Kinetic resolution of heteroaryl β-hydroxy sulfides catalyzed by Humicola lanuginosa lipase

Article abstract of DOI:10.1016/S0957-4166(02)00148-9

Humicola lanuginosa lipase-catalyzed resolution of heteroaryl substituted β-hydroxy sulfides by irreversible transesterification using vinyl acetate as acylating agent is discussed. The ee of the resolved alcohols was determined from the ¹H NMR of their corresponding (S)-(+)-O-acetylmandelic acid esters.

Full text of DOI:10.1016/S0957-4166(02)00148-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 511–517
Kinetic resolution of heteroaryl b-hydroxy sulfides catalyzed by
Humicola lanuginosa lipase
Swapandeep Singh Chimni,* Satwinder Singh, Subodh Kumar and Savita Mahajan
Department of Chemistry, Guru Nanak Dev University, Amritsar 143 005, India
Received 21 February 2002; accepted 19 March 2002
Abstract—Humicola lanuginosa lipase-catalyzed resolution of heteroaryl substituted b-hydroxy sulfides by irreversible transesterifi-
1
cation using vinyl acetate as acylating agent is discussed. The ee of the resolved alcohols was determined from the H NMR of
their corresponding (S)-(+)-O-acetylmandelic acid esters. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
The synthetic utility of enantiomerically pure secondary
alcohols is well documented.5,6 Chiral hydroxy sulfides
serve as intermediates in the synthesis of chiral oxi-
The use of enzymes as chiral catalysts for the prepara-
tion of chiral non-racemic compounds has become an
increasingly attractive alternative to conventional
chemical methods. Lipases, have been shown to be
versatile enzymes for kinetic resolution and desym-
metrization of prostereogenic substrates in organic
media.1 However, it cannot be expected that every
lipase always transforms a non-natural substrate in an
optimal manner. Hence screening of all available lipases
is required in hope of finding the most enantioselective
one for a particular class of compound. Of all the
commercially available lipases Humicola lanuginosa
lipase (HLL), a fungal lipase, has not been extensively
studied. Our recent studies2 on HLL have shown that it
has good potential as a chiral catalyst for the resolution
of secondary alcohols in organic medium.
ranes,7
thiiranes,8
tetrahydrofurans,9
spiroketal
pheromones,10 and 4-acetoxyazetidinones.11 The pres-
ence of an additional heteroatom in the molecule,
placed at an appropriate position from the hydroxy
group can provide additional versatility to chiral alco-
hols. Also, chiral alcohols appended to heterocycles are
important synthons for the synthesis of biologically
active compounds and can be used as chiral ligands in
homogeneous asymmetric catalysis. Recently the syn-
thesis of thioalkylpyridines and their potential as pyri-
dine sp2-nitrogen donor ligands for palladium-catalyzed
allylic substitution have been reported by Chelucci12
and Kellogg.13 Similarly, enantiomerically pure 2-(1-
hydroxyalkyl)pyridines have been found to be effective
catalysts for the addition of diethylzinc to benzalde-
hyde.14 Keeping in mind these literature reports, we
planned to synthesize hydroxy sulfides linked to hetero-
cycles including pyridine. In continuation of our inter-
est in the application of HLL for the resolution of
racemic secondary alcohols,15 we report herein our
studies on the effect of the presence of a heteroatom in
the aromatic binding group on the rate of conversion
and enantioselectivity.
HLL (recently renamed Thermomyces lanuginosa lipase)
is a 1,3 specific lipase, mainly used as a component in
detergent formulations and is similar in structure to
Rhizomucor meihei lipase. It has a molecular weight of
30 kDa and its X-ray structure3 shows a helix, covering
the superficial active site of the lipase in its closed
conformation. According to the crystal structure of an
HLL-inhibitor complex, the lipase has a hydrophobic
crevice, which extends from the active site serine and
accommodates the acyl chain. Tryptophan 89 (Trp 89)
in the lid of the lipase plays an important role in
positioning a substrate optimally in the active site for
enantioselective acylation reaction.4
2. Results and discussion
The enzymatic resolution of ( )-1a (Scheme 1) was
carried out using two mass equivalent of lipase with
vinyl acetate (10 equiv.) as acyl donor and as solvent at
24 1°C. In the preliminary experiments the catalytic
efficiencies of HLL and CRL were evaluated and com-
* Corresponding author. Fax: +91-183-258820; e-mail: sschimni@
angelfire.com
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00148-9

512
S. S. Chimni et al. / Tetrahedron: Asymmetry 13 (2002) 511–517
Scheme 1. HLL-catalyzed acylation of racemic alcohols ( )-1a–e.
pared (Table 1). The reactions were monitored by TLC
and H NMR to observe the degree of conversion. It
hydrolysis of the acetate and conversion of the resulting
alcohols to the respective diastereomeric (S)-O-acetyl-
mandelate ester derivatives. The enantiomeric ratio was
calculated using the equations given by Chen et al.16
According to Kazlauskas’ rule for resolution of sec-
ondary alcohols with lipases,17 which holds for Rhi-
zomucor meihei lipase,18 a lipase structurally similar to
HLL,19 transesterification should provide the acetates
having (R)-configuration. So, the resolved acetates can
be assigned (R)-configuration and the unreacted alco-
hol (S)-configuration. Also, in a homologous series the
sign of the optical rotation remains the same for enan-
tiomers so by comparison with the literature report20 on
1-phenylthio-2-propanol, the (S)-alcohol is dextrorota-
tory. In the case of 1-(3-pyridylthio)propan-2-ol the
unreactive enantiomer is dextrorotatory and the enan-
tiomer kinetically acylated by lipase is levorotatory,
1
was observed that although the reaction is faster with
CRL as compared to HLL, the latter shows better
enantiodiscrimination. So, all further reactions have
been performed with HLL. It was also observed that
when the extent of conversion reaches near 50% or
more, the ee of the resolved acetate decreases and that
of the unreacted alcohol increases. Thus, by controlling
the extent of conversion both the enantiomers can be
obtained in high enantiomeric purities (Table 2, entries
1 and 2). The exact degree of conversion was deter-
mined from the 1H NMR of the crude reaction mixture.
Column chromatography was used to separate the ace-
tate from the unreactive alcohol. The absolute configu-
ration and enantiomeric excess (ee) of the separated
acetate and unreacted alcohol was determined by
Table 1. Percentage conversion and [a]2D7 of 1a with HLL and CRL at 24+
6 1°C
S. No.
Lipase
Reaction time (h)
Conv. (%)
(S)-alcohol
[h]2D7
(R)-alcohol
[h]2D7
Yield
ee (%)
Yield
ee (%)
1
2
3
4
HLL
HLL
CRL
CRL
20
17
20
22
50
45
52
57
45
52
40
43
+28.8
+29.5
+17.3
+26.1
65
66
39
52
42
44
49
52
−26.0
−32.6
−20.9
−21.6
58
81
47
48
Table 2. Enantioselective acylation of 1a–e by HLLa at 2491°C

S. S. Chimni et al. / Tetrahedron: Asymmetry 13 (2002) 511–517
513
carbons directly attached to heterocyclic ring, resolu-
tion of 1e was carried out. The reaction of 1e under
similar conditions was allowed to run for nine days to
achieve 25% conversion and an enantioselectivity ratio
(E) value of 14. But, a similar reaction with a phenyl
ring attached directly to the stereogenic carbon showed
no conversion even after 11 days. Naemura et al.22 have
observed similar inertness with Pseudomonas fluores-
cence lipase. Thus, the presence of a heteroatom (N or
O) in the aromatic binding group modulates the enzy-
matic activity of HLL in such a way so as to enhance
its activity.
Figure 1. (S)-O-Acetylmandelic esters of 1b.
which is in agreement with that predicted by
Kazlauskas’ rule.
3. Determination of enantiomeric excess (ee)
The enantiomeric excess of the resolved alcohols were
determined using H NMR. Chiral shift reagents like
Another important observation made in comparison
with our earlier results15 on the enzymatic resolution of
1-phenylthio-2-propanol (HLL, conv.=46%, 36 h;
CRL, conv.=35%, 76 h) was that the time taken by 1a
to achieve approximately 50% conversion (24 1°C) was
less in the cases of both CRL and HLL (Table 1). This
effect may be attributed to the involvement of the
pyridine nitrogen (a) in modulation of the general
acid–base behavior of the lipase through changes in the
protonation state of protein groups at the catalytic site
of the enzyme, which enhances the catalytic activity of
the lipase or (b) interaction with the a-helix forming the
lid or flap covering the active site in such a way that it
leads to opening of the lid, thus exposing the active site.
The ability of organic bases like Et3N and pyridine to
enhance the activity of lipases in organic medium has
been reported,21 but their mode of action is not known.
Since similar enhancement of the reaction was observed
in the reaction of 3- and 4-pyridyl derivatives 1b, 1c and
1d, so the increase in rate of reaction can be attributed
to the p–p interactions between the electron deficient
heterocyclic ring with the electron rich aromatic ring of
the a-helix forming the lid. This results in opening of
the lid, exposing the catalytic site of the lipase and
hence giving the higher rate of reaction. Similar enan-
tioselection (E=56) was observed in the case of 1-(2-
furylmethylthio)-2-propanol 1d.
1
Pr(tfc)3 and Eu(hfc)3 were not effective in resolving the
methyl and methine signals in the enantiomers, which is
required for enantiomeric excess determination. To
overcome this, diastereomeric S-(+)-O-acetylmandelate
esters of the resolved (R)- and (S)-1b were prepared
with S-(+)-O-acetylmandelic acid. The enantiomeric
excess of the resolved alcohols could be calculated via
integration of the signal for the methine protons of the
1
mandelate ester in the H NMR spectra of the respec-
tive (S)-(+)-O-acetylmandelic acid ester. Proton NMR
has since been used to determine the absolute configu-
ration of secondary alcohols, by correlating the NMR
spectra of mandelic acid esters with absolute configura-
tion.23 Similarly, from the observed chemical shift of
methyl and methine protons, a correlation of the chem-
ical shift with absolute configuration at the carbinol
1
carbon (Ca) can be developed (Fig. 1). In the H NMR
(Table 3) of the S-(+)-O-acetylmandelic esters of the
(S)-alcohols, methyl (CH3) and methine proton (H%) are
observed downfield, while for (R)-alcohols the signals
1
are upfield. The H NMR showed separate signals for
these protons in all the diastereomeric esters except 4a,
where the methine signal at l 5.87 ppm was not resolv-
able initially. This signal was resolved by titrating with
0.1 M Pr(tfc)3 to give two signals at l 5.88 and 5.85
ppm for (S,S)-4a and (S,R)-4a diastereomers, respec-
tively (Fig. 2).
In the above examples the heterocyclic ring is separated
from the stereogenic carbon center by a two-atom
spacer. So as to assess the scope of HLL in catalyzing
the acylation of secondary alcohols with stereogenic
Further, we performed energy minimization24 studies
on (S,S)-4b and (S,R)-4b diastereomers using augu-
mented MM3, followed by an optimized geometry cal-
Table 3. Chemical shift values of methine (lH%) and methyl protons(lCH3) of the (S,S)-4 and (S,R)-4 diastereomers
Substrate
Chemical shifts (ppm)
lH%(S,S)
l
DlH%
lCH3(S,S)
l
DlCH3
H% (S,R)
CH3 (S,R)
4a
4b
4c
4d
4e
5.88a
5.88
5.82
5.86
5.98
5.85a
5.84
5.80
5.83
5.96
0.03a
0.04
0.02
0.03
0.02
1.38
1.26
1.37
1.19
–
1.18
1.13
1.20
1.01
–
0.20
0.13
0.17
0.18
–
a The initial overlapping signal at l 5.87 ppm due to both of the diastereomers were resolved by addition of Lanthanide shift reagent Pr(tfc)3.

514
S. S. Chimni et al. / Tetrahedron: Asymmetry 13 (2002) 511–517
field around the phenyl ring (Table 3). Thus this differ-
ence in chemical shift (Dl) for the same proton in
(S,S)- and (S,R)-diastereomers allows the determina-
tion of the absolute configuration of the chiral alcohols.
4. Conclusion
We have shown that heteroaryl b-hydroxy sulfides can
be resolved with HLL, with enantiomeric ratios (E)
ranging from 14 to 71. By hydrolysis of the optically
active acetates 3a–e, which are the products of the
lipase-catalyzed acetylation, both enantiomers of these
potentially useful building blocks are available. The
utilization of S-(+)-O-acetylmandelic acid has allowed
evaluation of enantiomeric purity and based on 1H
NMR and energy minimization studies, a correlation of
chemical shift with absolute stereochemical assignment
can be done. It is also concluded that Kazlauskas’ rule,
1H NMR of S-(+)-O-acetylmandelic acid esters and
energy minimization studies are in close agreement.
5. Experimental
5.1. General
1H and 13C NMR spectra were recorded in CDCl3
containing 0.03% Me4Si as internal standard on Bruker
NMR spectrometers at 200 or 300 MHz. Chemical
shifts are expressed as l downfield from the TMS and
J values are in Hz. When necessary, assignments were
aided by DEPT-135 and decoupling experiments. IR
spectra were obtained with Nicolet Avatar 320 FTIR.
Mass spectra were recorded on GCMS-QP-2000 mass
spectrometer by EI method. The specific rotation [h]D27
was measured in CH2Cl2 with a Jasco DIP-360 digital
polarimeter.
Figure 2. 200 MHz 1H NMR spectrum (a) (S,R)-4a; (b)
(S,R)-4a+0.1 M Pr(tfc)3; (c) (S,S)-4a; (d) (S,S)-4a+0.1 M
Pr(tfc)3.
culations in MOPAC using PM3 parameters and have
found that the (S,R)-diastereomer has approximately 1
kcal/mole lower energy than the (S,S)-diastereomer.
Also, comparison of the energy minimized structures
(Fig. 3), shows that the methine proton and the C=O
group of the mandelate esters are synperiplanar (sp) to
each other in the (S,S)-diastereomer (lH%(S,S)=5.88
ppm) and antiperiplanar (ap) in (S,R)-diastereomer
(lH%(S,R)=5.84 ppm), indicating that the configuration
at the carbinol carbon (Ca) controls the conformation
around the C%1ꢀCꢁO bond, which gives rise to chemical
shift differences of C1%-H% signal. The difference in
chemical shifts of methyl protons of the esters is due to
their different orientations in the anisotropic magnetic
5.2. General procedure for the synthesis of racemic
1a–e
The method given by Crumbie et al.20 was used for the
preparation of starting compounds 1a–e. To a well
stirred solution of the sodium thiolate, prepared from
sodium ethoxide (0.11 moles) and the respective thiol
(0.10 moles) was added dropwise, a solution of corre-
Figure 3. Energy minimized conformations of (S,S) and (S,R)-4b.

S. S. Chimni et al. / Tetrahedron: Asymmetry 13 (2002) 511–517
515
sponding a-haloketone (0.12 moles) in absolute alcohol
(10 mL) over 30 min. Stirring was further continued for
2 h before filtering off the precipitated sodium chloride.
The filtrate was concentrated under reduced pressure
and the resulting viscous oil was diluted with water (10
mL) and extracted with ethyl acetate (3×50 mL). The
organic layer was dried over anhydrous Na2SO4 and
concentrated under reduced pressure to give crude
thioketone, which was reduced with NaBH4 in ethanol.
To a stirred solution of the parent ketone (0.1 moles) in
ethanol (30 mL), NaBH4 (1.85 g, 0.05 moles) was added
in small portions. The mixture was stirred until the
reduction was complete (TLC). The reaction mixture
was extracted with ethyl acetate. The organic layer was
dried and evaporated to yield the crude product, which
was purified by column chromatography with 60–120
mesh silica gel using hexane–ethyl acetate (90:10) as
eluent. All compounds have been completely
characterized.
5.2.4. (RS)-1-(Furan-2-ylmethylthio)propan-2-ol 1d.
Brown oil; yield=64%; IR (Neat): 3398, 2940, 1580,
1430, 730 cm−1; MS (m/z): 172 (M+), 129, 128, 127,
1
113, 112, 81, 71, 57 (100); H NMR (CDCl3): l 1.23 (d,
3H, J=6.2 Hz, CH3), 2.39 (dd, 2H, J=13.6 and 8.7 Hz,
1H of CH2 and 1H of OH), 2.68 (dd, 1H, J=13.8 and
3.5 Hz, CH2), 3.65–3.82 (m, 3H, 2H of CH2 and 1H of
CH), 6.17 (d, 1H, J=3.13 Hz, ArH), 6.31–6.35 (m, 1H,
ArH), 7.35 (d, 1H, J=1.27 Hz, ArH); 13C NMR/DEPT
(CDCl3): l 22.06 (+ve, CH3), 28.33 (-ve, CH2), 40.42
(-ve, CH2), 65.98 (+ve, CH), 107.50 (+ve, C-Ar), 110.36
(+ve, C-Ar), 141.93 (+ve, C-Ar), 151.44 (C-Ar).
5.2.5. (RS)-2-Ethylthio-1-thiophen-2-yl-ethanol 1e. Yel-
low liquid; yield=63%; IR (Neat): 3450, 2930, 2890,
1460, 1045, 715 cm−1; MS (m/z): 188 (M+), 187, 170,
149, 143, 125 (100), 83, 71; 1H NMR (CDCl3): l 1.27 (t,
3H, J=7.4 Hz, CH3), 2.57 (q, 2H, J=7.4 Hz, CH2),
2.86 (dd, 1H, J=13.8 and 8.5 Hz, CH2), 3.02 (dd, 1H,
J=13.8 and 4.2 Hz, CH2), 3.17 (d, 1H, J=3.0 Hz,
OH), 4.99–5.03 (m, 1H, CH), 6.95–7.01 (m, 2H, ArH),
7.24–7.27 (m, 1H, ArH); 13C NMR (CDCl3): l 14.76
(CH3), 26.20 (CH2), 41.44 (CH2), 68.17 (CH), 123.84
(C-Ar), 124.69 (C-Ar), 126.62 (C-Ar), 146.26 (C-Ar).
5.2.1. (RS)-1-(2-Pyridylthio)propan-2-ol 1a. Yellow liq-
uid; yield=80%; IR (Neat): 3391, 2972, 1579, 1351,
1043, 759, 722 cm−1; MS (m/z): 169 (M+), 151 (M−18),
1
124, 111, 94, 79, 71 (100); H NMR (CDCl3): l 1.31 (d,
3H, J=6.2 Hz, CH3), 1.63 (bs, 1H, OH), 3.15 (dd, 1H,
J=14.7 and 6.8 Hz, CH2), 3.35 (dd, 1H, J=14.7 and
2.8 Hz, CH2), 4.16 (d quartet, 1H, J=6.4 and 2.8 Hz,
CH), 7.01–7.07 (m, 1H, ArH), 7.28–7.33 (m, 1H, ArH),
7.48–7.52 (m, 1H, ArH), 8.35–8.38 (m, 1H, ArH); 13C
NMR/DEPT (CDCl3): l 21.51 (+ve, CH3), 37.94 (-ve,
CH2), 66.05 (+ve, CH), 118.58 (+ve, C-Ar), 121.33 (+ve,
C-Ar), 135.20 (+ve, C-Ar), 147.76 (+ve, C-Ar), 157.89
(C-Ar).
5.2.6. (RS)-2-Propylthio-1-phenylethanol 2. Colorless
liquid; yield=74%; IR (Neat): 3482, 3029, 2960, 1087
cm−1; MS (m/z): 197 (M+), 182, 168, 154, 122, 77, 58
(100); 1H NMR (CDCl3): l 1.00 (t, 3H, J=7.3 Hz,
CH3), 1.63 (sextet, 2H, J=7.3 Hz, CH2), 2.53 (t, 2H,
J=7.3 Hz, CH2), 2.70 (dd, 1H, J=13.8 and 9.5 Hz,
CH2), 2.94 (dd, 1H, J=13.8 and 3.6 Hz, CH2), 3.02 (d,
1H, 2.4 Hz, OH), 4.70–4.77 (m, 1H, CH), 7.29–7.38 (m,
5H, ArH); 13C NMR/ DEPT (CDCl3): l 13.25 (+ve,
CH3), 22.80 (-ve, CH2), 34.06 (-ve, CH2), 41.74 (-ve,
CH2), 71.66 (+ve, CH), 125.65 (+ve, C-Ar), 127.58 (+ve,
C-Ar), 128.27 (+ve, C-Ar), 142.52 (C-Ar).
5.2.2. (RS)-1-(3-Pyridylthio)propan-2-ol 1b. Pale yellow
liquid; yield=75%; IR (Neat): 3310, 3023, 2967, 1404,
1272, 704 cm−1; MS (m/z): 169 (M+), 151 (M −18), 135,
1
124, 96, 78, 73, 71; H NMR (CDCl3): l 1.31 (d, 3H,
5.3. General procedure for resolution
J=6.2 Hz, CH3), 2.99 (dd, 1H, J=13.6 and 8.0 Hz,
CH2), 3.11 (dd, 2H, J=13.6 and 4.2 Hz, 1H of CH2
and 1H of OH), 3.85–3.94 (m, 1H, CH), 7.21–7.28 (m,
1H, ArH), 7.70–7.76 (m, 1H, ArH), 8.43–8.46 (m, 1H,
ArH), 8.61–8.62 (d, 1H, J=1.8 Hz); 13C NMR/
(CDCl3): l 22.14 (CH3), 42.64 (CH2), 65.76 (CH),
123.62 (C-Ar), 133.84 (C-Ar), 137.26 (C-Ar), 146.43
(C-Ar), 149.48 (C-Ar).
To a solution of the (RS)-1a (338 mg, 2 mmol) and
vinyl acetate (1.8 mL, 20 mmol) in a 25 mL round
bottom flask, HLL (676 mg, 2 equiv. w/w) was added
and the reaction mixture stirred at 24 1°C and moni-
1
tored by taking H NMR of aliquots taken at regular
intervals. The reaction was stopped by filtering the
enzyme on a sintered glass funnel. Concentration of the
filtrate followed by column chromatography provided
(R)-3a and (S)-1a.
5.2.3. (RS)-1-(4-Pyridylthio)propan-2-ol 1c. Light brown
solid; yield=83%; MP: 52°C (CH2Cl2/hexane); IR
(KBr): 3380, 3020, 2971, 1550, 1030, 694 cm−1; MS
(m/z): 169 (M+), 152, 151 (M−18), 124, 110, 92, 83, 77,
5.4. (R)-(−)-1-(2-Pyridylthio)propan-2-yl acetate 3a
1
71, 58 (100); H NMR (CDCl3): l 1.34 (d, 3H, J=6.2
Pale yellow liquid; [h]2D7=−42.2 (c 0.62, CH2Cl2); IR:
3060, 2980, 2935, 1735, 1115, 758 cm−1; MS (m/z): 211
Hz, CH3), 2.55 (brs, 1H, OH), 2.99 (dd, 1H, J=13.6
and 7.3 Hz, CH2), 3.11 (dd, 1H, J=13.6 and 4.7 Hz,
CH2), 3.95–4.05 (m, 1H, CH), 7.13 (d, 2H, J=6.2 Hz,
ArH), 8.37 (d, 2H, J=6.1 Hz, ArH); 13C NMR/DEPT
(CDCl3): l 22.51 (+ve, CH3), 39.28 (-ve, CH2), 65.48
(+ve, CH), 120.70 (+ve, C-Ar), 148.33 (+ve, C-Ar),
149.73 (C-Ar). Found C, 56.62; H, 6.43; N, 8.41; S,
18.86; C8H11NOS requires C, 56.77; H, 6.55; N, 8.28
and S, 18.95%.
1
(M+), 196, 169 (100), 168, 136, 125, 111, 110, 71; H
NMR (CDCl3): l 1.35 (d, 3H, J=6.3 Hz, CH3), 1.98 (s,
3H, OAc), 3.31 (dd, 1H, J=13.9 and 6.6 Hz, CH2),
3.48 (dd, 1H, J=13.9 and 5.4 Hz, CH2), 5.11 (sextet,
1H, J=6.0 Hz, CH), 6.93–6.99 (m, 1H, ArH), 7.15–7.27
(m, 1H, ArH), 7.41–7.50 (m, 1H, ArH), 8.40 (d, 1H,
ArH, J=4.7 Hz); 13C NMR/DEPT (CDCl3): l 18.90
(+ve, CH3), 20.74 (+ve, CH3), 34.12 (-ve, CH2), 69.37

516
S. S. Chimni et al. / Tetrahedron: Asymmetry 13 (2002) 511–517
1
(+ve, CH), 119.08 (+ve, C-Ar), 121.86 (+ve, C-Ar),
135.47 (+ve, C-Ar), 148.96 (+ve, C-Ar), 157.69 (ab,
C-Ar), 169.44 (CꢁO).
(m/z):230 (M+), 201, 187, 169, 155; H NMR (CDCl3):
1.23 (t, 3H, J=7.4 Hz, CH3), 2.10 (s, 3H, OAc), 2.52
(q, 2H, J=7.3 Hz, CH2), 2.80 (dd, 1H, J=13.5 and 5.9
Hz, CH2), 3.03 (dd, 1H, J=13.8 and 7.4 Hz, CH2),
4.62–4.74 (m, 1H, CH), 6.97–7.00 (m, 2H, ArH), 7.26–
7.29 (m, 1H, ArH); 13C NMR (CDCl3): 14.71 (CH3),
22.95 (CH3), 23.75 (CH2), 38.74 (CH2), 67.73 (CH),
128.69 (C-Ar), 130.51 (C-Ar), 132.55 (C-Ar), 136.52
(C-Ar), 167.06 (CꢁO).
5.4.1. (S)-(+)-1-(2-Pyridylthio)propan-2-ol (S)-(+)-1a.
Yellow liquid; [h]D27=+15.8 (c 0.85 CH2Cl2) for 38% ee.
5.4.2. (R)-(−)-1-(3-Pyridylthio)propan-2-yl acetate 3b.
Colorless liquid; [h]D27=−1.2 (c 0.50, CH2Cl2); IR (film):
3048, 2921, 1737, 1404, 1372, 1238 cm−1; MS (m/z): 211
1
(M+), 210, 196, 165, 149 (100), 124, 110, 78, 73; H
5.4.9. (S)-(+)-2-Ethylthio-1-thiophen-2-yl-ethanol (S)-(−)-
NMR (CDCl3): 1.34 (d, 3H, J=6.3 Hz, CH3), 1.98 (s,
3H, OAc), 3.00 (dd, 2H, J=13.9 and 5.9 Hz, 1H of
CH2), 3.16 (dd, 1H, J=13.9 and 6.3 Hz, CH2), 4.98–
5.08 (m, 1H, CH), 7.20–7.25 (m, 1H, ArH), 7.71–7.78
(m, 1H, ArH), 8.42–8.46 (m, 1H, ArH), 8.61–8.62 (d,
1H, J=2.0 Hz, ArH); 13C NMR/(CDCl3): 19.13 (CH3),
21.03 (CH3), 39.16 (CH2), 69.45 (CH), 123.67 (C-Ar),
137.47 (C-Ar), 147.44 (C-Ar), 150.67 (C-Ar), 170.39
(CꢁO).
1e. Brown liquid: [h]2D7=−6.9 (c 1.50, CH2Cl2) for 32%
ee.
5.5. Chemical hydrolysis of the (R)-acetates 3a–e
To a solution of (R)-3a–e (2 mmol) in a solution of
methanol and water (4:1, 8 mL), 1 N aqueous NaOH
(2.0 mL, 2 mmol) was added. The solution was stirred
at room temperature until the hydrolysis was complete
(TLC). The solution was extracted with chloroform,
dried with anhydrous Na2SO4 and evaporated to give
(R)-1a–e.
5.4.3. (S)-(+)-1-(3-Pyridylthio)propan-2-ol[(S)-(+)-1b].
Pale yellow liquid; [h]2D7=+18.6 (c 0.62, CH2Cl2) for
36% ee.
5.5.1. (R)-(−)-1-(2-Pyridylthio)propan-2-ol (R)-(−)-1a.
[h]2D7=−37.4 (c 0.40, CH2Cl2) for 96% ee.
5.4.4. (R)-(+)-1-(4-Pyridylthio)propan-2-yl acetate (3c).
Colorless oil; [h]D27=+8.2 (c 0.36, CH2Cl2); IR (film):
3052, 2970, 1732, 1450, 702 cm−1; MS (m/z): 211 (M+),
5.5.2. (R)-(−)-1-(3-Pyridylthio)propan-2-ol (R)-(−)-1b.
[h]2D7=−49.2 (c 0.44, CH2Cl2) for 95% ee.
1
210, 196, 165, 149 (100), 124, 110, 78, 73; H NMR
(CDCl3):1.38 (d, 3H, J=6.3 Hz, CH3), 1.98 (s, 3H,
OAc), 2.94 (dd, 1H, J=13.8 and 7.0 Hz, CH2), 3.28
(dd, 1H, J=13.8 and 5.6 Hz, CH2), 5.06 (sextet, 1H,
J=6.3 Hz, CH), 7.20 (d, 2H, J=6.1 Hz, ArH), 8.40 (d,
2H, J=5.6 Hz, ArH); 13C NMR/DEPT (CDCl3): 19.20
(+ve, CH3), 20.52 (+ve, CH3), 36.44 (-ve, CH2), 69.11
(+ve, CH), 120.52 (+ve, C-Ar), 149.55 (+ve, C-Ar),
148.65 (ab, C-Ar), 170.24 (ab, CꢁO).
5.5.3. (R)-(−)-1-(4-Pyridylthio)propan-2-ol (R)-(−)-1c.
[h]2D7=-26.2 (c 0.22, CH2Cl2) for 96% ee.
5.5.4. (R)-(−)-1-(Furan-2-ylmethylthio)propan-2-ol (R)-
(−)-1d. [h]2D7=−67.9 (c 0.47, CH2Cl2) for 92% ee.
5.5.5. (R)-(−)-2-Ethylthio-1-thiophen-2-yl-ethanol (R)-(+)-
1e. [h]2D7=+25.1 (c 0.43, CH2Cl2) for 82% ee.
5.4.5. (S)-(+)-1-(4-Pyridylthio)propan-2-ol (S)-(+)-1c.
Colorless liquid; [h]2D7=+10.2 (c 0.56, CH2Cl2) for 34%
ee.
Acknowledgements
5.4.6. (R)-(+)-1-(Furan-2-ylmethylthio)propan-2-yl acet-
ate 3d. Brown oil; [h]2D7=+20.4 (c 0.76, CH2Cl2); IR
(film): 3050, 2984, 2940, 1730, 760 cm−1; MS (m/z): 214,
S.S.C. thanks CSIR (India) for a research grant
[01(1592)/99/EMR-II], Dr. J. S. Rao (Novo Nordisk,
India) for the gift of HLL. S.S. thanks Professor Harjit
Singh for financial support, CSIR for Senior Research
Fellowship and Dr. Dharam Paul (Osaka University,
Japan) for his kind help.
1
199, 169, 112, 71, 53, 51; H NMR (CDCl3): 1.29 (d,
3H, J=6.3 Hz, CH3), 2.05 (s, 3H, OAc), 2.52 (dd, 1H,
J=13.9 and 6.2 Hz, CH2), 2.64 (dd, 1H, J=13.9 and
6.3 Hz, CH2), 3.72 (s, 2H, CH2), 4.97 (sextet, 1H,
J=6.2 Hz, CH), 6.17–6.18 (m, 1H, ArH), 6.28–6.29 (m,
1H, ArH), 7.34 (m, 1H, ArH); 13C NMR/DEPT
(CDCl3): 19.16 (+ve, CH3), 21.07 (+ve, CH3), 28.36
(-ve, CH2), 36.51 (-ve, CH2), 69.26 (+ve, CH), 107.69
(+ve, C-Ar), 110.31 (+ve, C-Ar), 141.99 (+ve, C-Ar),
151.22 (ab, C-Ar), 169.72 (ab, CꢁO).
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