A new chiral oxathiane: Synthesis, resolution and absolute configuration determination by vibrational circular dichroism

Article abstract of DOI:10.1016/S0957-4166(01)00441-4

A new oxathiane, derived from 5-hydroxy-1-tetralone has been synthesized in eight steps, fully characterized as cis-fused rings by 1D and 2D NMR and resolved by preparative chiral chomatography (CHIRALCEL OD-R). The second eluting (+, MeOH)-isomer was ass

Full text of DOI:10.1016/S0957-4166(01)00441-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2605–2611
A new chiral oxathiane: synthesis, resolution and absolute
configuration determination by vibrational circular dichroism
A. Solladie´-Cavallo,a,* M. Balaz,a,b M. Salisova,b C. Suteu,c,* L. A. Nafie,d,* X. Caod and
T. B. Freedmand,*
aLaboratoire de Ste´re´ochimie Organome´tallique associe´ au CNRS, ECPM, Universite´ de Strasbourg, 25 rue Becquerel,
67087 Strasbourg, France
bDepartment of Organic Chemistry, Comenius University, Bratislava, Slovakia
cChiral Technologies Europe, 67404 Illkirch, France
dDepartment of Chemistry, Syracuse University, Syracuse, NY 13244-4100, USA
Received 18 September 2001; accepted 10 October 2001
Abstract—A new oxathiane, derived from 5-hydroxy-1-tetralone has been synthesized in eight steps, fully characterized as
cis-fused rings by 1D and 2D NMR and resolved by preparative chiral chromatography (CHIRALCEL OD-R). The second
eluting (+, MeOH)-isomer was assigned (S,S)-configuration by VCD-ab initio simulation. © 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
However, a drawback of these asymmetric syntheses is
the necessary separation of the chiral auxiliary 3 from
the desired epoxide or cyclopropane by chromatogra-
phy,9 we designed chiral oxathianes which could either
be grafted onto a solid support (to allow easy separa-
tion by filtration) or derivatized with a polyfluoro
group (to allow separation by extraction with a
fluorous phase).10,11 Such oxathianes should also be
rigid enough to provide a single isomer of the corre-
sponding sulfonium salts,12 they should have a structure
similar to that of 3 (with a gem-dimethyl group a to the
sulfur atom) and both enantiomers should be available.
Since the first use, in 1978,1 of chiral 1,3-oxathianes 1
for the enantioselective synthesis of atrolactic acid
methyl ester, Eliel et al. developed 1,3-oxathianes 22
and 33 derived from natural products. In 1992 we
showed that oxathiane 3 could also be successfully used
as a chiral sulfide4,5 for asymmetric synthesis of
monoaryl-epoxides, trans-diaryl-epoxides and trans-
cyclopropanes and succeeded later to obtain in all cases
high conversions (ꢀ90–95%) and high e.e.s (95–
100%).6–8
R
We present herein oxathiane 4, which fulfils the above
conditions. The synthesis, chromatographic resolution
and assignment of absolute configuration, which has
been done by vibrational circular dichroism (VCD)13–16
(the difference in the infra red absorbance of a molecule
for left versus right circularly polarized radiation) will
be described.
S
R'
Me
S
O
O
O
S
Me
1 R = H, R' = Me
R = Me, R' = H
3
2
Grafting / derivatization
S
O
OH
O
gem-dimethyl
S
rigidity induced by the gem-dimethyl
O
S
4 cis
* Corresponding authors.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00441-4

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A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 2605–2611
2. Results and discussion
in refluxing benzene, in the presence of trace p-TsOH.
( )-cis-4 was thus isolated in 46% overall yield.
2.1. Synthesis
2.2. Determination of the cis-structure of oxathiane 4:
NMR
Oxathiane 4 has been obtained in eight steps from
commercially available 5-hydroxy-1-tetralone (Scheme
1).
From H–C correlation, the multiplets at 1.95 and 2.30
ppm (Table 1) were assigned to one of the CH2, those
at 2.52 and 2.96 to the other CH2, the double-triplet at
1.45 and the triplet at 4.69 to the two saturated CH.
The silyl enolate 6 was obtained from the benzyl-pro-
tected ketone in quantitative yield after modification of
the literature work-up.17a,b Compound 5 was obtained
through TiCl4-catalyzed condensation of acetone onto
6, followed by dehydration (using 90% AcOH18). Then
1,4-addition of BnSH, using DBU as base, provided 7
in 97% isolated yield. BH3/THF reduction of 7 afforded
8 as the single cis-diastereomer.19 After debenzylation
of 8 using NH3/Na and Et2O/MeOH (10/1) as solvent,
oxathiane cis-4 was formed by heating a mixture of the
debenzylated compound and dried paraformaldehyde
Examination of the COSY experiment then showed
that the double-triplet at 1.45 was correlated with the
two multiplets at 1.95 and 2.30, which were thus
assigned to the H(3) protons. As a consequence, the
double-triplet at 1.45, the multiplets at 2.52 and 2.96
and the triplet at 4.69 ppm were assigned to protons
H(2), H(4), H(4) and H(1), respectively.
OH
OBn
OBn
OBn
98%
a
90%
c
96%
b
O
O
OSiMe3
6
O
5
OH
d
97%
OBn
OBn
OH
56%
f
100%
e
SBn
O
SBn
S
O
OH
8 cis
7
4 cis
Scheme 1. (a) i. PhCH2Br/K2CO3/acetone, reflux, ii. NEt3/TMSCl/NaI/MeCN/pentane, reflux; (b) Me2CO/TiCl4/CH2Cl2, −20°C;
(c) AcOH 90%/ꢀ105°C; (d) BnSH/DBU/THF, rt; (e) BH3/THF, rt; (f) i. NH3/Na/MeOH/EtOH, −78°C, ii. (CH2O)n/benzene/p-
TsOH, reflux.
Table 1. 1H NMR parameters of oxathiane cis-4 (CDCl3/TMS, 400 MHz)

A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 2605–2611
2607
Full analysis of the multiplets, (Table 1), suggested that
the ring junction was cis with a vicinal coupling constant,
3J12 of 2 Hz and that the CꢀO bond was axial (within
ring A) while the CꢀC (gem-dimethyl) was equatorial
(within ring A) with a W-long range coupling constant
between H(1e) (equatorial in ring A) and H(3e) (equato-
rial) of 2 Hz and a 3J180 of 12.5 Hz between H(2a) (axial
in ring A) and H(3a) (axial).20
sists of measuring the VCD and IR spectra of one
enantiomer and, in parallel, carrying out an ab initio
calculation of the VCD and IR spectra of one absolute
configuration. Comparison of the calculated VCD spec-
trum of the compound with known absolute configura-
tion, to the measured VCD spectrum of the sample
molecule with the unknown absolute configuration yields
the desired assignment as follows. If the calculated
principal VCD bands have the same sign as the corre-
sponding experimental VCD bands, the absolute configu-
ration chosen for the calculations is the same as that for
the measured sample, and if opposite, the absolute
configuration chosen for the calculations is the opposite
of that for the sample.
This conclusion was then confirmed by a NOESY
experiment which exhibits a correlation spot between one
of the methyl groups of the gem-dimethyl system and
H(1) (axial in ring B), one of H(11) (axial in ring B) and
H(2), while there is no correlation between this methyl
group and any H(3) proton (which would be the case if
the ring junction were trans).21
The absolute configuration of 4 was thus determined by
comparing the measured VCD spectrum of a sample of
(+, MeOH)-4-2 (eluted second) having 100% e.e. and 99%
chemical purity with that of an ab initio quantum
calculation of the enantiomer (S,S)-4.
2.3. Resolution
Resolution of oxathiane 4 was performed by liquid
chromatography. After screening several polysaccha-
ride-derived chiral stationary phases using pure acetoni-
trile as the eluent at a flow rate of 1 mL/min at 25°C,
analytical separation was obtained on CHIRALCEL
OD-R (ƒ=4.6 mm). Only few applications in pure
acetonitrile with modest resolution have been reported in
the literature using this stationary phase. The semi-
preparative separation was transferred onto a CHIRAL-
CEL OD (ƒ=20 mm). Since the quantities to be
prepared were small, an analytical HPLC system was
used for this purpose. A global recovery of 81% was
obtained, the first eluting enantiomer (4-1) having 100%
e.e. and 96% chemical purity and the second eluting
enantiomer (4-2) having 100% e.e. and 99% chemical
purity (from a CHIRALCEL OD-R analysis). The
optical rotation of the first eluted enantiomer 4-1 is:
[h]2D0=−58 (c=2.2, MeOH).
Several conformers of the molecule in the (S,S)-configu-
ration were calculated, which differed in the conforma-
tion of the oxathiane ring, the sense of twist of the pair
of adjacent methylene groups and the CCOH dihedral
angle. Optimized geometries were calculated with Gaus-
sian 9826 at the B3LYP/6-31G* DFT level. Two having
the same chair conformation for the oxathiane ring were
more than 4 kcal/mol lower in energy than the others.
The optimized geometries and relative energies of these
two conformers, which differ in the OH orientation, are
shown in Fig. 1.27 We note that the conformation of the
rings calculated for these two lowest energy conformers
corresponds to that found by NMR.
Vibrational frequencies, IR and VCD intensities were
calculated with Gaussian 98 at the B3LYP/6-31G* DFT
level for both conformers C1 and C2 of the (S,S) isomer.
This method could be applied for larger scale preparation
by using a semi-preparative liquid chromatography
device instead of an analytical one.
The observed spectrum is then compared to the sum of
the calculated spectra of conformers C1 and C2 weighted
by their Boltzmann populations ([C1]*0.723+[C2]*0.276)
(Fig. 2).
2.4. Determination of absolute configuration: VCD
Within the past few years, VCD has been shown to be
a reliable new method for the determination of absolute
configuration in chiral molecules.22–25 The method con-
The agreement between the observed and calculated
VCD and IR spectra is consistent with the (S,S)-configu-
ration for the (+, MeOH)-4-2 studied.
Figure 1. Optimized geometries of the two lowest energy conformers, C1 and C2, and potential energy as a function of HOCC
dihedral angle.

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A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 2605–2611
Figure 2. Comparison of observed IR and VCD spectra of (+, MeOH)-4-2 with Boltzmann-population-weighted sum of spectra
of conformers C1 and C2 of (S,S)-4.
carried out on a larger CHIRALCEL®OD-R (250*20
mm, 10 mM) column which was previously washed with
2-propanol for 2 h and then used in pure acetonitrile.
Merck Hitachi L7100 Pump fixed at 9 mL/min,
Autosampler L7250 with 2 mL injection loop, DAD
L7450 fixed at 250 nm. Four injections of 2 mL each of
a saturated (12.5 g/L) racemic solution in the mobile
phase were performed. The chromatographic parame-
ters of a 25 mg injection are as follows: t1=8.48 min,
3. Experimental
1H and 13C NMR spectra were recorded on a Bruker
AC 200 (200 MHz) or a Bruker Avance (400 MHz)
spectrometer with CDCl3 or C6D6 as solvent. Chemical
shifts (l) are reported in ppm downfield from TMS.
TLC were performed on Merck glass plates with silica
gel 63 F254. Silica gel Si 60 (40–60 mm) from Merck was
used for the chromatographic purifications. 5-Hydroxy-
1-tetralone, benzyl bromide and benzyl mercaptan were
purchased from Fluka, Acros and Aldrich, respectively,
and used without further purification. Usual IR spectra
and rotations were recorded/determined on a Perkin–
t2=18.24 min, k1=0.41, k2=2.12, alpha=4.94, Rs=
4.68. Fractions were collected between 8.4–9.7 min and
17.2–24 min, the solvent evaporated under vacuum and
the enantiomeric purity checked on CHIRAL-
CEL®OD-R. The first eluted enantiomer, 4-1 (44 mg)
has 100% e.e. and 95.4% chemical purity, while the
second eluted enantiomer 4-2 (37 mg) has 100% e.e. and
99% chemical purity.
For the VCD determination of absolute configuration,
infrared absorption and VCD spectra were recorded in
a 100 mm path length BaF2 cell, at 4 cm−1 resolution,
using the Chiralir Fourier transform VCD spectrometer
from Bomem/BioTools, Quebec, Canada,28,29 optimized
for operation at 1400 cm−1. VCD spectra were recorded
for 2 h by co-adding approximately 4800 interferomet-
ric scans. The sample was dissolved in CCl4 (100mg/
mL). DFT calculations were performed using Gaussian
98 (Gaussian, Inc. Pittsburgh, PA).
Elmer Spectrum one and
respectively.
a
Perkin–Elmer 341,
Resolution of ( )-4 has been optimized analytically
using a CHIRALCEL®OD-R (250*4.6 mm, 10 mM)
column with conditions: t1=3.79 min, t2=9.36 min,
k1=0.26, k2=2.12, alpha=8.08, Rs=14. (Detection
DAD 230 nm). Then semi-preparative resolution was

A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 2605–2611
2609
3
3.1. Benzyl protection
(1H, t, J=8 Hz, H7), 7.35–7.5 (5H, m, Hphenyl), 7.68
3
(1H, d, J=8 Hz, H8). 13C NMR (CDCl3): 23.5 (CH2),
5-Hydroxy-1-tetralone (5 g, 30.83 mmol, 1 equiv.) was
dissolved in dry acetone (200 mL) and K2CO3 (8.52 g,
61.66 mmol, 2 equiv.) was added in one portion under
argon, the mixture was stirred for 10 min at room
temperature then PhCH2Br (3.85 mL, 32.37 mmol, 1.05
equiv.) was added dropwise. After stirring the mixture
under reflux for 4 h, the reaction was complete (as seen
from TLC), acetone was removed under reduced pres-
sure and the residue was crystallized from hot hexane
25.2 (CH3), 25.9 (CH2), 28.9 (CH3), 57.1 (CH), 70.7
(CH2-O), 73.1 (C-OH), 116.5 (CH), 119.7 (CH), 127.4
(CH), 127.6 (CHph), 128.5 (CHph), 129.1 (CHph), 134.1
(C), 134.5 (C), 137.1 (C), 156.1 (C), 203.1 (CꢁO). IR:
wOH=3479 cm−1, wCꢁO=1664 cm−1.
3.3.2. Dehydration. The above cetol (5.66 g) was dehy-
drated following the usual procedure32 and the residue,
crystallized from ether, was purified by flash chro-
matography to afford a white crystalline solid (4.32 g,
1
to afford a white solid (7.6 g, 98%), mp 50–51°C; H
3
1
NMR (CDCl3): 2.13 (2H, m, H3), 2.66 (2H, dd, J=5
90%). H NMR (CDCl3): 1.98 (3H, s, CH3), 2.21 (3H,
Hz, 3J=7 Hz, H2), 2.98 (2H, t, 3J=6 Hz, H4), 5.12 (2H,
s, CH3), 2.81 (2H, t, J=6.5 Hz, H3a+H3b), 3.01 (2H, t,
3
3
4
s, O-CH2), 7.09 (1H, dd, J=8 Hz, J=1 Hz, H6), 7.26
3J=6.5 Hz, H4a+H4b), 5.13 (2H, s, CH2-O), 7.07 (1H, d,
3
3
(1H, t, J=8 Hz, H7), 7.3–7.5 (5H, m, Hphenyl), 7.69
3J=8 Hz, H6), 7.29 (1H, t, J=8 Hz, H7), 7.36–7.48
(1H, dd, J=8 Hz, J=1 Hz, H8); 13C NMR (CDCl3):
22.9 (CH2), 23.4 (CH2), 39.3 (CH2), 70.7 (CH2-O),
116.2 (CH), 119.5 (CH), 127.1 (CH), 127.6 (CHph),
128.5 (CHph), 129.1 (CHph), 134.2 (C), 134.4 (C), 137.2
(C), 156.3 (C), 199.1 (CꢁO); IR: wCꢁO 1680 cm−1.
(5H, m, Hphenyl), 7.78 (1H, dd, 3J=8 Hz, 4J=1 Hz, H8).
13C NMR (CDCl3): 23.3 (CH3), 23.8 (CH3), 24.0 (CH2),
28.3 (CH2), 70.7 (CH2-O), 115.5 (CH), 120.3 (CH),
127.2 (CH), 127.6 (CHph), 128.4 (CHph), 129.0 (CHph),
130.8 (C), 133.4 (C), 136.5 (C), 137.4 (C), 145.3 (C),
156.0 (C), 190.5 (CꢁO). IR: wCꢁO=1665 cm−1.
3
4
3.2. Silyl enol–ether 6
3.4. Conjugate-addition of PhCH2SH: 7
The above benzyl-protected hydroxytetralone (5 g,
19.82 mmol, 1 equiv.) was dissolved, under argon in dry
acetonitrile (5 mL). Then pentane (25 mL), triethyl-
amine (3.87 mL, 27.74 mmol, 1.4 equiv.) and chloro-
trimethylsilane (3.27 mL, 25.76 mmol, 1.3 equiv.) were
added, followed by dropwise addition of anhydrous
sodium iodide (3.86 g, 25.76 mmol, 1.3 equiv.) in
acetonitrile (25 mL). After stirring at room temperature
for 30 min, then stirring under reflux for 90 min, the
reaction mixture was allowed to cool and the upper
organic layer (pentane) was transferred into a dry flask.
The remaining mixture was extracted with dry pentane
(5×10 mL). The pentane layer was evaporated to give 6
as a colorless oil, pure by NMR analysis (6.25 g, 96%).
The usual method30 leads to lower yields and avoiding
water is essential. 1H NMR: (CDCl3): 0.27 (9H, s,
The usual procedure33 was modified to provide ca.
quantitative conversion; DBU (1 equiv.) was used
instead of NaOH and the reaction was carried out at
room temperature instead of refluxing THF. After
chromatography on silica gel (toluene) 7 was obtained
1
as a colorless oil (6.98 g, 97%; from 5.11 g of 5). H
NMR (CDCl3): 1.45 (3H, s, CH3) 1.80 (3H, s, CH3),
2
3
2.01 (1H, dq, J=3J=3J=12.5 Hz, J=4.5 Hz, H3a),
3
2.60 (1H, dd, J=12.5 Hz, J=4.5 Hz, H2), 2.60 (1H,
2
3
3
ddd, J=18 Hz, J=12.5 Hz, J=4.5 Hz, H4b), 2.78
(1H, dq, J=12.5, J=3J=3J=4.5 Hz, H3b), 3.19 (1H,
2
3
2
3
td, J=18 Hz, J=3J=4.5 Hz, H4a), 3.78 (2H, s, CH2-
S), 5.12 (2H, AB, CH2-O), 7.06 (1H, dd, 3J=8 Hz,
4J=1 Hz, H6), 7.20–7.50 (6H, m, Harom), 7.59 (1H, dd,
3J=8 Hz, 4J=1Hz, H8). 13C NMR (CDCl3): 24.3
(CH2), 24.6 (CH3), 26.1 (CH2), 29.6 (CH3), 33.7 (CH2-
S), 49.5 (C-S) 55.4 (CH-CO), 70.6 (CH2-O), 115.7 (CH),
119.5 (CH), 127.2 (CH), 127.3 (CH), 127.6 (CH), 128.5
(CH), 129.0 (CH), 129.1 (CH), 129.5 (CH), 133.3 (C),
136.1 (C), 137.3 (C), 138.8 (C), 156.2 (C), 199.3 (CꢁO).
IR: wCꢁO=1687 cm−1.
3
3
3
CH3Si), 2.31 (2H, ddd, J=8.5 Hz, J=8 Hz, J=4.5
3
3
Hz, H3), 2.85 (2H, dd, J=8.5 Hz, J=8 Hz, H4), 5.09
3
(2H, s, CH2-O), 5.21 (1H, t, J=4.5 Hz, ꢁCH), 6.87
3
4
(1H, dd, J=7 Hz, J=2.5 Hz), 7.1–7.2 (2H, m, Harom),
7.3–7.5 (5H, m, Hphenyl); 13C NMR: (CDCl3): 0.3 (CH3),
20.5 (CH2), 21.6 (CH2), 70.4 (CH2-O), 105.7 (CH),
111.7 (CH), 115.3 (CH), 125.6 (C), 126.4 (CH), 127.3
(CH), 127.9 (CH), 128.6 (CH), 134.9 (C), 137.6 (C),
148.0 (C), 155.0 (C).
3.5. Reduction with BH3·THF, 8
A solution of 7 (6.98 g) in dry THF (70 mL) was
treated with BH3 (1 M solution in THF, 33.5 mL)
dropwise at room temperature under an argon atmo-
sphere. The mixture was stirred overnight, quenched
carefully with saturated aqueous NH4Cl (300 mL) and
extracted with ether (5×15 mL). The combined organic
layer was washed with water (1×10 mL), dried
(Na2SO4) and concentrated. The residue (7.02 g, 100%)
3.3. Synthesis of 5
3.3.1. Condensation with acetone. The silyl enol ether 6
(6.25 g, 19.26 mmol) was condensed with acetone fol-
lowing the usual procedure31 and the product (5.66 g,
96%) was used for the next reaction without purifica-
1
tion. H NMR (CDCl3): 1.32 (3H, s, CH3), 1.34 (3H, s,
CH3), 1.85 (1H, dq, 2J=3J=3J=13 Hz, 3J=4.5 Hz,
was used for the next reaction without purification. H
1
3
3
H3a), 2.29 (1H, m, H3b), 2.63 (1H, dd, J=13 Hz, J=4
Hz, H2), 2.75 (1H, ddd, J=17.5 Hz, J=13 Hz, J=
NMR (CDCl3): 1.55 (3H, s, CH3), 1.61 (3H, s, CH3),
2
3
3
3
3
1.78 (1H, dt, J=12.5 Hz, J=3J=2 Hz, H2), 2.00 (1H,
2
3
4.5 Hz, H4b), 3.34 (1H, ddd, J=17.5 Hz, J=4.5 Hz,
dq, J=3J=3J=12.5 Hz, J=5.5 Hz, H3a), 2.13 (1H,
2 3
m, H3b), 2.39 (1H, d, J=4 Hz, OH), 2.53 (1H, ddd,
3J=3 Hz, H4a), 5.08 (1H, s, OH), 5.14 (2H, AB,
3
4
3
3
CH2-O), 7.12 (1H, dd, J=8 Hz, J=0.5 Hz, H6), 7.29
2J=18 Hz, J=12.5 Hz, J=6 Hz, H4b), 3.16 (1H, ddd,

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A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 2605–2611
3
3
2J=18 Hz, J=5.5 Hz, J=1.5 Hz, H4a), 3.82 (2H, AB,
CH2-S), 5.09 (1H, m, H1), 5.11 (2H, CH2-O), 6.86 (1H,
dd, 3J=8 Hz, 4J=1 Hz, H6), 6.97 (1H, d, 3J=8 Hz, H8),
6. Solladie-Cavallo, A.; Diep-Vohuule, A. J. Org. Chem.
1995, 60, 3494.
7. Solladie-Cavallo, A.; Diep-Voluule, A.; Sunjic, V.; Vin-
covic, V. Tetrahedron: Asymmetry 1996, 7, 1783.
8. Solladie-Cavallo, A.; Diep-Volhuule, A.; Isarno, T.
Angew. Chem., Int. Ed. 1998, 37, 1689.
3
7.20 (1H, t, J=8 Hz, H7), 7.21–7.48 (10 H, m, Hphenyl).
13C NMR (CDCl3): 18.5 (CH2), 25.1 (CH2), 27.9 (CH3),
28.0 (CH3), 33.6 (CH2-S), 48.7 (CH), 49.6 (C-S), 70.0
(CH-OH), 70.2 (CH2-O), 110.9 (CH), 122.7 (CH), 126.5
(C), 127.1 (CH), 127.3 (CH), 127.4 (CH), 128.2 (CH),
128.9 (CH), 129.4 (CH), 137.8 (C), 138.5 (C), 140.7 (C),
156.8 (C). IR: wO-H=3435 cm−1.
9. Most of the time some epoxide is lost during chromato-
graphic separation.
10. Studer, A.; Curran, D. P. Tetrahedron 1997, 1997, 6681.
11. Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org.
Chem. 1997, 62, 2917.
12. Only one diastereoisomer of sulfonium salts must be
3.6. Oxathiane 4
formed (which, as
a consequence, gives only one
diastereoisomer for the corresponding ylide) as a condi-
tion for obtaining high e.e.
13. Nafie, L. A. Annu. Rev. Phys. Chem. 1997, 48, 357–386.
14. Nafie, L. A.; Freedman, T. B. Enantiomer 1998, 3, 283–
297.
15. Nafie, L. A.; Freedman, T. B. In Circular Dichroism,
Theory and Practice; Nakanishi, K.; Berova, N.; Woody,
W., Eds.; Wiley: New York, 2000; pp. 97–131.
16. Nafie, L. A.; Freedman, T. B. In Infrared and Raman
Spectroscopy of Biological Materials; Yan, B.; Gremlish,
H.-U., Eds.; Marcel Dekker: New York, 2001; pp. 15–54.
17. (a) No addition of water. CH3CN was extracted with
pentane and the extraction monitored by TLC. More-
over, NEt3 and TMSCl must be dry and distilled, and
NaI dried; (b) Cazeau, P.; Duboudin, F.; Moulines, F.;
Badot, O.; Dunogues, J. Tetrahedron 1987, 43, 2075.
18. Anhydrous AcOH does not work.
3.6.1. Deprotection with Na/NH3. The benzylic deprotec-
tion was carried out following usual procedure33 and
yielded 3.19 g (90%, from 6.2 g of 8) of a crude product,
which was used without further purification in the next
step. 1H NMR (CDCl3): 1.60 (3H, s, CH3),
1.61 (3H, s, CH3), 1.7 (1H, m, H2), 2.04 (2H, m, H3a+
H3b), 2.07 (s, 1H, SH), 2.33 (1H, d, J=4 Hz, CHOH),
2.56 (1H, ddd, 2J=17.5 Hz, 3J=10.5 Hz, 3J=7 Hz, H4b),
3.02 (1H, ddd, J=17.5 Hz, J=4 Hz, J=3 Hz, H4a),
4.96 (1H, s, OH-Ar), 5.07 (1H, dd, H1), 6.73 (1H, dd,
3J=8 Hz, 4J=1 Hz, H6), 6.94 (1H, d, 3J=8 Hz, H8), 7.13
(1H, t, J=8 Hz, H7). 13C NMR (CDCl3): 18.8 (CH2),
24.3 (CH2), 31.5 (CH3), 33.1 (CH3), 47.2 (C-S), 50.4
(CH), 69.9 (CH-O), 114.7 (CH), 122.7 (CH), 123.4 (C),
127.5 (CH), 140.9 (C), 153.7 (C-O). IR: wOH=3369 and
wS-H=2561 cm−1.
2
3
3
19. LiAlH4/Et2O and NaBH4/MeOH/THF lead to a 70/30
cis/trans mixture.
3.6.2. Bridging. This last step was done following the
usual procedure33 and led to oxathiane 4 in 62% yield
(after chromatographic purification). 1H NMR (CDCl3):
1.34 (3H, s, CH3eq), 1.45 (1H, td, 3J=12.5 Hz, 3J=3J=2
Hz, H2), 1.68 (3H, s, CH3ax), 1.95 (1H, m, H3b), 2.30 (1H,
dq, 2J=3J=3J=12.5 Hz, 3J=6 Hz, H3a), 2.52 (1H, ddd,
20. It must be noted that H(1) is equatorial within ring A, but
axial within ring B, while it is the reverse for H(2).
21. In a trans ring junction, one of the methyls of the
gem-dimethyl system would be correlated to H(1), one
H(11) and, at least one H(3).
22. Freedman, T. B.; Long, F.; Citra, M.; Nafie, L. A.
Enantiomer 1999, 4, 103–109.
3
3
2J=17 Hz, J=12 Hz, J=6 Hz, H4b), 2.96 (1H, ddd,
2J=17 Hz, 3J=6 Hz, 3J=2 Hz, H4a), 4.69 (1H, t,
3J=4J=2 Hz, H1), 4.78 (1H, OH), 4.79 (1H, B of AB,
JAB=11 Hz, Heq), 5.21 (1H, A of AB, JAB=11 Hz,
Hax3), 6.72 (1H, dd, 3J=7.5 Hz, 4J=1 Hz, H6), 6.88 (1H,
23. Stephens, P. J.; Aamouche, A.; Devlin, F. J. J. Org.
Chem. 2001, 66, 3671–3677.
24. Diatkin, A. B.; Freedman, T. B.; Cao, X.; Dukor, R. K.;
Maryanoff, B. E.; Maryanoff, C. A.; Matthews, J. M.;
Shah, R. K.; Nafie, L. A. Chirality 2001, in press.
25. Freedman, T.; Dukor, R., K.; van Hoof, P. J. C. M.;
Kellenbach, E.; Nafie, L. A. Helv. Chim. Acta, to be
submitted.
3
d, J=7.5 Hz, H8), 7.09 (1H, t, J=7.5 Hz, H7). 13C
NMR (CDCl3): 18.0 (CH2), 23.2 (CH2), 28.3 (CH3), 29.3
(CH3), 42.1 (C), 43.8 (CH), 68.1 (CH2), 74.1 (CH-O),
114.6 (CH), 123.4 (CH), 124.0 (C), 126.8 (CH), 137.2
(C), 153.2 (C-O). IR: wOH=3391 cm−1. After resolution
on CHIRALCEL OD (eluent=MeCN) the first eluting
enantiomer has an e.r. of 100/0 and a chemical purity of
96%: [h]2D0=−58 (c=2.2, MeOH).
26. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria,
G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V.
G.; Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J.
C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.;
Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.;
Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.;
Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challa-
combe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gor-
don, M.; Replogle, E. S.; Pople, J. A. Gaussian 98; A.9
ed.; Gaussian, Inc.: Pittsburgh, PA, 1998.
References
1. Eliel, E. L.; Koskimies, J. K.; Lohri, B. J. Am. Chem.
Soc. 1978, 100, 1614.
2. Eliel, E. L.; Frazee, W. J. J. Org. Chem. 1979, 44, 3598.
3. Lynch, J. E.; Eliel, E. L. J. Am. Chem. Soc. 1984, 106,
2943.
4. Solladie-Cavallo, A.; Adib, A. Tetrahedron 1992, 48,
2453.
5. Oxathiane 2 has also been used by Aggarwall in 1995:
Aggarwal, V. K.; Thompson, A.; Jones, R. V. H.;
Standen, M. Tetrahedron: Asymmetry 1995, 6, 2557.

A. Solladie´-Ca6allo et al. / Tetrahedron: Asymmetry 12 (2001) 2605–2611
27. The conformers C1 and C2 represent well defined local London, 2000; pp. 2391–2402.
2611
minima on the potential energy surface, as determined
from the relaxed potential energy surface scan for differ-
ent OH orientation (the CCOH dihedral angle varied by
300 intervals) while allowing the geometry of the rest of
the molecule to optimize.
30. Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.;
Dunogues, J. Tetrahedron 1987, 43, 2075.
31. Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem.
Soc. 1974, 96, 7503.
32. Demole, E.; Enggist, P. Helv. Chim. Acta 1978, 61, 1335.
33. (a) Eliel, E. L.; Lynch, J. E. Tetrahedron Lett. 1981, 22,
2855; (b) Eliel, E. L.; Lynch, J. E.; Kume, F.; Frye, S. V.
Org. Synth. 1986, 65, 215.
28. Nafie, L. A. Appl. Spectrosc. 2000, 54, 1634–1645.
29. Nafie, L. A. In Encyclopedia of Spectroscopy; Linden, J.
C.; Tranter, G. E.; Holmes, J. L., Eds.; Academic Press: