Direct conversion of tert-butyl 2-hydroxyalkyl sulfides to 1,3-oxathiolanes

Article abstract of DOI:10.1016/j.tet.2005.10.026

tert-Butyl 2-hydroxyalkyl sulfides, prepared by reaction of epoxides with 2-methylpropane-2-thiol, are converted directly to 1,3-oxathiolanes upon treatment with pivalaldehyde and boron trifluoride diethyl etherate in the presence of thioanisole.

Full text of DOI:10.1016/j.tet.2005.10.026

Tetrahedron 62 (2006) 931–936
Direct conversion of tert-butyl 2-hydroxyalkyl sulfides
to 1,3-oxathiolanes
*
Michael J. Porter, Fabienne Saez and Amandeep Kaur Sandhu
Department of Chemistry, University College London, Christopher Ingold Building, 20 Gordon Street, London WC1H 0AJ, UK
Received 15 August 2005; revised 23 September 2005; accepted 13 October 2005
Available online 7 November 2005
Abstract—tert-Butyl 2-hydroxyalkyl sulfides, prepared by reaction of epoxides with 2-methylpropane-2-thiol, are converted directly to
1,3-oxathiolanes upon treatment with pivalaldehyde and boron trifluoride diethyl etherate in the presence of thioanisole.
q 2005 Elsevier Ltd. All rights reserved.
HO CONH2
S
1. Introduction
S
AcO
As part of a research programme1 targeted towards the
synthesis of the RNA polymerase inhibitor tagetitoxin 1,2
we wished to synthesise the cis-disubstituted 1,3-oxathio-
lane ester 2-c as a single enantiomer. It was hoped that
subsequent deprotonation and reaction with an appropriate
aldehyde would allow stereospecific construction of the
C1–C8 bond of tagetitoxin.3 Literature reports concerning
the enolates of related sulfur-containing heterocycles left
some doubt as to whether the proposed coupling would be
feasible. Seebach et al. reported that the lithium enolate of
thiazolidine 3 rapidly decomposed by a b-elimination
process and could not be induced to react with electro-
philes.4 Conversely, Pattenden et al. were successful in
alkylating the enolate of thiazolidine 4, which differs from 3
only in the nature of the nitrogen protecting group.5 It was
thus unclear prior to this study whether the enolate of 2-c
would be sufficiently stable to allow reaction with an
aldehyde to take place. While 2-c had not previously been
synthesised, it was anticipated that it should be readily
prepared by acid-catalysed condensation of the correspond-
ing b-hydroxythiol with pivalaldehyde.
+H3N
8
O
CO2H
1
O
MeO2C
–HO3PO
1
2-c
S
S
N
N
MeO2C
MeO2C
CO2Me
CHO
3
4
2. Results and discussion
L-Serine was converted via potassium (R)-glycidate to
carboxylic acid 5 by literature procedures.6 Esterification
was accomplished with thionyl chloride/methanol to afford
ester 6 (Scheme 1).7
SR1
S
ii
tBu
R2O2C
OH
O
MeO2C
2
5 R1=But, R2=H
6 R1=But, R2=Me
7 R1=H, R2=Me
i
(2:1 trans:cis)
×
Keywords: Heterocycles; Sulfur; Protecting groups; tert-Butyl sulfides;
Lewis acids.
Scheme 1. Reagents and conditions: (i) SOCl2, MeOH, 45%; (ii) tBuCHO
(1 equiv), BF3$OEt2 (2 equiv), PhSMe (1 equiv), CH2Cl2, 55%.
*
Corresponding author. Tel.: C44 20 7679 4710; fax: C44 20 7679 7463;
e-mail: m.j.porter@ucl.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.026

932
M. J. Porter et al. / Tetrahedron 62 (2006) 931–936
Table 1. Conversion of tert-butyl sulfides to 1,3-oxathiolanes
The next step, removal of the tert-butyl protecting group to
generate a vicinal hydroxythiol 7,7 proved problematic.
Treatment of 6 with a range of protic and Lewis acids
(including Hg(OAc)2/TFA followed by H2S;7b TFA/Et3-
SiH,7c and HBF4/TFA)7d failed to give efficient deprotec-
tion, and attempts to generate the corresponding disulfide by
treatment with oxidising agents (I2 or PhI(OAc)2)7e were
also unsuccessful. We were thus forced to develop a new
method for removal of the tert-butyl group, and were
gratified to discover that treatment of 6 with pivalaldehyde,
BF3$OEt2 and thioanisole in dichloromethane led directly to
the formation of the desired 1,3-oxathiolane 2, which was
obtained as a 2:1 mixture of isomers. NOE experiments on
this mixture (Fig. 1), together with analysis of 1H–1H
coupling constants,8 indicated that the major component
was the trans-isomer 2-t.
tBuCHO
BF3·OEt2
PhSMe
StBu
OH
S
tBu
R2
R1
R2
R1
CH2Cl2
O
8a-8h
9a-9h
Sulfide
R1
R2
Time (h) Yield (%)
(trans:cis)a
8a
8b
8c
8d
8e
8f
CO2Et
n-C3H7
CH2Ph
CH2OPh
CH2OBn
CH2OCH2CH]CH2
(CH2)6CH]CH2
CH2OPh
H
H
H
H
H
H
H
4
4
22
5
24
25
5
67 (2.2:1)
15 (1:2.5)b
47 (1:3.8)
74 (1:3.1)
82 (1:3.0)
36 (1:2.9)
12 (1:3.7)
91
8g
8h
CH2OPh 23
a Isolated yields of mixtures of diastereomers. The figures in parentheses
represent the trans:cis isomeric ratio in the crude reaction mixture, as
S
S
1
determined by H NMR spectroscopy.
H
O
O
H
CH3O2C
CH3O2C
b Isolated yield of cis-isomer.
H
2-t (major)
2-c (minor)
give the trans-isomer, analogous to 2-t, as the major
isolated product.10
Figure 1. Selected nuclear Overhauser enhancements in 2-t and 2-c.
Attempts to improve the yield of the reaction by use of other
Lewis or Brønsted acids (ZnCl2, InCl3, ZrCl4, Dowex-50)
were unsuccessful, with only boron trifluoride, of the acids
investigated, giving the desired product. Replacement of
pivalaldehyde with other aldehydes or ketones also proved
unsuccessful, while omission of the thioanisole gave a much
slower reaction, with appreciable quantities of starting
material still present after 40 h.
Yields of oxathiolanes were moderate to good, with the
exceptions of 9b, whose volatility made isolation trouble-
some, and of 9g, where isolation of a pure product was
hampered by problems in separating the oxathiolane
product from non-polar impurities.
The mechanism for this combined deprotection–cyclisation
transformation is presumed to be that outlined in Scheme 2.
Condensation of the alcohol functionality of 8 with
pivalaldehyde, catalysed by the Lewis acid, gives cation
10, which is attacked in an intramolecular fashion by
the sulfur atom to afford 11. Loss of a tert-butyl cation,
which is scavenged by thioanisole, leads to the observed
product 9.
Our attention next turned to the scope of this transformation.
A range of racemic or achiral tert-butyl 2-hydroxyalkyl
sulfides was prepared by opening of the corresponding
mono- or 1,1-disubstituted epoxides with 2-methylpropane-
2-thiol under basic conditions.9 These compounds were
subjected to the deprotection–cyclisation conditions
developed for compound 6: the results are summarised in
Table 1.
tBuCHO
BF3·OEt2
S
S
R1
R2
R1
R2
Sulfides derived from monosubstituted epoxides (8a–8g)
were converted to the corresponding 1,3-oxathiolanes
9a–9g as mixtures of diastereomers, which were in general
not separable by column chromatography. In the case of 9a,
as for 2, the trans-isomer was the major one; in all other
cases, the cis-isomer predominated. Achiral sulfide 8h,
which incorporates a tertiary alcohol, could also be
converted to the corresponding 1,3-oxathiolane in high
yield under the same conditions.
OH
O
8
10
S
S
R1
R2
R1
R2
O
O
9
11
Given the ready interconversion of 1,3-oxathiolane stereo-
isomers in the presence of BF3$OEt2,8 the product ratios
observed may reflect the relative thermodynamic stability of
the two diastereomers. Indeed, previous equilibration
studies have indicated that the cis-isomer of 2,5-dialkyl-
1,3-oxathiolanes is the more stable.8 By contrast, Brønsted
acid-catalysed condensation of methyl 3-mercapto-2-
hydroxypropanoate with acetaldehyde was reported to
Scheme 2. Proposed mechanism for deprotection–cyclisation.
An alternative mechanism in which acid-catalysed removal
of the tert-butyl group to yield a hydroxythiol is followed by
condensation with pivalaldehyde was ruled out by a control
experiment carried out in the absence of pivalaldehyde; in
this case, no reaction occurred and the starting material was
recovered unchanged.

M. J. Porter et al. / Tetrahedron 62 (2006) 931–936
933
We have investigated the possibility of generating the
lithium enolate of 2 with LDA (for initial studies a mixture
of 2-c and 2-t was employed) and reacting it with an
aldehyde electrophile. Under all conditions tested to date11
(temperatures from K90 to K78 8C, in the presence or
absence of DMPU and lithium bromide as additives;
trapping by addition of isobutyraldehyde, or in situ with
benzaldehyde), decomposition of the starting material 2
occurred, but none of the desired adduct was formed. These
results suggest that the lithium enolate of oxathiolane ester
2, like that of thiazolidine 3, decomposes more rapidly than
it reacts with aldehyde electrophiles, presumably through
b-elimination.
4.2.2. Ethyl 3-tert-butylsulfanyl-2-hydroxypropanoate
(8a). A solution of sodium ethoxide was prepared by
adding sodium (11.86 mg, 0.5 mmol) to dry ethanol
(0.26 mL) at 0–5 8C. 2-Methylpropane-2-thiol (0.43 mL,
3.8 mmol) was then added and the resultant solution was
stirred for 30 min at room temperature. A solution of ethyl
glycidate (400 mg, 3.4 mmol) in dry ethanol (6.9 mL) was
added dropwise to the ethoxide/thiol solution, and heated
under reflux for 2 h. The reaction mixture was quenched
with water (10 mL) and the ethanol removed in vacuo.
The aqueous layer was then extracted with diethyl ether
(2!10 mL). The combined organic extracts were washed
with brine (10 mL), dried (MgSO4) and concentrated.
Purification by flash chromatography (silica, petroleum
ether/ethyl acetate 85:15) afforded 8a (193 mg, 27%) as a
colourless oil; nmax/cmK1 (film) 3444, 2962, 2931, 2902,
1732, 1461; dH (300 MHz; CDCl3) 1.31 (3H, t, JZ7.2 Hz),
1.32 (9H, s), 2.85 (1H, dd, JZ13.0, 5.8 Hz), 3.02 (1H, dd,
JZ13.0, 4.3 Hz), 4.26 (2H, q, JZ7.1 Hz), 4.37–4.40 (1H,
m); dC (75 MHz; CDCl3) 14.2, 30.9, 33.0, 42.4, 62.0, 69.9,
173.1; m/z (CIC) 207 (MHC, 10%), 188 (11), 151 (100),
133 (81), 105 (25); HRMS (CIC) found 207.1048;
C9H19O2S (MHC) requires 207.1055.
3. Conclusions
We have developed a mild method for the direct conversion
of tert-butyl 2-hydroxyalkyl sulfides into 1,3-oxathiolanes
in a single step. This method circumvents the difficulties
encountered in removal of the tert-butyl group to form a
thiol. A variety of functional groups is tolerated, and yields
of up to 91% are obtained for the reaction.
4.2.3. 1-tert-Butylsulfanylpentan-2-ol (8b) (general
procedure A). 1,2-Epoxypentane (1.12 g, 13.0 mmol) was
dissolved in methanol (130 mL). 2-Methylpropane-2-thiol
(1.46 mL, 13.0 mmol) and triethylamine (0.91 mL,
6.5 mmol) were added and the resulting mixture was heated
under reflux for 5 h. The solvent was then removed in vacuo
to give the crude product. Flash chromatography (silica,
petroleum ether/ethyl acetate 95:5) afforded 8b as a
colourless oil (1.76 g, 77%); nmax/cmK1 (film): 3385,
2929, 2872, 1460, 1363, 1163; dH (300 MHz; CDCl3) 0.92
(3H, broad t, JZ7.0 Hz), 1.32 (9H, s), 1.37–1.53 (4H, m),
2.35 (1H, s), 2.50 (1H, dd, JZ12.8, 8.6 Hz), 2.76 (1H, dd,
JZ12.7, 3.6 Hz), 3.61–3.69 (1H, m); dC (75 MHz; CDCl3)
14.1, 19.0, 31.1, 36.6, 38.7, 42.4, 69.8; m/z (EI) 176 (MC,
93%), 133 (43), 119 (52); HRMS (EI) found 176.1239;
C9H20OS (MC) requires 176.1235.
4. Experimental
4.1. General
Reactions were performed under an atmosphere of nitrogen
or argon. Methanol and ethanol were dried by distillation
from the corresponding magnesium alkoxides. Dichloro-
methane was dried by passage through an alumina column.
Triethylamine was distilled from calcium hydride prior to
use. Other reagents were used as obtained from commercial
sources.
All new compounds or mixtures of stereoisomeric
compounds were judged to contain !5% impurities by H
NMR.
1
4.2.4. 1-tert-Butylsulfanyl-3-phenylpropan-2-ol (8c).
Prepared in 72% yield from 2-benzyloxirane by general
The relative stereochemistries of compounds 9a–9g were
ascertained by the observation of nuclear Overhauser
enhancements in each diastereomer.
procedure A, using ethanol as solvent; colourless oil; nmax
/
cmK1 (film) 3418, 2899, 2864, 1456, 1366, 1163, 1032; dH
(300 MHz; CDCl3) 1.31 (9H, s), 2.26 (1H, broad s), 2.58
(1H, dd, JZ12.8, 7.8 Hz), 2.75 (1H, dd, JZ12.8, 4.4 Hz),
2.84 (2H, app. d, JZ6.4 Hz), 3.87–3.96 (1H, m), 7.20–7.26
(3H, m), 7.29–7.35 (2H, m); dC (75 MHz; CDCl3) 31.1,
35.6, 42.5, 42.9, 71.3, 126.6, 128.5, 129.4, 138.0; m/z (EI)
224 (MC, 21%), 206 (100), 150 (83), 133 (70), 117 (100);
HRMS (EI) found 224.1239; C13H20OS (MC) requires
224.1235.
4.2. Synthesis of sulfides 6 and 8a–8h
4.2.1. Methyl (2S)-3-tert-butylsulfanyl-2-hydroxy-
propanoate (6). (2S)-3-tert-Butylsulfanyl-2-hydroxypropa-
noic acid6b (5, 2.0 g, 11 mmol) was added to a solution of
thionyl chloride (8.3 mL, 11.4 mmol) in methanol (50 mL),
and the mixture was heated to reflux for 18 h. After cooling
to room temperature, the reaction mixture was concentrated
in vacuo. Purification by flash chromatography (silica,
hexane/ethyl acetate 2:1) afforded 6 (0.98 g, 45%); as a
colourless oil; [a]2D5 C28.3 (c 0.92, EtOH); nmax/cmK1
(film) 3444, 2960, 1743, 1460, 1365, 1215, 1096; dH
(300 MHz; CDCl3) 1.33 (9H, s), 2.87 (1H, dd, JZ13.1,
6.0 Hz), 3.01 (1H, dd, JZ13.1, 4.3 Hz), 3.81 (3H, s), 4.39
(1H, dd, JZ6.0, 4.4 Hz); dC (75 MHz; CDCl3) 31.0 (CH3),
38.5 (CH2), 44.6 (C), 52.7 (CH3), 70.3 (CH), 173.7 (C); m/z
(CIC) 193 (MHC, 35%), 137 (100).
4.2.5. 1-tert-Butylsulfanyl-3-phenoxypropan-2-ol (8d).12
Prepared in 97% yield from glycidyl phenyl ether by
general procedure A, using ethanol as solvent; yellow oil;
nmax/cmK1 (film) 3395, 2926, 2864, 1601, 1495, 1245; dH
(300 MHz; CDCl3) 1.38 (9H, s), 2.51 (1H, broad s), 2.78
(1H, dd, JZ13.0, 6.9 Hz), 2.89 (1H, dd, JZ13.0, 5.6 Hz),
3.97–4.14 (3H, m), 6.90–6.99 (3H, m), 7.26–7.32 (2H, m);
dC (75 MHz; CDCl3) 31.0, 32.3, 42.7, 69.3, 70.6, 114.6,
121.2, 129.5, 158.5; m/z (FABC) 240 (MC, 20%), 222 (22),

934
M. J. Porter et al. / Tetrahedron 62 (2006) 931–936
149 (29), 133 (49), 94 (100); HRMS (FABC) found
100%), 181 (29), 183 (29), 185 (23), 173 (67); HRMS (CIC)
240.1186; C13H20O2S (MC) requires: 240.1184.
found 257.1169; C16H17O3 (MHC) requires 257.1178.
Sulfide 8h was prepared from 2,2-di(phenoxymethyl)-
oxirane by general procedure A; white solid (mp
68–70 8C); nmax/cmK1 (KBr) 3377, 2951, 2924, 2932,
1599, 1590, 1497; dH (400 MHz; CDCl3) 1.33 (9H, s),
3.04 (2H, s), 4.11 (4H, s), 6.94–6.98 (6H, m), 7.26–7.31
(4H, m); dC (75 MHz; CDCl3) 30.9, 33.3, 42.6, 70.0, 72.8,
114.7, 121.2, 129.5, 158.5; m/z (EI) 346 (MC, 13%), 235
(100), 179 (46), 131 (65), 107 (84), 94 (58); HRMS (EI)
found 346.1610; C20H26O3S (MC) requires 346.1603.
4.2.6.
1-Benzyloxy-3-tert-butylsulfanylpropan-2-ol
(8e).13 Prepared in 53% yield from benzyl glycidyl ether
by general procedure A; colourless oil; nmax/cmK1 (film)
3443, 2961, 2924, 2862, 2899, 1454, 1364; dH (300 MHz;
CDCl3) 1.33 (9H, s), 2.40 (1H, broad s), 2.67 (1H, dd, JZ
12.8, 7.1 Hz), 2.75 (1H, dd, JZ12.8, 5.9 Hz), 3.49 (1H, dd,
JZ9.6, 6.3 Hz), 3.58 (1H, dd, JZ9.6, 4.0 Hz), 3.87–3.95
(1H, m), 4.57 (2H, s), 7.27–7.38 (5H, m); dC (75 MHz;
CDCl3) 31.0, 32.3, 42.4, 69.7, 73.1, 73.5, 127.8, 128.5,
137.9; m/z (CIC) 255 (MHC, 32%), 289 (28), 236 (100),
199 (20), 181 (69), 147 (40); HRMS (CIC) found 255.1412;
C14H23O2S (MHC) requires 255.1419.
4.3. Conversion of sulfides to 1,3-oxathiolanes
4.2.7. 1-Allyloxy-3-tert-butylsulfanylpropan-2-ol (8f).
Prepared in 80% yield from allyl glycidyl ether by general
procedure A; colourless oil; nmax/cmK1 (film) 3445, 2961,
2899, 2862, 1645, 1460, 1366; dH (300 MHz; CDCl3) 1.32
(9H, s), 2.54 (1H, broad s), 2.66 (1H, dd, JZ12.8, 7.0 Hz),
2.74 (1H, dd, JZ12.8, 5.9 Hz), 3.44 (1H, dd, JZ9.6,
6.4 Hz), 3.54 (1H, dd, JZ9.6, 4.0 Hz), 3.84–3.92 (1H, m),
4.01–4.04 (2H, m), 5.17–5.31 (2H, m), 5.84–5.97 (1H, m);
dC (75 MHz; CDCl3) 31.0, 32.3, 42.4, 69.7, 72.3, 73.0,
117.3, 134.5; m/z (CIC) 205 (MHC, 10%), 159 (20), 149
(45), 131 (100), 97 (38); HRMS (CIC) found 205.1259;
C10H21O2S (MHC) requires 205.1262.
4.3.1. Methyl (5S)-2-tert-butyl-1,3-oxathiolane-5-
carboxylate (2) (general procedure B). To a solution of
methyl (2S)-3-tert-butylsulfanyl-2-hydroxypropanoate (6,
0.38 g, 2 mmol) in dry dichloromethane (5 mL) were
added successively pivalaldehyde (0.22 mL, 2 mmol),
thioanisole (0.24 mL, 2 mmol) and boron trifluoride diethyl
etherate (0.50 mL, 4 mmol). The mixture was stirred at
room temperature for 3 h then quenched with saturated
aqueous NaHCO3 (5 mL). The aqueous phase was extracted
with dichloromethane (3!10 mL), and the combined
extracts were washed with brine (10 mL), dried (MgSO4)
1
and concentrated in vacuo. H NMR analysis showed the
ratio of products to be 2:1 in favour of the trans isomer.
Purification of the residue by flash chromatography (silica,
hexane/ethyl acetate 90:10) afforded 2 (0.22 g, 55%) as a
colourless oil, as a 2:1 trans:cis diastereomeric mixture:
nmax/cmK1 (film) 2962, 1743, 1365, 1209, 1107; dH
(500 MHz; CDCl3); (2R,5S)-trans-isomer 2-t. 0.98 (9H, s),
3.12 (1H, dd, JZ10.8, 6.6 Hz), 3.26 (1H, dd, JZ10.8,
2.5 Hz), 3.77 (3H, s), 4.97 (1H, dd, JZ6.5, 2.5 Hz), 5.22
(1H, s). (2S,5S)-cis-isomer 2-c. 1.02 (9H, s), 3.00 (1H, dd,
JZ10.4, 9.1 Hz), 3.23 (1H, dd, JZ10.4, 5.8 Hz), 3.78 (3H,
s), 4.49 (1H, dd, JZ9.1, 5.8 Hz), 4.99 (1H, s); dC (125 MHz;
CDCl3); (2R,5S)-trans-isomer 2-t. 25.6, 34.3, 35.7, 52.3,
80.6, 95.9, 171.3; (2S,5S)-cis-isomer 2-c. 25.8, 34.6, 35.3,
52.4, 80.8, 96.3, 169.6; m/z (electrospray) 227 (MCNa,
100%), 217 (30); HRMS (electrospray) found: 227.0714;
C9H16O3SNa (MCNa) requires 227.0712.
4.2.8. 1-tert-Butylsulfanyldec-9-en-2-ol (8g). Prepared in
98% yield from 1,2-epoxydec-9-ene by general procedure
A, using ethanol as solvent; pale yellow oil; nmax/cmK1
(film) 3404, 2928, 2856, 1639, 1458, 1364, 1163; dH
(300 MHz; CDCl3) 1.31–1.40 (10H, m), 1.33 (9H, s), 2.00–
2.07 (2H, m), 2.50 (1H, dd, JZ12.8, 8.6 Hz), 2.77 (1H, dd,
JZ12.8, 3.6 Hz), 3.59–3.67 (1H, m), 4.90–5.02 (2H, m),
5.80 (1H, ddt, JZ17.0, 10.3, 6.7 Hz); dC (75 MHz; CDCl3)
25.7, 28.9, 29.0, 29.5, 31.2, 33.8, 36.6, 36.7, 42.4, 70.0,
114.2, 139.2; m/z (FABC) 245 (MHC, 100%), 227 (23),
187 (25), 171 (68); HRMS (FABC) found 245.1928;
C14H29OS (MHC) requires 245.1939.
4.2.9.
2-(tert-Butylsulfanylmethyl)-1,3-diphenoxy-
propan-2-ol (8h). 1,3-Diphenoxy-2-methylenepropane14
(802 mg, 3.3 mmol) was dissolved in CH2Cl2 (8 mL) and
the solution was cooled to 0 8C. MCPBA (70–75%, 902 mg,
3.7 mmol) and saturated aqueous NaHCO3 (5 mL) were
added and the resulting mixture was stirred for 5 h at room
temperature. The mixture was cooled to 0 8C and another
equivalent of MCPBA was added. After stirring at room
temperature for 21 h, the mixture was cooled to 0 8C and
treated with a further equivalent of MCPBA and saturated
aqueous NaHCO3 (2 mL). After stirring at room tempera-
ture for 3 h, the reaction mixture was filtered through
Celitew and the filtrate was washed with brine (10 mL) and
dried (MgSO4). The solvent was removed in vacuo and
purification by flash chromatography (silica, petroleum
ether/ethyl acetate 94:6) afforded 2,2-di(phenoxymethyl)-
oxirane (415 mg, 49%); nmax/cmK1 (film) 3057, 3040, 2930,
1587, 1497, 1242; dH (300 MHz; CDCl3) 3.02 (2H, s), 4.24
(2H, d, JZ10.6 Hz), 4.28 (2H, d, JZ10.6 Hz), 6.92–7.01
(6H, m), 7.26–7.33 (4H, m); dC (75 MHz; CDCl3) 49.5,
56.9, 68.0, 114.7, 121.4, 129.5, 158.5; m/z (CIC) 256 (MC,
4.3.2. Ethyl 2-tert-butyl-1,3-oxathiolane-5-carboxylate
(9a). Prepared as a 2.2:1 trans:cis mixture (crude) from 8a
by general procedure B and isolated in 67% yield as a 2.4:1
trans:cis mixture; colourless oil; nmax/cmK1 (film) 2957,
2868, 1744, 1364, 1186, 1144; dH (500 MHz; CDCl3); (2RS,
5SR)-trans-isomer. 0.99 (9H, s), 1.23–1.31 (3H, m), 3.12
(1H, dd, JZ10.7, 6.6 Hz), 3.24–3.28 (1H, m), 4.18–4.28
(2H, m), 4.94 (1H, dd, JZ6.6, 2.5 Hz), 5.23 (1H, s); (2RS,
5RS)-cis-isomer. d 1.02 (9H, s), 1.23–1.31 (3H, m), 2.99
(1H, app. dd, JZ10.4, 9.0 Hz), 3.22–3.25 (1H, m), 4.18–
4.28 (2H, m), 4.47 (1H, dd, JZ9.0, 5.8 Hz), 4.99 (1H, s); dC
(75 MHz; CDCl3); (2RS, 5SR)-trans-isomer. 14.2, 25.7,
34.3, 35.7, 61.5, 80.6, 95.9, 170.9; (2RS, 5RS)-cis-isomer.
14.2, 25.9, 34.7, 35.4, 61.5, 80.9, 96.4, 169.2; m/z (CIC)
219 (MHC, 16%), 161 (81), 149 (24), 133 (100), 101 (41);
HRMS (CIC) found 219.1056; C10H19O3S (MHC)
requires: 219.1055.

M. J. Porter et al. / Tetrahedron 62 (2006) 931–936
935
4.3.3. 2-tert-Butyl 5-propyl-1,3-oxathiolane (9b). Pre-
pared as a 2.5:1 cis:trans mixture from 8b by general
procedure B; from this mixture a pure sample of the cis-
diastereomer could be isolated in 15% yield by flash
chromatography. Colourless oil; nmax/cmK1 (film) 2957,
2930, 2864, 1479, 1464, 1362; dH (500 MHz; CDCl3) 0.92
(3H, broad t, JZ7.4 Hz), 0.95 (9H, s), 1.33–1.50 (2H, m),
1.53–1.60 (1H, m), 1.68–1.75 (1H, m), 2.47 (1H, app. t, JZ
9.9 Hz), 2.94 (1H, dd, JZ9.8, 4.7 Hz), 3.83–3.88 (1H, m),
4.90 (1H, s); dC (75 MHz; CDCl3) 14.2, 19.6, 25.8, 35.1,
35.9, 36.9, 84.0, 95.4; m/z (EI) 188 (MC, 23%), 131 (100),
103 (31); HRMS (EI) found 188.1235; C10H20OS (MC)
requires 188.1235.
9.8, 6.2 Hz), 3.55 (1H, dd, JZ9.8, 5.8 Hz), 4.55–4.62 (3H,
m), 4.93 (1H, s), 7.31–7.37 (5H, m); dC (75 MHz; CDCl3);
(2RS, 5RS)-cis-isomer. 25.9, 34.3, 35.1, 70.9, 73.5, 82.9,
96.0, 127.7, 128.4, 138.1; (2RS, 5SR)-trans-isomer. 25.9,
34.1, 36.0, 70.0, 73.4, 82.0, 95.3, 127.7, 128.4, 138.1; m/z
(CIC) 267 (MHC, 15%), 271 (61), 209 (100), 181 (43);
HRMS (CIC) found 267.1410; C15H23O2S (MHC) requires
267.1419.
4.3.7. 5-Allyloxymethyl-2-tert-butyl-1,3-oxathiolane (9f).
Prepared as a 2.9:1 cis:trans mixture (crude) from 8f by
general procedure B and isolated in 36% yield as a 2.8:1
cis:trans mixture; colourless oil; nmax/cmK1 (film) 2955,
2951, 2926, 1724, 1641, 1479, 1464; dH (500 MHz; CDCl3);
(2RS, 5RS)-cis-isomer. 0.96 (9H, s), 2.63 (1H, app. t, JZ
9.8 Hz), 2.98 (1H, dd, JZ10.1, 5.2 Hz), 3.56 (1H, dd, JZ
10.5, 4.8 Hz), 3.64 (1H, dd, JZ10.5, 5.7 Hz), 4.02–4.05
(2H, m), 4.08–4.13 (1H, m), 4.95 (1H, s), 5.16–5.29 (2H,
m), 5.84–5.92 (1H, m); (2RS, 5SR)-trans-isomer. 0.96 (9H,
s), 2.89 (1H, dd, JZ10.7, 4.7 Hz), 2.98 (1H, dd, JZ10.7,
5.9 Hz), 3.46 (1H, dd, JZ9.9, 6.3 Hz), 3.51 (1H, dd, JZ9.9,
5.7 Hz), 4.00–4.02 (2H, m), 4.51–4.55 (1H, m), 4.94 (1H, s),
5.16–5.29 (2H, m), 5.84–5.92 (1H, m); dC (75 MHz;
CDCl3); (2RS, 5RS)-cis-isomer. 25.9, 34.4, 35.1, 70.9,
72.5, 82.9, 96.0, 117.2, 134.6; (2RS, 5SR)-trans-isomer.
25.9, 34.1, 36.0, 70.1, 72.4, 82.0, 95.3, 117.2, 134.6; m/z
(DCI): 235 (18%), 217 (MHC, 9), 159 (100), 131 (19),
97 (57).
4.3.4. 5-Benzyl-2-tert-butyl-1,3-oxathiolane (9c). Pre-
pared as a 3.8:1 cis:trans mixture (crude) from 8c by
general procedure B and isolated in 47% yield as a 3.8:1
cis:trans mixture; colourless oil; nmax/cmK1 (film) 2930,
2864, 1497, 1479, 1454, 1362, 1182, 1076; dH (500 MHz;
CDCl3); (2RS, 5RS)-cis isomer. 0.96 (9H, s), 2.56 (1H, app.
t, JZ9.9 Hz), 2.85–2.89 (2H, m), 3.11 (1H, dd, JZ13.8,
6.2 Hz), 4.06–4.11 (1H, m), 4.92 (1H, s), 7.19–7.24 (3H, m),
7.26–7.30 (2H, m); (2RS, 5SR)-trans-isomer. 0.96 (9H, s),
2.77–2.83 (2H, m), 2.85–2.89 (1H, m), 2.99 (1H, dd, JZ
13.5, 6.1 Hz), 4.57–4.59 (1H, m), 5.04 (1H, s), 7.19–7.24
(3H, m), 7.26–7.30 (2H, m); dC (75 MHz; CDCl3); (2RS,
5RS)-cis-isomer. 25.8, 35.9, 36.6, 40.1, 84.4, 95.4, 126.5,
128.4, 129.4, 137.9; (2RS, 5SR)-trans-isomer. 25.9, 35.2,
36.6, 39.2, 84.3, 94.6, 126.5, 128.5, 129.3, 138.1; m/z (CIC)
237 (MHC, 7%), 151 (55), 117 (100), 91 (50); HRMS (CIC)
found 237.1314; C14H21OS (MHC) requires 237.1313.
4.3.8. 2-tert-Butyl-5-(oct-7-enyl)-1,3-oxathiolane (9g).
Prepared as a 3.7:1 cis:trans mixture (crude) from 8g by
general procedure B and isolated in 12% yield as a 14:1
cis:trans mixture; colourless oil; nmax/cmK1 (film) 2928,
2856, 1641, 1479, 1362, 1072; dH (400 MHz; CDCl3);
(2RS, 5RS)-cis-isomer. 0.97 (9H, s), 1.25–1.79 (10H, m),
2.02–2.07 (2H, m), 2.49 (1H, app. t, JZ9.9 Hz), 2.96 (1H,
dd, JZ9.8, 4.7 Hz), 3.83–3.90 (1H, m), 4.92 (1H, s), 4.94–
5.02 (2H, m), 5.81 (1H, ddt, JZ17.0, 10.3, 6.7 Hz); dC
(75 MHz; CDCl3); (2RS, 5RS)-cis-isomer. 25.8, 26.2, 28.8,
29.0, 29.5, 33.7, 33.8, 35.1, 36.9, 84.2, 95.4, 114.2, 139.1;
m/z (CIC) 257 (MHC, 15%), 199 (80), 171 (100), 137 (31);
HRMS (CIC) found 257.1934; C15H29OS (MHC) requires
257.1939.
4.3.5. 2-tert-Butyl-5-phenoxymethyl-1,3-oxathiolane
(9d). Prepared as a 3.1:1 cis:trans mixture (crude) from 8d
by general procedure B and isolated in 74% yield as a 2.2:1
cis:trans mixture; colourless oil; nmax/cmK1 (CDCl3 cast)
2957, 2870, 1599, 1497, 1244, 1049, 908; dH (500 MHz;
CDCl3); (2RS, 5RS)-cis-isomer. 0.97 (9H, s), 2.79 (1H, app.
t, JZ9.6 Hz), 3.11 (1H, dd, JZ10.3, 5.2 Hz), 4.05 (1H, dd,
JZ9.8, 5.6 Hz), 4.19 (1H, dd, JZ9.8, 5.3 Hz), 4.29–4.34
(1H, m), 5.00 (1H, s), 6.89–6.96 (3H, m), 7.25–7.29 (2H,
m); (2RS, 5SR)-trans-isomer. 0.97 (9H, s), 3.03 (1H, dd, JZ
10.8, 4.3 Hz), 3.05–3.11 (1H, m), 3.99 (1H, dd, JZ9.4,
6.8 Hz), 4.03–4.08 (1H, m), 4.72–4.77 (1H, m), 5.00 (1H, s),
6.89–6.96 (3H, m), 7.25–7.29 (2H, m); dC (75 MHz;
CDCl3); (2RS, 5RS)-cis-isomer. 25.9, 34.4, 35.2, 68.6,
81.7, 96.1, 114.7, 121.1, 129.5, 158.6; (2RS, 5SR)-trans-
isomer. 25.9, 34.2, 36.1, 67.6, 81.2, 95.4, 114.7, 121.1,
129.5, 158.6; m/z (FABC) 252 (MC, 30%), 195 (100), 154
(56) 137 (33); HRMS (FABC) found 253.1254; C14H21O2S
(MHC) requires 253.1262.
4.3.9. 2-tert-Butyl-5,5-di(phenoxymethyl)-1,3-oxathio-
lane (9h). Prepared in 91% yield from 8h by general
procedure B; colourless oil; nmax/cmK1 (film) 2955, 2932,
1599, 1587, 1497, 1244; dH (400 MHz; CDCl3) 0.99 (9H, s),
3.13 (1H, d, JZ11.4 Hz), 3.27 (1H, d, JZ11.4 Hz), 4.13
(1H, d, JZ9.4 Hz), 4.19 (1H, d, JZ9.4 Hz), 4.21 (2H, s),
5.08 (1H, s), 6.92–6.80 (6H, m), 7.26–7.30 (4H, m); dC
(75 MHz; CDCl3) 26.0, 35.2, 35.4, 67.6, 69.0, 87.8, 96.1,
114.8, 114.9, 121.1, 129.5, 158.7, 158.8; m/z (EI) 358 (MC,
50%), 301 (100), 145 (98), 107 (53), 94 (30); HRMS (EI)
found 358.1592; C21H26O3S (MC) requires 358.1603.
4.3.6. 5-Benzyloxymethyl-2-tert-butyl-1,3-oxathiolane
(9e). Prepared as a 3.0:1 cis:trans mixture (crude) from 8e
by general procedure B and isolated in 82% yield as a 2.7:1
cis:trans mixture; colourless oil; nmax/cmK1 (film) 2955,
2864, 1479, 1454, 1364, 1090; dH (500 MHz; CDCl3); (2RS,
5RS)-cis-isomer. 0.97 (9H, s), 2.65 (1H, app. t, JZ9.8 Hz),
2.99 (1H, dd, JZ10.1, 5.2 Hz), 3.60 (1H, dd, JZ10.4,
4.7 Hz), 3.67 (1H, dd, JZ10.4 5.7 Hz), 4.12–4.17 (1H, m),
4.55–4.62 (2H, m), 4.97 (1H, s), 7.31–7.37 (5H, m); (2RS,
5SR)-trans-isomer. 0.96 (9H, s), 2.90 (1H, dd, JZ10.7,
4.6 Hz), 2.99 (1H, dd, JZ10.7, 5.9 Hz), 3.49 (1H, dd, JZ
Acknowledgements
We thank Pfizer for the award of a summer scholarship (to
A.K.S.) and the Engineering and Physical Sciences
Research Council for PhD studentships (to F.S. and A.K.S.).

936
M. J. Porter et al. / Tetrahedron 62 (2006) 931–936
Tetrahedron Lett. 1992, 33, 5441–5444. (d) Akaji, K.; Yoshida,
References and notes
M.; Tatsumi, T.; Kimura, T.; Fujiwara, Y.; Kiso, Y. J. Chem.
Soc., Chem. Commun. 1990, 288–290. (e) Kolovos, M. G.;
Moutevelis-Minakakis, P. Tetrahedron Lett. 1984, 25,
4153–4156.
1. Ioannou, M.; Porter, M. J.; Saez, F. Tetrahedron 2005, 61,
43–50.
2. (a) Mitchell, R. E.; Durbin, R. D. Physiol. Plant Pathol. 1981,
18, 157–168. (b) Mitchell, R. E.; Coddington, J. M.; Young, H.
Tetrahedron Lett. 1989, 30, 501–504.
¨
8. Keskinen, R.; Nikkila, A.; Pihlaja, K. Tetrahedron 1972, 28,
3943–3955.
9. Luly, J. R.; Yi, N.; Soderquist, J.; Stein, H.; Cohen, J.;
Perun, T. J.; Plattner, J. J. J. Med. Chem. 1987, 30,
1609–1616.
3. For a review of related reactions, see: Seebach, D.; Sting,
A. R.; Hoffmann, M. Angew. Chem., Int. Ed. 1996, 35,
2708–2748.
10. Teodori, E.; Gualtieri, F.; Angeli, P.; Brasili, L.; Giannella,
M.; Pigini, M. J. Med. Chem. 1986, 29, 1610–1615.
11. For typical reaction conditions, see: (a) Corey, E. J.;
Reichard, G. A. J. Am. Chem. Soc. 1992, 114,
10677–10678. (b) Seebach, D.; Weber, T. Tetrahedron
Lett. 1983, 24, 3315–3318. (c) Seebach, D.; Amstutz, R.;
Laube, T.; Schweizer, W. B.; Dunitz, J. D. J. Am. Chem.
Soc. 1985, 107, 5403–5409; see also Ref. 3.
12. Wielechowska, M.; Plenkiewicz, J. Tetrahedron: Asymmetry
2003, 14, 3203–3210.
4. Jeanguenat, A.; Seebach, D. J. Chem. Soc., Perkin Trans. 1
1991, 2291–2298.
5. Pattenden, G.; Thom, S. M.; Jones, M. F. Tetrahedron 1993,
49, 2131–2138.
ˆ
6. (a) Petit, Y.; Larcheveque, M.; Organic Syntheses; Wiley:
New York, 2004; Collect. Vol. 10, pp 401–404. (b)
Cavelier, F.; Yim, A.-M. Org. Prep. Proced. Int. 1998,
30, 103–106.
7. For deprotection conditions, see: Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, 3rd ed.; Wiley-
Interscience: New York, 1999; pp 470–471. (b) Nishimura, O.;
Kitada, C.; Fujino, M. Chem. Pharm. Bull. 1978, 26, 1576–1585.
(c) Mehta, A.; Jaouhari, R.; Benson, T. J.; Douglas, K. T.
13. Kraynack, E. A.; Pedersen, S. F. J. Org. Chem. 1993, 58,
6114–6117.
14. Weiss, F.; Isard, A. Bull. Soc. Chim. Fr. 1967, 6, 2033–2038.