Conformationally constrained 2-methylidene 1,3-oxathiane S-oxides: Synthesis and nucleophilic additions

Article abstract of DOI:10.1016/j.tet.2014.12.098

The properties of vinyl sulfoxides are significantly influenced by stereoelectronic effects, where the relative orientation of sulfoxide group and alkene moiety is responsible for reactivity and selectivity, e.g., in the addition of nucleophiles. Conformationally constrained derivatives of 2-methylidene 1,3-oxathiane S-oxides allow the quantification of stereoelectronic effects. Suitable substrates were prepared by oxidation of 2-hydroxymethyl-1,3-oxathianes and pyrolysis of the respective xanthogenates. Nucleophilic additions of ethyl thiolate, piperidine, and dimethyl malonate anion are over 100 times faster to axial sulfoxides than to the respective equatorial substrates. The oxathiane derivatives turned out to be about 1000 times less reactive than the respective 1,3-dithianes.

Full text of DOI:10.1016/j.tet.2014.12.098

Tetrahedron 71 (2015) 1261e1268
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Conformationally constrained 2-methylidene 1,3-oxathiane
S-oxides: synthesis and nucleophilic additions
,
Daniel Weingand a, Claude Kiefer b, Joachim Podlech a
*
a
€
€
Institut fur Organische Chemie, Karlsruher Institut fur Technologie (KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Institut fur Anorganische Chemie, Karlsruher Institut fur Technologie (KIT), Engesserstraße 15, 76131 Karlsruhe, Germany
b
€
€
a r t i c l e i n f o
a b s t r a c t
Article history:
The properties of vinyl sulfoxides are significantly influenced by stereoelectronic effects, where the
relative orientation of sulfoxide group and alkene moiety is responsible for reactivity and selectivity, e.g.,
in the addition of nucleophiles. Conformationally constrained derivatives of 2-methylidene 1,3-oxathiane
S-oxides allow the quantification of stereoelectronic effects. Suitable substrates were prepared by oxi-
dation of 2-hydroxymethyl-1,3-oxathianes and pyrolysis of the respective xanthogenates. Nucleophilic
additions of ethyl thiolate, piperidine, and dimethyl malonate anion are over 100 times faster to axial
sulfoxides than to the respective equatorial substrates. The oxathiane derivatives turned out to be about
1000 times less reactive than the respective 1,3-dithianes.
Received 25 November 2014
Received in revised form 22 December 2014
Accepted 29 December 2014
Available online 3 January 2015
Keywords:
Sulfoxides
Sulfur heterocycles
Stereoelectronic effects
Conjugate addition
syn-Elimination
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
nucleophile from the top leads to an axial lone pair, perfectly sta-
bilized by the antiperiplanar S]O bond. An attack from the bottom
Stereoelectronic effects havedtogether with charge, dipole, and
steric effectsda significant influence on the structure, the physical
properties, and the reactivity of chemical compounds.1 We have
investigated stereoelectronic interactions between anionic lone
is preferred for the equatorial vinyl sulfoxide 2; the equatorial lone
pair is no longer stabilized by interaction with the S]O bond but
benefits from a stereoelectronic effect with both of the SeC bonds
(Scheme 1). These nC/
with 2ꢀ44.6 kJ/mol, which is thus of similar magnitude and of
conflictive influence as the above mentioned nC/ SeO interaction
s
*
stereoelectronic effects contribute
SeC
pairs at a-carbon atoms and SeC and S]O bonds in sulfides, sulf-
oxides, and sulfones.2e4 Suitable substrates for the investigation of
these effects turned out to be conformationally constrained
dithianes due to their rigidity and the antiperiplanar orientation of
bonds favoring possible stereoelectronic effects. In fact, a carbanion
is best stabilized, when the lone pair is in an antiperiplanar ori-
entation to an axial S]O bond of a sulfoxide. With NBO analysis we
calculated that this interaction contributes with 111 kJ/mol to the
total stabilization of the molecule.3 In this context we investigated
nucleophilic additions to vinyl sulfoxides derived from conforma-
tionally constrained 1,3-dithianes and found that the configuration
of the sulfoxide has significant influence on selectivity and rate of
the reaction. An axial S]O bond (as in 1) leads to the preferential
formation of an equatorially substituted product and the reaction is
about 100 times faster than a reaction of the respective equatorial
sulfoxide, where the selectivity is furthermore inverted toward an
axially substituted product.2 We reasoned that attack of the
s
*
in axial sulfoxides (111 kJ/mol). To allow for a better analysis of the
* Corresponding author. Tel.: þ49 721 608 43209; fax: þ49 721 608 47652;
Scheme 1. Nucleophilic addition to vinyl sulfoxides derived from dithianes.2
e-mail address: joachim.podlech@kit.edu (J. Podlech).
http://dx.doi.org/10.1016/j.tet.2014.12.098
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

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D. Weingand et al. / Tetrahedron 71 (2015) 1261e1268
stereoelectronic effects we planned to investigate related reactions
in sulfoxides derived from thianes or oxathianes. Here the com-
methylene oxathiane 10 could neither be achieved with trimethy-
laluminium,11 borontrifluoride etherate, or titanium tetrachloride,
nor with sodium hydride in the presence of borontrifluoride
etherate. To take advantage of the higher nucleophilicity of sulfur
we tried to synthesize the isomeric O-acetyl hydroxythiol: Never-
theless, disulfide formation from hydroxythiol with oxidative con-
ditions,12 O-acetylation, and reductive cleavage13 of the disulfide
function yielded the transacetylated,14 i.e., the S-acetyl hydroxythiol
9. 5-tert-Butyl-1,3-oxathiane 11 could be obtained from hydrox-
ythiol 4 in quantitative yield by acetal formation with dimethoxy-
methane. We tested methylenation with various protocols
including Peterson olefination,15 HornereWadswortheEmmons
reaction,16 or reaction with the Eschenmoser salt17 (with an inten-
ded subsequent Hofmann elimination18). While deprotonation of
oxathiane 11 with butyl lithium led to the lithiated substrate,
neither of the performed further reactions was successful in the
preparation of methylene derivative 10.
We thus aimed for a hydroxymethyl-substituted oxathiane 8
suitable for elimination. This derivative was easily prepared either
by using in situ-prepared glycolaldehyde (6) for the acetal forma-
tion or by reaction with a silyl-protected glycolaldehyde 7 (Scheme
2). Both protocols furnished the product in good yields. For the
elimination we considered a Chugaev reaction,19 in which methyl
xanthogenate 13 was pyrolyzed at 450 ꢁC (Scheme 4). Nevertheless
instead of methylene oxathiane 10 we isolated a rearranged oxa-
thiepine 14 (35%). This is presumably formed in a concerted re-
action with elimination of S-methyl dithiocarbonate and migration
of either the SeC or the OeC (depicted) bond to the exocyclic car-
bon. A two-step mechanism either involving (hardly stabilized)
carbene or carbenium species is possible but seems to be not very
likely. Basic elimination of tosylate 12 at 180 ꢁC was neither pos-
sible; decomposition of the material occurred.
peting nC/
s
*
interaction occurs only once; the related
SeC
nC/ effect should be significantly smaller.
s
*
OeC
In this manuscript we present the synthesis of conformationally
constrained 2-methylene 1,3-oxathiane S-oxides and their appli-
cation in nucleophilic additions to investigate stereoelectronic and
other effects.
2. Synthesis of methylidene oxathiane S-oxides
A fixed conformation in six-membered rings avoiding a ring flip
is usually achieved either by tert-butyl or by dimethyl substitution.5
From a synthetic point of view we considered it advantageous to
prepare 5-tert-butyl-1,3-oxathianes instead of the respective cis-
4,6-dimethyl derivative (Scheme 2). Condensation of diethyl mal-
onate with acetone in the presence of acetic anhydride and zinc
chloride, conjugate addition of a methyl cuprate prepared from
methyl magnesium bromide with copper(I) chloride,6 and re-
duction with lithium aluminum hydride7 yielded diol 3 with 31%
yield. A published procedure8 including benzylation, mesylation,
SN2 reaction with benzyl mercaptane, and debenzylation using
Birch conditions furnished thiol 4 in a total yield of 22%. An alter-
nate route consisting of tosylation, substitution with thioacetate,
and hydrolysis of the thioester with methanolic hydrogen chloride
gave a superior 34% yield.9
Scheme 2. Reaction conditions: (i) (a) acetone, ZnCl2, Ac2O,
D (50%), (b) MeI, Mg, Et2O,
then CuCl (93%), (c) LiAlH4, Et2O (66%); (ii) (a) BnBr, NaH, THF, (b) MsCl, pyridine,
CH2Cl2, (c) BnSH, NaH, DMF, (d) Na, NH3(l), Et2O (22%, four steps); (iii) (a) TsCl, pyri-
dine, CH2Cl2, 0 ꢁC to rt, 12 h (75%),7 (b) KSAc, DMF, 80 ꢁC, 40 min (45%), (c) HCl/MeOH,
Scheme 4. (i) TosCl, pyridine, CH2Cl2, 0 ꢁC to rt (97%); (ii) KOH, triethylene glycol,
180 ꢁC (decomp.); (iii) (a) NaH, THF, 0 ꢁC, (b) CS2, 60 ꢁC, 5 h, (c) MeI, rt, 1 h (82%, three
steps); (iv) pyrolysis, 450 ꢁC (35%).
D, 4 h, (quant.); (iv) HCl/MeOH, rt, 12 h; (v) BF3$OEt2, CH2Cl2,
D (81%); (vi) BF3$OEt2,
CH2Cl2, (70%).
D
We tested a direct approach toward the methylene oxathiane 10
(Scheme 3), which had been successful in the preparation of the
respective dithiane derivatives.2 Nevertheless, reaction of
hydroxythiol 4 with acetyl chloride in the presence of perchloric
acid and subsequent elimination with triethylamine10 did not
furnish the desired alkene 10, which was detected only in trace
amounts. Dehydration of the S-acetyl hydroxythiol 9 toward
However, we were successful in preparing the methylene oxa-
thianes by first oxidizing the sulfur to sulfoxides or sulfones,
transferring the hydroxyl function into a leaving group, and sub-
sequent elimination (Scheme 5). Sulfone 1820 could be obtained by
oxidation with oxone at room temperature, while performing the
reaction at 0 ꢁC with a short reaction time furnished the respective
equatorial sulfoxide 20. A sulfone function (in 16) could alterna-
tively be prepared by oxidation of the benzoyl-protected oxathiane
15 with sodium periodate and then with potassium permanganate.
Elimination was either achieved by Chugaev reaction of xan-
thogenates 19 or 21 or by elimination of tosylate 22 or benzoate 16.
The configuration of the equatorial sulfoxide was unambiguously
elucidated by X-ray crystallographic analysis of tosylate 22
(Fig. 1).20
The axial vinyl sulfoxide 25 was synthesized in quantitative
yield by elimination of tosylate 26 (not depicted) in analogy to the
elimination of 22, which furnished the equatorial vinyl sulfoxide 23
(Schemes 5 and 6). Nevertheless, no clean method could be de-
veloped for the synthesis of the axial sulfoxide 25. Oxidation of
alcohol 8 with various oxidation protocols including tert-butyl hy-
droperoxide,21 hydrogen peroxide,22,23 meta-chloroperbenzoic acid
(mCPBA), and cumene hydroperoxide led to various amounts of
Scheme 3. Reaction conditions: (i) various basic and Lewis-acidic conditions (see
text); (ii) HCl/MeOH,
D, 4 h, (quant.); (iii) AcCl, HClO4, then Et3N; (iv) CH2(OMe)2,
BF3$OEt2, , 30 min (quant.); (v) various protocols.
D

D. Weingand et al. / Tetrahedron 71 (2015) 1261e1268
1263
Scheme 5. (i) BzOCH2CHO, TMSCl, D, 30 min (44%); (ii) (a) NaIO4, THF/H2O, rt, 23 h (77%), (b) KMnO4, acetone/H2O, 3 d (44%); (iii) DBU, tBuOH/CH2Cl2, rt (25%); (iv) oxone, THF/H2O,
rt (90%); (v) (a) NaH, THF, 0 ꢁC, (b) CS2, 60 ꢁC, 5 h, (c) MeI, rt, 1 h; (vi) spontaneously (57% from 18); (vii) oxone, THF/H2O, 0 ꢁC (66%); (viii) as in (v) (52%); (ix) NaH, THF, rt, 1 h (53%);
(x) TsCl, Et3N, CH2Cl2, rt, 24 h; (xi) as in (ix) (quant., two steps).
(entry 8). The sulfoxides could easily be separated by column
chromatography. The configuration of 25 was determined by
crystallographic analysis (Fig. 2).20
Fig. 1. Structure of 22 in the crystal.20
Fig. 2. Structure of 25 in the crystal.20
3. Nucleophilic additions to methylidene oxathiane S-oxides
In prior work, we tested nucleophilic additions to vinyl sulfox-
ides and sulfones with different configurations and a variety of
heteroatom patterns. Additions of enolates and other nucleophiles
to alkylidene bissulfoxides 27 derived from 1,3-dithiane (one S]O
bond equatorial, one axial) proceed slowly and with selectivities
about 95:5 (Scheme 7).25 Similar additions to 1,3-dithiolane-de-
rived substrates 28 are significantly faster but show hardly any
selectivity.26 Here a stabilized carbanion is formed during the at-
Scheme 6. (i) Conditions given in Table 1, separation; (ii) (a) TsCl, pyridine, CH2Cl2, rt,
tack irrespective whether the nucleophile approaches from the top
or the bottom of the molecule.
12 h (/26), (b) NaH, THF,
D, 12 h (quant., two steps).
equatorial and axial sulfoxides 20 and 24 together with sulfone 18
(Table 1). Best results were obtained with tert-butyl hydroperoxide
together with titanium tetra(isopropoxide),24 where an over-
oxidation was avoided by utilization of only 0.5 equiv of the oxidant
Table 1
Synthesis of methylidene oxathiane S-oxides (Scheme 6)
# Conditions (equiv)
Products (%)
1 tBuOOH (1), CH2Cl2, rt, 2 d21
Undefined products
20 (Traces)a
20a
2 H2O2 (2), TMSCl (1), MeCN, rt, 2 h22
3 mCPBA (1), CH2Cl2, rt, 12 h21
4 H2O2 (1), VCl3 (0.05) THF, 0 ꢁC, 5 min23
20 (40), 18a
5 Cumene hydroperoxide (1), Ti(OiPr)4 (1) CH2Cl2, rt, 24 h 18 (57)
6 tBuOOH (1), Ti(OiPr)4 (1), CH2Cl2, 0 ꢁC to rt, 18 h24
7 tBuOOH (0.9), Ti(OiPr)4 (1), CH2Cl2, 0 ꢁC to rt, 12 h24
18a
20/24 (14), 18 (41)
8 tBuOOH (0.5), Ti(OiPr)4 (1), CH2Cl2, ꢂ78 ꢁC to rt, 12 h24 20 (21), 24 (21)
a
Scheme 7. Nucleophilic additions to alkylidene bissulfoxides.
Not isolated. Detection by TLC.

1264
D. Weingand et al. / Tetrahedron 71 (2015) 1261e1268
When similar reactions were performed with conformationally
validity of our analysis). Because of the low reactivity and thus too
much side reactions, reaction rates of other addition reactions
could not be determined properly (e.g., 23 with piperidine, 25 with
the dimethyl malonate anion). It turned out that the addition of
ethanethiolate to the axial vinyl sulfoxide 25 is over 100 times
faster than that to the equatorial sulfoxide 23 (Table 3, entries 1 and
2). This is in line with our assumption that the intermediately
constrained alkylidene dithiane monoxides, the rate of the nucle-
ophilic attacks was not high2 and selectivities were only moderate.
The latter seemed to be due to a competing effect of different
stereoelectronic interactions (nC/
s
*
vs nC/
s SeO).
*
SeC
Significantly different results were obtained in nucleophilic
additions to the corresponding oxathiane derivatives 23 and 25.
Results for a variety of additions are given in Scheme 8 and Table 2.
Addition of sulfur, oxygen, and nitrogen nucleophiles (entries 1ꢂ5)
exclusively yielded adducts with an equatorial substituent in po-
sition C-2. This supports the reasoning that the absence of one
formed carbanion is significantly stabilized by an nC/
s
*
in-
SeO
teraction only possible in sulfoxide 29eq. The addition of piperidine
to 2-methylidene 1,3-oxathianes is about 1000 times slower than
addition to the respective 1,3-dithiane derivatives (entries 3 and 4).
competing nC/
s
*
interaction puts forward other effects and
The special ability of sulfur atoms to stabilize negative charges in
a
-
SeC
favors an axial lone pair at C-2 (giving rise to equatorially
substituted products). Yield and reaction rates were higher with
good nucleophiles like ethanethiolate, piperidine (entries 1 and 3),
but these criteria were especially influenced by the acceptors’
configuration. The axial monosulfoxide reacted significantly faster
than its equatorial analog (vide infra) and yields turned out to be
significantly higher. Addition of the dimethyl malonate anion led to
a mixture of both diastereoisomers with a slight preference for the
axial product 31ax (entry 6). A similar deviation with this nucleo-
phile had already been observed with the corresponding dithiane
analogs.2b Thermodynamic effects might be relevant in this case,
but an unambiguous explanation for this observation is still miss-
ing. No reaction occurred, when equatorial sulfoxide 23 was reac-
ted with the malonate anion (entry 7). Here a low nucleophilicity
comes along with a significantly smaller reactivity of the equatorial
sulfoxide.
position is well-known from various investigations.27
Table 3
Reaction ratesa
#
Sulfoxide
Nucleophile
Time
Yield [%]
k [L molꢂ1 sꢂ1
]
1
2
3
4
5
25
23
25
1
EtSH, NaH
EtSH, NaH
Piperidine
Piperidine
Piperidine
6.5 h
27 d
20 d
5.5 h
26 h
85
50
45
62
67
1.8ꢀ10ꢂ4
1.3ꢀ10ꢂ6
1.0ꢀ10ꢂ6
1.0ꢀ10ꢂ3
1.0ꢀ10ꢂ5
2
a
All reactions were performed in dimethyl sulfoxide-d6 at room temperature.
4. Conclusion
Conformationally constrained 2-methylene 1,3-oxathiane S-ox-
ides are suitable substrates for a nucleophilic addition of S-, N, and
C-nucleophiles. It turned out that sulfoxides with an axial SeO
bond are over 100 times more reactive than the respective equa-
torially oriented sulfoxides. Oxathianes are about 1000 times less
reactive than the respective 1,3-dithiane derivatives.
5. Experimental section
5.1. General
Scheme 8. Nucleophilic additions to methylidene oxathiane S-oxides.
Abbreviations: mCPBA, meta-chloroperbenzoic acid; NBO, nat-
ural bond orbital; TBDMS, tert-butyl-dimethylsilyl; DBU, 1,8-
diazabicyclo[5.4.0]undec-7-en; Tos, para-toluenesulfonyl. Anhy-
drous solvents were used as purchased. All moisture-sensitive re-
actions were carried out under oxygen-free argon using oven-dried
glassware and a vacuum line. Flash column chromatography28 was
carried out using Merck silica gel 60 (230e400 mesh) and thin layer
chromatography (TLC) was carried out using commercially avail-
able Merck F254 pre-coated sheets. 1H and 13C NMR spectra were
recorded on a Bruker Avance AV 300, an AV-400 or a DRX 500.
Chemical shifts are given in parts per million down field of tetra-
methylsilane. 13C NMR spectra were recorded with broad band
proton decoupling and were assigned using DEPT 135 and DEPT 90
experiments. IR spectra were recorded on a Bruker IFS-88 spec-
trometer. Electrical ionization and high-resolution mass spectra
were recorded on a Finnigan MAT-95.
Table 2
Nucleophilic additions to methylidene oxathiane S-oxides
#
Sulfoxide
Nucleophile
Product
Yield [%]
Ratio
1
2
3
4
5
6
7
25
23
25
23
23
25
23
EtSH, NaH
EtSH, NaH
Piperidine
29eq
32eq
30eq
86
19
83
db
8
0:100
0:100
0:100
Piperidine
MeOH, NaHa
33eq
31ax/31eq
0:100
70:30
Dimethyl malonate, NaH
Dimethyl malonate, NaH
25
db
a
33eq was obtained as a side product of entry 2.
No conversion.
b
To allow for the comparison with dithiane derivatives we per-
formed kinetic investigations and determined reaction rates for the
addition of ethanethiol and piperidine. It already had turned out
that the addition to 2-methylidene 1,3-oxathiane S-oxides is slower
than addition to the respective dithianes; a quantitative de-
termination of reaction rates in the addition of ethanethiol and
piperidine, respectively, was possible with the help of 1H NMR
spectroscopy, where the conversion was monitored by integration
of the vinylic signals. The analysis was made assuming a second
order reaction, where details of the method had been described
earlier.2 A higher order reaction (e.g., with more than 1 equiv of the
piperidine cannot be excluded, but would not alter the general
5.2. S-[2-(Hydroxymethyl)-3,3-dimethylbutyl] ethanethioate
(9)
Potassium thioacetate (3.64 g, 31.8 mmol) was added to a solu-
tion of 2-(hydroxymethyl)-3-3-dimethylbutyl 4-methylbenzene-
sulfonate (7.60 g, 26.5 mmol) in DMF (20 mL) and the mixture
was stirred for 40 min at 80 ꢁC, cooled to rt, and concentrated. The
precipitate was suspended with EtOAc and filtered. The filtrate was
concentrated and purified by column chromatography (silica gel,
cyclohexane/EtOAc, 20:1/10:1) to yield thioester 9 (2.27 g,
11.9 mmol, 45%) as yellow evil-smelling oil. Rf¼0.52 (cyclohexane/

D. Weingand et al. / Tetrahedron 71 (2015) 1261e1268
1265
(cmꢂ1)¼3489 (m), 2961 (s), 1739 (s), 1690
3.4, 5.9, 8.2, 8.2 Hz, 1H, 5-H), 2.26 (br s, 1H, OH), 2.82 (m, 1H, 6-H),
2.84 (m, 1H, 6-H), 3.41 (t, 3J 11.5 Hz, 1H, 2-H), 3.70 (dd, 2J 1.0 Hz, 3J
3.3 Hz, 1H, 4-H), 3.71 (m, 1H, 4-H), 4.28 (dd, 2J 4.0 Hz, 3J 11.6 Hz, 1H,
~
EtOAc, 2:1); IR (film):
n
(m), 1473 (m), 1367 (m), 1243 (s), 1040 (m), 960 (w), 634 (w); 1H
NMR (400 MHz, CDCl3) d
0.92 (s, 9H, tBu), 1.42 (dd, 3J 8.1, 8.1 Hz, 1H,
OH), 1.50 (dddd, 3J 3.2, 4.6, 4.6, 7.8 Hz, 1H, CH), 2.02 (s, 3H, CH3),
2.44 (ddd, 3J 8.3, 9.6 Hz, 2J 13.5 Hz, 1H, SCH2), 2.74 (ddd, 3J 3.2,
8.0 Hz, 2J 13.5 Hz, 1H, SCH2), 4.17 (dd, 3J 4.7 Hz, 2J 11.6 Hz, 1H, OCH2),
4.36 (dd, 3J 4.4 Hz, 2J 11.6 Hz, 1H, OCH2); 13C NMR (100 MHz, CDCl3)
10-H), 4.79 (dd, 2J 4.0 Hz, J 6.0 Hz, 1H, 10-H); 13C NMR (100 MHz,
3
CDCl3) d 27.3 (s), 28.7 (d), 32.1 (q), 44.9 (t), 64.8 (d), 71.8 (d), 83.0 (t);
m/z (FAB) 191 (MHþ); HRMS (FAB): MHþ, found 191.1098. C9H19O2S
requires 191.1100.
d
21.0 (s), 22.6 (d), 28.1 (s), 33.3 (q), 51.1 (t), 63.0 (d), 170.9 (q); m/z
(EI) 190 (Mþ); HRMS (EI): Mþ, found 190.1027. C9H18O2S requires
190.1028.
5.6. (2S,5S)-(5-tert-Butyl-1,3-oxathian-2-yl)methyl 4-
methylbenzenesulfonate (12)
5.3. 2-(Mercaptomethyl)-3,3-dimethylbutan-1-ol (4)
Et3N (1 mL) and TosCl (392 mg, 2.06 mmol) were added to
a solution of alcohol 8 (356 mg, 1.87 mmol) in CH2Cl2 (10 mL) and
the mixture was stirred for 24 h at rt. H2O (5 mL) was added and the
aqueous layer was extracted with CH2Cl2 (3ꢀ3 mL). The combined
organic layers were dried (Na2SO4), concentrated, and purified by
column chromatography (silica gel, cyclohexane/EtOAc, 2:1) to
yield tosylate 12 (628 mg, 1.82 mmol, 97%) as a colorless solid.
~
HCl (1.4 M, 2 mL AcCl in 20 mL MeOH) was added to thioester 9
(2.27 g, 11.9 mmol) and the mixture was heated to reflux for 4 h,
cooled to rt, and concentrated to yield thiol 4 (1.76 g, quant.) as
a yellowish oil, which was used without further purification. 1H
NMR (300 MHz, CDCl3)
d 0.92 (s, 9H, tBu), 1.38 (m, 1H, 2-H), 1.49
(dd, 3J 7.1, 8.9 Hz, 1H, SH), 2.10 (m, 1H, OH), 2.50 (ddd, 3J 8.8, 9.8 Hz,
2J 13.3 Hz, 1H, 1-H), 2.84 (ddd, 3J 3.5, 7.0 Hz, 2J 13.4 Hz, 1H, 1-H), 3.74
(dd, 3J 5.6 Hz, 2J 11.4 Hz, 1H, 3-H), 3.92 (ddd, 3J 0.6, 3.8 Hz, 2J 11.4 Hz,
1H, 3-H).
Rf¼0.60 (cyclohexane/EtOAc, 2:1); IR (ATR):
n
(cmꢂ1)¼2952 (w),
2867 (w), 1367 (m), 1188 (s), 1083 (s), 1005 (s), 812 (m), 784 (m),
663 (m), 552 (s); 1H NMR (400 MHz, CDCl3)
d 0.87 (s, 9H, tBu), 1.62
(m, 1H, 5-H), 2.45 (s, 3H, ArCH3), 2.81 (m, 2H), 3.32 (dd, J 11.2,
11.8 Hz, 1H), 4.09 (m, 2H), 4.21 (ddd, 4J 1.7 Hz, 3J 3.3 Hz, 2J 11.8 Hz,
1H), 4.90 (dd, 4J 3.8 Hz, 3J 6.7 Hz, 1H, 2-H), 7.34 (d, 3J 8.3 Hz, 2H, Ar),
5.4. (S)-5-tert-Butyl-1,3-oxathiane (11)
7.80 (d, 3J 8.3 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3)
d 21.7 (s), 27.3
A solution of thiol 4 (1.56 g, 10.5 mmol) in CHCl3 (5 mL) was
added dropwise via the reflux condenser to a boiling solution of
CH2(OMe)2 (800 g, 10.5 mmol) and BF3$OEt2 (2,66 mL, 21.0 mmol)
in CHCl3 (20 mL). The mixture was cooled and saturated aqueous
NaHCO3 solution (10 mL) was added. The organic layer was
extracted with CH2Cl2 (3ꢀ5 mL) and the combined organic layers
were dried (Na2SO4), concentrated to yield oxathiane 11 (1.70 g,
10.6 mmol, quant.) as a yellowish oil, which was used without
~
(s), 29.0 (d), 32.1 (q), 44.3 (t), 70.6 (d), 71.7 (d), 79.7 (t), 128.1 (t),
129.8 (t), 132.7 (q), 144.9 (q); m/z (EI) 344 (Mþ); HRMS (EI): Mþ,
found 344.1113. C16H24O4S2 requires 344.1111.
5.7. (2S,5S)-O-[(5-tert-Butyl-1,3-oxathian-2-yl)methyl] S-
methyl carbonodithioate (13)
A solution of alcohol 8 (1.61 g, 8.46 mmol) in THF (10 mL) was
added dropwise at 0 ꢁC to a suspension of NaH (305 mg, 12.7 mmol)
in THF (15 mL). CS2 (2.55 mL, 42.3 mmol) was added and the
mixture was heated to 60 ꢁC for 5 h and cooled to rt. MeI (3.16 mL,
50.8 mmol) was added and stirring was continued for 1 h. The
reaction was stopped by addition of saturated aqueous NH4Cl so-
lution (5 mL), the aqueous layer was extracted with EtOAc
(3ꢀ10 mL), and the combined organic layers were dried (Na2SO4),
concentrated, and purified by column chromatography (silica gel,
cyclohexane/EtOAc, 10:1) to yield xanthogenate 13 (1.95 g,
7.00 mmol, 82%) as dark yellow evil-smelling oil. Rf¼0.69 (cyclo-
~
further purification. Rf¼0.30 (cyclohexane/EtOAc, 5:1); IR (ATR):
n
(cmꢂ1)¼2955 (m), 2872 (w), 1736 (m), 1467 (m), 1365 (m), 1229
(m), 1033 (s), 918 (w), 736 (w); 1H NMR (400 MHz, CDCl3)
d 0.89 (s,
9H, tBu), 1.74 (m, 1H, 5-H), 2.75 (dd, 3J 11.9 Hz, 2J 11.9 Hz, 1H, 6-Hax),
2.78 (m, 1H, 6-Heq), 3.32 (dd, 3J 11.2 Hz, 2J 11.6 Hz, 1H, 4-Hax), 4.20
(dddd, 4J 0.6, 1.6 Hz, 3J 3.4 Hz, 2J 11.6 Hz, 1H, 4-Heq), 4.70 (d, 2J
10.9 Hz, 1H, 2-H), 4.76 (ddd, 4J 0.6, 1.6 Hz, 2J 10.8 Hz, 1H, 2-Heq); 13
C
NMR (100 MHz, CDCl3) d 27.2 (s), 28.7 (t), 32.3 (q), 45.5 (d), 70.8 (d),
71.7 (d). The substance was too volatile for mass spectrometry.
5.5. (2S,5S)-(5-tert-Butyl-1,3-oxathian-2-yl)methanol (8)
hexane/EtOAc, 10:1); IR (ATR):
n
(cmꢂ1)¼2957 (m), 2868 (w), 1647
(w), 1366 (w), 1078 (s), 865 (m), 698 (w); 1H NMR (400 MHz, CDCl3)
A solution of thiol 4 (865 mg, 5.83 mmol) and TBDMSO-
acetaldehyde (90%, 1.13 g, 5.83 mmol) in CH2Cl2 (8 mL) was
added dropwise via the reflux condenser to a solution of BF3$OEt2
(1.48 mL, 11.7 mmol) in CH2Cl2 (40 mL). Stirring was continued for
further 10 min and saturated aqueous NaHCO3 solution (20 mL)
was added. The organic layer was extracted with EtOAc (3ꢀ15 mL)
and the combined organic layers were dried (Na2SO4), concen-
trated, and purified by column chromatography (silica gel, cyclo-
hexane/EtOAc, 5:1) to yield oxathiane 8 (784 mg, 4.11 mmol, 70%)
as colorless oil, which solidified after a while.
d
0.90 (s, 9H, tBu), 1.70 (m, 1H, 5-H), 2.56 (s, 3H, SCH3), 2.85 (m, 2H),
2.75 (s,1H), 3.42 (t, 2J 11.5 Hz,1H), 4.29 (m,1H), 4.71 (d, 3J 5.1 Hz, 2H,
10-H), 5.08 (t, 3J 5.1 Hz, 1H, 2-H); 13C NMR (100 MHz, CDCl3)
19.2
d
(s), 27.3 (s), 29.0 (d), 32.1 (q), 44.4 (t), 71.9 (d), 73.8 (d), 79.7 (t),
215.5 (q); m/z (EI) 280 (Mþ); HRMS (EI): Mþ, found 280.0622.
C
11H20O2S3 requires 280.0620.
5.8. 6-tert-Butyl-6,7-dihydro-5H-1,4-oxathiepine (14)
Xanthogenate 13 (3.11 g, 11.1 mmol) was pyrolyzed at 450 ꢁC in
vacuo in a pyrolysis apparatus. Purification by column chroma-
tography (silica gel, cyclohexane/EtOAc, 20:1) to yield olefin 14
(663 mg, 3.85 mmol, 35%) as smelly yellow oil. The xanthogenate
could partially be recovered. Rf¼0.84 (cyclohexane/EtOAc, 10:1); IR
~
Alternative preparation: Glycolaldehyde dimer (260 mg,
2.16 mmol) was added to a solution of acetyl chloride (1 mL) in
MeOH (10 mL) and the mixture was stirred at rt overnight, con-
centrated, and dissolved in CH2Cl2 (15 mL). A solution of thiol 4
(520 mg, 3.51 mmol) and BF3$OEt2 (0.89 mL, 7.01 mmol) in CH2Cl2
(3 mL) was added dropwise via a reflux condenser. Stirring was
continued for further 10 min. Work-up was performed according to
the protocol described above (519 mg, 2.73 mmol, 81%). Rf¼0.42
~
(ATR):
n
(cmꢂ1)¼2958 (m), 2867 (w), 1601 (s), 1468 (w), 1366 (w),
1266 (m), 1231 (m), 1081 (s), 876 (m), 719 (m), 471 (m); 1H NMR
(400 MHz, CDCl3)
d
0.97 (s, 9H, tBu), 1.85 (m, 1H, 5-H), 2.98 (tdd, 4J
1.0 Hz, 3J 5.8 Hz, 2J 13.9 Hz, 1H, 6-Heq), 3.30 (dd, 3J 9.8 Hz, 2J 14.0 Hz,
1H, 6-Hax), 4.29 (ddd, 4J 1.0 Hz, 3J 3.3 Hz, 2J 12.6 Hz, 1H, 4-Heq), 4.79
(dd, 3J 4.7 Hz, 2J 12.7 Hz, 1H, 4-Hax), 4.97 (ddd, 4J 0.9, 0.9 Hz, 3J
6.2 Hz, 1H, 2-H), 6.37 (d, 3J 6.3 Hz, 1H, 3-H); 13C NMR (100 MHz,
(cyclohexane/EtOAc, 2:1); IR (ATR):
n
(cmꢂ1)¼3227 (w), 2957 (m),
1469 (w), 1365 (m), 1256 (w), 1080 (m), 1033 (s), 995 (w), 840 (w),
776 (s). 1H NMR (400 MHz, CDCl3)
d
0.89 (s, 9H, tBu), 1.68 (dddd, 3J

1266
D. Weingand et al. / Tetrahedron 71 (2015) 1261e1268
CDCl3)
d
27.9 (s), 33.2 (q), 33.6 (t), 49.8 (d), 71.7 (d), 99.6 (t), 146.6
(silica gel, CH2Cl2/acetone, 3:2) to yield a mixture of sulfoxides 20
and 24 (1:1.1, 266 mg, 1.29 mmol, 42%), which could not be sepa-
rated. Not converted alcohol was recovered. Both isomers: Rf¼0.30
~
(t); m/z (EI) 172 (Mþ); HRMS (EI): MHþ, found 172.0916. C9H16OS
requires 172.0916.
(CH2Cl2/acetone, 2:1). Compound 20: IR (ATR):
n
(cmꢂ1)¼3324 (w),
5.9. (2S,5S)-5-tert-Butyl-2-(hydroxymethyl)-1,3-oxathiane
3,3-dioxide (18)
2956 (w), 2868 (w), 1366 (w), 1082 (m), 1010 (s), 607 (w); 1H NMR
(400 MHz, CDCl3) d
0.97 (s, 9H, tBu), 1.83 (dddd, 3J 2.4, 3.9, 11.2,
12.9 Hz,1H, 5-H), 2.59 (dd, 2J 11.8 Hz, 3J 12.7 Hz,1H, 6-Hax), 3.48 (dd,
3J 11.3 Hz, 2J 11.3 Hz, 1H, 4-Hax), 3.67 (ddd, 4J 2.3 Hz, 3J 2.3 Hz, 2J
11.6 Hz,1H, 6-Heq), 4.06 (dd, 3J 3.7 Hz,1H, 2-H), 4.12 (d, 3J 3.7 Hz, 2H,
10-H), 4.20 (ddd, 4J 2.1 Hz, 3J 3.9 Hz, 2J 11.5 Hz, 1H, 4-Heq); 13C NMR
Oxone (3.73 g, 6.07 mmol) was added to a solution of alcohol 8
(519 mg, 2.73 mmol) in THF/H2O (1:1, 20 mL) and the mixture was
stirred for 18 h at rt and filtered. The filtrate was concentrated to
remove most of the THF and the aqueous layer was extracted with
CH2Cl2 (3ꢀ10 mL) and the combined organic layers were dried
(Na2SO4), concentrated, and purified by column chromatography
(silica gel, CH2Cl2/acetone, 5:1) to yield sulfone 18 (507 mg,
2.28 mmol, 90%) as a colorless solid. Rf¼0.50 (CH2Cl2/acetone, 5:1);
~
(100 MHz, CDCl3)
d 27.5 (s), 32.1 (q), 44.7 (d), 52.3 (t), 60.4 (t), 71.5
(t), 97.3 (d); m/z (EI) 206 (Mþ); HRMS (EI): Mþ, found 206.0970.
C9H18O3S requires 206.0971.
5.12. (2S,3S,5S)-O-[(5-tert-Butyl-3-oxido-1,3-oxathian-2-yl)-
methyl] S-methyl carbonodithioate (21)
IR (ATR):
n
(cmꢂ1)¼3304 (w), 2959 (w), 2877 (w), 1300 (s), 1098 (s),
870 (m), 519 (s); 1H NMR (400 MHz, CDCl3)
d 0.95 (s, 9H, tBu), 2.38
(dddd, 3J 3.3, 3.3, 11.2, 13.0 Hz, 1H, 5-H), 2.95 (dd, 3J 12.9 Hz, 2J
13.9 Hz, 1H, 4-Hax or 6-Hax), 3.27 (ddd, 4J 2.2 Hz, 3J 3.1 Hz, 2J 13.8 Hz,
Sulfoxide 20 (134 mg, 0.650 mmol) was reacted according to the
procedure given for 13 to yield xanthogenate 21 (100 mg,
0.337 mmol, 52%) as a yellow oil. Rf¼0.35 (cyclohexane/EtOAc, 1:1);
~
1H, 4-Heq or 6-Heq), 3.54 (dd, 3J 11.1 Hz, 2J 12.1 Hz, 1H, 6-Hax or 4-
2
H
ax), 4.06 (dd, 3J 5.8 Hz, J 12.7 Hz, 1H, 10-H), 4.14 (dd, 3J 4.1 Hz, J
IR (ATR):
n
(cmꢂ1)¼2961 (w), 2871 (w), 1368 (m), 1201 (s), 1075 (s),
12.7 Hz, 1H, 1-H0), 4.36 (ddd, 4J 2.2 Hz, 3J 3.5 Hz, 2J 12.0 Hz, 1H, 6-Heq
1036 (s), 729 (m); 1H NMR (400 MHz, CDCl3)
d 0.97 (s, 9H, tBu), 1.87
or 4-Heq), 4.40 (dd, 3J 4.1, 5.8 Hz, 1H, 2-H); 13C NMR (100 MHz,
(dddd, 3J 2.2, 3.8, 11.4, 11.4 Hz, 1H, 5-H), 2.58 (s, 3H, SCH3), 2.60 (m,
1H, 6-Hax), 3.49 (ddd, 4J 1.6 Hz, 3J 11.4 Hz, 2J 11.5 Hz, 1H, 4-Hax), 3.70
(ddd, 4J 2.2 Hz, 3J 2.2 Hz, 2J 11.8 Hz, 1H, 6-Heq), 4.21 (ddd, 4J 1.9 Hz, 3J
3.8 Hz, 2J 11.5 Hz, 1H, 4-Heq), 4.31 (dd, 3J 1.9, 5.3 Hz, 1H, 2-H), 4.99
(dd, 3J 5.4 Hz, 2J 12.3 Hz, 1H, 10-H), 5.13 (dd, 3J 1.9 Hz, 2J 12.2 Hz, 1H,
CDCl3) d 27.2 (s), 31.9 (q), 46.0 (t), 53.2 (d), 58.0 (d), 71.3 (d), 92.1 (t);
m/z (FAB) 223 (MHþ); HRMS (FAB): MHþ, found 223.0997. C9H19O4S
requires 223.0999.
5.10. (S)-5-tert-Butyl-2-methylene-1,3-oxathiane 3,3-dioxide
(17)
10-H); 13C NMR (100 MHz, CDCl3)
d 19.3 (s), 27.4 (s), 32.1 (q), 44.6 (t),
53.0 (d), 69.5 (d), 71.7 (d), 95.1 (t), 215.3 (q); m/z (FAB) 297 (MHþ);
HRMS (FAB): MHþ, found 297.0647. C11H21O3S3 requires 297.0647.
Sulfone 18 (507 mg, 2.28 mmol) was converted into the xan-
thogenate according to the procedure given for 13. The elimination
occurred during work-up. Purification by column chromatography
(silica gel, cyclohexane/EtOAc, 2:1) yielded vinyl sulfone 17
(264 mg,1.29 mmol, 57%) as a colorless solid. Rf¼0.75 (cyclohexane/
~
5.13. (3S,5S)- and (3R,5S)-5-tert-Butyl-2-methylene-1,3-
oxathiane 3-oxide (23 and 25)
(A) NaH (7.92 mg, 0.330 mmol) was added under Ar to a solution of
xanthogenate 20 (98.0 mg, 0.330 mmol) in THF (10 mL). The
suspension was heated to reflux for 1 h, cooled to rt, and sat-
urated aqueous NH4Cl solution was added. Most of the THF was
removed at reduced pressure and the remnant was dissolved in
CH2Cl2/H2O (1:1, 10 mL). The aqueous layer was extracted with
CH2Cl2 (3ꢀ5 mL), and the combined organic layers were dried
(Na2SO4), concentrated, and purified by column chromatogra-
phy (silica gel, cyclohexane/EtOAc, 2:1) yielding vinyl sulfoxide
23 (33 mg, 0.175 mmol, 53%) as a colorless solid.
EtOAc, 1:1); IR (ATR):
n
(cmꢂ1)¼2964 (w), 1643 (m), 1297 (s), 1095
(s), 1037 (m), 910 (m), 851 (m), 506 (m); 1H NMR (400 MHz, CDCl3)
d
0.96 (s, 9H, tBu), 2.55 (m, 1H, 5-H), 2.96 (dd, 3J 12.7 Hz, 2J 13.6 Hz,
1H, 4-Hax or 6-Hax), 3.34 (dddd, 4J 0.8, 2.3 Hz, 3J 3.0 Hz, 2J 13.7 Hz,
1H, 4-Heq or 6-Heq), 3.74 (dd, 3J 11.4 Hz, 2J 11.4 Hz, 1H, 6-Hax or 4-
H
ax), 4.44 (ddd, 4J 2.2 Hz, 3J 3.6 Hz, 2J 11.5 Hz, 1H, 6-Heq or 4-Heq),
5.27 (d, 2J 2.8 Hz, 1H), 5.63 (d, 2J 2.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 27.2 (s), 32.0 (q), 45.6 (t), 53.2 (d), 73.5 (d), 103.1 (d), 158.1
(q); m/z (FAB) 205 (MHþ); HRMS (FAB): MHþ, found 205.0891.
C9H17O3S requires 205.083.
(B) NaH (100 mg, 4.17 mmol) was added to a solution of tosylate 22
(1.05 g, 2.92 mmol) in THF (30 mL) and the suspension was
heated to reflux for 12 h. Work-up as given under (A) yielded
vinyl sulfoxide 23 (558 mg, 2.92 mmol, quant.) as a beige solid.
(C) A mixture of 22 and 25 (1:1, 1.64 g, 4.55 mmol) was reacted
according to the protocol (A) to yield vinyl sulfoxides 23
(304 mg, 1.62 mmol, 36%) and 25 (294 mg, 1.56 mmol, 34%) as
colorless solids. Compound 23: Rf¼0.44 (cyclohexane/EtOAc,
~
5.11. (2S,3S,5S)- and (2S,3R,5S)-5-tert-Butyl-2-(hydrox-
ymethyl)-1,3-oxathiane 3-oxide (20 and 24)
Oxone (315 mg, 0.51 mmol) was added at 0 ꢁC to a solution of
alcohol 72 (195 mg, 1.02 mmol) in THF/H2O (1:1, 10 mL) and the
mixture was stirred at rt for 1 h and filtered. The filtrate was con-
centrated to remove most of the THF and the aqueous layer was
extracted with CH2Cl2 (3ꢀ8 mL) and the combined organic layers
were dried (Na2SO4), concentrated, and purified by column chro-
matography (silica gel, CH2Cl2/acetone, 3:2) to yield sulfoxide 20
(135 mg, 0.65 mmol, 64%) as a colorless solid.
1:1); IR (ATR):
n
(cmꢂ1)¼2962 (w), 2877 (w), 1637 (m), 1160
(m), 1047 (s), 897 (s); 1H NMR (400 MHz, CDCl3)
d 0.93 (s, 9H,
tBu), 2.01 (dddd, 3J 3.3, 3.3, 11.6, 13.0 Hz, 1H, 5-H), 2.63 (dd, 2J
11.3 Hz, 3J 12.7 Hz, 1H, 4-Hax), 3.56 (m, 1H, 4-Heq), 3.59 (ddd, 4J
1.0 Hz, 3J 11.1 Hz, 2J 11.1 Hz, 1H, 6-Hax), 4.27 (ddd, 4J 2.5 Hz, 3J
3.7 Hz, 2J 11.0 Hz,1H, 6-Heq), 5.27 (ddd, J 1.0,1.0 Hz, 2J 2.6 Hz,1H,
]CHaHb), 5.34 (dd, J 1.0 Hz, 2J 2.7 Hz, 1H, ]CHaHb); 13C NMR
Alternative protocol: Ti(OiPr)4 (909 mL, 3.04 mmol) was added
under Ar to a solution of alcohol 8 (578 mg, 3.04 mmol) in CH2Cl2
(10 mL). After 10 min the solution was cooled to ꢂ78 ꢁC and
(100 MHz, CDCl3)
d 27.4 (s), 32.2 (q), 44.5 (t), 53.5 (d), 73.9 (d),
tBuOOH (6 M, 254
mL, 1.52 mmol) was added dropwise within
99.7 (d), 164.2 (q); m/z (FAB) 189 [MHþ]; HRMS (FAB): MHþ,
10 min. The mixture was allowed to warm to rt within 2 h and H2O
(5 mL) was added. After vigorous stirring for 5 min, the mixture was
filtered and the aqueous layer of the filtrate was extracted with
CH2Cl2 (2ꢀ3 mL). The combined organic layers were dried
(Na2SO4), concentrated, and purified by column chromatography
found 189.0945. C9H17O2S requires 189.0944. Compound 25:
Rf¼0.23 (cyclohexane/EtOAc,1:1); IR (ATR):
n
(cmꢂ1)¼2964 (w)
~
2875 (w), 1622 (m), 1169 (m), 1034 (s), 893 (m), 563 (m), 452
(m); 1H NMR (400 MHz, CDCl3)
3.21 (m, 1H), 3.80 (m, 1H), 4.45 (m, 1H), 5.10 (dd, 4J 0.7 Hz, 3J
d 0.96 (s, 9H, tBu), 2.63 (m, 2H),

D. Weingand et al. / Tetrahedron 71 (2015) 1261e1268
1267
2.1 Hz, 1H, ]CHaHb), 5.13 (d, 3J 2.0 Hz, 1H, ]CHaHb); 13C NMR
saturated aqueous NH4Cl solution (1 mL) was added and most of
the MeOH was removed in vacuo. The remnant was dissolved in
CH2Cl2/H2O (1:1, 10 mL) and the aqueous layer was extracted with
CH2Cl2 (2ꢀ3 mL). The combined organic layers were dried
(Na2SO4), concentrated, and purified by columns chromatography
(silica gel, CH2Cl2/acetone, 10:1/5:1) to yield adduct 32eq (25 mg,
0.100 mmol, 19%) as a colorless solid together with MeOH adduct
33eq (10 mg, 0.045 mmol, 3%) and starting material 23 (3 mg,
0.016 mmol, 3%). Compound 32eq: Rf¼0.77 (CH2Cl2/acetone, 5:1); IR
(100 MHz, CDCl3)
d 27.3 (s), 31.8 (q), 33.9 (t), 47.9 (d), 72.8 (d),
104.1 (d), 160.3 (q); m/z (FAB) 189 (MHþ); HRMS (FAB): MHþ,
found 189.0946. C9H17O2S requires 189.0944.
5.14. (2S,3S,5S)- and (2S,3R,5S)-(5-tert-Butyl-3-oxido-1,3-
oxathian-2-yl)methyl 4-methylbenzenesulfonate (22 and 26)
(ATR): (cmꢂ1)¼2960 (m), 2870 (w), 1469 (w), 1368 (m), 1107 (m)
~
n
Alcohols 20 and 24 (1:1, 780 mg, 3.79 mmol) were reacted
according to the procedure given for tosylate 12 to yield a mixture
of tosylates 22 und 26 (1.05 g, 2.92 mmol, 98%) as a viscous oil,
which solidified after a while. Compound 22: Rf¼0.47 (CH2Cl2/ace-
~
1036 (s), 978 (m); 1H NMR (400 MHz, CDCl3)
d
0.94 (s, 9H, tBu), 1.25
(t, 3J 7.4 Hz, 3H, CH2CH3), 1.83 (dddd, 3J 2.4, 3.9, 11.2, 13.1 Hz, 1H, 5-
H), 2.53 (dd, 2J 11.8 Hz, 3J 12.8 Hz, 1H, 6-Hax), 2.65 (q, 3J 7.4 Hz, 2H,
CH2CH3), 2.95 (dd, 3J 8.6 Hz, 2J 14.3 Hz, 1H, CHaHbSEt), 3.24 (dd, 3J
2.2 Hz, 2J 14.3 Hz,1H, CHaHbSEt), 3.44 (dd, 3J 11.4,11.4 Hz,1H, 4-Hax),
3.62 (ddd, 4J 2.3 Hz, 3J 2.3 Hz, 2J 11.7 Hz, 1H, 6-Heq), 4.09 (dd, 3J 2.2,
8.6 Hz, 1H, 2-H), 4.18 (ddd, 4J 2.2 Hz, 3J 3.9 Hz, 2J 11.5 Hz, 1H, 4-Heq);
tone, 5:1); IR (ATR):
n
(cmꢂ1)¼3226 (w), 2957 (w), 2872 (w), 1365
(m), 1180 (m), 1032 (s), 970 (m), 551 (m); 1H NMR (400 MHz, CDCl3)
d
0.87 (s, 9H, tBu), 1.72 (m, 1H, 5-H), 2.38 (s, 3H, ArCH3), 2.47 (dd, J
11.8, 12.6 Hz, 1H, 4-Hax or 6-Hax), 3.33 (t, 3J 11.5 Hz, 1H, 2-H), 3.58
(m, 1H, 6-Hax or 4-Hax), 4.08 (m, 2H, 10-H), 4.36 (ddd, 4J 0.7 Hz, 3J
5.9 Hz, 2J 11.4 Hz, 1H, 4-Heq or 6-Heq), 4.45 (ddd, J 1.1, 2.1 Hz, 2J
11.6 Hz, 1H, 6-Heq or 4-Heq), 7.29 (d, 3J 8.1 Hz, 2H, Ar), 7.74 (d, 3J
13C NMR (100 MHz, CDCl3)
d 14.6 (s), 27.3 (d), 27.4 (s), 31.7 (d), 32.1
(q), 44.8 (t), 52.5 (d), 71.7 (d), 98.2 (t); m/z (FAB) 251 (MHþ); HRMS
(FAB): MHþ, found 251.1133. C11H23O2S2 requires 251.1134. Com-
8.2 Hz, 2H, Ar); 13C NMR (100 MHz, CDCl3)
d
21.6 (s), 27.4 (s), 32.1
n
pound 33eq: Rf¼0.57 (CH2Cl2/acetone, 5:1); IR (ATR): (cmꢂ1)¼
~
2958 (w), 2874 (w), 1469 (w), 1093 (s), 1036 (s); 1H NMR (400 MHz,
(q), 44.5 (t), 53.0 (d), 66.5 (d), 71.5 (d), 94.9 (t), 128.1 (t), 129.9 (t),
132.4 (q), 145.2 (q); m/z (FAB) 361 (MHþ); HRMS (FAB): MHþ, found
361.1136. C16H25O5S2 requires 361.1138. Compound 26: Rf¼0.69
~
CDCl3)
d
0.94 (s, 9H, tBu), 1.84 (dddd, 3J 2.3, 3.8, 11.1, 12.2 Hz, 1H, 5-
H), 2.53 (dd, 3J 11.9 Hz, 2J 12.7 Hz, 1H, 6-Hax), 3.44 (dd, 3J 11.3 Hz, 2J
11.3 Hz, 1H, 4-Hax), 3.45 (s, 3H, OCH3), 3.65 (ddd, 4J 2.2 Hz, 3J 2.2 Hz,
2J 11.6 Hz, 1H, 6-Heq), 3.87 (dd, 3J 2.3 Hz, 2J 11.2 Hz, 1H, CHaHbOCH3),
3.92 (dd, J 4.4 Hz, 2J 11.2 Hz, 1H, CHaHbOCH3), 4.07 (dd, 3J 2.2, 4.4 Hz,
1H, 2-H), 4.19 (ddd, 4J 2.2 Hz, 3J 3.9 Hz, 2J 11.5 Hz, 1H, 4-Heq); 13C
(CH2Cl2/acetone, 5:1); IR (ATR):
n
(cmꢂ1)¼3326 (m), 2959 (m), 1472
(w), 1367 (w), 1075 (s), 1010 (s), 971 (s), 848 (m), 582 (m); 1H NMR
(400 MHz, CDCl3)
d J
0.91 (s, 9H, tBu), 2.32 (m, 1H, 5-H), 2.45 (dd, 3
12.5 Hz, 2J 13.9 Hz, 1H, 6-Hax), 2.44 (s, 3H, ArCH3), 3.28 (ddd, 3J
2.5 Hz, 4J 2.5 Hz, 2J 13.8 Hz, 1H, 6-Heq), 3.50 (dd, 3J 11.4 Hz, 2J 11.4 Hz,
1H, 4-Hax), 4.20 (dd, 3J 6.6 Hz, 2J 11.0 Hz,1H, CHaHbOTs), 4.26 (ddd, 4J
2.7 Hz, 3J 3.6 Hz, 2J 11.8 Hz, 1H, 4-Heq), 4.28 (dd, 3J 6.2 Hz, 2J 11.0 Hz,
1H, CHaHbOTs), 4.40 (dd, 3J 6.4 Hz, 1H, 2-H); 13C NMR (100 MHz,
NMR (100 MHz, CDCl3) d 27.4 (s), 32.1 (q), 44.7 (t), 52.6 (d), 59.7 (s),
69.1 (d), 71.7 (d), 96.7 (t); m/z (FAB) 220 (Mþ); HRMS (EI): Mþ,
found 220.1126. C10H22O3S requires 220.1128.
CDCl3) d 21.7 (s), 27.2 (s), 31.4 (q), 32.2 (t), 46.2 (d), 66.3 (d), 71.4 (d),
5.17. (2S,3R,5S)-5-tert-Butyl-2-(piperidin-1-ylmethyl)-1,3-
87.9 (t), 128.1 (t), 130.0 (t), 132.0 (q), 135.4 (q).
oxathiane 3-oxide (30eq)
5.15. (2S,3R,5S)-5-tert-Butyl-2-(ethylthiomethyl)-1,3-
Piperidine (195 mL, 1.98 mmol) and DBU (1 drop) were added to
oxathiane 3-oxide (29eq)
a solution of vinyl sulfoxide 25 (93.0 mg, 0.49 mmol) in MeOH
(5 mL). The solution was heated for 5 d at 60 ꢁC and cooled to rt.
H2O (5 mL) and CH2Cl2 (20 mL) were added, the aqueous layer was
extracted with CH2Cl2 (2ꢀ2 mL), the combined organic layers were
dried (Na2SO4), concentrated, and purified by column chromatog-
raphy (silica gel, CH2Cl2/acetone, 2:1) to yield adduct 30eq (112 mg,
0.410 mmol, 83%) as a colorless solid. Rf¼0.16 (CH2Cl2/acetone, 2:1);
~
NaH (44.8 mg, 1.87 mmol) was added to a solution of vinyl
sulfoxide 25 (87.8 mg, 0.47 mmol) and ethanethiol (172
mL,
2.34 mmol) in MeOH (5 mL). After stirring for 24 h at rt saturated
aqueous NH4Cl solution (1 mL) was added and most of the MeOH
was removed in vacuo. The remnant was dissolved in CH2Cl2/H2O
(1:1, 10 mL) and the aqueous layer was extracted with CH2Cl2
(2ꢀ3 mL). The combined organic layers were dried (Na2SO4), con-
centrated, and purified by columns chromatography (silica gel,
CH2Cl2/acetone, 5:1) to yield adduct 29eq (101 mg, 0.403 mmol,
86%) as a colorless solid. Rf¼0.24 (cyclohexane/EtOAc, 1:1); IR
~
IR (ATR):
n
(cmꢂ1)¼3505 (w), 2936 (m), 2799 (w), 1467 (w), 1304
(w), 1100 (s), 1023 (s), 781 (m), 616 (m), 460 (m); 1H NMR
(400 MHz, CDCl3)
d 0.92 (s, 9H, tBu), 1.41 (m, 2H, piperidine), 1.57
(m, 4H, piperidine), 2.35 (m, 2H, 5-H, 6-Hax), 2.50 (m, 4H, piperi-
dine), 2.68 (ddd, 4J 0.6 Hz, 3J 6.2 Hz, 2J 13.6 Hz, 1H, CHaHbNR2), 2.87
(ddd, 4J 1.0 Hz, 3J 6.7 Hz, 2J 13.6 Hz, 1H, CHaHbNR2), 3.26 (dd, 3J
2.3 Hz, 2J 11.3 Hz, 1H, 6-Heq), 3.49 (dd, 3J 10.9 Hz, 2J 11.6 Hz, 1H, 4-
(ATR):
n
(cmꢂ1)¼2958 (w), 2872 (w), 1374 (w), 1080 (s), 1022 (s),
1009 (s), 972 (m), 602 (m), 452 (m); 1H NMR (400 MHz, CDCl3)
d
0.93 (s, 9H, tBu), 1.27 (t, 3J 7.4 Hz, 3H, CH2CH3), 2.35 (m, 1H, 5-H),
H
ax), 4.22 (ddt, 4J 0.9, 1.6 Hz, 3J 6.4 Hz, 1H, 2-H), 4.29 (ddd, 4J 3.0 Hz,
2.46 (dd, 3J 13.0 Hz, 2J 13.0 Hz, 1H, 6-Hax), 2.65 (q, 3J 7.4 Hz, 2H,
3J 3.0 Hz, 2J 11.5 Hz,1H, 4-Heq); 13C NMR (100 MHz, CDCl3)
d 23.9 (d),
CH2CH3), 2.95 (dd, 2J 1.9 Hz, 1H, 3J 6.9 Hz, CH2SEt), 3.32 (m, 1H, 6-
25.6 (d), 27.2 (s), 31.4 (q), 32.5 (t), 46.2 (d), 55.3 (d), 58.3 (d), 71.4 (d),
H
eq), 3.53 (dd, 3J 10.9 Hz, 2J 11.6 Hz, 1H, 4-Hax), 4.13 (t, J 6.9 Hz,
89.0 (t); m/z (FAB) 274 (MHþ); HRMS (FAB): MHþ, found 274.1836.
1H, 2-H), 4.31 (ddd, 4J 2.6 Hz, 3J 3.4 Hz, 2J 11.6 Hz, 1H, 4-Heq); 13C
C14H28NO2S requires 276.1835.
NMR (100 MHz, CDCl3) d 14.7 (s), 27.2 (s), 27.2 (d), 31.3 (q), 31.7 (d),
32.3 (t), 46.4 (d), 71.8 (d), 91.3 (t); m/z (FAB) 251 (MHþ); HRMS
5.18. (2R,3R,5S) and (2S,3R,5S) Dimethyl 2-[(5-tert-butyl-3-
oxido-1,3-oxathian-2-yl)methyl]malonate (31ax and 31eq)
(FAB): MHþ, found 251.1135. C9H17O2S requires 251.1135.
5.16. (2S,3S,5S)-5-tert-Butyl-2-(ethylthiomethyl)-1,3-
oxathiane 3-oxide (32eq) and (2S,3S,5S)-5-tert-butyl-2-(me-
thoxymethyl)-1,3-oxathiane 3-oxide (33eq)
NaH (38.6 mg, 1.61 mmol) was added to a solution of vinyl
sulfoxide 25 (75.6 mg, 0.40 mmol) and dimethyl malonate (185 mL,
1.61 mmol) in THF (6 mL) and the suspension was stirred for 22 d at
50 ꢁC. Saturated aqueous NH4Cl solution (1 mL) was added and
most of the THF was removed in vacuo. The remnant was dissolved
in CH2Cl2/H2O (1:1, 10 mL) and the aqueous layer was extracted
with CH2Cl2 (2ꢀ3 mL). The combined organic layers were dried
NaH (25.8 mg, 1.07 mmol) was added to a solution of vinyl
sulfoxide 23 (101 mg, 0.54 mmol) and ethanethiol (79.3
mL,
1.07 mmol) in MeOH (10 mL). After stirring for 23 d at 50 ꢁC

1268
D. Weingand et al. / Tetrahedron 71 (2015) 1261e1268
Chem. 2007, 72, 1143e1147; (l) Alabugin, I. V. J. Org. Chem. 2000, 65, 3910e3919;
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14014e14031.
(Na2SO4), concentrated, and purified by columns chromatography
(silica gel, cyclohexane/EtOAc, 1:1) to yield adducts 31ax (18.3 mg,
0.057 mmol, 14%) and 31eq (13.7, 0.043 mmol, 11%) as colorless
solids. Compound 31ax: Rf¼0.31 (cyclohexane/EtOAc, 1:2); IR (ATR):
~
€
2. (a) Ulshofer, R.; Podlech, J. J. Am. Chem. Soc. 2009, 131, 16618e16619; (b)
€
€
Ulshofer, R. Ph.D. thesis; Karlsruhe: Karlsruher Institut fur Technologie (KIT),
n
(cmꢂ1)¼2954 (m), 1732 (s), 1435 (m) 1154 (m), 1031 (s), 909 (w),
2010.
3. Podlech, J. J. Phys. Chem. A 2010, 114, 8480e8487.
831 (w), 729 (m); 1H NMR (400 MHz, CDCl3) 0.91 (d, 4J 1.5 Hz, 9H,
d
€
€
4. Ulshofer, R.; Wedel, T.; Suveges, B.; Podlech, J. Eur. J. Org. Chem. 2012,
tBu), 2.44 (m, 4H, 5-H, 6-Hax, 20-H), 3.27 (dddd, 4J 1.3, 2.5 Hz, 3J
2.6 Hz, 2J 13.6 Hz, 1H, 6-Heq), 3.44 (ddd, 4J 1.1 Hz, 3J 11.5 Hz, 2J
11.6 Hz, 1H, 4-Hax), 3.72 (d, 4J 1.4 Hz, 3H, OCH3), 3.72 (m, 1H, 10-H),
3.76 (d, 4J 1.5 Hz, 3H, OCH3), 4.23 (m, 1H, 2-H), 4.27 (m, 1H, 4-Heq);
6867e6877.
5. Eliel, E. L.; Hutchins, R. O. J. Am. Chem. Soc. 1969, 91, 2703e2715.
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12. Kirihara, M.; Asai, Y.; Ogawa, S.; Noguchi, T.; Hatano, A.; Hirai, Y. Synthesis 2007,
3286e3289.
13C NMR (100 MHz, CDCl3)
d 27.2 (q), 30.1 (d), 31.3 (q), 32.2 (t), 46.5
(d), 46.8 (t), 52.7 (s), 52.7 (s), 71.6 (d), 87.6 (t), 169.2 (q); m/z (EI) 320
(Mþ); HRMS (EI): Mþ, found 320.1287. C14H24O6S requires
320.1288. Compound 31eq: Rf¼0.25 (cyclohexane/EtOAc, 1:2); IR
~
(ATR):
n
(cmꢂ1)¼2954 (m), 1732 (s), 1435 (m), 1154 (m), 1032 (s),
910 (w), 832 (w), 729 (m); 1H NMR (400 MHz, CDCl3)
d 0.94 (s, 9H,
13. Muttenthaler, M.; Andersson, A.; de Araujo, A. D.; Dekan, Z.; Lewis, R. J.; Ale-
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676e684.
tBu), 2.19 (m, 1H, 5-H), 2.46 (m, 1H, 20-H), 2.67 (ddd, 4J 3.6 Hz, 3J
7.9 Hz, 2J 14.6 Hz, 1H, 20-H), 2.86 (m, 2H, H-6), 3.62 (dd, J 6.6, 7.8 Hz,
1H, 10-H), 3.85 (ddd, 4J 0.8 Hz, 3J 6.3 Hz, 2J 11.7 Hz, 1H, 4-H), 3.91
(ddd, 4J 0.7 Hz, 3J 7.2 Hz, 2J 11.7 Hz, 1H, 4-H), 4.01 (ddd, 4J 0.7 Hz, 3J
15. Aggarwal, V. K.; Steele, R. M.; Ritmaleni; Barrell, J. K.; Grayson, I. J. Org. Chem.
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18. Le, N. A.; Jones, M., Jr.; Bickelhaupt, F.; de Wolf, W. H. J. Am. Chem. Soc. 1989, 111,
8491e8493.
3.5, 9.4 Hz, 1H, 2-H); 13C NMR (100 MHz, CDCl3)
d 27.6 (s), 30.1 (d),
31.3 (q), 36.7 (t), 46.1 (d), 48.1 (t), 52.8 (s), 52.8 (s), 68.2 (d), 94.2 (t),
168.6 (q), 169.0 (q); m/z (EI) 320 (Mþ); HRMS (EI): Mþ, found
320.1287. C14H24O6S requires 320.1288.
19. (a) DePuy, C. H.; King, R. W. Chem. Rev. 1960, 60, 431e457; (b) Tschugaeff, L. Ber.
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Acknowledgements
20. Crystallographic data (excluding structure factors) for the structures 18, 22, and
25 have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 1034556, 1034554, and 1034555, re-
spectively. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44-(0)1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk).
This work was supported by the Deutsche For-
schungsgemeinschaft (DFG). We thank Sybille Schneider and Peter
Roesky for their help in determining the crystal structures.
21. Johnson, C. R.; McCants, D., Jr. J. Am. Chem. Soc. 1965, 87, 1109e1114.
22. Bahrami, K.; Khodaei, M. M.; Yousefi, B. H.; Sheikh Arabi, M. Tetrahedron Lett.
2010, 51, 6939e6941; Corrigendum: Tetrahedron Lett. 2011, 52, 2002e2003.
23. Trivedi, R.; Lalitha, P. Synth. Commun. 2006, 36, 3777e3782.
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