Lipase-catalyzed separation of the enantiomers of 1-substituted-3-arylthio- 2-propanols

Article abstract of DOI:10.1016/j.tetasy.2005.01.040

Optically active (R)- and (S)-1-substituted-3-(arylthio)propan-2-ols have been prepared in the reaction of the appropriate 2-(arylthiomethyl)oxiranes with chloride and azide anions followed by a lipase-catalyzed transesterification. The effects of the enzyme preparation as well as of the reaction conditions have been compared in terms of the enantiomeric excess of the obtained acetate and unreacted alcohol.

Full text of DOI:10.1016/j.tetasy.2005.01.040

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1199–1205
Lipase-catalyzed separation of the enantiomers of
1-substituted-3-arylthio-2-propanols
Monika Wielechowska and Jan Plenkiewicz*
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
Received 20 December 2004; accepted 30 January 2005
Abstract—Optically active (R)- and (S)-1-substituted-3-(arylthio)propan-2-ols have been prepared in the reaction of the appropriate
2-(arylthiomethyl)oxiranes with chloride and azide anions followed by a lipase-catalyzed transesterification. The effects of the
enzyme preparation as well as of the reaction conditions have been compared in terms of the enantiomeric excess of the obtained
acetate and unreacted alcohol.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
easily prepared from 2-arylthiomethyloxiranes. Their
optically active forms may be interesting as sulfur ana-
logues of the intermediates leading to b-blockers.
The opening of the oxirane ring with various nucleo-
philes (e.g., halogen ions, CNꢀ, N3ꢀ, OHꢀ) is a very
important synthetic transformation. It leads to racemic
mixtures of 1,3-disubstituted secondary propanols,
known as useful building blocks in the synthesis of many
biologically active compounds. Having two reactive sub-
stituents, these compounds can be easily transformed
into many new structures. The hydroxy group on the
stereogenic carbon at the 2-position of the propane
chain makes them very interesting models for the inves-
tigation of the hydrolase-catalyzed reactions capable of
yielding pure enantiomers. For example, enantiomeri-
cally pure (S)-1-azido-3-aryloxypropanols are conve-
nient intermediates in the preparation of several b-
blockers and antidepressant drugs. The lipase-catalyzed
reactions described to date have been successfully car-
ried out with 1-substituted-3-aryloxy-2-propanols;
which means that the aryloxy substituent is always pres-
ent at the 3-position of the propane chain.
2. Results and discussion
2.1. Synthesis of 1-azido- and 1-chloro-3-thioaryloxy-2-
propanols
2-Arylthiomethyloxiranes 1a–c were prepared in high
yields (80–85%) from the corresponding thiophenols
and epichlorohydrin in a NaOH/THF suspension
according to the method described.4 1-Chloro-3-aryl-
thiopropan-2-ol ( )-3a–c was the primary product of
the reaction. It was subsequently converted into the
appropriate 2-arylthiomethyloxirane 1a–c by the NaOH
excess present in the reaction mixture. The opening of
the oxirane ring of 1a–c by chloride or azide anions
leads to racemic mixtures of 1-chloro- and 1-azido-3-
arylthiopropan-2-ol, ( )-3a–c or ( )-2a–c, respectively.
The reactions were carried out with potassium chlo-
ride or sodium azide in the presence of ammonium
To the best of our knowledge, similar 1-substituted-3-
arylthiopropan-2-ols have not been investigated as sub-
strates in hydrolase-catalyzed reactions. Continuing our
interest in the lipase-catalyzed transesterifications of the
racemic 1,3-disubstituted-2-propanols1–3 we recently
focused our attention on 1-azido- and 1-chloro-3-aryl-
thiopropan-2-ols, 2 and 3, respectively, which can be
chloride in
(Scheme 1).
a methanol–water (8:1 v/v) solution
2.2. Kinetic resolution of ( )-2a–c and ( )-3a–c
The conditions of the lipase-catalyzed acetylation of
racemic alcohols ( )-2a–c and ( )-3a–c were optimized
according to the conventional methods5 (Scheme 2).
The effects of the lipase type, solvent and acyl donor
*
Corresponding author. Tel.: +48(22)660 7570; fax: +48(22)628
2741; e-mail: plenki@ch.pw.edu.pl
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.040

1200
M. Wielechowska, J. Plenkiewicz / Tetrahedron: Asymmetry 16 (2005) 1199–1205
OH
O
S
S
N3
NaH3; NH4Cl
MeOH/H2O
SH
NaOH
THF
Cl
O
+
R
R
R
Yield 80-85%
( )-2a-c
Yield > 95%
a: R = H
b: R = Cl
c: R = CH3
OH
S
Cl
KCl; NH4Cl
MeOH/H2O
R
Yield 50-60%
( )-3a-c
Scheme 1. Synthesis of ( )-2a–c and ( )-3a–c.
OH
OH
OCOCH3
R'
S
R'
S
R'
S
R''
O
Lipase
+
+
O
R
R
R
R = H; Cl; CH3
R' = N3; Cl
R' = N3 (R)-(-)-4a-c
R' = Cl (S)-(-)-5a-c
R'' = H; CH3
R' = N3 (S)-(+)-2a-c
R' = Cl (R)-(+)-3a-c
Scheme 2. Acylation reaction of ( )-2a–c and ( )-3a–c.
as well as of the substituent in the aromatic ring on the
enantioselectivity of the reaction were estimated by
determining the reaction enantioselectivity.
The absolute configurations of the products, that is,
alcohol 2a and acetate 4a, were determined by the modi-
fied MosherÕs method as described by Riguera and co-
workers.7 The method depends on comparing the differ-
1
2.2.1. Screening of different lipases. The catalytic effi-
ciencies of the different commercially available lipases
in the acylation reaction of the title alcohols were inves-
tigated. For this purpose, 2a, used as a model substrate,
was allowed to react at 20 ꢁC in a tert-butyl methyl ether
(TBME) solution with 3 equiv of vinyl acetate in the
presence of the tested lipase. Control experiments re-
vealed that the reaction failed to proceed in the absence
of an enzyme. The transesterification reactions were
monitored by thin layer chromatography and were
arrested once the conversion reached 30–50%. The
enzyme was then removed by filtration and the resulting
solution of enantiomerically enriched acetate 4a and
unchanged alcohol 2a was used for an exact determina-
tion of the conversion degree and enantiomeric excesses.
The results are summarized in Table 1.
ence between the H NMR chemical shifts recorded for
the diastereomeric ester prepared from a separated
enantiomer of a given alcohol and the (R)- and (S)-enan-
tiomers of methoxyphenylacetic acid. Our investigation
has shown that the unchanged alcohol 2a and its acetate
4a have the (S)-(+)- and (R)-(ꢀ)-configurations, respec-
tively. This assignment is in good agreement with the
KazlauskasÕ rule.8 The results presented in Table 1 show
that the (S)-(+)-alcohol 2a reacts with the tested lipases
considerably slower than the (R)-(ꢀ) enantiomer and
that the reactions show poor-to-good enantioselectivi-
ties (E = 2–56). Among the tested enzymes, only lipase
preparations from Candida antarctica-B (Novozym SP
435; Chirazyme L-2, c-f, lyo and Chirazyme L-2, c-f,
C2, lyo) exhibited promising catalytic activity and
enantioselectivity with this substrate.
Table 1. Results of the lipase-catalyzed kinetic resolution of ( )-2a by transesterificationa
cb (%)
Eb
d
Eesub (%)
c
Eeprod (%)
Entry
Enzyme
Time (h)
1
2
3
4
5
6
Amano AK (Pseudomonas fluorescens)
Amano PS (Pseudomonas cepacia)
30
110
24
32
17
57
36
24
48
12
17
25
79
77
45
93
90
2
9
Novozym SP 435 (Candida antarctica-B (10 kU/g))
Chirazyme L-1, c-f, lyo (Pseudomonas cepacia)
Chirazyme L-2, c-f, lyo (Candida antarctica-B (200 U/g))
Chirazyme L-2, c-f, C2, lyo (Candida antarctica-B (10 kU/g))
>99
25
56
3
25
25
29
82
37
51
26
a Conditions: 1 mmol of ( )-2a, 3 mmol of vinyl acetate, 100 mg of the appropriate lipase and 12 mL of TBME at rt.
b Conversions and E-values were calculated6 from the enantiomeric excess of substrate 2a (ees) and product 4a (eep) using the known formula:
E = Ln[(1 ꢀ ees)(eep/(ees + eep))]/Ln[(1 + ees)(eep/(ees + eep))], conversion c = ees/(ees + eep).
c Determined by HPLC analysis using Chiralcel OD-H column.
d Determined by 1H NMR spectra taken with the shift reagent Eu(tfc)3 added.

M. Wielechowska, J. Plenkiewicz / Tetrahedron: Asymmetry 16 (2005) 1199–1205
1201
Table 2. Results of the Candida antarctica-catalyzed acetylation of ( )-2a by vinyl acetate in TBME and toluene solutionsa
cb (%)
Eb
d
Eesub (%)
c
Eeprod (%)
Entry
Enzyme
Solvent
Log P
Time (h)
1
2
3
4
5
6
7
Novozym SP 435
Novozym SP 435
TBME
Toluene
Hexane
i-Pr2O
THF
1.3
2.5
3.5
1.1
0.49
1.3
2.5
24
24
23
23
64
25
72
57
45
54
55
19
24
42
>99
75
77
94
77
77
94
93
96
56
68
54
30
43
37
Novozym SP 435
Novozym SP 435
>99
96
Novozym SP 435
Chirazyme L-2, c-f, c-2, lyo
Chirazyme L-2, c-f, c-2, lyo
22
29
TBME
Toluene
70
>100
a Conditions: 1 mmol of ( )-2a, 3 mmol of vinyl acetate, 100 mg of the appropriate lipase and 12 mL of TBME at rt.
b Conversions and E-values were calculated6 from the enantiomeric excess of substrate 2a (ees) and product 4a (eep) using the known formula:
E = Ln[(1 ꢀ ees)(eep/(ees + eep))]/Ln[(1 + ees)(eep/(ees + eep))], conversion c = ees/(ees + eep).
c Determined by HPLC analysis using Chiralcel OD-H column.
d Determined by 1H NMR spectra taken with the shift reagent Eu(tfc)3 added.
2.2.2. Solvent effect. As it is well known, changing the
solvent almost always affects the enantiomeric selectivity
and the reaction rate of the lipase-catalyzed kinetic reso-
lutions. In this research, the acetylation of ( )-2a with
vinyl acetate at room temperature in the presence of
Novozym SP 435 or Chirazyme L-2, c-f, lyo was carried
out in five different solvents. According to the litera-
ture,2,9 toluene and hexane are the solvents of choice in
the transesterification reactions catalyzed by lipases from
C. antarctica. Our results reported in Table 2 confirm this
statement showing the highest enantioselectivity of the
enzymes in these solvents. However, the activities were
a little lower than in TBME and ethyl ether.
lyzed transesterification reaction has been well docu-
mented by Ema et al.10 In general, among the various
types of acyl donors they had examined, enol esters,
owing to their high reactivity and irreversibility of the
reaction, have been considered as the most suitable for
the kinetic resolution by transesterification. As it is
known, vinyl acetate is the ester of choice, although
iso-propenyl acetate is also frequently used in these reac-
tions. Usually, the reaction with iso-propenyl acetate is
slower than that with vinyl acetate but the enantioselec-
tivity is sometimes higher. The most important results of
enzyme-catalyzed transesterifications of ( )-2a–c and
( )-3a–c are presented in Tables 3 and 4.
2.2.3. Acyl donor effect. The effect of the structure of
the acyl donor on the enantioselectivity of a lipase-cata-
With 1-azido-3-thiophenoxy-propan-2-ol ( )-2a, the
highest enantioselectivities were obtained with vinyl
Table 3. Selected results obtained in the enzyme-catalyzed transesterifications of ( )-2a–c in toluene solution at room temperaturea
cb (%)
Eeprodc(%)
Eb
c
Eesub (%)
Entry
Substrate
Acyl donor
Enzyme
Time (h)
1
2
3
4
5
6
7
8
2a
2a
2a
2b
2b
2b
2c
2c
Vinyl acetate
Vinyl acetate
Chirazyme L-2, c-f, lyo
Novozym SP 435
Novozym SP 435
Novozym SP 435
Chirazyme L-2, c-f, lyo
Novozym SP 435
Novozym SP 435
Novozym SP 435
24
72
50
24
52
69
24
52
44
42
33
40
44
37
45
35
75
70
47
61
75
56
73
50
94
96
94
92
94
96
90
93
68
>100
48
iso-Propenyl acetate
Vinyl acetate
45
75
iso-Propenyl acetate
iso-Propenyl acetate
Vinyl acetate
87
43
iso-Propenyl acetate
47
a Conditions: 1 mmol of ( )-2a, 3 mmol of vinyl acetate, 100 mg of the appropriate lipase and 12 mL of TBME at rt.
b Conversions and E-values were calculated6 from the enantiomeric excess of substrate 2a (ees) and product 4a (eep) using the known formula:
E = Ln[(1 ꢀ ees)(eep/(ees + eep))]/Ln[(1 + ees)(eep/(ees + eep))], conversion c = ees/(ees + eep).
c Determined by HPLC analysis using Chiralcel OD-H column.
Table 4. Selected results obtained in the enzyme-catalyzed transesterifications of ( )-3a–c in a toluene solution at room temperaturea
Entry
Substrate
Acyl donor
Enzyme
Time (h)
cb (%)
Eesub (%)
Eeprod (%)
E
1
2
3
4
5
6
7
8
3a
3a
3a
3b
3b
3c
3c
3c
Vinyl acetate
Vinyl acetate
Novozym SP 435
23
192
72
27
43
40
55
39
19
25
23
35c
72c
61c
93
95
93
57e
63e
37e
25f
19f
30a
28a
30a
Chirazyme L-2, c-f, lyo
Novozym SP 435
Novozym SP 435
iso-Propenyl acetate
Vinyl acetate
Vinyl acetate
90
45
24
77d
83d
92
Amano AK
Novozym SP 435
54
22
Vinyl acetate
Vinyl acetate
iso-Propenyl acetate
24
43
Chirazyme L-2, c-2, c-f, lyo
Chirazyme L-2, c-2, c-f, lyo
30
27
91
92
168
a Conditions: 1 mmol of ( )-2a, 3 mmol of vinyl acetate, 100 mg of the appropriate lipase and 12 mL of TBME at rt.
b Conversion determined by GC.
c Enantiomeric excesses calculated from: eesub = eeprod c/(1 ꢀ c).
*
d Enantiomeric excesses calculated from: eeprod = eesub(1 ꢀ c)/c.
e E-values calculated11 from the equation: E = Ln[1 ꢀ c (1 + eeprod)]/Ln[1 ꢀ c (1 ꢀ eeprod)].
*
*
f E-values calculated11 using the equation: E = Ln[(1 ꢀ c)(1 ꢀ eesub)]/Ln[(1 ꢀ c)(1 + eesub)]. Experimental ee values obtained according to ÔcÕ in Table 1.

1202
M. Wielechowska, J. Plenkiewicz / Tetrahedron: Asymmetry 16 (2005) 1199–1205
Figure 1. Dependence of the enantiomeric purities ee (%) of 2c and 4c (graph A) and 3c and 5c (graph B) on conversion of ( )-2c and ( )-3c in the
Novozym SP 435-catalyzed acetylation with vinyl acetate in a toluene solution at 20 ꢁC.
acetate acting as the acyl donor (E = 68–100). However,
in the case of ( )-2b and ( )-2c, iso-propenyl acetate re-
vealed a higher selectivity. With ( )-3a–c, the results of
the reactions with both vinyl and iso-propenyl acetate
were much worse than those obtained with ( )-2a–c.
Also Amano AK lipase exhibited with these compounds
a moderate enantioselectivity.
in a CDCl3 solution, with chemical shifts (d) reported
in ppm. IR spectra were taken with a Carl Zeiss Specord
M80 instrument. Enantiomeric purities of alcohols 2a–h
and esters 3a–h were determined on a Thermo-Separa-
tion Products P-100 instrument and Chiralcel OD-H
column (in n-hexane:iso-propanol 9:1; 0.8 mL/min for
alcohols and in n-hexane:iso-propanol 99:1; 0.4 mL/
min for esters) using the corresponding racemic com-
pounds for reference. Optical rotations were measured
in CHCl3 with a PolAAr 32 polarimeter. Elemental
analyses were performed with a CHNS/O Perkin–Elmer
type 2400 instrument. The reactions were monitored by
TLC on silica gel 60 F254 plates and by column chroma-
tography on silica gel 60 (230–400 mesh). The arylthio-
glycidyl ethers were prepared from the appropriate
thiophenols and epichlorohydrin according to the meth-
od described earlier.4 Amano AK, and Amano PS lip-
ases 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).
Analysis of the present results indicates that incorpora-
tion of a substituent into the phenyl ring of the substrate
results in a decrease of the acetylation enantioselectivity
(E) for all of the investigated alcohols. The effect was
most pronounced with 1-chloro-3-(4-chlorophenylthio)-
propan-2-ol ( )-3b.
Experimentally obtained dependence of the enantio-
meric excess of the substrate (alcohol) and the product
(acetate) on conversion of ( )-1-azido-3-(p-tolylthio)-
propan-2-ol and ( )-1-chloro-3-(p-tolylthio)propan-2-
ol is presented in Figure 1 graph A and graph B, respec-
tively, together with the calculated enantioselectivity E
of the reactions. The plots indicate good enantioselectiv-
ities of both reactions and only a slight influence of the
substituent at the b-position.
4.2. Preparation of 3-substituted-1-arylthio-propan-2-ols
( )-2a–c and ( )-3a–c
The arylglycidyl thioether (0.01 mol), sodium azide or
potassium chloride (0.05 mol), and ammonium chloride
(1.28 g, 0.024 mol) were added to 30 mL of a methanol/
water mixture. The reaction was carried out at 70 ꢁC
and the conversion monitored by TLC with hexane/
ethyl acetate 5:1 (v/v). Upon completing the reaction,
the methanol was evaporated, 30 mL of water was
added to the residue and the product extracted with
CH2Cl2 (3 · 30 mL). The organic layers were combined
and dried over Na2SO4. The alcohols were purified by
column chromatography using hexane/ethyl acetate
10:1 (v/v) for ( )-2a–c or hexane/CH2Cl2 1:4 (v/v) for
( )-3a–c as the eluents.
3. Conclusions
A general and efficient method for a lipase-catalyzed
kinetic resolution of the racemic mixtures of 3-thioaryl-
oxy-propan-2-ols by their acetylation leading to the
optically active compounds has been presented. The
highest enantioselectivity values (E = 68–100) were ob-
tained with 1-azido-3-arylthiopropan-2-ols when the C.
antarctica-B lipase (Novozym SP 435 and two Chira-
zymes L-2) was used in a toluene solution at 20 ꢁC.
4. Experimental
4.1. General
4.2.1. 1-Azido-3-phenylthiopropan-2-ol ( )-2a. 1H
NMR (CDCl3) d 2.67 (1; 1H; OH); 2.98 (dd; 1H;
Jgem = 14 Hz; J = 7.8 Hz; SCHaHb); 3.10 (dd; 1H;
J = 4.8 Hz; SCHaHb); 3.38 (dd; 1H; Jgem = 12.7 Hz;
J = 6 Hz; CHcHdN3); 3.45 (dd; 1H; J = 4 Hz;
1H (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on a Varian Mercury 400 MHz spectrometer

M. Wielechowska, J. Plenkiewicz / Tetrahedron: Asymmetry 16 (2005) 1199–1205
1203
CHcHdN3); 2.84 (m; 1H; CH); 7.24–7.41 (m; 5H; aro-
mat.); 13C NMR (CDCl3) d 38.74; 54.97; 68.78;
127.03; 129.21; 130.30; 134.33; IR (film; cmꢀ1): 3440;
2100; 1480; 1440; 1280; 1080; 740; 690. Anal. Calcd
for C9H11N3OS: C, 51.66; H, 5.30; N, 20.08; S, 15.32.
Found: C, 51.42; H, 5.39; N, 19.42; S, 15.42.
NMR (CDCl3) d 21.00; 38.98; 47.92; 69.41; 129.95;
130.30; 130.93; 137.26; IR (film; cmꢀ1): 3400; 1475;
1425; 1385; 1095; 1010; 810. Anal. Calcd for
C10H13ClOS: C, 55.42; H, 6.04. Found: C, 55.44; H,
6.08.
4.3. Typical transesterification procedure for ( )-2a–c and
( )-3a–c
4.2.2. 1-Azido-3-(4-chlorophenylthio)propan-2-ol ( )-
2b. 1H NMR (CDCl3) d 2.79 (s; 1H; OH); 2.97 (dd;
1H; Jgem = 14 Hz; J = 7.6 Hz; SCHaHb); 3.06 (dd; 1H;
J = 5.2 Hz; SCHaHb); 3.37 (dd; 1H; Jgem = 12.8 Hz;
J = 6 Hz; CHcHdN3); 3.44 (dd; 1H; J = 4 Hz;
CHcHdN3); 3.83 (m; 1H; CH); 7.25–7.28 (m; 2H; aro-
mat.); 7.95–7.33 (m; 2H; aromat.); 13C NMR (CDCl3)
d 38.73; 54.92; 68.78; 129.25; 131.40; 132.95; 133.05;
IR (film; cmꢀ1): 3420; 2110; 1475; 1285; 1100; 1015;
715. Anal. Calcd for C9H10N3ClOS: C, 44.35; H, 4.13:
N, 17.24. Found: C, 44.32; H, 3.94; N, 17.45.
The appropriate alcohol ( )-2a–c or ( )-3a–c (1 mmol)
was dissolved in 12 mL of TBME and vinyl acetate
(3 mmol) and 100 mg of lipase were added. The mixture
was stirred at room temperature (20–22 ꢁC) and the con-
version monitored by TLC. When the reaction was com-
pleted, the enzyme was filtered off and the solvent
evaporated under reduced pressure. The mixture of ace-
tate and unchanged alcohol was separated by column
chromatography on silica gel with a hexane–ethyl ace-
tate (5:1 v/v) mixture as the eluent. The enantiomeric ex-
cess was determined by chiral HPLC analysis using a
Chiralcel OD-H column or 1H NMR analysis with
Eu(tfc)3 as the shift reagent.
4.2.3. 1-Azido-3-(4-methylphenylthio)propan-2-ol ( )-
2c. 1H NMR (CDCl3) d 2.33 (s; 3H; CH3); 2.68 (d;
1H; J = 4 Hz; OH); 2.93 (dd; 1H; Jgem = 14 Hz;
J = 8 Hz; SCHaHb); 3.04 (dd; 1H; J = 4.6 Hz; SCHaHb);
3.35 (dd; 1H; Jgem = 12.4 Hz; J = 6 Hz; CHcHdN3); 3.43
(dd; 1H; J = 4 Hz; CHcHdN3); 3.81 (m; 1H: CH); 7.11–
7.14 (m; 2H; aromat.); 7.30–7.32 (m; 2H; aromat.); 13C
NMR (CDCl3) d 21.01; 39.52; 54.97; 68.73; 130.00;
130.44; 131.17; 137.43; IR (film; cmꢀ1): 3425; 2105;
1480; 1290; 1110; 1025; 815. Anal. Calcd for
C10H13N3OS: C, 53.79; H, 5.87; N, 18.82. Found: C,
53.89; H, 5.62; N, 18.89.
With the aim of defining the absolute configuration we
prepared the alcohols in very high enantiomeric excess
by extending conversions of the transesterifications up
to 65%. NMR spectra of enantiomerically enriched alco-
hols (S)-(+)-2a–c and (R)-(+)-3a–c were identical with
those of ( )-2a–c and ( )-3a–c. The optical rotations
of enantiomerically enriched alcohols obtained in the
Novozym 435 catalyzed reactions measured in CHCl3
solutions are as follows:
4.2.4. 1-Chloro-3-phenylthiopropan-2-ol ( )-3a. 1H
NMR (CDCl3) d 2.65 (d; 1H; J = 4.8 Hz; OH); 3.08
(dd; 1H; Jgem = 14 Hz; J = 7 Hz; SCHaHb); 3.17 (dd;
1H; J = 5.6 Hz; SCHaHb); 3.66 (dd; 1H; Jgem = 11.2 Hz;
J = 5.2 Hz; CHcHdCl); 3.70 (dd; 1H; J = 4.4 Hz;
CHcHdCl); 3.93 (m; 1H; CH); 7.21–7.26 (m; 1H; aro-
mat.); 7.29–7.33 (m; 2H; aromat.); 7.39–7.42 (m; 2H;
aromat.); 13C NMR (CDCl3) d 38.22; 47.95; 69.44;
126.92; 129.18; 130.11; 134.53; IR (film; cmꢀ1): Anal.
Calcd for C9H11ClOS: C, 53.33; H, 5.47; S, 15.82; Cl,
17.49. Found: C, 53.08; H, 5.54; S, 15.75; Cl, 17.60.
22
(S)-(+)-2a: ½aŠ ¼ þ27:3 (c 0.99; ee = 99%)
D
22
(S)-(+)-2b: ½aŠ ¼ þ16:8 (c 1.07; ee = 95%)
D
22
(S)-(+)-2c: ½aŠ ¼ þ30:8 (c 1.03; ee = 99%)
D
22
(R)-(+)-3a: ½aŠ ¼ þ5:7 (c 1.05; ee = 89%)
D
22
(R)-(+)-3b: ½aŠ ¼ þ6:8 (c 1.03; ee = 93%)
D
22
(R)-(+)-3c: ½aŠ ¼ þ27:8 (c 0.99; ee = 99%)
D
1H and 13C NMR spectra, IR data, elemental analyses
and optical rotations of obtained acetates (R)-(ꢀ)-4a–c
and (S)-(ꢀ)-5a–c are reported below:
4.2.5. 1-Chloro-3-(4-chlorophenylthio)propan-2-ol ( )-
3b. 1H NMR (CDCl3) d 2.68 (d; 1H; J = 4.8 Hz;
OH); 3.05 (dd; 1H; Jgem = 14 Hz; J = 7.2 Hz; SCHaHb);
3.14 (dd; 1H; J = 5.6 Hz; SCHaHb); 3.65 (dd; 1H;
Jgem = 11.2 Hz; J = 5.2 Hz; CHcHdCl); 3.68 (dd; 1H;
J = 4.4 Hz; CHcHdCl); 3.92 (m; 1H; CH); 7.25–7.35
(m; 4H; aromat.); 13C NMR (CDCl3) d 38.35; 47.88;
69.47; 129.27; 131.34; 132.94; 133.21; IR (film; cmꢀ1):
3410; 1495; 1425; 1210; 1190; 1145; 810. Anal. Calcd
for C9H10Cl2OS: C, 45.58; H, 4.25. Found: C, 45.69;
H, 4.34.
4.3.1. (R)-(ꢀ)-1-Azido-3-phenylthiopropan-2-ol acetate
4a. Yield: 94%; 1H NMR (CDCl3) d 2.02 (s; 3H;
CH3); 3.09 (dd; 1Ha; Jgem =14 Hz; J = 7.4 Hz; SCHaHb);
3.21 (dd; 1Hb; J = 5.6 Hz; SCHaHb); 3.55 (m; 2H;
CH2N3); 5.06 (m; 1H; CH); 7.20–7.33 (m; 3H; aromat.);
7.39–7.42 (m; 2H; aromat.); 13C NMR (CDCl3) d 20.79;
34.35; 51.96; 71.59; 126.78; 129.12; 129.84; 134.73;
170.11; IR (film; cmꢀ1): 2110; 1745; 1445; 1375; 1225;
22
D
1040; 745; 700; ½aŠ ¼ ꢀ2:8 (c 1.05; ee = 96%). Anal.
Calcd for C11H13N3O2S: C, 52.57; H, 5.21; N, 16.72.
Found: C, 52.75; H, 5.08; N, 16.81.
4.2.6. 1-Chloro-3-(4-methylphenylthio)propan-2-ol ( )-
3c. 1H NMR (CDCl3) d 2.71 (d; 1H; J = 4.8 Hz;
OH); 3.02 (dd; 1Ha; Jgem = 14 Hz; J = 7.2 Hz; SCHaHb);
3.12 (dd; 1Hb; J = 5.6 Hz; SCHaHb); 3.64 (dd; 1Hc;
Jgem = 11.2 Hz; J = 5.2 Hz; CHcHdCl); 3.68 (dd; 1Hd;
J = 4.4 Hz; CHcHdCl); 3.88 (m; 1H; CH); 7.11–7.13
(m; 2H; aromat.); 7.29–7.32 (m; 2H; aromat.); 13C
4.3.2. (R)-(ꢀ)-1-Azido-3-(4-chlorophenylthio)propan-2-ol
acetate 4b. 1H NMR (CDCl3) d 2.04 (s; 3H; CH3); 3.07
(dd; 1Ha; Jgem = 14 Hz; J = 7.4 Hz; SCHaHb); 3.18 (dd;
1Hb; J = 6 Hz; SCHaHb); 3.54 (m; 2H; CH2N3); 5.03
(m; 1H; CH); 7.26 (m; 2H; aromat.); 7.32–7.35 (m;

1204
M. Wielechowska, J. Plenkiewicz / Tetrahedron: Asymmetry 16 (2005) 1199–1205
2H; aromat.); 13C NMR (CDCl3) d 20.82; 34.56; 51.94;
71.40; 129.28; 131.18; 132.91; 133.26; 170.11; IR (film;
4.4. Assignment of absolute configuration
cmꢀ1): 2120; 1750; 1495; 1375; 1230; 1045; 810
The enantiomers of (+)-2a, isolated from the reaction of
the lipase-catalyzed transesterification of the racemates,
were made to react7 with optically pure (R)- and (S)-
enantiomers of methoxyphenylacetic acid (MPA). Next,
1H NMR spectra of the resulting esters were taken in a
CDCl3 solution and the differences in the chemical shifts
(DdRS) 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 stereogenic center as shown by the fol-
lowing equations:
22
D
½aŠ ¼ ꢀ8:06 (c 1.025; ee = 94%). Anal. Calcd for
C11H12N3ClO2S: C, 46.24; H, 4.23; N, 14.71. Found:
C, 46.31; H, 4.28; N, 14.66.
4.3.3. (R)-(ꢀ)-1-Azido-3-(4-methylophenylthio)propan-2-
ol acetate 4c. 1H NMR (CDCl3) d 2.03 (s; 3H;
CH3CO); 2.32 (s; 3H; CH3); 3.04 (dd; 1Ha; Jgem = 14 Hz;
J = 7.4 Hz; SCHaHb); 3.15 (dd; 1Hb; J = 5.8 Hz;
SCHaHb); 3.53 (m; 2H; CH2N3); 5.03 (m; 1H; CH);
7.10–7.13 (m; 2H; aromat.); 7.30–7.32 (m; 2H; aromat.);
13C NMR (CDCl3) d 20.84; 21.00; 35.98; 51.98; 71.65;
22
D
DdRSL1 ¼ dRL1 ꢀ dSL1 ¼ 3:09 ꢀ 2:86 ¼ þ0:23 ppm
DdRSL2 ¼ dRL2 ꢀ dSL2 ¼ 3:42 ꢀ 3:50 ¼ ꢀ0:08 ppm
129.90; 130.68; 130.88; 137.11; 170.12; ½aŠ ¼ ꢀ5:7 (c
1.10; ee = 96%). Anal. Calcd for C12H15N3O2S: C,
54.32; H, 5.70; N, 15.84. Found: C, 54.15; H, 5.55; N,
15.59.
The negative value of DdRS, which corresponds to the
signal of protons of the substituent L2 (CH2N3), and
the plus sign resulting for the L1 (CH2SPh) protons
determine the (S)-configuration according to the draw-
ing (Scheme 3). In the case of 1-chloro-3-phenylthiopro-
pan-2-ol ( )-3a the values of DdRS are similar, the minus
sign corresponds to the signal of protons of the substitu-
ent L2 (CH2Cl) and the plus sign to the substituent L1
(CH2SPh). Following the equations, they suggest an
(R)-configuration. The opposite configurations of (S)-
(+)-2a and (R)-(+)-3a results from the substituents rank-
ing in Cahn-Ingold-Prelog system.
4.3.4. (S)-(ꢀ)-1-Chloro-3-phenylthiopropan-2-ol acetate
5a. 1H NMR (CDCl3) d 2.01 (s; 3H; CH3); 3.20 (dd;
1Ha; Jgem = 14.4 Hz; J = 6.6 Hz; SCHaHb); 3.24 (dd;
1Hb; J = 6 Hz; SCHaHb); 3.77 (m; 2H; CH2Cl); 5.12
(m; 1H; CH); 7.20–7.24 (m; 1H; aromat.); 7.28–7.33
(m; 2H; aromat.); 7.39–7.43 (m; 2H; aromat.); 13C
NMR (CDCl3) d 20.79; 34.61; 44.27; 71.60; 126.81;
129.13; 129.98; 134.76; 170.13; IR (film; cmꢀ1);
22
D
½aŠ ¼ ꢀ3:2 (c 0.99; ee = 95%). Anal. Calcd for
C11H13ClO2S: C, 53.98, H, 5.35; Cl, 14.49; S, 13.10.
Found: C, 54.16; H, 5.39; Cl, 14.38; S, 13.21.
DdRSL1 ¼ dRL1 ꢀ dSL1 ¼ 3:14 ꢀ 2:96 ¼ þ0:18 ppm
DdRSL2 ¼ dRL2 ꢀ dSL2 ¼ 3:58 ꢀ 3:73 ¼ ꢀ0:15 ppm
4.3.5. (S)-(ꢀ)-1-Chloro-3-(4-chlorophenylthio)propan-2-
ol acetate 5b. 1H NMR (CDCl3) d 2.03 (s; 3H; CH3);
3.17 (dd; 1Ha; Jgem = 14.2 Hz; J = 6.6 Hz; SCHaHb);
3.21 (dd; 1Hb; J = 6.2 Hz; SCHaHb); 3.75 (m; 2H;
CH2Cl); 5.10 (m; 1H; CH); 7.26–7.29 (m; 2H; aromat.);
7.33–7.36 (m; 2H; aromat.); 13C NMR (CDCl3) d 20.77;
34.92; 44.17; 71.45; 129.27; 131.36; 133.32; 170.10; IR
The same procedure was applied to the enantiomers of
the alcohols isolated after hydrolysis of the acetates
(ꢀ)-4a-c and (ꢀ)-5a–c. As compared with (S)-(+)-2a–c
and (R)-(+)-3a–c, the respective DdRS values are of
opposite signs thus indicating the (R)- and (S)-
configuration.
(film; cmꢀ1): 1745; 1480; 1425; 1370; 1230; 1095; 1030;
22
D
820; ½aŠ ¼ ꢀ8:5 (c 1.08; ee = 83%). Anal. Calcd for
C11H12Cl2O2S: C, 47.31; H, 4.33. Found: C, 47.18; H,
4.50.
DdRSL1 ¼ dRL1 ꢀ dSL1 ¼ 2:90 ꢀ 3:09 ¼ ꢀ0:19 ppm
4.3.6. (S)-(ꢀ)-1-Chloro-3-(4-methylphenylthio)propan-2-
ol acetate 5c. 1H NMR (CDCl3) d 2.02 (s; 3H;
DdRSL2 ¼ dRL2 ꢀ dSL2 ¼ 3:52 ꢀ 3:42 ¼ þ0:10 ppm
CH3CO); 2.32 (s; 3H; CH3); 3.14 (dd; 1Ha; Jgem
=
14.4 Hz; J = 6.6 Hz; SCHaHb); 3.19 (dd; 1Hb; J = 6 Hz;
SCHaHb); 3.76 (m; 2H; CH2Cl); 5.10 (m; 1H; CH);
7.10–7.13 (m; 2H; aromat.); 7.30–7.33 (m; 2H; aromat.);
13C NMR (CDCl3) d 20.79; 21.01; 35.41; 44.33; 71.66;
Acknowledgements
129.91; 130.84; 130.96; 137.11; 170.12; IR (film; cmꢀ1):
22
1740; 1490; 1370; 1225; 1030; 800; ½aŠ ¼ ꢀ11:1
This work was in part supported by the Polish State
Committee for Scientific Research. Grant 2 PO4B 010
26.
D
(c 1.08; ee = 92%). Anal. Calcd for C12H15ClO2S: C,
55.70; H, 5.84. Found: C, 55.67; H, 6.01.
Scheme 3. Description of substituents for determination of the absolute configuration of (+)-2a.

M. Wielechowska, J. Plenkiewicz / Tetrahedron: Asymmetry 16 (2005) 1199–1205
1205
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