(9), 104 (14), 91 (9), 77 (7), 44 (100%). Found: C, 66.29; H,
6.02; N, 4.77. C17H18F3NO requires C, 66.01; H, 5.87; N,
4.53.
(3S) 3-Phenyl-3-(2-methylphenoxy)propyl methanesulfo-
nate.37 Colorless oil; [a]D20ZC7.8 (c 1.00, CHCl3). nmax
(liquid film) 3065, 3030, 2938, 1493, 1357, 1239, 1176, 970,
753, 702 cmK1; dH (300 MHz, CDCl3) 7.35–7.25 (5H, m,
C6H5), 7.20 (1H, d, JZ7.5 Hz, C6H4), 6.96 (1H, t, JZ
7.8 Hz, C6H4), 6.81 (1H, t, JZ7.8 Hz, C6H4), 6.60 (1H, d,
JZ8.1 Hz, C6H4), 5.33 (1H, dd, JZ4.5, 8.4 Hz, PhCHCH2),
4.51–4.35 (2H, m, CHCH2CH2OSO2), 2.90 (3H, s, CH2-
OSO2CH3), 2.42–2.25 (2H, m, PhCHCH2CH2), 2.32 (3H, s,
ArCH3); m/z (EI) 320 (MC, 3), 224 (4), 213 (2), 117 (100),
108 (7), 91 (7), 79 (6), 77 (6), 65 (2%).
(3R) 3-Phenyl-3-(2-methylphenoxy)propyl methanesulfo-
nate. Colorless oil; [a]2D0ZK7.8 (c 1.70, CHCl3). All of
its spectrums were identical with its enantiomer.
(S) Fluoxetine. Colorless oil; [a]2D0ZK1.4 (c 1.70, CHCl3).
Found: C, 66.07; H, 5.92; N, 4.80. C17H18F3NO requires C,
66.01; H, 5.87; N, 4.53. All of its other spectrums were
identical with its enantiomer.
4.8.7. Preparation of (S) tomoxetine and (R) tomoxetine.
The reaction process was identical with preparation of (1R)
3-(methylamino)-1-phenyl-1-propanol and (1S) 3-(methyl-
amino)-1-phenyl-1-propanol. We obtained (S) tomoxetine
0.212 g, yield: 83% and (R) tomoxetine 0.209 g, yield: 82%.
4.8.5. Preparation of (R) fluoxetine hydrochloride ((R)-
II) and (S) fluoxetine hydrochloride ((S)-II). The oil (R)
fluoxetine (or (S) fluoxetine) (42 mg, 0.14 mmol) was
dissolved in ether and acidified with HCl (gas). The solution
was concentrated to give a solid (R) fluoxetine hydro-
chloride ((R)-II) (or (S) fluoxetine hydrochloride ((S)-II))
46 mg, yield: 98% (or 46 mg, yield: 98%).
(S) Tomoxetine.35 Colorless oil; [a]2D0ZC36.8 (c 0.50,
CHCl3). nmax (liquid film) 3320, 3064, 2947, 2794, 1493,
1240, 1120, 750, 701 cmK1; dH (300 MHz, CDCl3) 7.34–
7.22 (5H, m, C6H5), 7.12 (1H, d, JZ6.9 Hz, C6H4), 6.96
(1H, t, JZ8.1 Hz, C6H4), 6.77 (1H, t, JZ7.2 Hz, C6H4),
6.60 (1H, d, JZ8.4 Hz, C6H4), 5.59 (1H, dd, JZ4.2, 8.1 Hz,
PhCHCH2), 2.80 (2H, t, JZ7.2 Hz, CHCH2CH2N), 2.43
(3H, s, CH2NHCH3), 2.32 (3H, s, ArCH3), 2.22–2.02 (3H,
m, NH,PhCHCH2CH2); m/z (EI) 255 (MC, 17), 151 (18),
148 (32), 108 (9), 104 (11), 91 (11), 77 (14), 44 (100%).
Found: C, 80.21; H, 8.09; N, 5.52. C17H21NO requires C,
79.96; H, 8.29; N, 5.49.
(R) Fluoxetine hydrochloride ((R)-II).9g,37 White solid; mp
140–141 8C; [a]D20ZK10.1 (c 1.00, CHCl3); [a]2D0ZC12.0
(c 1.00, H2O). nmax (liquid film) 3016, 2962, 2793, 2733,
2455, 1616, 1518, 1331, 1243, 1164, 1109, 1070, 843,
699 cmK1; dH (300 MHz, CDCl3) 9.64 (2H, s, NH,HCl),
7.42 (2H, d, JZ8.4 Hz, C6H4), 7.39–7.24 (5H, m, C6H5),
6.90 (2H, d, JZ8.7 Hz, C6H4), 5.46 (1H, dd, JZ4.2, 7.8 Hz,
PhCHCH2), 3.23–3.04 (2H, m, CHCH2CH2NH), 2.63 (3H,
s, CH2NHCH3), 2.56–2.38 (2H, m, PhCHCH2CH2); m/z
(EI) 309 (MCKHCl, 6), 252 (1), 183 (2), 162 (2), 148 (4),
104 (8), 91 (5), 77 (4), 59 (4), 44 (100%). Found: C, 59.12;
H, 5.50; N, 4.32. C17H19ClF3NO requires C, 59.05; H, 5.54;
N, 4.05.
(R) Tomoxetine. Colorless oil; [a]2D0ZK35.4 (c 0.55,
CHCl3). Found: C, 80.00; H, 8.15; N, 5.62. C17H21NO
requires C, 79.96; H, 8.29; N, 5.49. All of its other
spectrums were identical with its enantiomer.

C. Xu, C. Yuan / Tetrahedron 61 (2005) 2169–2186
2185
4.8.8. Preparation of (S) tomoxetine hydrochloride
((S)-I) and (R) tomoxetine hydrochloride ((R)-I).
The reaction process was identical with preparation
(R) fluoxetine hydrochloride ((R)-II) and (S)
fluoxetine hydrochloride ((S)-II). And we obtained S)
tomoxetine hydrochloride ((S)-I) 41 mg, yield: 99%
and (R) tomoxetine hydrochloride ((R)-I) 41 mg, yield:
99%.
4.10. Preparation of (R) methyl 4-oxo-2,6-diphenyl-
tetrahydropyran-3-carboxylatete (18).39
In 25 mL flask was added substrate 7a (111 mg, 0.5 mmol),
benzaldehyde (66 mg, 0.63 mmol), BF3$Et2O (119 mg,
0.75 mmol) and CH2Cl2 (4 mL). After the mixture was
reacted 3 h, ethyl acetate (35 mL) was added then washed
with saturated NaHSO3 solution (3!10 mL) and brine (2!
10 mL). The organic phase dried and solvent was removed
under reduced pressure, and the residues were purified by
flash chromatography to give (R) methyl 4-oxo-2,6-
diphenyl-tetrahydropyran-3-carboxylatete (14) 132 mg,
yield: 85%.
(S) Tomoxetine hydrochloride ((S)-I).37 White solid; mp
162–163 8C; [a]D20ZC40.9 (c 1.18, CHCl3); [a]2D0ZC43.1
(c 1.00, MeOH); [a]D20ZC42.6 (c 1.18, EtOH). nmax (liquid
film) 3018, 2961, 2761, 2717, 1493, 1235, 1118, 1037, 767,
711 cmK1; dH (300 MHz, CDCl3) 9.64 (2H, s, NH,HCl),
7.34–7.21 (5H, m, C6H5), 7.10 (1H, d, JZ7.5 Hz, C6H4),
6.94 (1H, t, JZ7.8 Hz, C6H4), 6.77 (1H, t, JZ7.5 Hz,
C6H4), 6.59 (1H, d, JZ8.4 Hz, C6H4), 5.37 (1H, t, JZ
6.6 Hz, PhCHCH2), 3.15–3.11 (2H, t, JZ7.2 Hz,
CHCH2CH2N), 2.60 (3H, s, CH2NHCH3), 2.53–2.47
(2H, m, PhCHCH2CH2), 2.30 (3H, s, ArCH3); m/z (EI)
255 (MCKHCl, 5), 197 (1), 151 (9), 148 (16), 115 (3),
104 (7), 91 (7), 77 (8), 44 (100%). Found: C, 70.05; H,
7.85; N, 5.02. C17H22ClNO requires C, 69.97; H, 7.60;
N, 4.80.
Colorless oil; [a]D20ZC23.7 (c 1.30, CHCl3). nmax (liquid
film) 3063, 3034, 2952, 1748, 1718, 1454, 1274, 1139,
1070, 761, 701 cmK1; dH (300 MHz, CDCl3) .42–7.19
(10H, m, C6H5), 5.05 (1H, d, JZ10.8 Hz, PhCHCHCO),
4.87 (1H, dd, JZ3.3, 10.8 Hz, PhCHCH2CO), 3.69 (1H, d,
JZ10.8 Hz, COCHCHPh), 3.57 (3H, s, OCH3), 2.81–2.65
(2H, m, PhCHCH2CO); m/z (EI) 310 (7, MC), 278 (7), 233
(14), 204 (16), 201 (16), 172 (32), 145 (15), 131 (49), 104
(100), 77 (32%). Found: C, 73.52; H, 5.89. C19H18O4
requires C, 73.53; H, 5.85.
(R) Tomoxetine hydrochloride ((R)-I). White solid; mp 161–
162 8C; [a]2D0ZK34.9 (c 1.18, CHCl3); [a]2D0ZK39.0 (c
1.00, MeOH); [a]2D0ZK38.4 (c 1.18, EtOH). Found: C,
69.98; H, 7.75; N, 4.99. C17H22ClNO requires C, 69.97; H,
7.60; N, 4.80. All of its other spectrums were identical with
its enantiomer.
Acknowledgements
This project was supported by the National Natural Science
Foundations of China (Grant No. 20272075 and 20072052).
4.9. Prepraration of (R) 4-hydroxy-6-aryl-5,6-dihydro-2-
pyones (16) and (S) 4-hydroxy-6-aryl-5,6-dihydro-2-
pyones (17).38
References and notes
1. (a) Foster, B. J.; Lavagnino, E. R. In Drugs of the Future, Vol.
11; Prous Science: Barcelona, Spain, 1986; pp 134–200.
(b) Robertson, D. W.; Krushins, J. H.; Fuller, R. W.; Leander,
J. D. J. Med. Chem. 1988, 31, 1412–1417.
In a 25 mL flask was added substrates 7a or 7i (15a or 15i)
(0.1 mmol) and 0.2 M solution of NaOH. After the mixture
was stirred for 20 min, 2.0 M solution of HCl was added and
the PH values !2. The solid was filtered and dried to get
(R) 4-hydroxy-6-aryl-5,6-dihydro-2-pyones (16) (or (R)
4-hydroxy-6-aryl-5,6-dihydro-2-pyones (17)) 19 mg, yield:
98%.
2. Ankier, S. I. Prog. Med. Chem. 1986, 23, 121–140.
3. (a) Endo, A.; Kuroda, M.; Tsujita, Y. J. Antibiot. 1976, 29,
1346–1352. (b) Brown, A. G.; Smale, T. C.; King, T. J.;
Hasenkamp, R.; Thompson, R. H. J. Chem. Soc., Perkin Trans.
1 1976, 1165–1170.
4. (a) Soriente, A.; De-Rosa, M.; Apicella, A.; Scettri, A.;
Sodano, G. Tetrahedron: Asymmetry 1999, 10, 4481–4484.
(b) Lattman, E.; Coombs, J.; Hoffmann, H. M. R. Synthesis
1996, 171–177.
(R) 4-Hydroxy-6-aryl-5,6-dihydro-2-pyones (16). White
solid; mp 124–125 8C; [a]2D0ZC96.3 (c 1.00, CHCl3).
nmax (liquid film) 3038, 2899, 1720, 1292, 1012, 756,
695 cmK1; dH (300 MHz, CDCl3) 7.48–7.27 (5H, m, C6H6),
5.72 (1H, dd, JZ3.9, 9.6 Hz, PhCHOCO), 3.69 (1H, d, JZ
18.9 Hz, COCH]COH), 3.49 (1H, d, JZ18.9 Hz,
COCH]COH), 2.93 (2H, dq, JZ4.2, 9.9, 18.3 Hz,
PhCHCH2C]); m/z (EI) 190 (64, MC), 144 (2), 131 (4),
105 (72), 104 (100), 103 (28), 84 (58), 78 (28), 77 (32), 51
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