Enzymatic desymmetrization of 3-arylglutaric acid anhydrides

Article abstract of DOI:10.1016/j.tetasy.2005.06.025

Optically active (R)- and (S)-3-arylglutaric acid monoesters 3 were synthesized in quantitative yields and good stereoselectivities by lipase-catalyzed desymmetrization of the corresponding 3-arylglutaric anhydrides 2 with alcohols. It was observed that the stereochemical outcome of the reaction was influenced by the substituents present on the aromatic ring. The influence of the enzyme, alcohol, and solvent was systematically examined. Absolute configurations of the monoesters 3 were assigned by chemical correlation to corresponding lactones 4.

Full text of DOI:10.1016/j.tetasy.2005.06.025

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2475–2485
Enzymatic desymmetrization of 3-arylglutaric acid anhydrides
Anna Fryszkowska,a Marta Komar,a Dominik Koszelewskia and Ryszard Ostaszewskia,b,
*
aFaculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
bInstitute of Organic Chemistry PAS, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 25 May 2005; accepted 13 June 2005
Abstract—Optically active (R)- and (S)-3-arylglutaric acid monoesters 3 were synthesized in quantitative yields and good stereose-
lectivities by lipase-catalyzed desymmetrization of the corresponding 3-arylglutaric anhydrides 2 with alcohols. It was observed that
the stereochemical outcome of the reaction was influenced by the substituents present on the aromatic ring. The influence of the
enzyme, alcohol, and solvent was systematically examined. Absolute configurations of the monoesters 3 were assigned by chemical
correlation to corresponding lactones 4.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Cl
F
Chiral 3-arylglutaric acid derivatives are important
building blocks for the synthesis of a number of biolog-
.1/2 HCl
O
+
Cl-
H3N
COOH
ically active compounds (Fig. 1). Two of the most
important are: (ꢀ)-paroxetine hydrochloride I1,2—a
selective serotonine receptor antagonist and (R)-Baclo-
fen II—a selective GABAB receptor agonist, which is
used clinically in the treatment of spasticity.3 Three
other biologically active compounds: compound III4—
antiasthmatic drug; compound IV5—antagonist of
receptor CCR5 involved in HIV-1 transmission to
cells; compound V, 2-azaspiro[3.5]nonan-1-one, SCH
54016—a potent cholesterol inhibitor6—all possess a
chiral glutaric fragment in their structures, which is
essential for their activity.
O
O
II
(R)-Baclofen
N
H
I
(-)- Paroxetine
OMe
Cl
Cl
Me
N
H
N
N
O
O
(+)-SCH 54016
V
III
O
Cl
The lipase catalysis is a well-established method for the
preparation of enantiomerically pure building blocks for
the synthesis of structurally complex molecules with
controlled stereochemistry.7–9 Chiral glutaric derivatives
can be obtained via an enzymatic route as well. A com-
monly applied path to access the enantiomerically pure
3-arylglutaric acid monoesters is the lipase-catalyzed
hydrolysis of respective prochiral glutarate diest-
ers.2,10–13 Optically active products were obtained in
good yields with good to excellent enantioselectivities in
hydrolyses catalyzed by PLE,2,6,10–12 PPL,13 a-chymo-
Cl
O
S
Me
N
Me
N
N
O
IV
Figure 1. Biologically active compounds containing a 3-arylglutaric
building block.
trypsin,10,11 or Candida antarctica lipase, type B.13
Despite its high efficiency, this methodology requires
the use of aqueous reaction media, which complicates
the overall process and product purification.
*
Corresponding author. Tel.: +48 22 343-2120; fax: +48 22 632 66
81; e-mail: rysza@icho.edu.pl
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.025

2476
A. Fryszkowska et al. / Tetrahedron: Asymmetry 16 (2005) 2475–2485
R1
R1
2.1. Preliminary screening of biocatalysts for the desym-
metrization reaction of anhydride 2a
R2
R3OH, lipase
R2
O
solvent
In a preliminary study, 16 commercially available en-
zymes were screened as biocatalysts for the desymmetri-
zation of 3-phenylglutaric anhydride 2a with ethanol.
These reactions were conducted in iso-propyl ether,
based on the literature data on the desymmetrization
of 3-alkylglutaric anhydrides.15–19 We tested 2 esterases
[rabbit liver esterase (RLE) and porcine liver esterase
(PLE)], 8 native lipases [Candida lypolytica, Candida
rugosa, Mucor javanicus, Rhisophus niveus, Pseudomonas
cepacia (Amano PS), wheat germ, porcine kidney, and
porcine pancreas lipase], and 6 immobilized lipases
(Amano PS-C, Amano PS-D, Chirazyme L-1, c.-f., lyso
(lipases from Ps. cepacia) and Novozym 435, Chirazyme
L-2, c.-f., C3, lyo., Chirazyme L-2, c.-f., C2, lyo. (lipases
from C. antarctica type B)].
O
HO
OR3
O
O
O
3
2
Scheme 1. Enzymatic desymmetrization of 3-arylglutaric anhydrides 2.
Enzymatic desymmetrization of the corresponding
meso-anhydride with an alcohol is a complementary/
parallel approach to the diester hydrolysis.14 This syn-
thetic path leads to the same monoester products, but
working with aqueous media is avoided. As the reaction
is conducted in organic solvents, tedious product isola-
tion is eliminated.
We found that only immobilized lipases showed high
activity in the desymmetrization of 2a. Generally, the
reactions reached full conversion within 1–3 days. In
the case of the native, non-immobilized enzymes, either
no product formation was observed, or the reaction pro-
ceeded sluggishly.
In the literature, only desymmetrizations of 3-alkyl- and
3-hydroxyglutaric anhydride derivatives have been
described.15–19 Recently, we announced the lipase-
catalyzed desymmetrization of the 3-arylglutaric
anhydrides 2a–c in the synthesis of chiral peptidomimet-
ics.20,21 Encouraged by our preliminary results and the
importance of monoesters 3 for the pharmaceutical
industry,1–5,22 we herein report on the enzymatic desym-
metrization of 3-arylglutaric anhydrides 2 (Scheme 1).
The influence of the aromatic ring substituent, enzyme,
alcohol, and solvent on the stereochemical outcome of
the reaction was investigated in detail.
2.2. Comparison of various solvents
In the next step, the objective was to find the most
advantageous solvent for the desymmetrization reac-
tion. Anhydride 2a and ethanol were used as substrates,
and Novozym 435 was chosen as the biocatalyst. Enan-
tiomeric excesses of the products were determined by
chiral HPLC analysis. The results are summarized in Ta-
ble 1. These experiments demonstrated that the reaction
proceeds efficiently in ethers (entries 1–5, Table 1). The
enantioselectivities obtained in various ethers are com-
parable (76–78% ee). The reaction times ranged from
43 h (TBME and iso-propyl ether, entries 1 and 2 in
Table 1) to 3–7 days for the other ethers.
2. Results and discussion
The substrates, that is, anhydrides 2, were obtained by a
three-step methodology from the respective aryl alde-
hydes according to literature procedures (Scheme
2).23,24 3-Arylglutaric acids were obtained by the con-
densation of 2 equiv of ethyl acetylacetate with respec-
tive benzaldehydes 1, followed by hydrolysis and
decarboxylation catalyzed by potassium hydroxide.23
These products were dehydrated to give anhydrides 224
in 19–80% overall yield. Model racemic 3-arylglutaric
acid monoesters 3 were obtained in reaction with the
appropriate alcohol in pyridine, according to the pub-
lished procedure.24
Although the reaction in cyclohexane reached full con-
version within 20 h, the enantioselectivity obtained was
lower (62% ee, entry 6 in Table 1). In other organic sol-
vents, for example, toluene, xylene, and chloroform, the
reactions proceed sluggishly, and the monoesters 3a
were obtained in either low enantiomeric excess or with
no optical activity at all. These results are consistent
R1
1. Ethyl acetylacetate (2eq)
R1
R1
R2
Piperidine, 3 days, rt
2. KOHaq, 80-95oC, 3h
3. AcCl, 3h
R2
R2
R3OH, Pyr, reflux, 3h
O
O
HO
OR3
O
H
O
O
O
1
1a R1 = R2 = H
2
3
1b R1 = Cl, R2 = H
1c R1 = OMe, R2 = H
1d R1 = R2 = Cl
1e R1 = F, R2 = H
Scheme 2. Synthesis of 3-arylglutaric anhydrides 2 and model racemic monoacids 3.

A. Fryszkowska et al. / Tetrahedron: Asymmetry 16 (2005) 2475–2485
2477
Table 1. Influence of the solvents on desymmetrization of 3-phenyl-
glutaric acid anhydride 2a with ethanol by Novozym 435a
few days. The reaction time and enantioselectivity were
strongly dependent on the enzyme carrier.
Entry
Solvent
Time
% ee of 3a
We observed that all the lipases immobilized in Sol–
Gel–AK were much less reactive than other immobilized
enzymes (entries 4, 6, 9, and 10 in Table 2). In the pres-
ence of these enzymes, the reactions proceeded slowly
and monoacid 3a was obtained in low enantiomeric
excess.
1
2
3
4
5
6
7
8
tert-Butyl-methyl ether
iso-Propyl ether
n-Propyl ether
n-Butyl ether
Ethyl ether
Cyclohexane
Dioxane
Benzene
Toluene
Xylene
Chloroform
Methylene chloride
Acetone
43 h
43 h
76
78
78
75
76
62
26
7
34
31
0
0
45
31
7 days
3 days
5 days
20 h
6 days
8 days
5 weeksb
5 weeksb
5 weeksb
5 weeksb
4 weeksb
5 weeksb
All immobilized lipases from Candida antarctica type B
(CALB) showed pro-(S)-stereoselectivity in reaction
with all anhydrides 2, catalyzing the formation of (S)-
monoesters 3a–d. Novozym 435, Chirazyme L-2, C3,
and Chirazyme L-2, C2 (Table 2, entries 1–3) catalyzed
the desymmetrization reaction ranging from several
hours to a few days leading to the monoester formation
in good enantiomeric excess. Among lipases used in this
study, Chirazyme L-2, C3 (Table 2, entry 2) appeared to
catalyze the formation of monoesters (S)-3 with highest
enantiomeric excess. Another lipase from the Candida
species—Candida cylindracea immobilized in Sol–Gel–
AK showed the same enantioselectivity [pro-(S)] but
the reaction was slow and the enantioselectivity poor.
9
10
11
12
13
14
Acetonitrile
a Reaction conditions: substrate 2a (0.05 mmol, 10.0 mg) in the
respective solvent (1 mL), ethanol (0.075 mmol), Novozym 435
(7.5 mg), rt.
b Conversion <100%.
with literature observations that the use of ether solvents
is advantageous for the reaction course.15–19 iso-Propyl
ether was the most appropriate, not only from the view-
point of solubility and reactivity of the substrates, but
also because of the highest resulting enantiomeric excess
of monoesters 3a.
Upon change of the enzyme for Pseudomonas sp. lipases
(Table 2, entries 5–8), we observed a different lipase
enantioselectivity. The (R)-3a was obtained by desym-
metrization of anhydride 2a with the use of this enzyme.
The highest enantiomeric excess for (R)-3a (77% ee) and
the shortest reaction time (19 h) were obtained for
desymmetrization catalyzed by Amano PS-C. Native li-
pase Amano PS catalyzed the reaction as well, but the
reaction time was more than 20 times longer in compar-
ison to the reaction time using the immobilized enzyme
(Table 2, entries 7 vs 8).
2.3. The influence of the biocatalyst on the desymmetri-
zation reaction of anhydrides 2a–d
As it was stated above, the initial lipase screening dem-
onstrated that the use of immobilized enzymes is benefi-
cial for the reaction course. Therefore, the influence of
several immobilized lipases on the desymmetrization of
anhydrides 2a–d was investigated. The results are sum-
marized in Table 2. The majority of the tested immobi-
lized enzymes catalyzed quantitatively the reaction of 3-
arylglutaric anhydrides 2 with ethanol in i-Pr2O within a
Surprisingly, the application of Amano PS-C lipase for
hydrolysis of three other anhydrides resulted in a change
of its enantioselectivity to pro-(S), since (S)-enantiomers
Table 2. Desymmetrization of 3-arylglutaric acid anhydrides 2a–d by various lipases with ethanol in iso-propyl ethera
Entry
Lipase
3a
3b
3c
3d
Time
% ee
Time
% ee
Time
% ee
Time
% ee
(h/days)
(Conf.)
(days)
(Conf.)
(days)
(Conf.)
(days)
(Conf.)
1
2
3
4
5
6
7
8
9
Novozym 435 (CALB)
61/—
19/—
—/18
—/46b
—/9
—/46b
—/16
19/—
—/18
—/46b
78 (S)
83 (S)
68 (S)
24 (S)
11 (R)
55 (R)
77 (R)
77 (R)
6 (R)
5
4
68 (S)
71 (S)
—
—
16 (S)
—
—
16 (S)
—
13
7
68 (S)
68 (S)
62 (S)
—
4
2
21
—
7
9
—
2
60 (S)
77 (S)
45 (S)
—
24 (S)
30 (S)
—
44 (S)
—
—
Chirazyme L-2, c.-f., C3, lyo. (CALB)
Chirazyme L-2, c.-f., C2, lyo. (CALB)
Candida cylindracea immob. in Sol–Gel–AK
Chirazyme L-1, c.-f., lyso. (Ps. cepacia)
Ps. cepacia immob. on Sol–Gel–AK
Amano PS (Ps. cepacia)
Amano PS-C immob. (Ps. cepacia)
Hog pancreas immob. in Sol–Gel–AK
Mucor miehei immob. in Sol–Gel–AK
—
—
4
—
—
4
45
—
—
—
—
8
—
—
—
52 (66c) (S)
—
—
—
—
—
—
—
—
10
48 (R)
—
a To a solution of anhydride 2 (0.05 mmol) in iso-propyl ether (1 mL), ethanol (0.075 mmol) was added, followed by respective lipase: Novozym 435:
7.6 mg; Chirazyme L-2, c.-f., C3, lyo.: 5.7 mg; Chirazyme L-2, c.-f., C2, lyo.: 2.8 mg; C. cylindracea immob.: 5.4 mg; SP 430: 6.2 mg; Chirazyme L-1,
c.-f., lyso.: 5.7 mg; Ps. cepacia immob. on Sol–Gel–AK: 9.1 mg; Amano PS: 6.2 mg; Amano PS-C: 6.0 mg; Hog pancreas immob.: 3.5 mg; Mucor
miehei immob.: 5.1 mg. For anhydride 2e, the enzyme quantities were as follows: Novozym 435: 5.3 mg; Chirazyme L-2, c.-f., C3, lyo.: 5.4 mg;
Chirazyme L-2, c.-f., C2, lyo.: 5.1 mg; Chirazyme L-1, c.-f., lyso.: 5.2 mg; Amano PS-D: 2.0 mg; Amano PS-C: 7.0 mg; Ps. cepacia immob. on Sol–
Gel–AK: 5.6 mg.
b Conversion <100%.
c After crystallization.

2478
A. Fryszkowska et al. / Tetrahedron: Asymmetry 16 (2005) 2475–2485
of monoesters 3b–d, R3 = Et were obtained (Table 2, en-
try 8). The same phenomenon was observed in case of
Chirazyme L-1, however products were characterized
by low ee (Table 2, entry 5).
tivity for all the alcohols, regardless of the nucleophile
used. Although the nucleophile does not change the en-
zyme selectivity, it can influence the enantiomeric excess
of the products and reaction kinetics.
Applying various enzymes, we obtained various stere-
oselectivities and the change of reaction kinetics. The
way of lipase immobilization is crucial for both catalytic
activity and selectivity.
As a general trend, the enzymatic synthesis of monoes-
ters proceeds most efficiently for small aliphatic alco-
hols: ethanol and methanol. Also, the enantiomeric
excesses obtained using these alcohols were the highest.
The use of longer-chain alcohols did not improve the
enantioselectivity. The monoesters of allyl alcohol were
obtained in lower stereoselectivities and the reaction
times were much longer. The desymmetrization with
butanol and benzyl alcohol was sluggish and, in most
cases, the enantiomeric excess was poor.
2.4. Effect of substituent of the phenyl ring
As a general trend, the reaction with 3-phenylglutaric
anhydride 2a is the fastest, while the anhydrides bearing
the substituents on aromatic ring 2b, 2c, and 2e require
longer reaction times. Also, the enantiomeric excesses of
monoesters 3a were generally the highest. The substitu-
ents on the phenyl ring influenced the enantioselectivity
of the enzyme and the enantiomeric excesses were lower
for compounds 3b–e.
We observed that the monoesters of the same configura-
tion may have different signs of optical rotary power.
Therefore, the sign of the rotation could not be used
for assigning the configuration of the product, and
transformation of the monoesters to lactones was a
requirement.
2.5. The influence of the nucleophile
Five different alcohols were used as nucleophiles in the
desymmetrization reaction of anhydrides 2a–e catalyzed
by Novozym 435. Herein we tested methanol, ethanol,
butanol, allyl, and benzyl alcohol. The results are sum-
marized in Table 3. Novozym 435 shows pro-(S) selec-
2.6. Absolute configuration assignment
The absolute configurations of the respective mono-
esters 3a–e were assigned by selective reduction of the
ester moiety and lactonization to lactones 4. The sign
Table 3. Influence of the alcohol on the desymmetrization reaction (the absolute configuration assignment of the chiral monoesters 3a by
transformation to lactone 4)
20
Ester 3
R3
Yield of chemical
reaction (%a)
Yield of enzymatic
reaction (%) (config.)b
Time
(days)
[a]D (CHCl3)
Lactone 4 yield
(%) (config.)c
½aꢁD (CHCl3)
3a
R3 = Me
R3 = Et
66
91
51
64
—
99 (80d) (S)
99 (72d) (S)
99 (93d) (S)
99 (61d) (S)
99 (85d) (S)
5
4
17
32
9
ꢀ3.6 (c 1.10)
ꢀ4.0 (c 1.10)
ꢀ2.1 (c 1.50)
+0.6 (c 0.90)
ꢀ4.9 (c 0.88)
ꢀ9.6 (c 0.88)
ꢀ3.8 (c 0.90)
ꢀ2.2 (c 0.90)
+0.4 (c 0.90)
ꢀ6.3 (c 0.40)
+7.6 (c 0.60, EtOH)
+8.3 (c 0.95, EtOH)
+2.3 (c 0.50, EtOH)
ꢀ0.4 (c 0.50, EtOH)
+7.3 (c 0.65, EtOH)
52 (R)
34 (R)
46 (R)
27 (R)
47 (R)
ꢀ5.7 (c 2.10)
ꢀ5.2 (c 1.40)
ꢀ7.1 (c 2.00)
ꢀ2.1 (c 1.00)
ꢀ4.1 (c 1.95)
R3 = Bu
R3 = Bn
R3 = Allyl
3b
3c
3d
3e
R3 = Me
R3 = Et
R3 = Bu
R3 = Bn
R3 = Allyl
75
89
72
29
—
99 (34d) (S)
99 (61d) (S)
99 (53d) (S)
99 (47d) (S)
99 (64d) (S)
5
4
23
33
17
—
—
36 (R)
62 (R)
16 (R)
41 (R)
ꢀ8.7 (c 1.38)
ꢀ4.5 (c 1.43)
ꢀ3.0 (c 0.70)
ꢀ6.3 (c 2.15)
ꢀ7.7 (c 3.20)
ꢀ6.7 (c 1.90)
ꢀ3.4 (c 2.00)
ꢀ6.7 (c 0.45)
ꢀ5.4 (c 2.60)
ꢀ8.1 (c 1.60)
ꢀ7.1 (c 2.00)
ꢀ3.5 (c 1.70)
ꢀ1.8 (c 1.60)
ꢀ5.0 (c 1.80)
ꢀ3.2 (c 1.90)
ꢀ1.7 (c 1.34)
ꢀ3.1 (c 0.50)
ꢀ1.8 (c 2.15)
ꢀ4.9 (c 1.69)
R3 = Me
R3 = Et
R3 = Bu
R3 = Bn
R3 = Allyl
87
63
87
44
—
99 (95d) (S)
99 (93d) (S)
28 (S)
36 (S)
67 (S)
8
19
25
33
25
71 (R)
28 (R)
69 (R)
15 (R)
65 (R)
R3 = Me
R3 = Et
R3 = Bu
R3 = Bn
R3 = Allyl
97
88
99
49
75
99 (80d) (S)
38 (S)
16 (S)
39 (S)
5
5
5
5
5
+5.0 (c 1.00, EtOH)
+3.8 (c 1.00, EtOH)
+1.3 (c 0.50, EtOH)
ꢀ1.5 (c 1.00, EtOH)
+1.7 (c 1.00, EtOH)
35 (R)
37 (R)
60 (R)
37 (R)
62 (R)
18 (S)
R3 = Me
R3 = Et
R3 = Bu
R3 = Bn
R3 = Allyl
85
91
86
86
89
99 (90d) (S)
99 (89d) (S)
99 (S)
99 (40d) (S)
99 (76d) (S)
1
1
25
7
ꢀ4.3 (c 1.00)
ꢀ4.7 (c 1.00)
ꢀ2.2 (c 0.50)
ꢀ1.7 (c 0.80)
ꢀ2.5 (c 0.90)
49 (R)
67 (R)
15 (R)
67 (R)
41 (R)
7
a Reaction conditions: anhydride 2 (2.4 mmol) in pyridine (3 mL) and absolute alcohol (14.8 mmol), reflux, 2 h.
b Reaction conditions for enzymatic desymmetrization: anhydride 2 (0.5 mmol), iso-propyl ether (10 mL), the respective absolute alcohol R3OH
(7.50 mmol), Novozym 435 (75.0 mg), rt.
c Reduction of ester group catalyzed by LiBH4 followed by dehydration in toluene with p-TsOH.
d Yield after crystallization.

A. Fryszkowska et al. / Tetrahedron: Asymmetry 16 (2005) 2475–2485
2479
F
F
F
1. LiBH4
.
1. BH3 SMe3
2. pTSA
2. pTSA
O
O
retension
inversion
HO
OEt
O
O
O
O
(
S)-4e
(
S)-3e
(R)-4e
Scheme 3. The absolute configuration assignment of 3-(4-fluorophenyl)glutaric monoethyl ester 3e.
of the specific rotation was compared to the literature
data. The results are summarized in Table 3.
derivatives. Non-aqueous reaction medium simplifies
the work-up procedure making this process attractive
for industrial purposes. Therefore these results can be
attractive alternative in the synthesis of important com-
pounds with biological activity, such as Paroxetine I or
Baclofen II.
Selective reduction of the ester or acid group can pro-
vide a product with either an (R)- or (S)-configuration,
according to Scheme 3. Reduction of the ester group
of monoester lactone (S)-3e by lithium borohydride, fol-
lowed by lactonization catalyzed by p-toluenesulfonic
acid (Scheme 3) always led to lactone (R)-4e. Reduction
of the acid group of ester 3e with BMS, followed by lact-
onization led to formation of the lactone (S)-4e with
retention of the configuration. That the two compounds
are enantiomeric is evident from their CD spectra pre-
sented in Figure 2. Moreover, independent of the result
of the enzymatic reaction, the lactone required for the
synthesis of Paroxetine is available.
4. Experimental
4.1. General
NMR spectra were recorded in CDCl3 with TMS as an
internal standard using a 200 MHz Varian Gemini 200
spectrometer. Chemical shifts are reported in parts per
million and coupling constants (J) given in hertz (Hz).
MS spectra were recorded on an API-365 (SCIEX)
apparatus. IR spectra were recorded in CHCl3 on a
Perkin–Elmer FT-IR Spectrum 2000 apparatus. Optical
rotations were measured in 1-dm cell of 1 mL capacity
using Jasco DIP-360 polarimeter operating at 589 nm.
CD spectra were measured using a JASCO J-715 spec-
tropolarimeter in 1-cm and 1-mm cells in acetonitrile
at the concentrations of approximately 2 · 10ꢀ4 M.
HPLC analyses were performed on a Chiracel OD-H
column (4.6 mm/ · 250 mm, from Diacel Chemical
Ind., Ltd.) equipped with a pre-column (4 mm/
· 10 mm, 5 l) using LC-6A Shimadzu apparatus with
UV SPD-6A detector and Chromatopac C-R6A ana-
lyzer. Elemental analyses were performed on CHN
Perkin–Elmer 240 apparatus. Melting points are
uncorrected. All reactions were monitored by TLC on
Merck silica gel plates 60 F254. Column chromatography
was performed on Merck silica gel 60/230–400 mesh.
Figure 2. Circular dichroism spectra for lactones (S)-4e (green) and
(R)-4e (blue).
3. Conclusions
A new enzymatic method for the synthesis of chiral 3-
arylglutaric monoesters 3 by the enantioselective desym-
metrization of anhydride 2 has been proposed. The use
of immobilized enzymes is favorable for the reaction
kinetics. Among several aprotic solvents tested, the
ethers, especially iso-propyl ether, gave the best results.
The use of various lipases for the transformation of 3-
phenylglutaric anhydride 2a led to different enantiomers
of monoester 3a, R3 = Et. Monoester (S)-3a, R3 = Et
was obtained in desymmetrization reaction catalyzed
by Novozym 435 with 78% ee and monoester (R)-3a,
R3 = Et with 77% ee in the reaction catalyzed by Amano
PS-C. The highest enantiomeric excess was obtained for
the desymmetrization of unsubstituted phenylglutaric
anhydride.
Lipases Amano PS-D, Amano PS-C immobilized, and
Amano PS-D were purchased from Amano. Lipases
from Candida lipolytica, C. rugosa, C. cylindracea immo-
bilized in Sol–Gel–AK, Mucor javanicus, M. miehei
immobilized in Sol–Gel–AK, porcine pancreas lipase
immobilized in Sol–Gel–AK, Ps. cepacia, Ps. cepacia
immobilized in Sol–Gel–AK, and Rhisopus niveus, C.
cylindracea were purchased from Fluka. Lipases from
porcine pancreas, wheat germ, acylase from porcine kid-
ney, and esterases from porcine liver and from rabbit
liver were purchased from Sigma. Chirazyme L-2, c.-f.,
C3, lyo. (C. antarctica lipase type B), and Chirazyme
L-2, c.-f., C2, lyo. (C. antarctica lipase type B), Chira-
zyme L-1, c.-f., lyso. (Ps. cepacia lipase) were purchased
from Roche. Novozym 435 was purchased from Novo
Nordisk.
We also transformed chiral monoesters 3 into lactones 4
with either retention or inversion of configuration.
Our approach undoubtedly provided a new methodol-
ogy for the synthesis of optically active 3-arylglutaric

2480
A. Fryszkowska et al. / Tetrahedron: Asymmetry 16 (2005) 2475–2485
All the chemicals were obtained from common chemical
sources. The solvents were of analytical grade. Absolute
THF was obtained by drying over KOH, followed by
distillation from sodium benzophenone ketyl.
4.3. General procedure for the chemical synthesis of
3-arylglutaric acid monoesters 3
Racemic monoesters 3 were synthesized by refluxing the
corresponding anhydride and alcohol in pyridine, as
described previously by Burger and Hoffstetter,24 and
then recrystallized from ethyl ether/hexane. Yields and
melting points are summarized in Table 3. The spectro-
scopic data and analyses are described for the respective
chiral monoesters 3.
4.2. General procedure for the synthesis of 3-arylglutaric
acid anhydrides 2
4.2.1. 3-Phenylglutaric acid anhydride 2a. Anhydride
2a was obtained according to literature procedures23,24
in 40% yield as white crystals (EtOAc/hexane): mp
104–105 ꢁC (lit. 104–10525); 1H NMR d 2.86 (dd,
J = 11.3 Hz, J = 17.2 Hz, 2H), 3.08 (dd, J = 4.5 Hz,
J = 17.2 Hz, 2H), 3.30–3.50 (m, 1H), 6.90–7.40 (m,
5H); 13C NMR d 33.5, 37.8, 126.2, 127.6, 128.8, 139.0,
165.9.
4.4. Enzymatic desymmetrization of 3-arylglutaric
anhydrides
4.4.1. General procedure for the synthesis of chiral
monoesters of 3-arylglutaric acids 3 with Novozym 435
in iso-propyl ether. To a solution of anhydride 2
(0.50 mmol) dissolved in iso-propyl ether (10 mL), lipase
(75.0 mg), and absolute ethanol (0.80 mmol) were
added. The reaction was carried out at room tempera-
ture and its progress monitored with TLC (CHCl3/
MeOH/HCOOH, 100:2:0.05, v:v:v). The enzyme was fil-
tered off and residue concentrated in vacuo to give
monoester 3 as a colorless oil. The product was recrys-
tallized from Et2O/hexane (or EtOAc/hexane).
4.2.2. 3-(4-Chlorophenyl)-glutaric acid anhydride
2b. Anhydride 2b was prepared in 80% overall yield
as white crystals (EtOAc/hexane): mp 126 ꢁC (lit. 131–
13326), Rf = 0.36 (CHCl3/MeOH/HCOOH, 100:2:0.05);
1H NMR d 2.82 (dd, J = 11.4 Hz, J = 17.2 Hz, 2H),
3.08 (dd, J = 4.5 Hz, J = 17.2 Hz, 2H), 3.34–3.50 (m,
1H), 6.91 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H);
13C NMR d 35.5, 37.0, 127.6, 129.2, 134.0, 137.5,
165.5. Anal. Calcd for C11H9ClO3: C, 58.81; H, 4.04.
Found: C, 58.19; H, 4.05.
4.4.2. (S)-3-Phenylglutaric acid monomethyl ester (S)-3a,
R3 = Me. The reaction reached its full conversion after
5 days to give (S)-3a, R3 = Me as a colorless oil. After
4.2.3. 3-(4-Methoxyphenyl)-glutaric acid anhydride
2c. Anhydride 2c was prepared in 19% overall yield
as white crystals (EtOAc/hexane): mp 155–156 ꢁC (lit.
crystallization from Et2O/hexane, the ester was obtained
20
in 80% yield as white crystals: mp 54–55 ꢁC; ½aꢁD ¼ ꢀ3.6
1
1
155–15727), Rf = 0.60 (hexane/EtOAc, 6:4); H NMR d
(c 1.10, CHCl3); H NMR d 2.73–2.79 (m, 4H), 3.61 (s,
2.82 (dd, J = 11.2 Hz, J = 17.0 Hz, 2H), 3.08 (dd,
J = 4.5 Hz, J = 17.0 Hz, 2H), 3.31–3.44 (m, 1H), 3.81
(s, 1H), 6.91 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.8 Hz,
2H); 13C NMR d 33.3, 37.3, 55.3, 114.7, 127.3, 131.0,
159.1, 166.0. Anal. Calcd for C12H12O4: C, 65.45; H,
5.49. Found: C, 65.90; H, 5.44.
3H), 3.62–3.80 (m, 1H), 7.20–7.33 (m, 5H); 13C NMR d
37.9, 40.2, 40.4, 51.6, 127.0, 137.1, 138.6, 142.2, 172.0,
177.6; LSIMS ((+), NBA) (m/z): 245 ([M+Na]+, 64%);
223 ([M+H]+, 100%); LSIMS ((+), NBA+NaOAc)
(m/z): 281 ([M+2Na]+, 100%), 245 ([M+Na]+, 72%).
Anal. Calcd for C12H14O4: C, 64.85; H, 6.35. Found:
C, 64.83; H, 6.22. The spectroscopic data are in agree-
ment with those obtained for the monoester synthesized
chemically in 66% yield as white crystals: mp 93–95 ꢁC
(lit. 93–9525).
4.2.4. 3-(3,4-Dichlorophenyl)-glutaric acid anhydride
2d. Anhydride 2d was prepared in 39% overall yield
as white crystals (EtOAc/hexane): mp 132–135 ꢁC (lit.
19828), Rf = 0.74 (hexane/EtOAc, 6:4); 1H NMR
(200 MHz, CDCl3)
d
2.79–2.94 (dd, J = 11.8 Hz,
4.4.3. (S)-3-Phenylglutaric acid monoethyl ester (S)-3a,
R3 = Et. The reaction reached its full conversion after
43 h to give (S)-3a, R3 = Et as a colorless oil. After crys-
tallization from Et2O/hexane, the ester was obtained in
66% yield as white crystals: mp 58–59 ꢁC (lit. 59–6024);
J = 17.4 Hz, 2H), 3.10 (dd, J = 4.5 Hz, J = 17.4 Hz,
2H), 3.35–3.60 (m, 1H), 7.10 (dd, J = 2.1 Hz, J =
8.2 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.52 (d,
J = 8.2 Hz, 1H); 13C NMR (50 MHz, CDCl3) d 32.3,
35.5, 125.6, 127.9, 130.0, 130.4, 121.7, 139.5, 165.2.
Anal. Calcd for C11H8Cl2O3: C, 50.99; H, 3.11. Found:
C, 50.70; H, 3.19.
20
25
½aꢁD ¼ ꢀ9.5 (c 1.10, benzene) {lit. ½aꢁD ¼ þ9.5 (c 1.1,
benzene), for (R)-enantiomer},29 Rf = 0.24 (CHCl3/
MeOH/HCOOH, 100:2:0.05); HPLC analysis [hexane/
i-PrOH/CH3COOH 185:14:1; k = 226 nm; 1.0 mL/min;
1
4.2.5.
3-(4-Fluorophenyl)-glutaric
acid
anhydride
tR (S) = 8.26 min, tR (R) = 8.95 min] 78% ee; H NMR
2e. Anhydride 2e was prepared in 28% overall yield
as white crystals (EtOAc/hexane): mp 98 ꢁC (lit. 98.5–
991); Rf = 0.60 (hexane/EtOAc, 6:4); 1H NMR
d 1.85 (t, J = 7.1 Hz, 3H), 2.68–2.81 (m, 4H), 3.10–3.25
(m, 1H), 4.08 (q, J = 7.1 Hz, 2H), 7.28 (m, 5H); 13C
NMR d 14.0, 38.0, 40.2, 40.7, 60.5, 127.0, 127.2, 128.6,
128.7, 142.2, 171.6, 177.5; LSIMS (+), NBA (m/z), 259
([M+Na]+, 56%), 237 ([M+H]+, 100%); LSIMS (+),
NBA+NaOAc (m/z), 281 ([M+2Na]+, 100%), 259
([M+Na]+, 41%); IR (CHCl3) mmax: 3513 (OH), 1727
(CO) cmꢀ1. The spectroscopic and physical data are in
agreement with those obtained for the monoester synthe-
sized chemically in 91% yield as white crystals.
(200 MHz, CDCl3)
d 2.80–2.92 (dd, J = 11.2 Hz,
J = 17.0 Hz, 2H), 3.14 (dd, J = 4.5, J = 17.4 Hz, 2H),
3.37 (m, 1H), 7.02–7.14 (m, 4H); 13C NMR (50 MHz,
CDCl3) d 37.0, 40.1, 114.6 (d, J = 21.3 Hz), 128.5 (d,
J = 8.0 Hz), 138.3 (d, J = 2.9 Hz), 160.9 (d,
J = 243.9 Hz), 166.0. Anal. Calcd for C11H9O3F: C,
63.46; H, 4.36. Found: C, 62.09; H, 4.46.

A. Fryszkowska et al. / Tetrahedron: Asymmetry 16 (2005) 2475–2485
2481
4.4.4. (S)-3-Phenylglutaric acid monobutyl ester (S)-3a,
R3 = Bu. The reaction reached its full conversion after
17 days to give (S)-3a, R3 = Bu in 99% yield. After crys-
4.4.8. (S)-3-(4-Chlorophenyl)-glutaric acid monoethyl
ester (S)-3b, R3 = Et. The reaction reached its full con-
version after 4 days to give (S)-3b, R3 = Et as an oil in
99% yield. After crystallization, white crystals were ob-
tallization, white crystals were obtained in 93% yield:
20
mp 41–43 ꢁC (Et2O/hexane); ½aꢁD ¼ ꢀ2.1 (c 1.50,
tained in 61% yield: mp 56 ꢁC (Et2O/hexane);
20
CHCl3); Rf = 0.39 (CHCl3/MeOH/HCOOH, 100:2:0.05);
½aꢁD ¼ ꢀ3.8 (c 0.90, CHCl3); HPLC analysis [hexane/i-
1H NMR
d
0.91 (t, J = 7.2 Hz, 3H), 1.30 (q,
PrOH/CH3COOH 185:14:1; k = 226 nm; 1.0 mL/min;
tR (S) = 9.0 min, tR (R) = 9.8 min]; Rf = 0.27 (CHCl3/
MeOH/HCOOH, 100:2:0.05); 1H NMR d 1.15 (t,
J = 7.1 Hz, 3H), 2.69 (m, 4H), 3.60 (m, 1H), 4.03 (q,
J = 7.1 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 7.34 (d,
J = 8.6 Hz, 2H), 10.7 (s, 1H); 13C NMR d 14.2, 37.3,
40.1, 40.5, 30.6, 128.6, 128.7, 128.8, 132.7, 140.6,
171.2, 177.2. Anal. Calcd for C13H15ClO4: C, 57.68; H,
5.59. Found: C, 57.59; H, 5.74. The spectroscopic data
are in agreement with those obtained for the monoester
synthesized chemically in 89% yield as white crystals: mp
69–70 ꢁC (Et2O/hexane).
J = 7.2 Hz, 2H), 1.46–1.56 (m, 2H), 2.68–2.79 (m, 4H),
3.62–3.70 (m, 1H), 4.01 (t, J = 6.5 Hz, 2H), 7.27–7.32
(m, 5H); 13C NMR d 13.6, 19.0, 30.5, 38.0, 40.2, 40.6,
34.4, 127.0, 127.1, 127.3, 128.6, 128.7, 142.1, 171.6,
177.3. Anal. Calcd for C15H20O4: C, 68.16; H, 7.63.
Found: C, 67.75; H, 7.83; ESI-MS HR (m/z): calcd for
C15H20NaO4 ([M+Na]+): 287.1254; found 287.1240
(100%). The spectroscopic and physical data are in
agreement with those obtained for the monoester syn-
thesized chemically in 51% yield as white crystals.
4.4.5. (S)-3-Phenylglutaric acid monobenzyl ester (S)-3a,
R3 = Bn. The reaction reached its full conversion after
32 days to give (S)-3a, R3 = Bn in 99% yield. After crys-
4.4.9. (S)-3-(4-Chlorophenyl)-glutaric acid monobutyl
ester [(S)-7b, R3 = Bu]. The reaction reached its full
conversion after 23 days to give (S)-3b, R3 = Bu as an
oil in 99% yield. After crystallization, white crystals were
tallization, white crystals were obtained in 61% yield;
20
½aꢁD ¼ þ0.6 (c 0.90, CHCl3); Rf = 0.40 (CHCl3/
MeOH/HCOOH, 100:2:0.05); 1H NMR d 2.28 (m,
4H), 3.70 (m, 1H), 5.06 (s, 2H), 7.15–7.40 (m, 5H);
13C NMR d 38.0, 40.2, 40.6, 66.5, 127.0, 127.2, 128.1,
128.5, 128.6, 135.6, 142.1, 171.3, 177.4. Anal. Calcd for
C18H18O4: C, 72.47; H, 6.08. Found: C, 72.39; H, 6.23.
The spectroscopic data are in agreement with those
obtained for the monoester synthesized chemically in
64% yield as white crystals: mp 84.5–86 ꢁC (Et2O/hexane).
obtained in 53% yield: mp 60 ꢁC (Et2O/hexane);
20
½aꢁD ¼ ꢀ2.2 (c 0.90, CHCl3); Rf 1= 0.32 (CH3Cl/
MeOH/HCOOH, 100:2:0.05; v/v/v); H NMR d 1.15
(t, J = 7.0 Hz, 3H), 1.10–1.35 (m, 2H), 1.35–1.60 (m,
2H), 2.68 (m, 4H), 3.50–3.70 (m, 1H), 3.67 (t,
J = 6.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.35 (d,
J = 8.6 Hz, 2H), 9.50–10.20 (br s 1H); 13C NMR d
13.6, 19.1, 30.6, 37.5, 40.2, 40.6, 64.6, 128.5, 128.6,
128.7, 129.0, 132.7, 141.6, 171.4, 177.2. Anal. Calcd
for C15H19ClO4: C, 60.30; H, 6.41. Found: C, 60.28;
H, 6.35. The spectroscopic data are in agreement with
those obtained for the monoester synthesized chemically
in 72% yield as white crystals: mp 58–59.5 ꢁC (Et2O/
hexane).
4.4.6. (S)-3-Phenylglutaric acid monoallyl ester (S)-3a,
R3 = Allyl. The reaction reached its full conversion
after 9 days to give (S)-3a, R3 = Allyl as an oil in 99%
yield. After crystallization from Et2O/hexane, white
crystals were obtained in 85% yield: mp 44–46 ꢁC;
20
½aꢁD ¼ ꢀ4.9 (c 0.88, CHCl3); Rf = 0.36 (CHCl3/
MeOH/HCOOH, 100:2:0.05); 1H NMR d 2.76 (m,
3H), 3.63 (t, J = 7.3 Hz, 2H), 4.47 (d, J = 5.8 Hz, 2H),
5.13 (s, H), 5.2 (d, J = 7.3 Hz, 1H), 5.69–5.85 (m, H),
7.29 (m, 5H), 10.62 (br s 1H); 13C NMR d 38.8, 41.3,
66.2, 119.5, 128.3, 129.9, 130.1, 133.2, 143.7, 172.8,
179.5. Anal. Calcd for C14H16O4: C, 66.76; H, 66.76.
Found: C, 66.49; H, 6.43.
4.4.10. (S)-3-(4-Chlorophenyl)-glutaric acid monobenzyl
ester (S)-3b, R3 = Bn. The reaction reached its full con-
version after 33 days to give (S)-3b, R3 = Bn as an oil in
99% yield. After crystallization, white crystals were ob-
tained in 47% yield: mp 126 ꢁC (Et2O/hexane);
20
½aꢁD ¼ þ0.4 (c 0.90, CHCl3). Rf = 0.31 (CHCl3/
MeOH/HCOOH, 100:2:0.05); 1H NMR d 2.65–2.75
(m, 4H), 3.56–3.64 (m, 1H), 5.00 (s, 2H), 7.05–7.25 (m,
9H); 13C NMR d 37.4, 40.1, 40.5, 66.5, 128.2, 128.4,
128.6, 128.8, 132.8, 140.3, 171.0, 177.2. Anal. Calcd
for C18H17ClO4: C, 64.97; H, 5.15. Found: C, 64.92;
H, 5.18. The spectroscopic and physical data are in
agreement with those obtained for the monoester syn-
thesized chemically in 29% yield as yellowish crystals.
4.4.7. (S)-3-(4-Chlorophenyl)-glutaric acid monomethyl
ester (S)-3b, R3 = Me. The reaction reached its full
conversion after 5 days to give (S)-3b, R3 = Me in 99%
yield as a colorless oil. After crystallization from
Et2O/hexane, the ester was obtained as white crystals
20
in 34% yield: ½aꢁD ¼ ꢀ9.6 (c 0.88, CHCl3) {lit.
20
½aꢁD ¼ 4.1 (c 2.60, CHCl3), for (R)-enantiomer10};
Rf = 0.40 (CHCl3/MeOH/HCOOH, 100:2:0.05); 1H
NMR d 2.66–2.70 (m, 4H), 3.50 (s, 3H), 3.40–3.60 (m,
1H), 7.14 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H);
13C NMR d 37.3, 40.1, 40.3, 51.7, 127.8, 128.2, 128.3,
128.6, 132.7, 140.5, 171.6, 177.2. Anal. Calcd for
C12H13ClO4: C, 56.15; H, 5.10. Found: C, 56.22; H,
5.11. The spectroscopic data are in agreement with those
obtained for the monoester synthesized chemically in
75% yield as white crystals: mp 100–101.5 ꢁC (Et2O/hex-
ane, lit. 100–101 ꢁC30).
4.4.11. (S)-3-(4-Chlorophenyl)-glutaric acid monoallyl
ester [(S)-3b, R3 = Allyl]. The reaction reached its full
conversion after 17 days to give (S)-3b, R3 = Allyl as an
oil in 99% yield. After crystallization, white crystals were
20
obtained in 64% yield: ½aꢁD ¼ ꢀ6.3 (c 0.40, CHCl3);
Rf = 0.31 (CHCl3/MeOH/HCOOH, 100:2:0.05); 1H
NMR (200 MHz, CDCl3) d 2.74 (m, 4H), 3.66 (m,
1H), 4.52 (d, J = 5.8 Hz, 2H) 5.20 (s, 1H), 5.27 (d,
J = 7.7 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 7.31 (d,
J = 8.6 Hz, 2H); 13C NMR (50 MHz, CDCl3) d 37.9,

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A. Fryszkowska et al. / Tetrahedron: Asymmetry 16 (2005) 2475–2485
20
40.6, 40.9, 65.9, 119.0, 129.2, 129.3, 132.3, 133.4, 141.1,
171.5, 177.4. Anal. Calcd for C14H15ClO4: C, 59.48; H,
5.35; Found: C, 59.45; H, 5.29.
yield: mp 95 ꢁC (Et2O/hexane); ½aꢁD ¼ ꢀ0.4 (c 0.50,
EtOH); Rf = 0.32 (CHCl3/MeOH/HCOOH, 100:2:0.05);
1H NMR d 2.67 (m, 4H), 3.58 (m, 1H), 3.76 (s, 3H),
5.00 (s, 2H), 6.76 (d, J = 8.3 Hz, 2H), 7.08 (d,
J = 8.3 Hz, 2H), 7.20 (m, 5H); 13C NMR d 37.3, 40.4,
40.8, 55.1, 66.3, 114.0, 128.2, 128.4, 134.0, 174.3,
177.3; IR (CHCl3) mmax: 3509 (OH), 2897 (Ar–OCH3),
4.4.12. (S)-3-(4-Methoxyphenyl)-glutaric acid mono-
methyl ester (S)-3c, R3 = Me. The reaction reached
its full conversion after 5 days to give (S)-3c, R3 = Me
in 99% yield as a colorless oil. After crystallization from
1720 (CO), 1713 (CO) cmꢀ1
. Anal. Calcd for
Et2O/hexane, the title product was obtained as white
C19H20O5: C, 69.50; H, 6.14. Found: C, 69.15; H, 6.24.
The spectroscopic and physical data are in agreement
with those obtained for the monoester synthesized
chemically in 44% yield as white crystals.
20
crystals in 95% yield: mp 55–57 ꢁC; ½aꢁD ¼ þ7.6
(c 0.60, EtOH); Rf = 0.37 (CHCl3/MeOH/HCOOH,
100:2:0.05); 1H NMR d 2.67 (m, 4H), 3.57 (s, 3H),
3.57 (m, 1H), 3.76 (s, 3H), 7.13 (d, J = 8.4 Hz, 2H),
7.45 (d, J = 8.4 Hz, 2H), 11.06 (s, 1H); 13C NMR d
37.2, 40.3, 40.6, 51.6, 55.1, 113.9, 128.1, 134.2, 157.3,
172.0, 177.5; IR (CHCl3) mmax: 3512 (OH), 2839 (Ar–
OCH3), 1732 (CO), 1713 (CO) cmꢀ1. Anal. Calcd for
C13H16O5: C, 61.90; H, 6.39. Found: C, 61.70; H, 6.57.
The spectroscopic data are in agreement with those
obtained for the monoester synthesized chemically in
87% yield as white crystals: mp 85 ꢁC (Et2O/hexane).
4.4.16. (S)-3-(4-Methoxyphenyl)-glutaric acid monoallyl
ester (S)-3c, R3 = Allyl. The reaction was terminated
after 25 days (70% conversion). After crystallization,
white crystals of (S)-3c, R3 = Allyl were obtained in
20
67% yield. ½aꢁD ¼ þ7.3 (c 0.65, EtOH); 1H NMR d
2.56–2.82 (m, 4H), 3.51–3.66 (m, 1H), 3.77 (s, 3H),
4.52 (d, J = 5.7 Hz, 2H), 5.10–5.28 (m, 2H), 5.70–5.89
(m, 1H), 6.82 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.6 Hz,
2H); 13C NMR d 37.2, 40.5, 40.8, 55.2, 65.2, 113.9,
118.2, 128.1, 131.8, 134.1, 158.3, 171.1, 177.4. Anal.
Calcd for C15H18O5: C, 64.74; H, 6.52. Found: C,
64.08; H, 6.37. The spectroscopic and physical data
are in agreement with those obtained for the monoester
synthesized chemically in 90% yield as white crystals: mp
71–72 ꢁC (Et2O/hexane).
4.4.13. (S)-3-(4-Methoxyphenyl)-glutaric acid monoethyl
ester (S)-3c, R3 = Et. The reaction reached its full con-
version after 13 days to give (S)-3c, R3 = Et as an oil in
93% yield. After crystallization from Et2O/hexane, white
crystals were obtained in 71% yield: mp 75–77 ꢁC (lit.
20
7831); ½aꢁD ¼ ꢀ6.4 (c 1.10, benzene); HPLC analysis
[hexane/i-PrOH/CH3COOH,
193:6:1;
k = 226 nm;
0.7 mL/min; tR (S) = 33.3 min, tR (R) = 36.3 min]: 68%
ee; Rf = 0.28 (CHCl3/MeOH/HCOOH, 100:2:0.05); H
4.4.17. (S)-3-(3,4-Dichlorophenyl)-glutaric acid monom-
ethyl ester (S)-3d, R3 = Me. The reaction reached its
full conversion after 5 days, to give the ester (S)-3d,
1
NMR d 1.20 (t, J = 7.2 Hz, 3H), 2.74 (m, 4H), 3.63
(m, 1H), 3.83 (s, 3H), 4.09 (q, J = 7.2 Hz, 2H), 6.9 (d,
J = 7.0 Hz, 2H), 7.19 (d, J = 7.2 Hz, 2H); 13C NMR d
14.6, 41.1, 41.1, 55.9, 60.9, 114.8, 129.4, 136.0, 159.4,
172.9, 174.8. Anal. Calcd for C14H18O5: C, 63.15; H,
6.81. Found: C, 63.12; H, 6.81. The spectroscopic and
physical data are in agreement with those obtained for
the monoester synthesized chemically in 85% yield as
white crystals: mp 76–78 ꢁC.
R3 = Me in 80% yield; white crystals: mp 79–89 ꢁC
20
(Et2O/hexane); ½aꢁD ¼ þ5.0 (c 1.00, EtOH); Rf = 0.20
(CHCl3/MeOH/HCOOH, 100:2:0.05); 1H NMR
d
2.55–2.88 (m, 4H), 3.55–3.75 (m, 1H), 3.61 (s, 3H),
7.13 (dd, J = 2.0 Hz, J = 8.7 Hz, 1H), 7.40–7.55 (m,
7H); 13C NMR d 32.0, 37.6, 42.6, 126.8, 128.2, 129.8,
131.4, 133.0, 134.2, 167.8, 177.0. Anal. Calcd for
C12H12Cl2O4: C, 49.51; H, 4.15. Found: C, 49.58; H,
4.17. The spectroscopic data are in agreement with those
obtained for the monoester synthesized chemically: mp
89–90 ꢁC (EtOAc/hexane).
4.4.14. (S)-3-(4-Methoxyphenyl)-glutaric acid monobutyl
ester (S)-3c, R3 = Bu. The reaction was terminated
after 25 days (conversion 44%). After crystallization,
white crystals of (S)-3c, R3 = Bu were obtained in 28%
4.4.18. (S)-3-(3,4-Dichlorophenyl)-glutaric acid mono-
ethyl ester (S)-3d, R3 = Et. The reaction was termi-
nated after 25 days (76% conversion). Crystallization
20
yield: mp 97 ꢁC (Et2O/hexane); ½aꢁD ¼ þ2.3 (c 0.50,
EtOH); Rf = 0.30 (CHCl3/MeOH/HCOOH, 100:2:0.05);
1H NMR
d
0.86 (t, J = 7.2 Hz, 3H), 1.25 (q,
gave white crystals of (S)-3d, R3 = Bu ester in 38% yield:
20
J = 7.2 Hz, 2H), 1.48 (m, 2H), 2.66 (m, 4H), 3.57
(m, 1H), 3.77 (s, 3H), 3.97 (t, J = 6.3 Hz, 2H), 6.81 (d,
J = 7.8 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 10.30–10.80
(br s 1H); 13C NMR d 13.6, 19.0, 30.5, 37.3, 40.5,
40.9, 55.2, 64.3, 113.9, 128.1, 134.2, 158.3, 171.7,
177.6. Anal. Calcd for C16H22O5 + 0.1H2O: C, 64.89;
H, 7.56. Found: C, 64.70; H, 7.78. The spectroscopic
and physical data are in agreement with those obtained
for the monoester synthesized chemically in 87% yield as
white crystals.
mp 76–77 ꢁC (Et2O/hexane); ½aꢁD ¼ þ3.8 (c 1.00, EtOH)
20
{lit. ½aꢁD ¼ þ6.9 (c 1.01, EtOH), for (S)-enantiomer13};
HPLC analysis [hexane/i-PrOH/CH3COOH 198:1:1;
k = 225 nm; 1.0 mL/min; tR (S) = 65.0 min, tR
(R) = 69.8 min] 60% ee Rf = 0.16 (CHCl3/MeOH/
1
HCOOH, 100:2:0.05); H NMR d 1.20 (t, J = 7.1 Hz,
3H), 2.55–2.88 (m, 4H), 3.55–3.75 (m, 1H), 4.03 (q,
J = 7.1 Hz, 2H), 7.13 (dd, J = 1.8 Hz, J = 8.2 Hz, 1H),
7.37–7.42 (m, 2H); 13C NMR d 14.1, 37.2, 40.3, 40.4,
60.8, 126.8, 129.3, 130.5, 130.9, 132.5, 142.5, 169.9,
177.0. Anal. Calcd for C13H14Cl2O4: C, 51.17; H, 4.62.
Found: C, 51.16; H, 4.78. The spectroscopic data are
in agreement with those obtained for the monoester syn-
thesized chemically in 88% yield as white crystals: mp
93–94 ꢁC (EtOAc/hexane).
4.4.15. 3-(4-Methoxyphenyl)-glutaric acid monobenzyl
ester (S)-3c, R3 = Bn. The reaction was terminated
after 33 days (63% conversion). After crystallization,
white crystals of (S)-3c, R3 = Bn were obtained in 36%

A. Fryszkowska et al. / Tetrahedron: Asymmetry 16 (2005) 2475–2485
2483
4.4.19. (S)-3-(3,4-Dichlorophenyl)-glutaric acid monobu-
tyl ester (S)-3d, R3 = Bu. The reaction was terminated
after 5 days (conversion 40%). Crystallization gave
thesized chemically in 85% yield as white crystals: mp
90–91 ꢁC (EtOAc/hexane, lit. 97–98 ꢁC30).
white crystals of (S)-3d, R3 = Bu in 16% yield: mp 76–
4.4.23. (S)-3-(4-Fluorophenyl)-glutaric acid monoethyl
ester 3e, R3 = Et. The reaction reached its full conver-
sion after 20 days to give (S)-3e, R3 = Et as an oil in
99% yield. After crystallization, white crystals were ob-
20
77 ꢁC (Et2O/hexane); ½aꢁD ¼ þ1.3 (c 0.50, ethanol);
Rf = 0.25 (CHCl3/MeOH/HCOOH, 100:2:0.05); 1H
NMR d 0.92 (t, J = 7.2 Hz, 3H), 1.24–1.35 (m, 2H),
1.36–1.70 (m, 2H), 2.73–2.88 (m, 4H), 3.60–3.75 (m,
1H), 4.03 (t, J = 6.6 Hz, 2H), 7.13 (dd, J = 1.8 Hz,
J = 8.2 Hz, 1H), 7.37–7.42 (m, 2H); 13C NMR d 14.2,
19.6, 31.1, 37.8, 40.4, 40.9, 65.2, 127.4, 129.9, 131.0,
131.5, 133.0, 143.0, 171.5, 176.9. Anal. Calcd for
C15H18Cl2O4: C, 54.07; H, 5.44. Found: C, 54.04; H,
5.69. The spectroscopic data are in agreement with those
obtained for the monoester synthesized chemically in
86% yield as white crystals.
tained in 89% yield: mp 59–60 ꢁC (Et2O/hexane);
20
½aꢁD ¼ ꢀ4.7 (c 1.00, CHCl3); Rf = 0.38 (hexane/EtOAc,
1
6:4); H NMR d 1.14 (t, J = 7.1 Hz, 3H), 2.51–2.82 (m,
4H), 3.58–3.64 (m, 1H), 4.03 (q, J = 7.1 Hz, 2H), 6.88–
7.02 (m, 2H), 7.10–7.26 (m, 2H); 13C NMR d 14.1,
37.3, 40.3, 40.7, 60.6, 115.4 (d, J = 21.3 Hz), 128.6 (d,
J = 7.9 Hz), 137.8 (d, J = 2.9 Hz), 161.7 (d,
J = 245.1 Hz), 171.3, 177.1. Anal. Calcd for
C13H15FO4: C, 61.41; H, 5.95. Found: C, 61.16; H,
5.95. The spectroscopic data are in agreement with those
obtained for the monoester synthesized chemically in
91% yield as white crystals: mp 35–36 ꢁC (EtOAc/
hexane).
4.4.20.
(S)-(ꢀ)-3-(3,4-Dichlorophenyl)-glutaric
acid
monobenzyl ester (S)-3d, R3 = Bn. The reaction was
terminated after 5 days (conversion 88%). Crystalliza-
tion gave white crystals of (S)-3d, R3 = Bn in 39% yield;
20
½aꢁD ¼ þ1.5 (c 1.00, EtOH); Rf = 0.24 (CHCl3/MeOH/
4.4.24. (S)-3-(4-Fluorophenyl)-glutaric acid monobutyl
ester (S)-3e, R3 = Bu. The reaction reached its full
conversion after 25 days to give (S)-3e, R3 = Bu as an
oil in 99% yield. After crystallization, white crystals were
1
HCOOH, 100:2:0.05); H NMR d 2.55–2.88 (m, 4H),
3.55–3.75 (m, 1H), 5.01 (s, 2H), 6.92–7.38 (m, 8H); 13C
NMR d 37.2, 40.0, 40.3, 66.8, 126.5, 126.8, 128.2,
128.3, 128.4, 128.5, 129.3, 130.5, 131.1, 132.6, 135.3,
142.2, 170.7, 177.0. Anal. Calcd for C18H16Cl2O4: C,
58.87; H, 4.39. Found: C, 58.94; H, 4.44. The spectro-
scopic data are in agreement with those obtained for
the monoester synthesized chemically in 49% yield as
white crystals: mp 78 ꢁC (EtOAc/hexane).
obtained in 44% yield: mp 44–46 ꢁC (Et2O/hexane);
20
½aꢁD ¼ ꢀ2.2 (c 0.50, CHCl3); Rf = 0.46 (hexane/EtOAc
6:4); 1H NMR d 0.87 (t, J = 7.3 Hz, 3H), 1.16–1.36
(m, 2H), 1.40–1.58 (m, 2H), 2.51–2.82 (m, 4H), 3.52–
3.70 (m, 1H), 3.97 (t, J = 6.6 Hz, 2H), 6.90–7.05 (m,
2H), 7.12–7.28 (m, 2H); 13C NMR d 13.6, 19.0, 30.5,
37.4, 40.3, 40.7, 64.4, 115.4 (d, J = 21.2 Hz), 128.7 (d,
J = 7.5 Hz), 137.8 (d, J = 2.8 Hz), 161.2 (d,
J = 245.0 Hz), 171.4, 177.0; IR (CHCl3) mmax: 1767
(CO), 1720 (CO) cmꢀ1. Anal. Calcd for C15H19FO44:
C, 63.82; H, 6.78. Found: C, 63.18; H, 6.98. The spectro-
scopic data are in agreement with those obtained for the
monoester synthesized chemically in 86% yield as white
crystals: mp 63–64 ꢁC (EtOAc/hexane).
4.4.21. (S)-3-(3,4-Dichlorophenyl)-glutaric acid monoallyl
ester (S)-3d, R3 = Allyl. The reaction was terminated
after 5 days (62% conversion). Crystallization gave
white crystals of (S)-3e, R3 = Bn in 18% yield;
20
½aꢁD ¼ þ1.7 (c 1.00, EtOH); Rf = 0.24 (CHCl3/MeOH/
1
HCOOH, 100:2:0.05); H NMR d 2.60–2.80 (m, 4H),
3.55–3.75 (m, 1H), 4.49 (d, J = 5.8 Hz, 2H), 5.23 (m,
2H), 5.70–5.90 (m, 1H), 7.13 (dd, J = 1.8 Hz,
J = 8.2 Hz, 1H), 7.37–7.42 (m, 2H); 13C NMR d 37.9,
40.4, 40.8, 66.1, 119.2, 127.0, 127.3, 129.9, 130.1,
131.1, 132.8, 142.9, 170.1, 171.1. Anal. Calcd for
C14H14Cl2O4: C, 53.02; H, 4.45. Found: C, 53.22; H,
4.50. The spectroscopic data are in agreement with those
obtained for the monoester synthesized chemically in
75% yield as white crystals: mp 65–66 ꢁC (Et2O/hexane).
4.4.25. (S)-3-(4-Fluorophenyl)-glutaric acid monobenzyl
ester (S)-3e, R3 = Bn. The reaction reached its full con-
version after 7 days to give (S)-3e, R3 = Bn as an oil in
99% yield. After crystallization, white crystals were ob-
20
tained in 40% yield; ½aꢁD ¼ ꢀ1.7 (c 0.80, CHCl3);
Rf = 0.37 (hexane/EtOAc 6:4); 1H NMR d 2.54–2.84
(m, 4H), 3.54–3.72 (m, 1H), 5.01 (s, 2H), 6.85–7.02 (m,
2H), 7.06–7.40 (m, 7H); 13C NMR d 37.2, 40.2, 40.6,
66.3, 115.4 (d, J = 21.12 Hz), 128.1, 128.4, 128.7 (d,
J = 7.89 Hz), 135.4, 138.2 (d, J = 2.90 Hz), 161.0 (d,
J = 245.0 Hz), 171.1, 177.0. Anal. Calcd for
C18H17FO4: C, 68.35; H, 5.42. Found: C, 68.39; H,
5.57. The spectroscopic data are in agreement with those
obtained for the monoester synthesized in 40% yield as
white crystals: mp 114–115 ꢁC (EtOAc/hexane).
4.4.22. (S)-3-(4-Fluorophenyl)-glutaric acid monomethyl
ester (S)-3e, R3 = Me. The reaction reached its full
conversion after 33 days to give (S)-3e, R3 = Me as an
oil in 99% yield. After crystallization, white crystals were
obtained in 90% yield: mp 42 ꢁC (Et2O/hexane);
20
½aꢁD ¼ ꢀ4.3 (c 1.00, CHCl3); Rf = 0.32 (hexane/EtOAc
1
6:4); H NMR d 2.53–2.84 (m, 4H), 3.58 (s, 3H), 3.61–
3.72 (m, 1H), 6.92–7.04 (m, 2H), 6.96 (d, J = 8.75 Hz,
2H), 7.18 (d, J = 8.56 Hz, 2H); 13C NMR d 37.2, 40.1,
40.5, 51.7, 115.6 (d, J = 21.5 Hz), 128.7 (d, J =
7.9 Hz), 137.4 (d, J = 2.9 Hz), 161.2 (d, J = 244.0 Hz),
171.7, 177.1; IR (CHCl3) mmax: 1733 (CO), 1715 (CO)
cmꢀ1. Anal. Calcd for C12H13FO4: C, 60.00; H, 5.45.
Found: C, 59.82; H, 5.79. The spectroscopic data are
in agreement with those obtained for the monoester syn-
4.4.26. (S)-3-(4-Fluorophenyl)-glutaric acid monoallyl
ester (S)-3e, R3 = Allyl. The reaction reached its full
conversion after 7 days to give (S)-3e, R3 = Allyl in
99% yield as an oil. After crystallization, white crystals
were obtained in 76% yield: mp 44–50 ꢁC (Et2O/hex-
20
ane); ½aꢁD ¼ ꢀ2.5 (c 0.90, CHCl3); Rf = 0.47 (hexane/
1
EtOAc 6:4); H NMR d 2.55–2.88 (m, 4H), 3.51–3.72

2484
A. Fryszkowska et al. / Tetrahedron: Asymmetry 16 (2005) 2475–2485
(m, 1H), 4.48 (d, J = 5.7 Hz, 2H), 5.10–5.28 (m, 2H),
5.68–5.90 (m, 1H), 6.90–7.05 (m, 2H), 7.10–7.28 (m,
2H); 13C NMR d 38.1, 41.0, 41.4, 66.2, 115.4 (d,
J = 21.3 Hz), 128.6 (d, J = 7.9 Hz), 137.8 (d,
J = 2.9 Hz), 161.7 (d, J = 245.1 Hz), 172.5, 179.4; IR
(CHCl3) mmax: 3516 (OH), 1818 (CH@CH2), 1729 (CO)
cmꢀ1. Anal. Calcd for C14H15FO4: C, 63.15; H, 5.68.
Found: C, 62.88; H, 5.90. The spectroscopic data are
in agreement with those obtained for the monoester syn-
thesized chemically in 89% yield as white crystals: mp
63–64 ꢁC (EtOAc/hexane).
was added dropwise. The solution was extracted with
methylene chloride (3 · 5 mL). Combined organic layers
were washed with brine (5 mL), dried (MgSO4), and
concentrated in vacuo to give a transparent oil. The
crude mixture was dissolved in toluene (5 mL) with cat-
alytic amount of p-toluenesulfonic acid. The solvent was
evaporated in vacuo and the procedure was repeated 3
times. Triethylamine was added (0.1 mL) and its excess
was evaporated in vacuo. The resulting oil was purified
by column chromatography (hexane/EtOAc, 8:2) to give
lactone (4S)-4e (0.023 g, 0.19 mmol) in 49% yield as a
20
colorless oil. ½aꢁD ¼ þ3.3 (c 1.25, CHCl3). The spectro-
4.4.27. Assigning the absolute configuration of chiral 3-
arylglutaric acid monoesters. All the chiral monoesters
(3S)-3 were transformed to lactones (4R)-4 according to
General procedure 1 described for (4R)-(4-fluorophen-
scopic and physical data are in agreement with those ob-
tained for racemic lactone ( )-4e.
4.4.30. (4R)-4-Phenyltetrahydro-2H-pyran-2-one 4a. Lac-
yl)tetrahydro-2H-pyran-2-one (4R)-4d. The reaction
tone (4R)-4a was synthesized according to General
20
20
procedure 1 in 52% yield as a colorless oil. ½aꢁD ¼ ꢀ5.7
20
yields and optical rotary dispersion values (½aꢁD ) of lac-
tones are summarized in Table 3.
(c 2.10, CHCl3), {lit. ½aꢁD ¼ þ3.8 (c 7.2, CHCl3), for
(S)-enantiomer32}; Rf = 0.39 (hexane/EtOAc, 6:4) 1H
NMR (200 MHz, CDCl3) d 1.94–2.12 (m, 2H), 2.56 (dd,
J = 10.6 Hz, J = 17.6, 1H), 2.86 (ddd, J = 1.5 Hz,
J = 5.8 Hz, J = 17.2 Hz, 1H), 3.08–3.28 (m, 1H), 4.30
(dt, J = 3.6 Hz, J = 11.4 Hz, 1H), 4.42 (ddd, J = 3.7 Hz,
J = 4.8 Hz, J = 11.3 Hz, 1H), 7.15 (d, J = 7.2 Hz, 2H),
7.28 (d, J = 7.2 Hz, 2H); 13C NMR (50 MHz, CDCl3) d
31.1, 31.2, 38.2, 69.5, 127.7, 128.5, 130.2, 171.1; IR
4.4.28. (4R)-(4-Fluorophenyl)tetrahydro-2H-pyran-2-one
(4R)-4d. General procedure 1: To the cooled (0 ꢁC)
solution of monoester (3S)-3e (R2 = Me) (0.058 g,
0.24 mmol) in dry THF, potassium tert-butoxide
(0.027 g, 0.24 mmol) was added. The mixture was
allowed to warm up to room temperature and lithium
borohydride (0.011 g, 0.51 mmol) was added. The mix-
ture was refluxed for 1 h and after cooling concd hydro-
chloric acid (0.5 mL) was added dropwise. The solution
was extracted with methylene chloride (3 · 5 mL). Com-
bined organic layers were washed with brine (5 mL),
dried (MgSO4), and concentrated in vacuo to give a
transparent oil. The crude mixture was dissolved in tol-
uene (5 mL) with catalytic amount of p-toluenesulfonic
acid. The solvents were evaporated in vacuo along with
formed water. The last operation (lactonization) was
repeated three times. Triethylamine was added (0.1 mL)
and its excess was evaporated in vacuo. The resulting
oil was purified by column chromatography (hexane/
(CHCl3) mmax
: . Anal. Calcd for
1730 (CO) cmꢀ1
C11H12O2: C, 74.98; H, 6.86. Found: C, 74.94; H, 7.89.
The spectroscopic and physical data are in agreement with
those obtained for racemic lactone ( )-4a synthesized
according to General procedure 1 from monoester ( )-
3a, R3 = Et in 19% yield.
4.4.31. (4R)-4-(4-Chlorophenyl)tetrahydro-2H-pyran-2-
one (4R)-4b. The lactone (4R)-4b was synthesized
according to General procedure 1 from (3S)-3b,
R3 = Et in 36% yield as white crystals: mp 80 ꢁC;
20
20
½aꢁD ¼ ꢀ8.7 (c 1.38, CHCl3) {lit. ½aꢁD ¼ þ8.4 (c 1.38,
EtOAc, 8:2) to give lactone (4R)-4e (0.023 g, 0.19 mmol)
CHCl3), for (S)-enantiomer33}; Rf = 0.34 (hexane/
EtOAc, 6:4); H NMR (200 MHz, CDCl3) d 1.70–2.15
20
1
in 49% yield as a colorless oil. ½aꢁD ¼ ꢀ3.2 (c 1.90,
CHCl3); Rf = 0.32 (hexane/EtOAc, 6:4) 1H NMR
(200 MHz, CDCl3) d 1.82–2.13 (m, 2H), 2.50 (dd,
J = 10.6 Hz, J = 17.5 Hz, 1H), 2.80 (ddd, J = 1.5 Hz,
J = 5.9 Hz, J = 17.5 Hz, 1H), 3.05–3.22 (m, 1H), 4.20–
4.45 (m, 2H), 6.92–7.14 (m, 4H); 13C NMR (50 MHz,
CDCl3) d 37.2, 40.2, 40.4, 51.7, 115.4 (d, J = 21.1 Hz),
128.6 (d, J = 7.9 Hz), 137.8 (d, J = 3.2 Hz), 161.7 (d,
J = 245.0 Hz), 170.8; IR (CHCl3) mmax: 1734 (CO)
cmꢀ1. Anal. Calcd for C11H11FO2: C, 68.03; H, 5.71.
Found: C, 68.01; H, 5.81. The spectroscopic and physi-
cal data are in agreement with those obtained for the
racemic lactone ( )-4e synthesized according to General
procedure 1 in 76% yield.
(m, 2H), 2.51 (dd, J = 10.6 Hz, J = 17.6 Hz, 1H), 2.85
(ddd, J = 1.5 Hz, J = 5.8 Hz, J = 17.2 Hz, 1H), 3.05–
3.28 (m, 1H), 4.28 (dt, J = 3.6 Hz, J = 11.4 Hz, 1H),
4.46 (ddd, J = 3.7 Hz, J = 4.8 Hz, J = 11.3 Hz, 1H),
7.07 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H); 13C
NMR (50 MHz, CDCl3) d 30.8, 37.5, 38.0, 69.0, 127.4,
127.7, 128.3, 128.5, 128.9, 129.0, 129.3, 129.4, 129.7,
141.7, 170.7; IR (CHCl3) mmax: 1732 (CO) cmꢀ1. Anal.
Calcd for C11H11ClO2: C, 62.72; H, 5.26. Found: C,
62.86; H, 5.21. The spectroscopic data are in agreement
with those obtained for racemic lactone ( )-4b synthe-
sized according to General procedure 1 from monoester
( )-3b, R3 = Et as white crystals in 43% yield: mp 79–
80 ꢁC (lit. 81–836).
4.4.29. (4S)-(4-Fluorophenyl)tetrahydro-2H-pyran-2-one
(4S)-4e. To the vigorously stirred solution of (3S)-3d
(R2 = Me) (0.061 g, 0.24 mmol) in dry THF at 0 ꢁC,
potassium tert-butoxide (0.027 g, 0.24 mmol) was
added. The mixture was allowed to warm up to room
temperature and lithium aluminum hydride (0.011 g,
0.51 mmol) was added. The mixture was refluxed for
1 h and after cooling 33% hydrochloric acid (2 mL)
4.4.32. (4R)-4-(4-Methoxyphenyl)tetrahydro-2H-pyran-
2-one (4R)-4c. The lactone (4R)-4c was synthesized
according to General procedure 1 in 71% yield as white
20
crystals: mp 75–77 ꢁC; ½aꢁD ¼ ꢀ7.7 (c 3.20, CHCl3) {lit.
20
½aꢁD ¼ ꢀ7.0 (c 0.96, CHCl3), for (R)-enantiomer34};
Rf = 0.32 (hexane/EtOAc, 6:4); 1H NMR (200 MHz,
CDCl3) d 1.91–2.26 (m, 2H), 2.61 (dd, J = 10.6 Hz,

A. Fryszkowska et al. / Tetrahedron: Asymmetry 16 (2005) 2475–2485
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J = 17.6, 1H), 2.95 (ddd, J = 1.6 Hz, J = 5.9 Hz,
J = 17.2 Hz, 1H), 3.12–3.31 (m, 1H), 3.82 (s, 1H), 4.37
(dt, J = 3.9 Hz, J = 11.4 Hz, 1H), 4.48 (ddd,
J = 3.8 Hz, J = 4.8 Hz, J = 11.3 Hz, 1H), 6.92 (d,
J = 8.8 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H); 13C NMR
(50 MHz, CDCl3) d 31.1, 37.2, 38.3, 55.9, 69.2, 114.8,
128.0, 135.5, 159.2, 171.3; IR (CHCl3) mmax: 1731 (CO)
cmꢀ1. Anal. Calcd for C12H14O3: C, 69.89; H, 6.84.
Found: C, 69.73; H, 6.72. The spectroscopic data are in
agreement with those obtained for racemic lactone ( )-
4c synthesized according to General procedure 1 as white
crystals in 45% yield: mp 79–80 ꢁC (lit. 83.4–83.634).
4.4.33. (4R)-(3,4-Dichlorophenyl)tetrahydro-2H-pyran-2-
one (4R)-4d. The lactone (4R)-4d was synthesized
according to General procedure 1 in 35% yield as a col-
20
orless oil. ½aꢁD ¼ ꢀ8.1 (c 1.60, CHCl3); Rf = 0.32 (hex-
1
ane/EtOAc, 6:4); H NMR (200 MHz, CDCl3) d 1.80–
2.15 (m, 2H), 2.48 (dd, J = 10.8 Hz, J = 17.5 Hz, 1H),
3.15 (ddd, J = 1.6 Hz, J = 6.0 Hz, J = 17.8 Hz, 1H),
4.20–4.50 (m, 3H), 6.80 (dd, J = 2.2 Hz, J = 8.3 Hz,
1H), 7.25 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H);
13C NMR (50 MHz, CDCl3) d 30.6, 37.3, 37.7, 68.8,
126.4, 129.2, 131.5, 131.9, 133.6, 143.5, 170.2; IR
(CHCl3) mmax: 1735 (CO) cmꢀ1. Anal. Calcd for
C11H10Cl2O2: C, 53.90; H, 4.11. Found: C, 53.78; H,
4.13. The spectroscopic and physical data are in agree-
ment with those obtained for racemic lactone ( )-4d
synthesized according to General procedure 1 from
monoester ( )-3d, R3 = Et in 47% yield.
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Acknowledgements
This work was supported by Polish State Committee for
Scientific Research, grant PZB-MIN-007/P04/2003.
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