Highly efficient synthesis of chiral β-hydroxy sulfides with high enantiomeric purity via CBS-oxazaborolidine-catalyzed borane reduction

Article abstract of DOI:10.1016/S0957-4166(02)00193-3

A simple and efficient synthesis of chiral β-hydroxy p-tolylsulfides with high enantiomeric purity by CBS-oxazaborolidine-catalyzed asymmetric borane reduction of β-keto p-tolylsulfides using N-ethyl-N-isopropylaniline-borane complex as the borane carrier is reported.

Full text of DOI:10.1016/S0957-4166(02)00193-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 697–703
Highly efficient synthesis of chiral b-hydroxy sulfides with high
enantiomeric purity via CBS-oxazaborolidine-catalyzed borane
reduction
Byung Tae Cho,* Ok Kyoung Choi and Dong Jun Kim
Department of Chemistry, Hallym University, Chunchon 200-702, South Korea
Received 19 February 2002; accepted 18 April 2002
Abstract—A simple and efficient synthesis of chiral b-hydroxy p-tolylsulfides with high enantiomeric purity by CBS-oxazaboro-
lidine-catalyzed asymmetric borane reduction of b-keto p-tolylsulfides using N-ethyl-N-isopropylaniline–borane complex as the
borane carrier is reported. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
the asymmetric reduction of various a-functionalized
ketones using chiral reducing agents,13 we undertook a
study into CBS–oxazaborolidine-catalyzed asymmetric
borane reduction of b-keto sulfides. We report herein a
highly efficient synthesis of optically active b-hydroxy
sulfides with high enantiomeric purity using this
methodology.
Enantiopure b-hydroxy sulfides are widely used as
intermediates in the synthesis of chiral oxiranes,1
aziridines,2 thiiranes,3 tetrahydrofurans4 and b-hydroxy
esters.5 Moreover, they are easily oxidized to b-hydroxy
sulfoxides6a,b or sulfones7 which serve as extremely use-
ful chiral building blocks for the synthesis of a variety
of chiral organic compounds, such as chiral oxi-
ranes,6c,d
allylic
alcohols,6e,f,7a
lactones,6g,7b–e
2. Results and discussion
macrolides,6h–l pheromones,6m–o and tetrahydrofurans7f
because the a-carbon atom of sulfenyl or sulfonyl
groups of the compounds can be further functionalized
by the formation of sulfur-stabilized carbanions.8 For
the synthesis of b-hydroxy sulfides, only biological
methods,9 such as asymmetric reduction of b-keto
sulfides using bakers’ yeast,1c,5,10 and lipase-mediated
kinetic resolution of racemic b-hydroxy sulfides,11 have
been presented. However, despite providing high enan-
tioselectivity, such biological methods suffer from the
disadvantage of affording the products in low chemical
yields. In recent years, a number of stoichiometric and
catalytic asymmetric reducing agents which give high
enantioselectivities for ketone reduction have been
reported.12 Although asymmetric reduction of b-keto
sulfides using these chiral reducing agents is expected to
be one of the most convenient methods for the prepara-
tion of optically active b-hydroxy sulfides, to our
knowledge, there have been no reports of such reduc-
tions. Therefore, as part of our ongoing programs on
We selected commercially available CBS–oxazaboro-
lidine reagent 114 and N-ethyl-N-isopropylaniline–
borane complex 2 as a representative catalyst and
borane carrier, respectively, because 1 consistently pro-
vided the best enantioselectivity12c and 2 proved to be
more useful than borane–THF and borane–dimethyl-
sulfide as borane carriers for oxazaborolidine-catalyzed
asymmetric borane reduction of various a-functional-
ized ketones.13b–f The reduction was carried out by slow
addition of b-keto sulfides 3 over 1.5 h to a solution of
1.0 equiv. of the reagent 2 in the presence of 10 mol%
of 1 in THF at 25°C (Scheme 1). As shown in Table 1,
all of the reductions examined afforded the correspond-
ing b-hydroxy sulfides 4 within 10 min in near quantita-
tive yields. Their enantiomeric purities were determined
by HPLC analysis using Whelk-O1, Chiralcel OD or
OD-H chiral column. We first examined the influence
of different substituents on sulfur (R%=n-Bu, t-Bu, Ph
and p-tolyl) on the enantioselectivity for the reduction
of a-sulfanylacetophenone derivatives 3a–d. Among
them, the reduction of 3d bearing a p-tolylsulfanyl
* Corresponding author. E-mail: btcho@hallym.ac.kr
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00193-3

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B. T. Cho et al. / Tetrahedron: Asymmetry 13 (2002) 697–703
Scheme 1.
Table 1. Asymmetric reduction of b-keto sulfides 3 in the presence of 0.1 equiv. of 1 with 1.0 equiv. of 2 in THF at 25°Ca
Entry
Optically active b-hydroxy sulfides 4
Cpd
R
R%
Yieldb (%)
[h]2D2 in CHCl3
% e.e.c
Config.f
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
Ph
Ph
Ph
Ph
n-Bu
t-Bu
Ph
94
91
98
98
97
98
97
98
98
97
98
99
96
96
98
97
97
98
97
+62.6 (c 1.33)
+53.8 (c 1.08)
−11.5 (c 1.00)
−17.1 (c 1.16)
−30.6 (c 1.20)
−40.1 (c 1.00)
−30.3 (c 1.13)
−45.1 (c 1.03)
−13.1 (c 1.15)
−80.9 (c 1.12)
−69.3 (c 1.37)
−30.4 (c 2.27)
+45.8 (c 1.60)
+44.0 (c 1.51)
+34.8 (c 1.02)
+80.0 (c 1.35)
+34.1 (c 1.17)
+117.8 (c 1.34)
+54.9 (c 1.05)
92
78
97
99
99
S
S
Sg
Sh
S
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
Ph
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
p-MeOC6H4
m-ClC6H4
p-ClC6H4
p-FC6H4
p-NO2C6H4
2-Naphthyl
2-Furyl
Et
Et
n-Pentyl
i-Pr
i-Bu
t-Bu
99
S
S
S
S
S
S
\99
\99
\99
\99
99
9
10
11
12
13
14
15
16
17
18
19
97
S
73d
74d
74
Si
S
S
S
S
S
88e
81d
99d
99
c-Hex
S
a [3]=0.5 M. The reduction was complete within 10 min to give the b-hydroxy sulfides 4.
b Isolated and purified yields.
c Determined by HPLC analysis using a 25 cm Whelk-O1 chiral column, unless otherwise indicated.
d Determined by HPLC analysis using a 25 cm Chiralcel OD-H chiral column.
e Determined by HPLC analysis of its sulfone obtained by oxidation using a 25 cm Chiralcel OD chiral column.
f Absolute configuration except for 4c,d and 4m is unknown, but probably S based on comparison of the elution order of HPLC analysis and/or
the sign of the specific rotation value with those of the p-tolyl- or phenylsulfanyl analogues 4c, 4d and 4m reported: Refs. 2, 16 and 17.
g Based on [h]D20 −12.5 (c 13.9, CHCl3), S, 100% e.e.: Ref. 16.
h Based on [h]D19 +20 (c 0.276, CHCl3), R: Ref. 2.
i Based on [h]D +64.3 (c 1.0, CHCl3), S, >98% e.e.: Ref. 17.
e.e. (entries 18 and 19 versus 14 and 15). The reduction
of aliphatic analogues having isopropyl and isobutyl
groups afforded e.e.s of 88 and 81%, respectively
(entries 16 and 17). It is a general phenomenon in the
oxazaborolidine-catalyzed borane reduction that a large
difference in the steric bulk between the two sub-
stituents adjacent to the carbonyl leads to high enan-
tioselectivity. All of the product b-hydroxy sulfides 4
obtained are consistently enriched in the (S)-enan-
tiomer. The stereochemical course can be explained by
the generally accepted mechanism for oxazaborolidine-
catalyzed borane reduction,12f where the b-keto sulfides
3 are attacked by hydride on their Re faces to provide
(S)-4 (Fig. 1).15 On the basis of the proposed mecha-
nism, it is an interesting observation that the ethyl
group acts unusually as the more bulky group than the
phenylthiomethyl or p-tolylthiomethyl groups in the
reduction of 3m and 3n to give products 4m and 4n
with (S)-configuration (entries 14 and 15). Such
group afforded the best result to give 4d in 99% e.e.
Compounds with aliphatic sulfanyl groups were
reduced with somewhat lower enantioselectivity. The
reduction of other aromatic b-keto sulfides 3e–k bear-
ing m- and p-substituted phenyl (m-XC6H4; X=Cl and
p-XC6H4; X=Me, MeO, F, Cl and NO2) and 2-naph-
thyl groups furnished the corresponding b-hydroxy
sulfides 4e–k with very high enantioselectivity
approaching 100% e.e. Inductive effects from the sub-
stituent groups of the phenyl ring on the enantioselec-
tivity were not observed (entries 4–11). Also, the same
reduction of a heterocyclic analogue having a 2-furyl
group provided high enantioselectivity (entry 12). For
aliphatic analogues, the reduction of more hindered
b-keto p-tolylsulfides bearing branched alkyl groups
such as tert-butyl and cyclohexyl groups gave very high
enantioselectivity (99% e.e.), whereas in the case of
unhindered b-keto sulfides containing unbranched alkyl
groups such as ethyl and n-pentyl groups provided 74%

B. T. Cho et al. / Tetrahedron: Asymmetry 13 (2002) 697–703
699
THF was distilled over sodium benzophenone ketyl and
stored in ampoules under nitrogen atmosphere. The
CBS reagent 1 and N-ethyl-N-isopropylaniline–borane
complex 2 were purchased from the Aldrich Chemical
Company. b-Keto p-tolylsulfides 3 were prepared by
reaction of 2-halo-1-arylethanones with the correspond-
ing sodium alkyl or arylthiolates according to the
known procedure.10a
Figure 1.
4.3. General procedure for CBS–oxazaborolidine-cata-
lyzed borane reduction of b-keto sulfides 3
unusual phenomena have also been observed in other
CBS–oxazaborolidine-catalyzed borane reductions of a-
functionalized ketones such as b-keto p-tolylsulfones,13a
a-sulfonyloxy ketones,13c a-siloxy ketones,13f a-(2-tetra-
hydropyranyloxy)ketones13d and a-keto acetals,13e
although the reason is so far unclear.
To a solution of 1 (0.2 mmol; 0.2 M, 1.0 mL) in THF
was added a solution of N-ethyl-N-isopropylaniline–
borane complex 2 (2.0 mmol; 2.0 M, 1.0 mL) in THF.
To this mixture was added slowly a THF solution of 3
(1 M, 2 mL, 2 mmol) over a period of 1.5 h using a
syringe pump at 25°C. After the addition, the reaction
mixture was stirred for 10 min, quenched cautiously
with methanol (0.5 mL), and stirred for additional 30
min. The solvent was evaporated under reduced pres-
sure. The crude b-hydroxy sulfides 4 obtained were
further purified by a flash column chromatography on
silica gel (230–400 mesh) using ethyl acetate/hexane
(1/4) (eluent A), ethyl acetate/hexane (1/2) (eluent B) or
ether/petroleum ether (1/9) (eluent C) as the eluent. The
enantiomeric excesses of 4 were determined by HPLC
analysis using Whelk-O1, Chiralcel OD, or Chiralcel
OD-H chiral column. Absolute configurations were
assigned by comparison of the values reported in the
literature or analogy based on the elution order of
HPLC analysis and/or the sign of the specific rotation
values compared to those of the p-tolyl- or phenylsul-
fanyl analogues published.
3. Conclusion
We have established a simple and efficient synthetic
method for optically active b-hydroxy p-tolylsulfides
with high enantiomeric purity which can be widely used
as starting materials, chiral building blocks, ligands and
intermediates for preparation of numerous optically
active substances by employing CBS–oxazaborolidine-
catalyzed asymmetric borane reduction of the corre-
sponding b-keto sulfides using N-ethyl-N-isopropylani-
line–borane complex as the borane carrier. The reduc-
tion provided almost enantiopure b-hydroxy p-tolyl-
sulfides in both aromatic and more hindered aliphatic
analogues. This is the first example of the synthesis of
such compounds by chemical methods. Further work to
extend the scope of this methodology is in progress and
will be reported in due course.
4.3.1. (S)-(+)-2-(n-Butylsulfanyl)-1-phenylethanol 4a. Rf
0.46 (eluent A); oil; 94% yield; IR (neat, cm−1): 3420,
1
2928, 1452, 1053, 697; H NMR (400 MHz, CDCl3) l
4. Experimental
4.1. General
0.92 (t, 3H, J=7.3 Hz), 1.42 (m, 2H), 1.59 (m, 2H),
2.54 (t, 2H, J=7.3 Hz), 2.71 (dd, 1H, J=13.8, 9.5 Hz),
2.92 (dd, 1H, J=13.8, 3.6 Hz), 3.03 (d, 1H, J=2.5 Hz),
4.73 (ddd, 1H, J=9.4, 3.6, 2.4 Hz), 7.28 (m, 1H),
7.33–7.38 (m, 4H); 13C NMR (100 MHz, CDCl3) l
13.62, 21.90, 31.71, 31.79, 42.10, 71.54, 125.75, 127.78,
128.47, 142.53. Anal. calcd for C12H18OS: C, 68.52; H,
8.63; S, 15.25. Found: C, 68.46; H, 8.67; S, 15.21%;
[h]2D2 +62.6 (c 1.33, CHCl3), S; HPLC analysis using a
Whelk-O1 chiral column [iso-PrOH/hexane: 1/9; flow
rate: 1.0 mL/min; detector: 254 nm] showed it to be
92% e.e. [tR(S) 4.45 min and tR(R) 5.15 min].
All operations with air-sensitive materials were carried
out under a nitrogen atmosphere with oven-dried glass-
ware. Liquid materials were transferred with a double-
ended needle. The reactions were monitored by TLC
using silica gel plates and the products were purified by
flash column chromatography on silica gel (Merck;
230–400 mesh). NMR spectra were recorded at 200 or
400 MHz for H and 50 or 100 MHz for 13C using
1
Me4Si as the internal standard in CDCl3. Optical rota-
tions were measured with a high resolution digital
polarimeter. Melting points are uncorrected. Enan-
tiomeric excesses (e.e.s) of the product b-hydroxy
sulfides were determined with a HPLC apparatus fitted
with a 25 cm Whelk-O1 (Regis), Chiralcel OD, or
Chiralcel OD-H (Daicel) chiral column.
4.3.2. (S)-(+)-2-(tert-Butylsulfanyl)-1-phenylethanol 4b.
Rf 0.44 (eluent A); oil; 91% yield; IR (neat, cm−1): 3413,
2929, 1455, 1364, 1162, 1056, 696; H NMR (400 MHz,
1
CDCl3) l 1.35 (s, 9H), 2.78 (dd, 1H, J=13.0, 9.5 Hz),
2.92 (br s, 1H), 2.97 (dd, 1H, J=13.0 and 3.7 Hz), 4.74
(dd, 1H, J=9.5, 3.6 Hz), 7.29 (m, 1H), 7.34–7.40 (m,
4H); 13C NMR (100 MHz, CDCl3) l 31.10, 38.72,
42.73, 72.44, 125.70, 127.80, 128.48, 142.81. Anal. calcd
for C12H18OS: C, 68.52; H, 8.63; S, 15.25. Found: C,
68.59; H, 8.74; S, 15.35%; [h]2D2 +53.8 (c 1.08, CHCl3),
S; HPLC analysis using a Whelk-O1 chiral column
[iso-PrOH/hexane: 1/9; flow rate: 1.0 mL/min; detector:
4.2. Materials
Most of the organic compounds utilized in this study
were commercial products of the highest purity. They
were further purified by distillation where necessary.

700
B. T. Cho et al. / Tetrahedron: Asymmetry 13 (2002) 697–703
254 nm] showed it to be 78% e.e. [tR(S) 4.38 min and
tR(R) 4.86 min].
Whelk-O1 chiral column [iso-PrOH/hexane: 1/9; flow
rate: 1.0 mL/min; detector: 254 nm] showed it to be
99% e.e. [tR(S) 8.47 min and tR(R) 14.29 min].
4.3.3. (S)-(−)-2-(Phenylsulfanyl)-1-phenylethanol 4c. Rf
0.56 (eluent B); oil; 98% yield; IR (neat, cm−1): 3415,
4.3.7.
(S)-(−)-2-(p-Tolylsulfanyl)-1-(m-chlorophenyl)-
1
3061, 1583, 1492, 1053, 738, 694; H NMR (200 MHz,
ethanol 4g. Rf 0.21 (eluent C); oil; 97% yield; IR (neat,
cm−1): 3424, 2922, 1598, 1492, 1094, 803; 1H NMR (400
MHz, CDCl3) l 2.34 (s, 3H), 2.97 (dd, 1H, J=14.0, 9.6
Hz), 2.98 (d, 1H, J=2.2 Hz), 3.25 (dd, 1H, J=13.9, 3.3
Hz), 4.62 (ddd, 1H, J=9.6, 3.3, 2.0 Hz), 7.14 (d, 2H,
J=7.8 Hz), 7.18–7.20 (m, 1H), 7.22–7.28 (m, 2H),
7.33–7.36 (m, 3H); 13C NMR (100 MHz, CDCl3) l
21.08, 44.96, 70.76, 124.00, 126.07, 127.99, 129.78,
130.04, 130.39, 131.38, 134.43, 137.48, 144.17. Anal.
calcd for C15H15ClOS: C, 64.62; H, 5.42; S, 11.50.
Found: C, 64.58; H, 5.63; S, 11.57%; [h]2D2 −30.3 (c 1.13,
CHCl3), S; HPLC analysis using a Whelk-O1 chiral
column [iso-PrOH/hexane: 1/9; flow rate: 1.0 mL/min;
detector: 254 nm] showed it to be >99% e.e. [tR(S) 5.22
min and tR(R) 5.63 min].
CDCl3) l 2.87 (d, 1H, J=2.4 Hz), 3.08 (dd, 1H,
J=13.9, 9.6 Hz), 3.34 (dd, 2H, J=13.9, 3.4 Hz), 4.72
(m, 1H), 7.26–7.46 (m, 9H); 13C NMR (50 MHz,
CDCl3) l 44.70, 72.26, 126.54, 127.52, 128.71, 129.27,
129.86, 130.93, 135.48, 142.79. Anal. calcd for
C14H14OS: C, 73.01; H, 6.13; S, 13.92. Found: C, 72.95;
H, 6.09; S, 13.87%; [h]2D2 −11.5 (c 1.0, CHCl3), S; {lit.16
[h]2D0 –12.5 (c 13.9, CHCl3), S, 100% e.e.}; HPLC analy-
sis using a Whelk-O1 chiral column [iso-PrOH/hexane:
1/9; flow rate: 1.0 mL/min; detector: 254 nm] showed it
to be 97% e.e. [tR(S) 5.29 min and tR(R) 6.49 min].
4.3.4. (S)-(−)-2-(p-Tolylsulfanyl)-1-phenylethanol 4d. Rf
0.55 (eluent B); oil; 98% yield; IR (neat, cm−1): 3420,
1510, 1452, 1054, 803, 697; 1H NMR (400 MHz,
CDCl3) l 2.33 (s, 3H), 2.61 (d, 1H, J=2.4 Hz), 3.03
(dd, 1H, J=13.9, 9.6 Hz), 3.27 (dd, 2H, J=13.9, 3.1
Hz), 4.67 (ddd, 1H, J=9.6, 3.1, 2.6 Hz), 7.12 (d, 2H,
J=8.0 Hz), 7.24–7.30 (m, 1H), 7.32–7.34 (m, 6H); 13C
NMR (100 MHz, CDCl3) l 21.02, 44.82, 71.47, 125.83,
125.84, 127.88, 128.49, 129.92, 130.93, 131.05, 137.10,
142.16. Anal. calcd for C15H16OS: C, 73.73; H, 6.60; S,
13.12. Found: C, 73.91; H, 6.69; S, 13.23%; [h]2D2 −17.13
(c 1.16, CHCl3), S; {lit.2 [h]D19 +20 (c 0.276, CHCl3), R};
HPLC analysis using a Whelk-O1 chiral column [iso-
PrOH/hexane: 1/9; flow rate: 1.0 mL/min; detector: 254
nm] showed it to be 99% e.e. [tR(S) 6.13 min and tR(R)
7.92 min].
4.3.8.
(S)-(−)-2-(p-Tolylsulfanyl)-1-(p-chlorophenyl)-
ethanol 4h. Rf 0.22 (eluent C); mp 50–51°C; 98% yield;
IR (neat, cm−1): 3416, 2922, 1597, 1492, 1089, 803; H
1
NMR (400 MHz, CDCl3) l 2.34 (s, 3H), 2.95 (d, 1H,
J=2.4 Hz), 2.97 (dd, 1H, J=14.0, 9.5 Hz), 3.23 (dd,
1H, J=14.0, 3.5 Hz), 4.63 (ddd, 1H, J=9.5, 3.5, 2.1
Hz), 7.13 (d, 2H, J=8.0 Hz), 7.25–7.29 (m, 4H), 7.30–
7.34 (m, 2H); 13C NMR (100 MHz, CDCl3) l 21.07,
44.94, 70.76, 127.24, 128.65, 130.02, 130.50, 131.31,
133.56, 137.42, 140.60. Anal. calcd for C15H15ClOS: C,
64.62; H, 5.42; S, 11.50. Found: C, 64.63; H, 5.72; S,
11.63%; [h]2D2 −45.1 (c 1.03, CHCl3), S; HPLC analysis
using a Whelk-O1 chiral column [iso-PrOH/hexane:
1/9; flow rate: 1.0 mL/min; detector: 254 nm] showed it
to be >99% e.e. [tR(S) 5.19 min and tR(R) 6.18 min].
4.3.5. (S)-(−)-2-(p-Tolylsulfanyl)-1-p-tolylethanol 4e. Rf
0.24 (eluent C); oil; 97% yield; IR (neat, cm−1): 3415,
1
2866, 1513, 1055, 804; H NMR (400 MHz, CDCl3) l
4.3.9.
(S)-(−)-2-(p-Tolylsulfanyl)-1-(p-fluorophenyl)-
2.34 (s, 6H), 2.83 (d, 1H, J=2.3 Hz), 3.03 (dd, 1H,
J=13.4, 9.5 Hz), 3.25 (dd, 1H, J=13.6, 3.5 Hz), 4.65
(ddd, 1H, J=9.5, 3.5, 1.8 Hz), 7.12–7.16 (m, 4H), 7.23
(d, 2H, J=8.1 Hz), 7.32–7.34 (m, 2H); 13C NMR (100
MHz, CDCl3) l 21.06, 21.15, 44.75, 71.34, 125.80,
129.21, 129.93, 131.01, 137.07, 137.66, 139.20. Anal.
calcd for C16H18OS: C, 74.38; H, 7.02; S, 12.41. Found:
C, 74.27; H, 7.17; S, 12.52%; [h]2D2 −30.6 (c 1.2, CHCl3),
S; HPLC analysis using a Whelk-O1 chiral column
[iso-PrOH/hexane: 1/9; flow rate: 1.0 mL/min; detector:
254 nm] showed it to be 99% e.e. [tR(S) 5.61 min and
tR(R) 7.26 min].
ethanol 4i. Rf 0.18 (eluent C); 32–34°C; 98% yield; IR
(neat, cm−1): 3413, 2974, 1605, 1511, 1224, 1059, 837,
1
805; H NMR (400 MHz, CDCl3) l 2.34 (s, 3H), 2.93
(d, 1H, J=2.2 Hz), 2.99 (dd, 1H, J=13.7, 9.5 Hz), 3.23
(dd, 1H, J=13.7, 3.5 Hz), 4.65 (ddd, 1H, J=9.5, 3.5,
2.0 Hz), 6.99–7.04 (m, 2H), 7.13 (d, 2H, J=8.1 Hz),
7.28–7.35 (m, 4H); 13C NMR (100 MHz, CDCl3) l
21.07, 44.99, 70.82, 115.26, 115.48, 127.51, 127.56,
130.00, 130.62, 131.25, 137.35, 137.86, 137.88, 161.15,
163.60. Anal. calcd for C15H15FOS: C, 68.67; H, 5.76;
S, 12.22. Found: C, 68.64; H, 5.59; S, 12.09%; [h]D22
−13.1 (c 1.15, CHCl3), S; HPLC analysis using a
Whelk-O1 chiral column [iso-PrOH/hexane: 1/9; flow
rate: 1.0 mL/min; detector: 254 nm] showed it to be
>99% e.e. [tR(S) 5.06 min and tR(R) 5.86 min].
4.3.6. (S)-(−)-2-(p-Tolylsulfanyl)-1-(p-methoxyphenyl)-
ethanol 4f. Rf 0.49 (eluent B); oil; 98% yield; IR (neat,
cm−1): 3422, 1612, 1513, 1248; 1H NMR (200 MHz,
CDCl3) l 2.34 (s, 3H), 2.85 (d, 1H, J=2.1 Hz), 3.03
(dd, 1H, J=13.7, 9.5 Hz), 3.24 (dd, 1H, J=13.7, 3.7
Hz), 3.80 (s, 3H), 4.63 (m, 1H), 6.87 (d, 2H, J=8.5 Hz),
7.13 (d, 2H, J=7.9 Hz), 7.24–7.28 (m, 2H), 7.34 (d, 2H,
J=7.9 Hz); 13C NMR (50 MHz, CDCl3) l 21.71, 45.35,
55.95, 71.77, 114.59, 127.83, 130.63, 131.71, 134.98,
137.77, 160.02. Anal. calcd for C16H18O2S: C, 70.04; H,
6.61; S, 11.69. Found: C, 70.17; H, 6.69; S, 11.73%;
[h]2D2 −40.1 (c 1.0, CHCl3), S; HPLC analysis using a
4.3.10.
(S)-(−)-2-(p-Tolylsulfanyl)-1-(p-nitrophenyl)-
ethanol 4j. Rf 0.09 (eluent C); 56–58°C; 97% yield; IR
(neat, cm−1): 3498, 1599, 1515, 1342; 1H NMR (400
MHz, CDCl3) l 2.35 (s, 3H), 2.96 (dd, 1H, J=14.0, 9.5
Hz), 3.15 (d, 1H, J=2.1 Hz), 3.27 (dd, 1H, J=14.0, 3.5
Hz), 4.74 (ddd, 1H, J=9.5, 3.5, 2.0 Hz), 7.15 (d, 2H,
J=8.0 Hz), 7.33–7.37 (m, 2H), 7.49–7.52 (m, 2H),
8.16–8.20 (m, 2H); 13C NMR (100 MHz, CDCl3) l
21.10, 45.10, 70.45, 123.73, 126.68, 129.88, 130.15,

B. T. Cho et al. / Tetrahedron: Asymmetry 13 (2002) 697–703
701
131.67, 137.89, 147.46, 149.35; Calcd. for C15H15NO3S:
C, 62.26; H, 5.23; N, 4.84; S, 11.08. Found: C, 62.25;
H, 5.37; N, 4.79; S, 10.90%; [h]2D2 −80.9 (c 1.12, CHCl3),
S; HPLC analysis using a Whelk-O1 chiral column
[iso-PrOH/hexane: 1/9; flow rate: 1.0 mL/min; detector:
254 nm showed it to be >99% e.e. [tR(S) 7.73 min and
tR(R) 8.36 min].
21.03, 28.91, 42.61, 70.47, 129.86, 130.90, 131.38,
136.91. Anal calcd for C10H14OS: C, 65.89; H, 7.74; S,
17.59. Found: C, 65.92; H, 7.80; S, 17.52%; [h]2D2 +44.0
(c 1.51, CHCl3), S; HPLC analysis using a Chiralcel
OD-H column [iso-PrOH/hexane: 1/99; flow rate: 0.3
mL/min; detector: 254 nm] showed it to be 74% e.e.
[tR(S) 54.14 min and tR(R) 57.82 min].
4.3.11. (S)-(−)-2-(p-Tolylsulfanyl)-1-(2%-naphthyl)ethanol
4k. Rf 0.15 (eluent C); 63–64°C; 98% yield; IR (neat,
cm−1): 3235, 1511, 1000, 825; 1H NMR (400 MHz,
CDCl3) l 2.33 (s, 3H), 3.03 (d, 1H, J=2.0 Hz), 3.10
(dd, 1H, J=13.9, 9.5 Hz), 3.34 (dd, 1H, J=13.9, 3.5
Hz), 4.83 (ddd, 1H, J=9.5, 3.5, 1.5 Hz), 7.12 (d, 2H,
J=7.9 Hz), 7.35 (d, 2H, J=8.1 Hz), 7.41–7.48 (m, 3H),
7.78–7.81 (m, 4H); 13C NMR (100 MHz, CDCl3) l
21.06, 40.79, 71.56, 123.77, 124.76, 125.96, 126.19,
127.68, 127.95, 128.32, 129.96, 130.81, 131.19, 133.09,
132.24, 137.21, 139.50. Anal. calcd for C19H18NOS: C,
77.51; H, 6.16; S, 10.89. Found: C, 77.46; H, 6.46; S,
10.86%; [h]2D2 −69.3 (c 1.37, CHCl3), S; HPLC analysis
using a Whelk-O1 chiral column [iso-PrOH/hexane:
1/9; flow rate: 1.0 mL/min; detector: 254 nm] showed it
to be 99% e.e. [tR(R) 7.67 min and tR(S) 10.63 min].
4.3.15. (S)-(+)-1-(p-Tolylsulfanyl)-2-heptanol 4o. Rf 0.4
(eluent A); oil; 98% yield; IR (neat, cm−1): 3404, 2911,
1
1490, 799; H NMR (200 MHz, CDCl3) l 0.87 (t, 3H,
J=6.4 Hz), 1.27–1.49 (m, 8H), 2.32 (s, 3H), 2.45 (d,
1H, J=3.1 Hz), 2.78 (dd, 1H, J=9.0, 13.6 Hz), 3.11
(dd, 1H, J=3.2, 13.6 Hz), 3.63 (m, 1H), 7.11 (d, 2H,
J=7.9 Hz), 7.31 (d, 2H, J=8.2 Hz); 13C NMR (50
MHz, CDCl3) l 14.67, 21.73, 23.22, 26.02, 32.46, 36.68,
43.68, 69.88, 130.57, 131.61, 132.05, 137.61. Anal calcd
for C14H22OS: C, 70.54; H, 9.30; S, 13.45. Found: C,
70.46; H, 9.36; S, 13.51%; [h]2D2 +34.8 (c 1.02, CHCl3),
S; HPLC analysis using a Whelk-O1 chiral column
[iso-PrOH/hexane: 1/9; flow rate: 0.3 mL/min; detector:
254 nm] showed it to be 74% e.e. [tR(S) 26.83 min and
tR(R) 28.72 min].
4.3.16.
(S)-(+)-1-(p-Tolylsulfanyl)-3-methyl-2-butanol
4.3.12. (S)-(−)-2-(p-Tolylsulfanyl)-1-(2%-furyl)ethanol 4l.
Rf 0.47 (eluent B); oil; 99% yield; IR (neat, cm−1): 3406,
4p. Rf 0.42 (eluent A); oil; 97% yield; IR (neat, cm−1):
1
3444, 2964, 1512, 803; H NMR (400 MHz, CDCl3) l
1
3026, 1493, 805,738; H NMR (200 MHz, CDCl3) l
0.92 (t, 3H, J=6.7 Hz), 0.95 (d, 1H, J=6.7 Hz), 1.76
(m, 1H), 2.32 (s, 3H), 2.46 (d, 1H, J=3.0 Hz), 2.78 (dd,
1H, J=9.6, 13.6 Hz), 3.15 (dd, 1H, J=2.9, 13.6 Hz),
3.38 (m, 1H), 7.11 (d, 2H, J=8.1 Hz), 7.30 (d, 2H,
J=8.1 Hz); 13C NMR (100 MHz, CDCl3) l 17.67,
18.65, 21.04, 32.80, 40.62, 73.64, 129.86, 130.87, 131.31,
136.89. Anal calcd for C12H18OS: C, 68.52; H, 8.22; S,
16.33. Found: C, 68.43; H, 8.23; S, 16.52%; [h]2D2 +80.0
(c 1.35, CHCl3), S; To determine its optical purity, 4p
was oxidized to the corresponding sulfone by m-
chloroperbenzoic acid. HPLC analysis of the sulfone
compound using a Chiralcel OD column [iso-PrOH/
hexane: 1/9; flow rate: 0.6 mL/min; detector: 254 nm]
showed it to be 88% e.e. [tR(R) 20.40 min and tR(S)
24.53 min].
2.33 (s, 3H), 2.79 (d, 1H, J=4.0 Hz), 3.23 (dd, 1H,
J=13.8, 8.5 Hz), 3.37 (dd, 1H, J=13.8, 4.5 Hz), 4.73
(m, 1H), 6.28–6.34 (m, 2H), 7.12 (d, 2H, J=8.2 Hz),
7.26–7.37 (m, 3H); 13C NMR (50 MHz, CDCl3) l
21.69, 41.80, 66.23, 107.67, 110.95, 130.63, 131.32,
131.93, 137.94, 142.99, 154.96. Anal calcd for
C13H14O2S: C, 66.64; H, 6.02; S, 13.68. Found: C,
66.56; H, 6.06; S, 13.56%; [h]2D2 −30.4 (c 2.27, CHCl3),
S; HPLC analysis using a Whelk-O1 chiral column
[iso-PrOH/hexane: 1/9; flow rate: 1.0 mL/min; detector:
254 nm] showed it to be 97% e.e. [tR(S) 5.55 min and
tR(R) 6.13 min].
4.3.13. (S)-(+)-1-(Benzenesulfanyl)-2-butanol 4m. Rf 0.38
(eluent A); oil; 96% yield; IR (neat, cm−1): 3406, 3042,
1
1581, 735; H NMR (200 MHz, CDCl3) l 0.97 (t, 3H,
4.3.17. (S)-(+)-1-(p-Tolylsulfanyl)-4-methyl-2-pentanol
4q. Rf 0.42 (eluent A); oil; 97% yield; IR (neat, cm−1):
J=7.6 Hz), 1.57 (m, 2H), 2.43 (d, 1H, J=3.4 Hz), 2.84
(dd, 1H, J=8.9, 13.4 Hz), 3.17 (dd, 1H, J=3.4, 13.4
Hz), 3.60 (m, 1H), 7.17–7.42 (m, 5H); 13C NMR (50
MHz, CDCl3) l 10.59, 29.62, 42.49, 71.27, 127.28,
129.76, 130.73, 136.01. Anal calcd for C10H14OS: C,
65.89; H, 7.74; S, 17.59. Found: C, 65.92; H, 7.80; S,
17.52%; [h]2D2 +45.78 (c 1.60, CHCl3), S; {lit.17 [h]D
+64.3 (c 1.0, CHCl3), S, >98% e.e.}; HPLC analysis
using a Chiralcel OD-H column [iso-PrOH/hexane:
1/99; flow rate: 1.0 mL/min; detector: 254 nm] showed
it to be 73% e.e. [tR(R) 28.20 min and tR(S) 33.31 min].
1
3423, 2911, 1508, 800; H NMR (200 MHz, CDCl3) l
0.87 (d, 3H, J=4.8 Hz), 0.90 (d, 3H, J=4.9 Hz), 1.27
(m, 1H), 1.48 (m, 1H), 1.79 (m, 1H), 2.32 (s, 3H), 2.42
(d, 1H, J=3.4 Hz), 2.77 (dd, 1H, J=8.9, 13.7 Hz), 3.09
(dd, 1H, J=3.4, 13.7 Hz), 3.71 (m, 1H), 7.11 (d, 2H,
J=7.9 Hz), 7.31 (d, 2H, J=8.2 Hz); 13C NMR (50
MHz, CDCl3) l 21.67, 22.74, 23.97, 25.48, 44.10, 45.82,
68.03, 130.56, 131.50, 132.11, 137.57. Anal calcd for
C13H20OS: C, 69.59; H, 8.98; S, 14.29. Found: C, 69.65;
H, 9.03; S, 14.34%; [h]2D2 +34.10 (c1.17, CHCl3), S;
HPLC analysis using a Chiralcel OD-H column [iso-
PrOH/hexane: 1/99; flow rate: 0.6 mL/min; detector:
254 nm] showed it to be 81% e.e. [tR(S) 21.28 min and
tR(R) 22.58 min].
4.3.14. (S)-(+)-1-(p-Tolylsulfanyl)-2-butanol 4n. Rf 0.23
(eluent C); oil; 96% yield; IR (neat, cm−1): 3416, 2968,
1
1511, 803; H NMR (400 MHz, CDCl3) l 0.97 (t, 3H,
J=7.5 Hz), 1.54 (m, 2H), 2.32 (s, 3H), 2.48 (br s, 1H),
2.79 (dd, 1H, J=8.9, 13.7 Hz), 3.10 (dd, 1H, J=3.4,
13.6 Hz), 3.56 (m, 1H), 7.11 (d, 2H, J=7.9 Hz), 7.30 (d,
2H, J=8.1 Hz); 13C NMR (100 MHz, CDCl3) l 10.00,
4.3.18.
(S)-(+)-1-(p-Tolylsulfanyl)-3,3-dimethyl-2-
butanol 4r. Rf 0.49 (eluent A); oil; 98% yield; IR (neat,
cm−1): 3488, 2869, 1512, 1364, 1008, 823; 1H NMR (400

702
B. T. Cho et al. / Tetrahedron: Asymmetry 13 (2002) 697–703
MHz, CDCl3) l 0.92 (s, 9H), 2.32 (s, 3H), 2.58 (d, 1H,
J=2.4 Hz), 2.69 (dd, 1H, J=11.0, 13.8 Hz), 3.22 (m,
1H), 3.25 (m, 1H), 7.11 (d, 2H, J=8.1 Hz), 7.28–7.30
(m, 2H); 13C NMR (100 MHz, CDCl3) l 21.04, 25.76,
34.58, 38.85, 76.08, 129.86, 130.81, 131.14, 136.88. Anal
calcd for C13H20OS: C, 69.59; H, 8.98; S, 14.29. Found:
C, 69.22; H, 9.23; S, 14.52%; [h]2D2 +117.8 (c 1.34,
CHCl3), S; HPLC analysis using a Chiralcel OD-H
column [iso-PrOH/hexane: 1/99; flow rate: 0.75 mL/
min; detector: 254 nm] showed it to be 99% e.e. [tR(R)
9.89 min and tR(S) 11.40 min].
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4.3.19. (S)-(+)-2-(p-Tolylsulfanyl)-1-cyclohexylethanol
4s. Rf 0.44 (eluent A); oil; 97% yield; IR (neat, cm−1):
1
3438, 2928, 1492, 1448, 1091, 1035, 803; H NMR (200
MHz, CDCl3) l 0.94–1.87 (m, 11H), 2.32 (s, 3H), 2.48
(d, 1H, J=3.1 Hz), 2.80 (dd, 1H, J=9.4, 13.7 Hz), 3.18
(dd, 1H, J=2.8, 13.4 Hz), 3.37 (m, 1H), 7.11 (d, 2H,
J=7.9 Hz), 7.30 (d, 2H, J=7.9 Hz); 13C NMR (100
MHz, CDCl3) l 21.69, 26.70, 26.81, 27.06, 28.85, 29.67,
41.34, 43.37, 73.69, 130.55, 131.46, 132.04, 137.58.
Anal. calcd for C15H22OS: C, 71.95; H, 8.86; S, 12.81.
Found: C, 72.02; H, 8.91; S, 12.72%; [h]2D2 +54.9 (c 1.05,
CHCl3), S; HPLC analysis using a Whelk-O1 column
[iso-PrOH/hexane: 1/99; flow rate: 0.6 mL/min; detec-
tor: 254 nm] showed it to be 99% e.e. [tR(S) 12.87 min
and tR(R) 14.26 min].
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Acknowledgements
9. For reviews, see: (a) Servi, S. Synthesis 1990, 1–25; (b)
Csuk, R.; Gla¨nzer, B. I. Chem. Rev. 1991, 91, 49–97; (c)
Santaniello, E.; Ferraboshi, P.; Grisenti, P.; Manzocchi,
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We are grateful to Korea Research Foundation (KRF-
2001-041-D00153) for financial support.
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