1-Alkylthio-3-aryloxypropan-2-ols: Synthesis and enantiomer separation by lipase-catalyzed transesterification

Article abstract of DOI:10.1016/j.tetasy.2003.08.005

The optically active (R)- and (S)-1-alkylthio-3-aryloxypropan-2-ols were prepared in the reaction of the appropriate arylglycidyl ethers and alkyl thiols followed by lipase-catalyzed transesterification. The effect of aryl and alkyl substituents, the enzyme preparation as well as the reaction conditions have been compared in terms of enantiomeric excess of the obtained acetate and the unreacted alcohol.

Full text of DOI:10.1016/j.tetasy.2003.08.005

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3203–3210
1-Alkylthio-3-aryloxypropan-2-ols: synthesis and enantiomer
separation by lipase-catalyzed transesterification
Monika Wielechowska and Jan Plenkiewicz*
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
Received 24 June 2003; accepted 6 August 2003
Abstract—The optically active (R)- and (S)-1-alkylthio-3-aryloxypropan-2-ols were prepared in the reaction of the appropriate
arylglycidyl ethers and alkyl thiols followed by lipase-catalyzed transesterification. The effect of aryl and alkyl substituents, the
enzyme preparation as well as the reaction conditions have been compared in terms of enantiomeric excess of the obtained acetate
and the unreacted alcohol.
© 2003 Elsevier Ltd. All rights reserved.
system (PTC conditions) was considered to be most
effective.
1. Introduction
The oxirane ring opening with various nucleophiles
(e.g. halogen ions, CN−, N3 , OH−, etc.) is an important
−
2. Results and discussion
synthetic transformation which provides an easy access
to a large number of functionalized intermediates in the
synthesis of natural and synthetic products. Continuing
our interest in the lipase-catalyzed resolutions of the
racemic mixtures of 1,3-disubstituted secondary
propanols1 we recently focused our attention on 1-
alkylthio-3-aryloxypropan-2-ols 1 which can be easily
prepared from arylglycidyl ethers and aliphatic thiols.
Their optically active forms are expected to be conve-
nient substrates for the preparation of chiral sulfoxides,
which further may be used for the synthesis of chiral
catalysts and chiral pharmaceuticals.
2.1. Synthesis of 1-alkylthio-3-aryloxypropan-2-ols ( )-
1a–h
The starting aryl glycidyl ethers were prepared in high
yields by the Williamson reaction from the correspond-
ing phenols and epichlorhydrin in a 10% sodium
hydroxide solution. The yields of the reaction depended
on the substituent in the phenyl ring and varied from 75
to 90%. The epoxide ring opening reaction with thiolate
anion as the nucleophile is well known and various
bases were used for the generation of the anion. Also
aryl glycidyl ethers were used as the substrates to yield
the appropriate 1, the yields were, however, moder-
ate.4c,e,5a,c In our procedure, the reaction conditions
have been adjusted to meet the two-phase (aqueous
KOH/diethyl ether) system conditions with tetra-n-
butylammonium bromide as the phase transfer catalyst.
The yields of 1 were nearly quantitative, much higher
than those reported earlier5 (Scheme 1).
The known methods of the synthesis of 1 depend
mostly on two reactions: alkylation of the appropriate
thiols with 1-chloro-3-aryloxypropan-2-ols;2 and epox-
ide ring opening of alkylsulfanylmethyloxiranes with
the appropriate aryloxy anion.3 In either case, the yields
do not exceed 70%. There are also reports on epoxide
ring opening with thiolate anions as the nucleophiles,
they concern, however, mostly aryl thiolates;4 the reac-
tions of aliphatic thiols with epoxides have been investi-
gated rarely.5 In our search for a simple method for the
synthesis of 1, the reaction of arylglycidyl ethers with
appropriate alkyl thiolates in a two-phase catalytic
2.2. Kinetic resolution of ( )-1a–h by lipase-catalyzed
transesterification
The conditions for the lipase-catalyzed acetylation of
racemic alkylthio alcohols ( )-1 were optimised accord-
ing to the conventional method described earlier6
(Scheme 2). The effects of lipase, solvent, acyl donor,
temperature, and substituent in the aromatic ring on
the enantioselectivity of enzymatic acetylation were
* Corresponding author. Tel.: +4822-660-7570; fax: +4822-628-2741;
e-mail: plenki@ch.pw.edu.pl
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.005

3204
M. Wielechowska, J. Plenkiewicz / Tetrahedron: Asymmetry 14 (2003) 3203–3210
Scheme 1.
Scheme 2.
evaluated by determination of the reaction enantiose-
lectivity (E).
show that with the tested lipases the (R)-(+) alcohol 2a
reacts slower than the (S)-(−)-enantiomer and that the
reactions show poor-to-moderate enantio-selectivities
(E=1–27). It is also evident how the results depend on
the kind of used enzyme preparation. Novozym SP-435,
Chirazyme L-2 c-f lyo, and Chirazyme L-2 c-f c-2 are
the same lipases produced by Candida antarctica, but
their catalytic properties are substantially different. The
same relates to Amano PS and Chirazyme L-1 c-f lyo
lipase preparations. Among the tested lipase prepara-
tions only Amano AK (Pseudomonas fluorescens) and
Chirazyme L-1 c-f lyo (Pseudomonas cepacia) exhibited
promising catalytic activities and enantioselectivities
with this substrate.
The catalytic efficacy of different commercially avail-
able lipases in the acylation reaction was investigated.
For this purpose, ( )-1a, used as a model substrate, was
allowed to react at 20°C in tert-butyl methyl ether with
two equivalents of vinyl acetate in the presence of
different lipases. In control experiments, the reaction
did not proceed in the absence of an enzyme. Generally,
the transesterifications were monitored by thin layer
chromatography and the reactions were arrested when
the conversion reached 30–50%. The enzyme was then
removed by filtration and the resulting solution of
enantiomerically enriched acetate 3a and unchanged
alcohol 2a was used for an exact determination of the
conversion degree and enantiomeric excesses. The
investigations were done by HPLC analyses with a
chiral column. The results are summarized in Table 1.
A substantial difference in the reaction rates of the two
enantiomers was obtained only with the Amano AK
lipase catalyst (a marked decrease of the reaction rate
was observed after a 50% conversion).
The absolute configurations of the products, i.e. the
alcohol 2a and the acetate 3a, were determined by the
modified Mosher’s method as described by Riguera et
al.7a The method depends on comparing the differences
of 1H NMR chemical shifts recorded for the
diastereomeric esters prepared from a separated enan-
tiomer of the alcohol and (R)- and (S)-enantiomers of
methoxyphenylacetic acid. The utility of the method
has been confirmed by several authors.7b–i According to
our investigation, the unchanged alcohol 2a and its
acetate 3a have the (R)-(+) and (S)-(+) configurations,
respectively. This assignment is in good agreement with
the Kazlauskas rule.8 The results presented in Table 1
A proper choice of the solvent used in enzymatic reac-
tions is known to be a very important factor.9 It is
well-documented that, generally speaking, lipases show
a higher activity in hydrophobic solvents of low polar-
ity,6 but they do work in polar solvents and there are
examples of kinetic resolutions in dioxane,10a,b
THF,10a,b chloroform,10c acetone,10d tert-butanol,10d
pyridine,10e and ionic liquid.10f Therefore, we have
investigated the trans-esterification of ( )-1a with vinyl
acetate catalyzed by Amano AK in various solvents at
room temperature. The reaction conditions were the
same as given in the footnote to Table 1. The results are
presented in Table 2.
Table 1. Kinetic resolution of ( )-1a by lipase-catalyzed acetylationa with vinyl acetate in tert-butyl methyl ether
Lipase
Time (h)
Conv. (%)b
Eesubstr (%)c
Eeprod. (%)c
Eb
Amano AK (Psaeudomonas fluorescens)
Amano PS (Pseudomonas cepacia)
Novozym SP 435 (Candida antarctica-B)
Chirazyme L-2; c-f; lyo (Candida antarctica-B)
Chirazyme L-1; c-f; lyo (Pseudomonas cepacia)
Chirazyme L-2; c-f; c-2; lyo (Candida antarctica-B)
48
193
33
75
48
45
36
27
31
40
44
69
44
4
4
57
4
86
78
10
9
87
5
27
12
1
1
26
1
48
a Conditions: 1 mmol of ( )-1a, 2 mmol of vinyl acetate, 120 mg of lipase and 12 mL of tert-butyl methyl ether at 20°C.
b Conversion and E values were calculated from the enantiomeric excess of substrate 2a (ees) and product 3a (eep) using the usual formula:
E=Ln[(1−ees)(eep/(ees+eep))]/Ln[(1+ees)(eep/(ees+eep))], Conv.=ees/(ees+eep).
c Determined by HPLC analysis using Chiralcel OD-H column.

M. Wielechowska, J. Plenkiewicz / Tetrahedron: Asymmetry 14 (2003) 3203–3210
3205
Table 2. Transesterification of ( )-1a with vinyl acetate catalyzed by Amano AK lipasea in various solvents
Entry
Solvent
Log P
Time (h)
C (%)b
Ees (%)c
Eep (%)c
Eb
1
2
3
4
5
6
TBME
i-Pr2O
Hexane
Benzene
Toluene
THF
1.3
1.1
3.5
2.0
2.5
0.49
48
44
44
92
92
45
41
45
35
34
22
69
59
67
48
46
25
86
83
82
89
90
89
27
19
20
28
29
25
166
a Conditions: 1 mmol of ( )-1a, 2 mmol of vinyl acetate, 120 mg of lipase and 12 mL of tert-butyl methyl ether at 20°C.
b Conversion and E values were calculated from the enantiomeric excess of substrate 2a (ees) and product 3a (eep) using the usual formula:
E=Ln[(1−ees)(eep/(ees+eep))]/Ln[(1+ees)(eep/(ees+eep))], Conv.=ees/(ees+eep).
c Determined by HPLC analysis using Chiralcel OD-H column.
The enantioselectivities E of the reactions were highest
with low polar aromatic hydrocarbons (Table 2, items 4
and 5). However, the reaction carried out in tert-butyl
methyl ether (item 1) was twice as fast with only a
slightly diminished E value. Another interesting obser-
vation is the lack of correlation between the solvent
polarity and the reaction rate.
the influence of the structure (especially the nature and
position of the substituents in the aromatic ring) of
1-alkylthio-3-aryloxypropan-2-ols ( )-1a–h on the rate
and enantioselectivity of the transesterification reaction.
For this purpose several alcohols were acetylated with
vinyl acetate in the presence of Amano AK lipase in a
TBME solution. The results are presented in Table 3.
The next parameter tested during this investigation was
The data presented below indicate that only the m-
Table 3. Transesterification of ( )-1a–h with vinyl acetate catalyzed by Amano AK lipasea
Entry
Substrate
Ar
R1
Time (h)
C (%)b
Ees (%)c
Eep (%)c
Eb
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
C6H5-
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Et
48
48
48
90
27
47
48
240
45
62
49
27
34
21
57
35
69
85
83
31
38
19
32
24
86
53
86
83
74
72
24
69
27
8
34
15
10
7
4-CH3-C6H4-
3-CH3-C6H4-
2-CH3-C6H4-
4-Cl-C6H4-
C6H5-
1g
1h
4-CH3-C6H4-
C6H5-
Et
tert-Bu
2
7
a Conditions: 1 mmol of ( )-1a, 2 mmol of vinyl acetate, 120 mg of lipase and 12 mL of tert-butyl methyl ether at 20°C.
b Conversion and E values were calculated from the enantiomeric excess of substrate 2a (ees) and product 3a (eep) using the usual formula:
E=Ln[(1−ees)(eep/(ees+eep))]/Ln[(1+ees)(eep/(ees+eep))], Conv.=ees/(ees+eep).
c Determined by HPLC analysis using Chiralcel OD-H column.
Figure 1. Dependence of enantiomeric purities ee [%] of (R)-(+)-2a and (S)-(+)-3a (Fig. 1A) and (R)-(+)-2b and (S)-(+)-3b (Fig.
1B) on the convertion of ( )-1a and ( )-1b in Amano AK lipase-catalyzed acetylation with vinyl acetate in TBME at 20°C.

3206
M. Wielechowska, J. Plenkiewicz / Tetrahedron: Asymmetry 14 (2003) 3203–3210
Table 4. Transesterification of ( )-1a–c,f with iso-propenyl acetate in TBME solution at room temperaturea
Entry
Substrate
Lipase
Time (h)
C (%)b
Ees (%)c
Eep (%)c
Eb
1
2
3
4
5
1a
1b
1c
1f
Amano AK
Amano AK
Amano AK
Amano AK
Amano PS
96
96
96
208
287
35
30
41
36
23
49
34
64
38
25
91
81
91
67
86
34
13
41
7
1a
17
a Conditions: 1 mmol of ( )-1a, 2 mmol of vinyl acetate, 120 mg of lipase and 12 mL of tert-butyl methyl ether at 20°C.
b Conversion and E values were calculated from the enantiomeric excess of substrate 2a (ees) and product 3a (eep) using the usual formula:
E=Ln[(1−ees)(eep/(ees+eep))]/Ln[(1+ees)(eep/(ees+eep))], Conv.=ees/(ees+eep).
c Determined by HPLC analysis using Chiralcel OD-H column.
methyl substituent improved the enantioselectivity of
the reaction (items 1 and 3). In comparison with the
n-butyl substituent, both the smaller ethyl group and
the bulkier tert-butyl one diminished the enantioselec-
tivity of the reaction E (item 1 versus 6 and 8).
for two of the investigated alcohols with the use of
Amano AK lipase and iso-propenyl acetate in tetra-
butyl methyl ether solution at 20°C. In general, the
obtained enantio-selectivities in the realized acetylation
reactions of 1-alkylthio-3-aryloxypropan-2-ols were a
little lower than for 1-azido- and 1-nitrato-3-aryl-
oxypropan-2-ols investigated earlier.1 This may be
explained by larger volume and lower polarity of the
substituent (thioalkyl versus azido or nitrato group).
The dependence of the enantiomeric excesses of the
substrate (alcohol) and the product (acetate) on the
conversion of ( )-1-butylthio-3-phenoxypropan-2-ol
and ( )-1-butylthio-3-(4-methylphenoxy)-propan-2-ol is
presented in Figure 1(A) and (B), respectively, together
with the calculated enantioselectivities E of the reac-
tions. The plots (Fig. 1(A) and (B)) substantiate the
data presented earlier indicating that the enantioselec-
tivity of the Amano AK lipase catalyzed acetylation of
p-methyl substituted 1 is much lower than that of the
parent compound.
4. Experimental
4.1. General
1H (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on Varian Mercury 400 MHz spectrometer in
CDCl3 solution, and chemical shifts (l) are reported in
ppm. IR spectra were taken on a Carl Zeiss Specord
M80 instrument. Optical purities of alcohols (R)-(+)-
2a–h and esters (S)-(+)-3a–h were determined on a
Thermo-Separation Products P-100 instrument and
Chiralcel OD-H column (in n-hexane:iso-propanol, 9:1;
0.8 mL/min for alcohols and n-hexane:iso-propanol,
99:1; 0.4 mL/min for esters) using racemic compounds
as references. Optical rotation was measured in CHCl3
with PolAAr 32 polarimeter. Elemental analyses were
performed on CHNS/O Perkin Elmer type 2400 instru-
ment. The reactions were monitored by TLC on silica
gel 60 F254 plates and by column chromatography on
silica gel 60 (230–400 mesh). The arylglycidyl ethers
were prepared by the Williamson reaction from the
appropriate phenols and epichlorohydrin in an aqueous
NaOH solution. Lipases Amano AK, and Amano PS
were generously provided by Amano Co (Japan).
Novozym SP 435 was kindly granted by Novo-Nordisk.
Chirazymes were supplied by Roche Molecular Bio-
chemicals (Germany).
The effect of the acyl donor structure on the enantiose-
lectivity of the lipase-catalyzed transesterification reac-
tion has been well documented by Ema et al.11 In
general, among the various types of acyl donors they
examined, enol esters, because of high reactivity and
irreversibility of the reaction, have been considered as
most suitable for the kinetic resolution by trans-esterifi-
cation. As it is known, iso-propenyl acetate is also
frequently used as an acyl donor in the enzyme-cata-
lyzed acetylation reactions. Usually, the reaction with
iso-propenyl acetate is slower than that with vinyl
acetate but enantioselectivities are sometimes higher.
Thus, in order to enhance the enantioselectivity of
lipase-catalyzed acetylation of few ( )-1, propenyl ace-
tate was examined as the acyl donor. The obtained
results are presented in Table 4. The rates of all investi-
gated reactions were much lower when iso-propenyl
acetate was used instead of vinyl acetate. However, a
considerable improvement of the reaction enantioselec-
tivity for three of the investigated compounds (1a, 1b
and 1c) was achieved. The obtained optical purities of
the acetates 3a and 3c (>90%) suggest that the described
method may be used for practical purposes.
4.2. Preparation of alcohols ( )-1a–h
The thiol (50 mmol) was dissolved in a warm solution
of KOH (20 g) in water (35 mL) and then the appropri-
ate aryl glycidyl ether (33 mmol) in diethyl ether (50
mL) and tert-butylammonium bromide (TBAB; 1 g)
were added. The mixture was stirred vigorously under
reflux for 2 h. Then the layers were separated and the
aqueous layer was extracted with 20 mL of TBME. The
organic layers were connected and washed with 20 mL
3. Conclusion
In summary, we have presented a general method for
enantioselective acetylation of 1-alkylthio-3-aryloxy-
propan-2-ols with various aromatic substituents.
Highest enantioselectivities (E=34–41) were obtained

M. Wielechowska, J. Plenkiewicz / Tetrahedron: Asymmetry 14 (2003) 3203–3210
3207
of water, dried over anhydrous MgSO4 and the solvent
was evaporated. The crude mixture was purified by
chromatography on a short silica gel column with
C14H22SO2: C, 66.10; H, 8.72. Found: C, 66.19; H,
8.60.
hexane:ethyl acetate (10:1 v/v) as the eluent. 1H and 13
C
4.2.5. ( )-1-Butylthio-3-(4-chlorophenoxy)propan-2-ol 1e.
Yield 95%. 1H NMR (CDCl3) l ppm: 0.91 (t; 3H
(CH3CH2CH2CH2); J=7.2 Hz); 1.40 (m; 2H
(CH3CH2CH2CH2)); 1.58 (m; 2H (CH3CH2CH2CH2));
2.56 (t; 2H (CH3CH2CH2CH2); J=7.2 Hz); 2.70 (dd;
1H (CHcCHbHa); Jab=14Hz; Jac=7.4Hz); 2.80 (s; 1H
(OH)); 2.84 (dd; 1H (CHcCHbHa); Jbc=5.2 Hz); 4.01
(m; 2H (OCH2CHc)); 4.10 (m; 1H (CHc)); 6.80–7.25 (m;
4H (aromatic H)); 13C NMR (CDCl3) l ppm: 13.6;
21.9; 31.7; 32.2; 35.8; 68.4; 70.7; 115.8; 126.0; 129.3;
157.0. IR (film; cm−1) 3430; 2950; 1590; 1490; 1240;
1085; 1030; 820. Anal. calcd for C13H19ClSO2: C, 56.82;
H, 6.70. Found: C, 56.89; H, 6.90.
NMR spectra, IR data, and elemental analyses of the
prepared alcohols ( )-1a–h are reported below:
4.2.1. ( )-1-Butylthio-3-phenoxypropan-2-ol 1a. Yield
93%. 1H NMR (CDCl3)
l ppm: 0.91 (t; 3H
(CH3CH2CH2CH2); J=7.6 Hz); 1.40 (m; 2H
(CH3CH2CH2CH2)); 1.57 (m; 2H (CH3CH2CH2CH2));
2.57 (t; 2H (CH3CH2CH2CH2); J=7.2 Hz); 2.72 (dd;
1H (CHcCHaHbS); Jab=13.6 Hz; Jac=7.2 Hz); 2.85
(dd; 1H (CHcCHaHbS); Jbc=5.2 Hz); 4.05 (m; 2H
(OCH2CHc)); 4.11 (m; 1H (CHc)); 6.90–7.30 (m; 5H
(aromatic H)); 13C NMR (CDCl3) l ppm: 13.6; 21.8;
31.7; 32.2; 35.8; 68.6; 70.3; 114.5; 121.1; 129.4; 158.4;
IR (film, cm−1) 3420; 2920; 1590; 1470; 1235; 1030; 740;
680. Anal. calcd for C13H20SO2: C, 64.96%; H, 8.39%.
Found: C, 64.94%; H, 8.28%.
4.2.6. ( )-1-Ethylthio-3-phenoxypropan-2-ol 1f. Yield
1
99%. H NMR (CDCl3) l ppm: 1.28 (t; 3H (CH3CH2);
J=7.2 Hz); 2.59 (q; 2H (CH3CH2)); 2.74 (dd; 1H
(CHcCHaHbS); Jab=13.6 Hz; Jac=7.2 Hz); 2.87 (dd;
1H (CHcCHaHbS); Jbc=5 Hz); 4.04 (m; 2H
(OCH2CHc)); 4.10 (m; 1H (CHc)); 6.90–7.30 (m; 5H
(aromatic H); 13C NMR (CDCl3); l 14.8; 26.4; 35.4;
68.6; 70.3; 114.5; 121.2; 129.5; 158.4. IR (film; cm−1)
3440; 2930; 1600; 1495; 1240; 1040; 750; 640. Anal.
calcd for C11H16SO2: C, 62.23; H, 7.60. Found: C,
62.30; H, 7.50.
4.2.2.
( )-1-Butylthio-3-(4-methylphenoxy)propan-2-ol
1
1b. Yield 95%. H NMR (CDCl3) l ppm: 0.92 (t; 3H
(CH3CH2CH2CH2); J=7.2 Hz); 1.41 (m; 2H
(CH3CH2CH2CH2)); 1.59 (m; 2H (CH3CH2CH2CH2));
2.29 (s; 3H (CH3)); 2.57 (t; 2H (CH3CH2CH2CH2)
J=7.6 Hz); 2.72 (dd; 1H (CHcCHaHbS); Jab=13.7 Hz;
Jac=7 Hz); 2.78 (s; 1H (OH)); 2.85 (dd; 1H
(CHcCHaHbS); Jac=5.2 Hz); 4.02 (m; 2H (OCH2CH));
4.07 (m; 1H (CHc)); 6.80–7.10 (m; 4H (aromatic H));
13C NMR (CDCl3) l ppm: 13.6; 20.4; 21.9; 31.7; 32.2;
35.8; 68.6; 70.5; 114.4; 129.9; 130.4; 156.3. IR (film;
cm−1) 3440; 2920; 1610; 1500; 1235; 1030; 810. Anal.
calcd for C14H22SO2: C, 66.10%; H, 8.72%. Found: C;
66.20%; H, 8.54%.
4.2.7.
( )-1-Ethylthio-3-(4-methylphenoxy)propan-2-ol
1
1g. Yield 91%. H NMR (CDCl3) l ppm: 1.28 (t; 3H
(CH3CH2); J=7.2 Hz); 2.29 (s; 3H (CH3)); 2.60 (q; 2H
(CH3CH2)); 2.73 (dd; 1H (CHcCHaHbS); Jab=13.8 Hz;
Jac=7 Hz); 2.86 (dd; 1H (CHcCHaHbS); Jbc=5.4 Hz);
4.02 (m; 2H (OCH2CHc)); 4.08 (m; 1H (CHc)); 6.80–
7.10 (m; 4H (aromatic H)); 13C NMR (CDCl3) l ppm:
14.8; 20.4; 26.4; 35.4; 68.6; 70.5; 114.4; 129.9; 130.4;
156.3. IR (film; cm−1) 3450; 2930; 1610; 1510; 1240;
1040; 815. Anal. calcd for C12H18SO2: C, 63.74%; H,
8.02%. Found: C, 63.74%; H, 7.94%.
4.2.3.
( )-1-Butylthio-3-(3-methylphenoxy)propan-2-ol
1
1c. Yield 96%. H NMR (CDCl3) l ppm: 0.92 (t; 3H
(CH3CH2CH2CH2); J=7.2 Hz); 1.41 (m; 2H
(CH3CH2CH2CH2)); 1.59 (m; 2H (CH3CH2CH2CH2));
2.33 (s; 3H (CH3)); 2.57 (t; 2H (CH3CH2CH2CH2);
J=7.2 Hz); 2.72 (dd; 1H (CHcCHaHbS); Jab=13.6 Hz;
Jac=7.2 Hz); 2.85 (dd; 1H (CHcCHaHbS); Jbc=5.2 Hz);
4.03 (m; 2H (OCH2CHc)); 4.10 (m; 1H (CHc)); 6.70–
7.20 (m; 4H (aromatic H)); 13C NMR (CDCl3) l ppm:
13.6; 21.4; 21.9; 31.7; 32.2; 35.8; 68.6; 70.2; 111.4; 115.3;
121.9; 129.2; 139.5; 158.4. IR (film; cm−1) 3410; 2920;
1580; 1485; 1450; 1255; 1150; 1035; 770; 685. Anal.
calcd for C14H22SO2: C, 66.10%; H, 8.72%. Found: C,
66.18%; H, 8.60%.
4.2.8. ( )-1-tert-Butylthio-3-phenoxypropan-2-ol 1h.
Yield 92%. 1H NMR (CDCl3) l ppm: 1.35 (s, 9H
(3×CH3)); 2.78 (dd; 1H (CHcCHaHbS); Jab=18.8 Hz;
Jac=6.6 Hz); 2.78 (s; 1H (OH)); 2.88 (dd; 1H
(CHcCHaHbS); Jbc=6 Hz); 4.0 (dd; 1H (OCHdHeCHc);
Jde=9.2 Hz; Jdc=6.2 Hz); 4.05 (dd; 1H (OCHdHeCHc);
Jec=4.2 Hz); 4.11 (m; 1H (CHc)); 6.90–7.30 (m; 5H
(aromatic H)) 13C NMR (CDCl3) l ppm: 30.9; 32.2;
42.5; 69.2; 70.5; 114.5; 121.1; 129.4; 158.4. IR (film;
cm−1) 3420; 2940; 1600; 1490; 1450; 1240; 1035; 750;
690. Anal. calcd for C13H20SO2: C, 64.50%; H, 8.39%.
Found: C, 64.86%; H, 8.31%.
4.2.4.
( )-1-Butylthio-3-(2-methylphenoxy)propan-2-ol
1
1d. Yield 93%. H NMR (CDCl3) l ppm: 0.92 (t; 3H
(CH3CH2CH2CH2); J=7.6 Hz); 1.42 (m; 2H
(CH3CH2CH2CH2)); 1.60 (m; 2H (CH3CH2CH2CH2));
2.24 (s; 3H (CH3)); 2.58 (t, 2H (CH3CH2CH2CH2);
J=7.2 Hz); 2.75 (dd; 1H (CHcCHaHbS); Jab=13.8 Hz;
Jac=7 Hz); 2.84 (dd; 1H (CHcCHaHbS); Jbc=5 Hz);
4.05 (m; 2H (OCH2CHc)); 4.15 (m; 1H (CHc); 6.80–7.20
(m; 4H (aromatic H)); 13C NMR (CDCl3) l ppm: 13.6;
16.2; 21.9; 31.7; 32.2; 35.9; 68.7; 70.2; 111.1; 120.8;
126.6; 126.8; 130.7; 156.4. IR (film; cm−1) 3420; 2940;
1600; 1490; 1460; 1240; 1115; 1025; 745. Anal. calcd for
4.3. Typical transesterification procedure for ( )-1a–h by
using Amano AK lipase in TBME solution at 20°C
Alcohol ( )-1a–h (1 mmol) was dissolved in 12 mL of
TBME (tert-butyl methyl ether) and vinyl acetate (2
mmol) and 125 mg of Amano AK lipase were added.
The mixture was stirred at 20°C and the conversion was
monitored by TLC. After the appropriate time, the
reaction was stopped by filtering off the enzyme and the
solvent was evaporated under reduced pressure. The

3208
M. Wielechowska, J. Plenkiewicz / Tetrahedron: Asymmetry 14 (2003) 3203–3210
crude mixture of acetate (S)-(+)-3a–h and unchanged
alcohol (R)-(+)-2a–h was separated by column chro-
matography on silica gel with a hexane:ethyl acetate
(5:1) mixture as the eluent. Enantiomeric excess was
determined by chiral HPLC analysis using a Chiralcel
OD-H column, but in the case of (S)-(+)-3c and (S)-
(+)-3d it was necessary to hydrolyze the acetates to the
corresponding alcohols. NMR spectra of enantiomeri-
cally enriched alcohols (R)-(+)-2a–h were identical with
those of ( )-1a–h. The optical rotations measured in
CHCl3 solutions for prepared enantiomerically enriched
alcohols are as follows:
(CHcCHaHbS); Jbc=7.2 Hz) 4.17 (d; 2H (OCH2CHc);
J=4.8 Hz); 5.25 (m; 1H (CHc)); 6.70–7.20 (m; 4H
(aromatic H)); 13C NMR (CDCl3) l ppm: 13.6; 21.1;
21.5; 21.9; 31.6; 32.0; 32.4; 67.1; 71.5; 111.4; 115.4;
121.9; 129.2; 139.5; 158.4; 170.5. IR (film; cm−1): 2940;
1740; 1570; 1485; 1225; 1035; 815; 680; [h]2D2=+6.1
(CHCl3, c 1.81; ee=83%). Anal. calcd for C16H24SO3:
C, 64.83%; H, 8.16%. Found: C, 64.96%; H, 8.02%.
4.3.4. (S)-(+)-1-Butylthio-3-(2-methylphenoxy)propan-2-
1
ol acetate 3d. H NMR (CDCl3) l ppm: 0.92 (t; 3H
(CH3CH2CH2CH2); J=7.6 Hz); 1.42 (m; 2H
(CH3CH2CH2CH2)); 1.59 (m; 2H (CH3CH2CH2CH2));
2.10 (s; 3H (CH3CO)); 2.23 (s; 3H (CH3)); 2.59 (t; 2H
(CH3CH2CH2CH2); J=7.6 Hz); 2.83 (dd; 1H
(CHcCHaHbS); Jab=14 Hz; Jac=6.4 Hz); 2.94 (dd; 1H
(CHcCHaHbS); Jbc=6.8 Hz); 4.18 (m; 2H (OCH2CHc));
5.31 (m; 1H (CHc)); 6.80–7.20 (m; 4H (aromatic H));
13C NMR (CDCl3) l ppm: 13.6; 16.1; 21.0; 21.8; 31.6;
32.2; 32.4; 67.3; 71.4; 111.0; 120.8; 126.7; 126.8; 130.7;
156.4; 170.4. IR (film; cm−1) 2940; 1740; 1490;
1365;1220; 1035; 745; [h]2D2=+13.9 (CHCl3, c 0.54; ee=
82%). Anal. calcd for C16H24SO3: C, 64.83; H, 8.16.
Found: C, 64.95; H, 8.05.
(R)-(+)-2a: [h]D22=+4.5 (c 1.76; ee=99%)
(R)-(+)-2b: [h]2D2=+4.9 (c 1; ee=85%)
(R)-(+)-2c: [h]D22=+5.8 (c 1.98; ee=86%)
(R)-(+)-2d: [h]D22=+1.6 (c 0.54; ee=43%)
(R)-(+)-2e: [h]D22=+3.6 (c 2.95; ee=38%)
(R)-(+)-2f: [h]D22=+2.9 (c 2.09; ee=47%)
(R)-(+)-2g: [h]D22=+1.6 (c 1.82; ee=22%)
(R)-(+)-2h: [h]D22=+1.6 (c 1.90; ee=24%)
1H and 13C NMR spectra, IR data, elemental analyses
and optical rotations of obtained acetates (S)-(+)-3a–h
are reported below.
4.3.1. (S)-(+)-1-Butylthio-3-phenoxypropan-2-ol acetate
4.3.5. (S)-(+)-1-Butylthio-3-(4-chlorophenoxy)propan-2-
1
1
3a. H NMR (CDCl3) l ppm: 0.90 (t; 3H (CH3CH2-
ol acetate 3e. H NMR (CDCl3) l ppm: 0.90 (t, 3H
CH2CH2); J=7.4 Hz); 1.38 (m; 2H (CH3CH2CH2-
CH2)); 1.57 (m; 2H (CH3CH2CH2CH2)); 2.09 (s; 3H
(CH3CO)); 2.57 (t; 2H (CH3CH2CH2CH2); J=7.2 Hz);
2.80 (dd; 1H (CHcCHaHbS); Jab=14 Hz; Jac=6 Hz);
2.89 (dd; 1H (CHcCHaHbS); Jbc=7 Hz); 4.18 (d, 2H
(OCH2CHc); J=4.8 Hz); 5.25 (m; 1H (CHc)); 6.90–7.30
(m; 5H (aromatic H)); 13C NMR (CDCl3) l ppm: 13.6;
21.1; 21.9; 31.6; 32.0; 32.4; 67.2; 71.5; 114.6; 121.2;
129.5; 158.4; 170.5. IR (film; cm−1): 2920; 1730; 1585;
1480; 1355; 1215; 1020; 735; 675; [h]2D2=+6.4 (CHCl3, c
1.72; ee=91%). Anal. calcd for C15H22SO3: C, 63.80%;
H, 7.85%. Found: C, 63.80%; H, 7.73%.
(CH3CH2CH2CH2); J=7.2 Hz); 1.38 (m; 2H
(CH3CH2CH2CH2)); 1.56 (m; 2H (CH3CH2CH2CH2));
2.09 (s; 3H (CH3CO)); 2.56 (t; 2H (CH3CH2CH2CH2);
J=7.4 Hz); 2.79 (dd; 1H (CHcCHaHbS); Jab=14 Hz;
Jac=5.6 Hz); 2.87 (dd; 1H (CHcCHaHbS); Jbc=7.4 Hz);
4.15 (d; 2H (OCH2CHc); =4.4 Hz); 5.23 (m; 1H
(CHc)); 6.80–7.25 (m; 4H (aromatic H)); 13C NMR
(CDCl3) l ppm: 13.6; 21.0; 21.8; 31.6; 32.0; 32.4; 67.6;
71.3; 115.9; 126.1; 129.3; 157.0. IR (film; cm−1) 2920;
1740; 1485; 1515; 1220; 1035; 820; [h]2D2=+4.6 (CHCl3,
c 1.83; ee=73%). Anal. calcd for C15H21ClSO3: C,
56.86%; H, 6.68%. Found: C, 56.80%; H, 6.50%.
4.3.2. (S)-(+)-1-Butylthio-3-(4-methylphenoxy)propan-2-
4.3.6. (S)-(+)-1-Ethylthio-3-phenoxypropan-2-ol acetate
1
1
ol acetate 3b. H NMR (CDCl3) l ppm: 0.80 (t; 3H
3f. H NMR (CDCl3) l ppm: 1.27 (t; 3H (CH3CH2);
(CH3CH2CH2CH2); J=7.2 Hz); 1.28 (m; 2H
(CH3CH2CH2CH2)); 1.46 (m; 2H (CH3CH2CH2CH2));
1.97 (s; 3H (CH3CO)); 2.18 (s; 3H (CH3)); 2.46 (t; 2H
(CH3CH2CH2CH2); J=7.2 Hz); 2.69 (dd; 1H
(CHcCHaHbS); Jab=14 Hz; Jac=6 Hz); 2.78 (dd; 1H
(CHcCHaHbS); Jbc=7 Hz); 4.04 (d; 2H (OCH2CHc);
J=4.8 Hz); 5.13 (m; 1H (CHc)); 6.65–7.00 (m; 4H
(aromatic H)); 13C NMR (CDCl3) l ppm: 13.6; 20.4;
21.1; 21.8; 31.6; 32.0; 32.4; 67.4; 71.5; 114.4; 129.9;
130.4; 156.3; 170.5. IR (film; cm−1): 2940; 1735; 1505;
1365; 1220; 1040; 810; [h]2D2=+5.0 (CHCl3, c 1.79; ee=
67%). Anal. calcd for C16H24SO3: C, 64.83%; H, 8.16%.
Found: C, 64.95%, H, 8.07%.
J=7.2 Hz); 2.10 (s; 3H (CH3CO)); 2.61 (q, 2H
(CH3CH2)); 2.83 (dd; 1H (CHcCHaHbS); Jab=14.4 Hz;
Jac=5.6 Hz); 2.92 (dd; 1H (CHcCHaHbS); Jbc=7.2 Hz);
4.18 (d; 2H (OCH2CHc); J=4.8 Hz); 5.26 (m; 1H
(CHc)); 6.90–7.30 (m; 5H (aromatic H)); 13C NMR
(CDCl3) l ppm: 14.7; 21.1; 26.6; 31.6; 67.2; 71.5; 114.6;
121.2; 129.5; 158.4; 170.5. IR (film; cm−1) 2940; 1745;
1600; 1495; 1370; 1230; 1045; 750; 690; [h]2D2=+5.6
(CHCl3, c 1.70; ee+83%). Anal. calcd for C13H18SO3: C,
61.39%; H, 7.13%. Found: C, 61%.45; H, 7.01%.
4.3.7. (S)-(+)-1-Ethylthio-3-(4-methylphenoxy)propan-2-
1
ol acetate 3g. H NMR (CDCl3) l ppm: 1.27 (t; 3H
(CH3CH2); J=7.2 Hz); 2.10 (s; 3H (CH3CO)); 2.29 (s;
3H (CH3)); 2.60 (q; 2H (CH3CH2)); 2.82 (dd; 1H
(CHcCHaHbS); Jab=14.2 Hz; Jac=6.2 Hz); 2.91 (dd;
1H (CHcCHaHbS); Jbc=7 Hz); 4.15 (d; 2H
(OCH2CHc); J=4.4 Hz); 5.25 (m; 1H (CHc)); 6.80–7.10
(m; 4H (aromatic H)); 13C NMR (CDCl3) l ppm: 14.6;
20.4; 21.0; 26.5; 31.6; 67.4; 71.5; 114.4; 129.8; 130.3;
156.2; 170.4. IR (film; cm−1) 2920; 1735; 1605; 1565;
4.3.3. (S)-(+)-1-Butylthio-3-(3-methylphenoxy)propan-2-
1
ol acetate 3c. H NMR (CDCl3) l ppm: 0.91 (t; 3H
(CH3CH2CH2CH2); J=7.6 Hz); 1.40 (m; 2H
(CH3CH2CH2CH2)); 1.58 (m; 2H (CH3CH2CH2CH2));
2.10 (s; 3H (CH3CO)); 2.33 (s; 3H (CH3)); 2.58 (t; 2H
(CH3CH2CH2CH2); J=7.2 Hz); 2.81 (dd; 1H
(CHcCHaHbS); Jab=14 Hz; Jac=6 Hz); 2.90 (dd, 1H

M. Wielechowska, J. Plenkiewicz / Tetrahedron: Asymmetry 14 (2003) 3203–3210
3209
Scheme 3.
1230; 1040; 810; [h]D22=+3.5 (CHCl3, c 1.70; ee=24%).
Anal. calcd for C14H20SO3: C, 62.66%; H, 7.51%.
Found: C, 62.75%; H, 7.40%.
4.3.8. (S)-(+)-1-tert-Butylthio-3-phenoxypropan-2-ol ace-
tate 3h. 1H NMR (CDCl3) l ppm: 1.33 (s; 9H (3×
CH3)); 2.09 (s; 3H (CH3CO)); 2.85 (dd; 1H
(CHcCHaHbS); Jab=13.2 Hz; Jac=5.8 Hz); 2.92 (dd;
1H (CHcCHaHbS); Jbc=7.2 Hz); 4.16 (m; 2H
(OCH2CHc)); 5.23 (m; 1H (CHc)); 6.90–7.30 (m; 5H
(aromatic H)); 13C NMR (CDCl3); l ppm: 21.0; 28.5;
30.8; 42.7; 67.2; 72.1; 114.5; 121.0; 129.4; 158.3; 170.4.
IR (film; cm−1) 2960; 1740; 1600; 1495; 1360; 1225;
1045; 750; 640; [h]2D2=+4.8 (CHCl3, c 1.60; ee=67%).
Anal. calcd for C15H22SO3: C, 63.80%; H, 7.85%.
Found: C, 63.78%; H, 7.75%.
Scheme 4.
optically pure (R)- and (S)-enantiomers of
methoxyphenylacetic acid (MPA) and H NMR spectra
1
of the resulting esters were taken in a CDCl3 solution
(Scheme 3). The differences in the chemical shifts
(DlRS) observed in the esters prepared from the (R)-
and (S)-acids, respectively, were calculated separately
for the protons attached to one and the other carbon
atom adjacent to the chirality center as shown by the
following equations:
4.4. Assignment of absolute configuration of 1-n-butyl-
thio-3-phenoxypropan-2-ol 1a and its acetate 3a
DlRS L1=lRL1−lSL1=2.71–2.86=−0.15 ppm
DlRS L3=lRL3−lSL3=4.16–4.03=+0.13 ppm
The enantiomer of 1-n-butylthio-3-phenoxypropan-2-
ol, isolated from the reaction of lipase catalyzed trans-
esterification of the racemate, was made to react7 with

3210
M. Wielechowska, J. Plenkiewicz / Tetrahedron: Asymmetry 14 (2003) 3203–3210
The negative value of DlRS, which corresponds to the
signal of protons of the substituent L1, and the opposite
plus sign resulting for the protons L3 determine the R
configuration according to the drawing (Scheme 4).
Albanese, D.; Landini, D.; Penso, M. Synthesis 1994, 34.
6. Faber, K. Biotransformations in Organic Chemistry, 3rd
ed.; Springer: New York, 1997; pp. 81–85.
7. (a) Seco, J. M.; Quinoa, E.; Riguera, R. Tetrahedron:
Asymmetry 2001, 12, 2915; (b) Kelly, D. R. Tetrahedron:
Asymmetry 1999, 10, 2927; (c) Gavagnin, M.; De Napoli,
A.; Cimino, G.; Iken, K.; Avila, C.; Garcia, F. J. Tetra-
hedron: Asymmetry 1999, 10, 2647; (d) Sy, L.-K.; Brown,
G. D. Phytochemistry 1998, 49, 1741; (e) Seco, J. M.;
Quinoa, E.; Riguera, R. Tetrahedron: Asymmetry 2000,
11, 2781; (f) Quezada, E.; Santana, L.; Uriarte, E. Tetra-
hedron: Asymmetry 2001, 12, 2637; (g) Latypov, S. K.;
Galiullina, N. F.; Aganov, A. V.; Kataev, V. E.; Riguera,
R. Tetrahedron 2001, 57, 2231; (h) Matsugi, M.; Itoh, K.;
Nojima, M.; Hagimoto, Y.; Kita, Y. Tetrahedron Lett.
2001, 42, 6903; (i) Ema, T.; Yoshii, M.; Korenaga, T.;
Sakai, T. Tetrahedron: Asymmetry 2002, 13, 1223.
8. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A.
T.; Cuccia, L. A. J. Org. Chem. 1991, 56, 2656.
9. (a) Sakurai, T.; Margolin, A. L.; Russel, A. J.; Klibanov,
A. M. J. Am. Chem. Soc. 1988, 110, 7236; (b) Nakamura,
K.; Takebe, Y.; Kitayama, T.; Ohno, A. Tetrahedron
Lett. 1991, 32, 4941; (c) Secundo, F.; Riva, S.; Carrea, G.
Tetrahedron: Asymmetry 1992, 3, 267; (d) Kvittingen, L.
Tetrahedron 1994, 50, 8253; (e) Rubio, E.; Alfonso, F.
M.; Klibanov, A. M. J. Am. Chem. Soc. 1991, 113, 695.
10. (a) Griebenow, K.; Laureano, Y. D.; Santos, A. M.;
Clemente, I. M.; Rodrigues, L.; Vidal, M. W.; Barlett, G.
J. Am. Chem. Soc. 1999, 121, 8157; (b) De Gonzalo, G.;
Brieva, R.; Sanchez, V. M.; Bayod, M.; Gotor, V. Tetra-
hedron: Asymmetry 2003, 14, 1725; (c) Ferraboschi, P.;
Pecora, S.; Reza-Elahi, S.; Santaniello, E. Tetrahedron:
Asymmetry 1999, 10, 2497; (d) Queiroz, N.; Da Graca
Nascimento, M. Tetrahedron Lett. 2002, 43, 5225; (e)
Gotor-Fernandez, V.; Ferrero, M.; Fernandez, S.; Gotor,
V. J. Org. Chem. 1999, 64, 7504; (f) Krishna, S. H.;
Persson, M.; Bornscheuer, U. T. Tetrahedron: Asymmetry
2002, 13, 2693.
The same procedure was applied to the second enan-
tiomer of the alcohol isolated after hydrolysis of the
acetate 3a. As compared with (R)-(+)-2a, the respective
DlRS values are of opposite signs thus indicating the
(S)-configuration.
DlRSL1=lRL1−lSL1=2.85–2.70=+0.15
DlRSL3=lRL3−lSL3=4.06–4.19=−0.13
References
1. (a) Pchelka, B. K.; Radomska, J.; Plenkiewicz, J. Synth.
Commun. 1998, 28, 4355; (b) Pchelka, B. K.; Loupy, A.;
Plenkiewicz, J.; Petit, A.; Blanco, L. Tetrahedron: Asym-
metry 2000, 11, 2719; (c) Pchełka, B. K.; Loupy, A.;
Plenkiewicz, J.; Petit, A.; Blanco, L. Tetrahedron: Asym-
metry 2001, 12, 2109.
2. Gasanov, V. S.; Alekperov, R. K. Zh. Org. Khim. 1983,
19, 92.
3. Derzhinskii, A. R.; Kalugin, V. E.; Prilezhaeva, E. N. Izv.
Akad. Nauk SSSR, Ser. Khim. 1985, 34, 1623.
4. (a) Iqbal, J.; Pandey, A.; Shukla, A.; Srivastava, R. R.;
Tripathi, S. Tetrahedron 1990, 46, 6423; (b) Maiti, A. K.;
Bhattacharyya, P. Tetrahedron 1994, 50, 10483; (c) Wang,
J.-X.; Zhang, Y.; Huang, D.; Hu, Y. J. Chem. Res.
Synop. 1998, 4; (d) Iizawa, T.; Goto, A.; Nishikubo, T.
Bull. Chem. Soc. Jpn. 1989, 62, 597; (e) Minor, W. F.;
Smith, R. R.; Cheney, L. C. J. Am. Chem. Soc. 1954, 76,
2993; (f) Lai, J.-Y.; Wang, F.-S.; Guo, G.-Z.; Dai, L.-X.
J. Org. Chem. 1993, 58, 6944; (g) Yoon, N. M.; Choi, J.;
Ahn, J. H. J. Org. Chem. 1994, 59, 3490.
11. Ema, T.; Maeno, S.; Takaya, Y.; Sakai, T.; Utaka, M.
5. (a) Vints, V. V. Izv. Akad. Nauk SSSR, Ser. Khim. 1973,
22, 1555; (b) Klein, H. A. Chem. Ber. 1979, 112, 3037; (c)
Tetrahedron: Asymmetry 1996, 7, 625.