Methods for the synthesis of chiral sulfur heterocycles and their application in the asymmetric Baylis-Hillman reactions

Article abstract of DOI:10.1016/j.tetasy.2013.03.021

Enantiomerically pure (2S,6S)-2,6-diphenyltetrahydro-2H-thiopyran, (2S)-2-phenyltetrahydro thiophene, and (2S)-2-phenyltetrahydro-2H-thiopyran were prepared in 70-72% yields and with 86-99% ee via cyclization of the corresponding dimesylate in an S_N2 cyclization reaction using sodium sulfide nonahydrate. The results on the application of various chiral sulfides in asymmetric Baylis-Hillman reactions are also described.

Full text of DOI:10.1016/j.tetasy.2013.03.021

Tetrahedron: Asymmetry 24 (2013) 568–574
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Methods for the synthesis of chiral sulfur heterocycles and their application
in the asymmetric Baylis–Hillman reactions
⇑
Mariappan Periasamy , Ramani Gurubrahamam, Gopal P. Muthukumaragopal
School of Chemistry, University of Hyderabad, Central University PO, Hyderabad 500046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 February 2013
Accepted 28 March 2013
Enantiomerically pure (2S,6S)-2,6-diphenyltetrahydro-2H-thiopyran, (2S)-2-phenyltetrahydro thio-
phene, and (2S)-2-phenyltetrahydro-2H-thiopyran were prepared in 70–72% yields and with 86–99%
ee via cyclization of the corresponding dimesylate in an SN2 cyclization reaction using sodium sulfide
nonahydrate. The results on the application of various chiral sulfides in asymmetric Baylis–Hillman reac-
tions are also described.
Dedicated to Professor D. Basavaiah for his
contribution to the development of the
Baylis–Hillman reaction
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
1d in good yield (90%) with 97% ee (enriched to 99% by crystalliza-
tion). The dimesylate of chiral diol 1d was prepared using MsCl/
9
Chiral molecules containing sulfide moieties are useful for var-
ious asymmetric transformations such as asymmetric epoxida-
NEt3 which upon cyclization using Na2Sꢀ9H2O in DMSO afforded
the C2-symmetric chiral sulfide 1 with 72% yield and 99% ee.
The absolute stereochemistry of chiral sulfide 1 was confirmed
to be (2S,6S) by single crystal X-ray structural analysis of its sul-
fone 1e obtained after m-CPBA oxidation (Scheme 1). The ORTEP
diagram of sulfone 1e is shown in Figure 2.
tions,1
aziridination
of
imines,2
catalytic
asymmetric
cyclopropanation of electron deficient alkenes,3 and the synthesis
of chiral alcohols and amines from organoboranes.4 They are also
useful in enantioselective cascade reactions5 and asymmetric Bay-
lis–Hillman reactions.6 Chiral sulfides are useful in the synthesis of
biologically active motifs such as iso-agatharesinol, swainsonine,
the side chain of taxol, and the anti-inflammatory agents neobeno-
dine, CDP-840, and cetirizine.4a,7 Herein we report methods for the
synthesis of C2-symmetric (2S,6S)-2,6-diphenyltetrahydro-2H-thi-
opyran 1 and C1-symmetric derivatives (2S)-phenyltetra hydrothi-
Recently, the C1-symmetric chiral (2S)-phenyltetrahydrothi-
ophene 2 has been prepared via the CBS reduction of a ketophosp-
horothioate ester and further treatment with NaH in DMF. The
procedure involves several steps and expensive reagents. This
method also suffers from racemization when the phenyl group
contains electron withdrawing groups.10 Herein we have devel-
oped a method for the synthesis of this chiral sulfide 2 from readily
available chemicals as outlined in Scheme 2 starting from succinic
anhydride 2a. The CBS reduction of methyl 4-benzoylpropionate 2c
gave the chiral (1R)-phenylbutan-1,4-diol 2e in 42% yield with 99%
ee along with (4R)-hydroxy-4-phenyl methyl butyrate 2d in 39%
yield. Fortunately, the hydroxy ester 2d could be readily converted
into chiral diol 2e in 94% yield using THFꢀBH3.11 The chiral diol 2e
obtained in this way was mesylated using MsCl/NEt3 and the crude
dimesylate was further cyclized using Na2Sꢀ9H2O in DMSO to
obtain (2S)-phenyl tetrahydrothiophene 2 in 70% yield with 93%
ee (Scheme 2).
The absolute stereochemistry of compound 2 was confirmed by
single crystal X-ray structural analysis of sulfone 2f obtained after
m-CPBA oxidation. The ORTEP diagram of sulfone 2f is given in
Figure 3.
(2S)-Phenyltetrahydro-2H-thiopyran 3 was also obtained by
following a similar protocol starting from glutaric anhydride
(Scheme 3). Methyl 5-oxo-5-phenylpentanoate 3c was reduced
using in situ prepared B-methoxy oxazaborolidine (10 mol %) and
ophene 2, (2S)-phenyltetrahydro-2H-thiopyran
3 (Fig. 1) and
detailed studies on the application of chiral sulfides in asymmetric
Baylis–Hillman reactions.
2. Result and discussion
2.1. Synthesis of chiral sulfur heterocycles
Previously, we have reported on the synthesis of chiral C2-sym-
metric diphenyltetrahydro thiophenes (2S,5S)-2,5-diphenyltetra-
hydrothiophene 4 and (3R,4R)-3,4-diphenyltetrahydrothio phene
5 (Fig. 1).8 Chiral sulfide 1 was synthesized following a similar syn-
thetic protocol as shown in Scheme 1 from glutaric anhydride 1a.
1,5-Diphenylpentan-1,5-dione 1c obtained upon asymmetric
reduction using B-methoxy oxazaborolidine (CBS catalyst, 10
mol %) and THFꢀBH3 afforded (1R,5R)-1,5-diphenylpentane-1,5-diol
⇑
Corresponding author. Tel.: +91 40 23134814.
E-mail address: mpsc@uohyd.ernet.in (M. Periasamy).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.03.021

M. Periasamy et al. / Tetrahedron: Asymmetry 24 (2013) 568–574
569
Ph
Ph
Ph
Ph
Ph
S
Ph
S
Ph
S
Ph
S
S
1
2
3
4
5
Figure 1.
O
O
O
O
O
PCl5
O
AlCl3
Cl
Cl
Ph
Ph
24 h, reflux
82%
benzene
94%
O
1b
1c
1a
(S)-DPP/B(OMe)3
THF·BH2
OH
(10 mol%)
i) MsCl / NEt3,
CH2Cl2
OH
Ph
m-CPBA
Ph
S
Ph
Ph
S
Ph
CH2Cl2
ii) Na2S·9H2O,
DMSO, 36 h
Ph
O
O
90%,
72% , >99% ee
96% de, 97% ee
98%
1
1e
1d
Scheme 1. (2S,6S)-2,6-Diphenyltetrahydro-2H-thiopyran 1.
Figure 2. ORTEP representation of the crystal structure of compound 1e (thermal
Figure 3. ORTEP representation of the crystal structure of compound 2f (thermal
ellipsoids are drawn at 35% probability).
ellipsoids are drawn at 35% probability).
O
O
AlCl3
Ph
MeOH
OMe
OH
Ph
O
O
H2SO4
88%
benzene
83%
O
O
O
2a
2b
2c
(S)-DPP, B(OMe)3
BH3·THF
OH
(10 mol%)
OH
i) MsCl / NEt3,
CH2Cl2
m-CPBA
OMe
OH
Ph
Ph
Ph
+
Ph
S
CH2Cl2
S
ii) Na2S·9H2O,
DMSO, 36 h
O
O
O
39%
42% , >99% ee
2e
70%, 93% ee
95%
2d
2
2f
BH3·THF
94%
Scheme 2. Synthesis of (2S)-phenyltetrahydrothiophene 2.

570
M. Periasamy et al. / Tetrahedron: Asymmetry 24 (2013) 568–574
O
O
O
O
MeOH
AlCl3
benzene
83%
Ph
OMe
Ph
OH
Ph
O
O
O
H2SO4
97%
3c
3b
3a
(S)-DPP, B(OMe)3
BH3·THF
OH
(10 mol%)
O
OH
i) MsCl/NEt3, CH2Cl2
+
Ph
OMe
OH
ii) Na2S·9H2O,
DMSO, 36 h
S
Ph
40%, 94% ee
45%
72%, 86% ee
3d
3e
3
BH3·THF
92%
Scheme 3. Synthesis of (2S)-phenyltetrahydro-2H-thiopyran 3.
THFꢀBH3 to obtain the hydroxyester12 3d (45% yield) and (1R)-phe-
nylpentan-1,5-diol 3e in 94% ee (40% yield) after which 3d was
converted into chiral diol 3e in 92% yield and 94% ee using
THFꢀBH3. The chiral diol 3e was mesylated using MsCl/NEt3 and
the crude dimesylate was cyclized using Na2Sꢀ9H2O in DMSO to
obtain (2S)-phenyltetrahydro-2H-thiopyran 3 in 72% yield and
with 86% ee.
man et al.6b reported that a chiral sulfide derivative prepared from
mannitol gave asymmetric induction with up to 53% ee. The results
obtained using chiral sulfides 1–5 in the Baylis–Hillman reaction
are given in this section.
We observed that the asymmetric Baylis–Hillman reaction of
methyl vinyl ketone (MVK) and p-nitrobenzaldehyde with chiral
sulfide 4 readily takes place in the presence of Et2O:BF3 in CH2Cl2
at 0 °C. In this case, the (S)-isomer of the product was obtained
with only 13% ee (Table 1, entry 4). The results obtained in various
solvents at different temperatures are summarized in Table 1. The
adduct was obtained in 38% ee when the reaction temperature was
lowered to ꢁ78 °C (Table 1, entry 5). When the reaction was car-
ried out using CH3CN as the solvent at 0 °C for 45 min, the (R)-iso-
mer was obtained with 44% ee and 66% yield (Table 1, entry 6).
When the reaction time was reduced to 30 min, the enantio-
meric purity was enhanced to 52% ee with a slightly lower yield
(62%) (Table 1, entry 7). A slightly higher asymmetric induction
was observed in CH3CN (54% ee) in 58% yield at ꢁ30 °C under
2.2. Asymmetric Baylis–Hillman reaction catalyzed by chiral
sulfur heterocycles
The Baylis–Hillman reaction of an activated alkene and an alde-
hyde has received much attention from researchers in recent
years.13 Different chalcogenides have been reported to promote
the Baylis–Hillman reaction in the presence of Lewis acids, such
as TiCl4 and Et2OꢀBF3.6,14 Previously, Kataoka et al.6areported on
the use of 10-methylthioisoborneol in asymmetric Baylis–Hillman
reactions, which gave the adducts with up to 72% ee. Later, Good-
Table 1
Baylis–Hillman Reaction using chiral sulfides 1–5a
CHO
O
OH
O
Lewis acid, temp.
solvent, time
+
+
4-NO2-C4H4
Ph
Ph
S
NO2
4
6
7
8
Entry
Chiral sulfide
Acid
Solvent
Temperature (ꢀC)
Time (min)
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
1
2
3
4
4
4
4
4
4
4
4
4
5
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
TfOH
CH3CN
CH3CN
CH3CN
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH3CN
THF
Toluene
CH3CN
CH3CN
CH3CN
ꢁ30
ꢁ30
ꢁ30
0
30
30
30
30
30
45
30
30
30
60
30
30
30
70
68
65
54
50
66
62
58
0
0
0
0
13 (S)
38 (S)
44 (R)
52 (R)
54 (R)
0
13 (S)
0
0
ꢁ78
0
0
ꢁ30
ꢁ30
0
ꢁ30
ꢁ30
ꢁ30
9e
10
11e
12e
13
26
0
0
TMSOTf
BF3ꢀEt2O
62
0
a
b
c
All the reactions were carried out by using 1.2 mmol of chiral sulfide 1–5, 1.0 mmol of 4-nitro benzaldehyde, 3.0 mmol of MVK, 1.2 mmol of Lewis acid in 5 mL of solvent.
Isolated yield.
Determined by chiral HPLC analysis using a Chiralcel OD-H column.
The absolute configuration was determined by comparison with the literature data.15
No reaction.
d
e

M. Periasamy et al. / Tetrahedron: Asymmetry 24 (2013) 568–574
571
Et2OꢀBF3 promotion (Table 1, entry 8). Lowering the temperature
further led to freezing of the contents.
charged sulfur and the negatively charged boron are closer in
space. The transition state 9B is expected to be favored since it
would have less steric interactions between the phenyl group of
the chiral auxiliary and the phenyl group of the aldehyde com-
pared to the other transition state 9A, which would have more ste-
ric interactions between the phenyl group of the auxiliary and axial
phenyl group of the aldehyde (Scheme 4). This would lead to ad-
duct 10, which upon reaction with Et3N gave (R)-8 as the major
enantiomeric product.
Presumably, the C1-symmetric chiral sulfides 2 and 3 may not
be able to discriminate between the diastereomeric transition
states (Scheme 4) since these C1-symmetric moieties could adopt
conformations which could avoid steric interactions with groups
surrounding the reaction center.16 Also, the phenyl groups in the
C2-symmetric six-membered chiral sulfide 1 may not be able to
discriminate the diastereomeric transition states (Scheme 4) com-
The reaction was highly sensitive to the nature of the solvent
and additives. The reaction did not take place in THF while the
use of other additives such as TfOH and TMSOTf in CH3CN was
not effective (Table 1, entry 9, 11–12). The use of other chiral sul-
fides 1, 2, 3, and 5 gave only racemic products under these condi-
tions (Table 1, entries 1–3, 13).
We also examined other aromatic aldehydes in this reaction
using Et2OꢀBF3 at ꢁ30 °C in CH3CN (Table 2). In these cases, the
(R)-enantiomers 8 were obtained with 14–55% ee (Table 2). In all
cases, the chiral sulfide 4 was recovered in 85% yield without a loss
in enantiomeric purity and could be reused in these studies.
The Baylis–Hillman reaction proceeded via Michael attack of
sulfide 4 on the activated alkene 6 to give the Z-enolate.6b The reac-
tion likely goes through a transition state in which the positively
Table 2
Asymmetric Baylis–Hillman reaction of MVK with various aldehydes using chiral sulfide 4a
OH
O
O
BF3·Et2O, -30 °C
Ar
ArCHO
Ph
Ph
+
+
S
CH3CN, 30 min.
4
6
7
8
Entry
Ar
Product
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
9
4-NO2-C6H4
2-NO2-C6H4
3-NO2-C6H4
4-Cl-C6H4
4-Br-C6H4
4-CN-C6H4
4-CF3-C6H4
C6H5
8a
8b
8c
8d
8e
8f
8g
8h
8i
58
47
52
68
59
52
41
45
46
54
22
37
24
42
55
32
48
14
2-Furyl
a
All the reactions were carried out by using 1.2 mmol of chiral sulfide 4, 1.0 mmol of benzaldehyde, 3.0 mmol of MVK, 1.2 mmol of
BF3ꢀEt2O in 5 mL of CH3CN.
b
Isolated yield.
c
Determined by chiral HPLC analysis using a Chiralcel AS-H column.
d
The absolute configuration was determined to be (R) by comparison with the literature data.15
O
H
Ph
BF3
O
BF3
O
O
S
BF3·Et2O
Ph
+
Ph
+
Ph
O
Ph
Ph
PhCHO
H
H
S
H
S
2
H
H
H
H
Ph
9B
Ph
9A
6
4
disfavoured
favoured
O
H
O
H
4
O
H
O
Ph
OBF3
OBF3
Ph
Et3N
H
H
Ph
Ph
S
OH
S
OH
Ph
Ph
Ph
Et3NH
Ph
11
10
(R)-8
(R)-8
Scheme 4. Tentative mechanism for formation of favored (R)-8 isomer in CH3CN.

572
M. Periasamy et al. / Tetrahedron: Asymmetry 24 (2013) 568–574
pared to the phenyl groups in the essentially flat five-membered
chiral sulfide 4. In the C2-symmetric five-membered chiral sulfide
5, the phenyl groups are far away from the reaction center and
hence would not be able to differentiate between the diastereo-
meric transition states (Scheme 4).
and spots were developed in an I2 chamber. For column chromato-
graphic separations under gravity, column grade silica gel (100–
200 and 230–400 mesh) were employed. HPLC analyses were
performed on an SCL-10ATVP SHIMADZU instrument.
However, the mechanism suggested in Scheme 4 still does not
explain the formation of the (S)-8 enantiomer as the major product
in CH2Cl2 and toluene solvents (Table 1, entries 4, 5, and 10). Pre-
sumably, in the relatively more polar solvent CH3CN, the solvent
dipoles could occupy the space around the charges in transition
state 9A and 9B, but that may not be the case in the less polar
CH2Cl2 or toluene solvents. Hence, in less polar solvents the reac-
tion may go through a boat like transition state (Scheme 5), in
4.1. Synthesis of (2S,6S)-trans-2,6-diphenyltetrahydro-2H-
thiopyran 1
To the dimesylate prepared using (1R,5R)-1,5-diphenylpentane-
1,5-diol 1d (1.282 g, 5 mmol) in DMSO (15 mL), sodium sulfide
nonahydrate (freshly recrystallized from EtOH, 4.8 g, 20 mmol)
was added and was stirred at 25 °C for 36 h. Water (15 mL) was
added and the aqueous layer was extracted with diethyl ether
Ph
H
Ph
H
S
S
H
H
Ph
H
H
H
BF3
O
BF3
O
Ph
H
H
Ph
Ph
Ph
Me
Me
OH
OH
H
O
O
Ph
O
O
Me
Me
12A
disfavoured
(R)-8
(S)-8
12B
favoured
Scheme 5. Tentative mechanism for the formation of the favored (S)-8 isomer in CH2Cl2.
which the positive and negative charges on sulfur and boron could
come closer in space for stability. In such a conformation, the tran-
sition state 12B would be favored over transition state 12A, leading
to the opposite enantiomer (S)-8 as the major product. However,
further systematic studies are required to better understand the
solvent effect observed in this transformation.
(3 ꢂ 30 mL). The combined organic extracts were washed with
water (5 mL) and brine (5 mL), concentrated and purified by col-
umn chromatography on silica gel (230–400 mesh) using hexane
as eluent. Yield: 0.916 g (72%). ½a D25
¼ þ36:9 (c 1.04, CHCl3). IR
ꢃ
(neat): (cmꢁ1) 3059, 3026, 2932, 1597, 1493, 756. 1H NMR
(400 MHz, CDCl3): d 7.53 (d, J = 7.4 Hz, 4H), 7.34 (t, J = 7.3 Hz,
4H), 7.26–7.22 (m, 2H), 4.08–4.05 (m, 2H), 2.32–2.30 (m, 4H),
1.75–1.69 (m, 2H). 13C NMR (100 MHz, CDCl3): d 142.3, 128.5,
127.9, 126.9, 43.8, 33.0, 21.7. HPLC: >99% ee (Daicel Chiralcel OJ-
H, iPrOH:Hexane 15:85, flowrate 1.0 mL/min, 254 nm, tR
(S,S) = 17.8 min, tR (R,R) = 26.3 min). LC–MS (m/z): 255 (M+1). Anal.
Calcd for C17H18S: C, 80.26; H, 7.13. Found: C, 80.31; H, 7.08.
3. Conclusion
In conclusion, we have developed convenient methods to
synthesize the enantiomerically pure chiral sulfides (2S,6S)-2,6-
diphenyltetrahydro-2H-thiopyran 1, (2S)-phenyltetrahydrothioph-
ene 2, and (2S)-phenyltetrahydro-2H-thiopyran 3 from readily
accessible reagents. We have also studied their utility in asymmet-
ric Baylis–Hillman reactions. Asymmetric induction to the extent
of 55% ee was observed. The results obtained using chiral sulfide
4 and the mechanistic aspects outlined herein are expected to be
useful in devising new C2-symmetric chiral sulfides containing aryl
groups with a longer range of steric influence so as to achieve high-
er asymmetric induction in the Baylis–Hillman reaction.
4.1.1. Synthesis of (2S,6S)-2,6-diphenyltetrahydro-2H-thiopyran-
1,1-dioxide 1e
Sulfone 1e was prepared by reacting the chiral sulfide1 (0.5 mmol,
0.127 g), with m-CPBA (0.172 g, 1.0 mmol) in DCM (4 mL) at 25 °C for
6 h. The reaction was quenched with aqueous NaHCO3 and the aque-
ous layer wasextracted with DCM (2 ꢂ 10 mL). The combined organic
extracts were washed with water (2 mL) and brine (2 mL), dried over
anhydrous Na2SO4 and concentrated in vacuo. The crude product was
purified by column chromatography using hexane:ethyl acetate
4. Experimental
(80:20). Yield: 0.140 g (98%). mp 128–130 °C. ½a D25
¼ ꢁ41:4 (c 0.39,
ꢃ
CHCl3). IR (KBr): (cmꢁ1) 3063, 3034, 2943, 1493, 1452, 1296, 1118,
773, 698. 1H NMR (400 MHz, CDCl3): d 7.54–7.52 (m, 4H), 7.42–7.36
(m, 6H), 4.29–4.25 (m, 2H), 2.74–2.65 (m, 2H), 2.58–2.51 (m, 2H),
2.16–2.10 (m, 2H). 13C NMR (100 MHz, CDCl3): d 132.0, 129.7,
128.64, 128.61, 64.6, 29.7, 21.5. LC–MS (m/z): 287 (M+1). Anal. Calcd
for C17H18O2S: C, 71.30; H, 6.34; Found: C, 71.45; H, 6.28. Crystal data
THF freshly distilled over benzophenone–sodium was used.
CH2Cl2 was distilled over CaH2 and dried over molecular sieves
4 Å. The melting points reported in this literature are uncorrected
and were determined using a superfit capillary point apparatus. IR
spectra were recorded on a JASCO FT-IR spectrophotometer Model
5300. 1H NMR and 13C NMR spectra were recorded on a Bruker
Advance-400 MHz Spectrometer with chloroform-d as a solvent
and TMS as reference. Optical rotations were measured in an
AUTOPOL-IV digital polarimeter (readability 0.001°). Liquid chro-
matography (LC) and mass analysis (LC–MS) were performed on
SHIMADZU-LCMS-2010A. Elemental analyses were carried out
using a Perkin–Elmer elemental analyzer model-240C and a
Thermo Finnigan analyzer series Flash EA1112. For TLC analysis,
plates coated with silica gel were run in a hexane/EtOAc mixture
ref. 17
.
4.2. Synthesis of (2S)-phenyltetrahydrothiophene 2
This compound was prepared from the chiral diol (1R)-phenylb-
utan-1,4-diol 2e (0.831 g, 5 mmol, 99% ee) by following the same
procedure for compound 1. Yield: 0.575 g (70%). ½a D25
¼ þ28:2 (c
ꢃ
2.0, CH2Cl2) {Lit.10
½
a 2D5
ꢃ
¼ þ28:9 (c 1.6, CH2Cl2) for 97% ee}. IR

M. Periasamy et al. / Tetrahedron: Asymmetry 24 (2013) 568–574
573
(neat): (cmꢁ1) 3060, 3024, 2943, 1599, 1491, 1440, 758, 698. 1H
NMR (400 MHz, CDCl3): d 7.43 (d, J = 7.6 Hz, 2H), 7.33–7.21 (m,
3H), 4.52 (t, J = 8.3 Hz, 1H), 3.20–3.14 (m, 1H), 3.05–3.0 (m, 1H),
2.43–2.37 (m, 1H), 2.32–2.26 (m, 1H), 2.06–1.91 (m, 2H). 13C
NMR (100 MHz, CDCl3): d 143.0, 128.4, 127.7, 127.1, 52.8, 40.6,
33.6, 31.1. HPLC: 94% ee; (Daicel Chiralcel OJ-H, hexane:iPrOH
85:15, flow rate 1.0 mL/min, 254 nm): tR(7.0 min), tS(7.7 min).
LC–MS (m/z): 165 (M+1). Anal. Calcd for C10H12S: C, 73.12; H,
7.36. Found: C, 73.26; H, 7.41.
same procedure as that followed for compound 1. Yield: 0.641 g.
(72%). ½a 2D5
ꢃ
¼ ꢁ31:2 (c 0.84 CHCl3). IR (Neat): (cmꢁ1) 3028, 2926,
1599, 1489, 1435, 756, 696. 1H NMR (400 MHz, CDCl3): d 7.31–
7.22 (m, 5H), 4.01 (t, J = 7.3 Hz, 1H), 3.11–3.06 (m, 1H), 2.80–2.73
(m, 1H), 2.37–2.32 (m, 2H), 2.26–2.18 (m, 1H), 2.09–1.99 (m,
2H), 1.82–1.75 (m, 1H). 13C NMR (100 MHz, CDCl3): d 143.4,
128.6, 127.3, 126.9, 57.6, 40.0, 37.7, 30.7, 25.8. HPLC: 86% ee; (Dai-
cel Chiralcel OJ-H, hexane:iPrOH 85:15, flow rate 1.0 mL/min,
254 nm): tS (8.4 min), tR (9.6 min). LC–MS (m/z): 179 (M+1). Anal-
ysis for C11H14S calculated: C, 74.10; H, 7.91. Found: C, 74.25; H,
7.85.
4.2.1. Synthesis of (2S)-phenyltetrahydrothiophene-1,1-dioxide
2f
Sulfone 2f was prepared by using the same procedure that was
followed for the preparation of 1e using chiral sulfide 2. Yield:
4.5. General procedure for the asymmetric Baylis–Hillman
reaction
0.093 g (95%). mp 88–90 °C. ½a D25
¼ ꢁ24:7 (c 0.58, CHCl3). IR
ꢃ
(KBr): (cmꢁ1) 3032, 2947, 1697, 1494, 1444, 1300, 1242, 1122,
763, 723, 696. 1H NMR (400 MHz, CDCl3): d 7.42–7.40 (m, 5H),
4.20–4.15 (dd, J = 7.0, 12.0 Hz, 1H), 3.34–3.28 (m, 1H), 3.21–3.13
(m, 1H), 2.58–2.33 (m, 3H), 2.28–2.16 (m, 1H). 13C NMR
(100 MHz, CDCl3): d 130.3, 129.1, 128.9, 128.7, 66.6, 50.5, 28.6,
To a solution of aldehyde (1 mmol), methyl vinyl ketone
(0.25 mL, 3 mmol), and chiral sulfide (1.2 mmol) in CH3CN (5 mL)
at ꢁ30 °C was added BF3ꢀEt2O (0.18 mL, 1.5 mmol). After stirring
the reaction for 30 min at this temperature, Et3N (0.14 mL,
1 mmol) was added and the mixture was stirred for further
10 min while warming to room temperature. The solution was
washed with dilute HCl, saturated NaHCO3 and brine, dried over
Na2SO4, and concentrated in vacuo to give the crude product.
Product 8 was eluted using hexane:ethyl acetate (70:30) on a silica
gel column. The spectroscopic data of products 8a–8i were in
agreement with previously reported data.15
19.6. LC–MS (m/z): 197 (M+1). Anal. Calcd for C10H12O2S: C,
17
61.20; H, 6.16. Found: C, 61.09; H, 6.23. Crystal data ref.
.
4.3. Synthesis of (1R)-phenylpentan-1,5-diol 3e
To a stirred solution of (S)-a,a-diphenyl-2-pyrrolidinemethanol
[(S)-DPP, 0.507 g, 2 mmol] in THF (5 mL), trimethyl borate (0.24 mL,
2.2 mmol) was added and stirred for 1 h at 25 °C. To this, the
THFꢀBH3 complex (20 mmol, 10 mL, 2 M) was added at 0 °C. The
ketoester (4.125 g, 20 mmol) dissolved in THF (100 mL) was added
to this suspension at 0 °C over 1 h. The reaction mixture was then
stirred at 25 °C for 1 h. The reaction was carefully hydrolyzed with
2 M HCl (2 mL) and the organic layer was separated. The aqueous
layer was then extracted with ether. The combined organic extract
was washed with brine (5 mL) and dried over anhydrous Na2SO4.
The solvent was evaporated under reduced pressure and the crude
product was purified on a silica gel column. Hexane:ethyl acetate
mixture (85:15) eluted methyl (5R)-methyl-5-hydroxy-5-phenyl-
pentanoate 3d while hexane:ethyl acetate (50:50) eluted (1R)-phe-
nylpentan-1,5-diol (3e).
Acknowledgements
R.G. and G.P.M. are thankful to the CSIR (New Delhi) for
research fellowship. DST support through a J. C. Bose Fellowship
grant to Professor M.P. is gratefully acknowledged. The authors
also thank the DST for the 400 MHz NMR facility under FIST pro-
gram and for the National single crystal X-ray diffractometer
facility. Support of the UGC under the ‘University of Potential
for Excellence’ and the Center for Advanced Study and UGC-
MHRD Chemistry Resources Centre Programmes is gratefully
acknowledged.
References
4.3.1. (5R)-Methyl-5-hydroxy-5-phenylpentanoate 3d12
1. (a) Julienne, K.; Metzner, P. J. Org. Chem. 1998, 63, 4532–4534; (b) Aggarwal, V.
K.; Ford, J. G.; Fonquerna, S.; Adams, H.; Jones, R. V. H.; Fieldhouse, R. J. Am.
Chem. Soc. 1998, 120, 8328–8339; (c) Julienne, K.; Metzner, P.; Henryon, V. J.
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Angew. Chem., Int. Ed. 2001, 40, 1433–1436; (b) Aggarwal, V. K.; Ferrara, M.;
O’Brien, C. J.; Thompson, A.; Jones, R. V. H.; Fieldhouse, R. J. Chem. Soc., Perkin
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Aggarwal, V. K. J. Am. Chem. Soc. 2010, 132, 1828–1830.
Yield: 1.874 g (45%). ½a D25
¼ þ35:7 (c 1.2, CHCl3). IR (Neat):
ꢃ
(cmꢁ1) 3429, 3028, 2951, 1734, 1726, 1440, 763, 702. 1H NMR
(400 MHz, CDCl3): d 7.36–7.28 (m, 5H), 4.70–4.69 (m, 1H), 3.66
(s, 3H), 2.37–2.34 (m, 2H), 2.0 (br s, 1H), 1.84–1.62 (m, 4H). 13C
NMR (100 MHz, CDCl3): d 174.2, 144.7, 128.4, 127.4, 125.9, 73.8,
51.5, 38.3, 33.7, 21.2. The isolated (5R)-methyl-5-hydroxy-5-phe-
nylpentanoate 3d was converted into (1R)-phenylpentane-1,5-diol
3e by reduction with THFꢀBH3 in 92% yield.
3. Aggarwal, V. K.; Smith, H. W.; Hynd, G.; Jones, R. V. H.; Fieldhouse, R.; Spey, S. E.
J. Chem. Soc., Perkin Trans. 1 2000, 3267–3276.
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Aggarwal, V. K. J. Am. Chem. Soc. 2007, 129, 14632–14639.
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1072–1080.
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H.; Kanematsu, K.; Tsurukami, Y.; Iwamura, T.; Watanabe, S.-I.; Kataoka, T.
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1743.
4.3.2. (1R)-Phenylpentan-1,5-diol 3e
Yield: 1.442 g (40%). ½a D25
ꢃ
¼ þ44:0 (c 1.0, CHCl3) {Lit.18
½ ꢃ
a 2D5
¼ ꢁ25:4 (c 1.28, benzene) for 65% ee of the (S)-isomer}. IR (Neat):
(cmꢁ1) 3294, 3061, 3030, 1448, 1028, 700. 1H NMR (400 MHz,
CDCl3): d 7.35–7.27 (m, 5H), 4.68 (t, J = 5.7 Hz, 1H), 3.62 (t,
J = 6.4 Hz, 2H), 2.10 (br s, 1H), 2.04 (s, 1H), 1.87–1.69 (m, 2H),
1.63–1.33 (m, 4H). 13C NMR (100 MHz, CDCl3): d 144.8, 128.5,
127.6, 125.9, 74.5, 62.7, 38.7, 32.4, 22.0. HPLC: 94% ee, Chiral OB-
H Hexane (90):Isopropanol (10). Flowrate 1.0 mL/min tS(11.2 min),
tR(15.0 min).
4.4. Synthesis of (2S)-phenyltetrahydro-2H-thiopyran 3
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pentane-1,5-diol 3e (0.901 g, 5 mmol, 94% ee) by following the

574
M. Periasamy et al. / Tetrahedron: Asymmetry 24 (2013) 568–574
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17. Crystal data for the compound 1e: Molecular formula: C17H18O2S, Mw = 286.39,
orthorhombic, space group: P212121, a = 5.72052(12) Å, b = 13.8308(3) Å,
12. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925–7926; (b) Downham, R.; Edwards, P. J.; Entwistle, D. A.;
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11813–11824; (b) Iwama, T.; Kinoshita, H.; Kataoka, T. Tetrahedron Lett. 1999,
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3553–3556.
c = 18.0541(4) Å,
q
a
l
= 90°,
b = 90°,
c
= 90°,
v
= 1428.43(5) Å3,
Z = 4,
c = 1.332 g cmꢁ3
,
= 1.993 mmꢁ1
,
T = 298(2) K. Of the 4579 reflections
collected, 2711 reflections were unique (Rint = 0.0120). Refinement on all
data converged at R1 = 0.0315, wR2 = 0.0900. (CCDC deposition number:
914856). Crystal data for the compound 2f: Molecular formula: C10H12O2S,
Mw = 196.27, orthorhombic, space group: P212121, a = 5.8362(7) Å,
b = 10.8236(10) Å,
v
c = 15.4677(17) Å,
q
a
,
= 90°,
l
b = 90°,
c = 90°,
= 977.07(18) Å3, Z = 13,
c = 1.334 mg mmꢁ3
= 0.295 mmꢁ1, T = 298(2) K.
Of the 2544 reflections collected, 1682 reflections were unique (Rint = 0.0333).
Refinement on all data converged at R1 = 0.0447, wR2 = 0.0732. (CCDC
deposition number: 914857).
18. Kamal, A.; Sandbhor, M.; Shaik, A. A. Tetrahedron: Asymmetry 2003, 14, 1575–
1580.
15. (a) Oishi, T.; Oguri, H.; Hirama, M. Tetrahedron: Asymmetry 1995, 6, 1241–1244;
(b) Yuan, K.; Zhang, L.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Tetrahedron Lett. 2008, 49,
6262–6264.