Stereoselective synthesis of homochiral substituted tetrahydrothiophenes by electrophile-promoted thioetherification

Article abstract of DOI:10.1002/1099-0690(200301)2003:1<209::AID-EJOC209>3.0.CO;2-S

In this paper we study the electrophile-promoted cyclization of 2-sulfanyl-4-penten-1-ol and 1-sulfanyl-4-penten-2-ol derivatives as a way of preparing cyclic sulfides. The reaction is completely chemoselective and always proceeds by activation of the sulfur centre. The reaction of 2-sulfanyl-4-penten-1-ol derivatives proceeds by a 5-endo mode. Unsaturated thiol 6 undergoes iodine-promoted cyclothioetherification to give the tetrahydrothiophene 9 in moderate yields and with excellent regio- and stereoselectivity. However, when the reaction starts from the benzyl sulfide 7, a diastereomeric mixture of 9 and 10 is obtained in good yields. Selenium-promoted cyclization of unsaturated thioacetate 5 provides the selenyltetrahydrothiophene 12 or the sulfanyl acetate 13, depending on the selenium reagent used. On the other hand, electrophile-induced cyclization of 1-sulfanyl-4-penten-2-ol derivatives 23-25 depends on the electrophile used. Iodothioetherification of benzyl sulfide 25 followed by oxidation affords unsaturated sulfone 26 as a result of 6-endo-cyclization, dehydroiodination and oxidation. In contrast, selenothiocyclization of 24 with PhSeX results in the formation of the 5-exo tetrahydrothiophenes 29/30 and/or 31/32. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/1099-0690(200301)2003:1<209::AID-EJOC209>3.0.CO;2-S

FULL PAPER
Stereoselective Synthesis of Homochiral Substituted Tetrahydrothiophenes by
Electrophile-Promoted Thioetherification
[a]
[a]
[a]
[a]
´
´
Gourhari Jana, Antonio Viso, Yolanda Dıaz,* and Sergio Castillon*
Keywords: Cyclization / Electrophilic addition / Iodine / Selenium / Tetrahydrothiophene
In this paper we study the electrophile-promoted cyclization
of 2-sulfanyl-4-penten-1-ol and 1-sulfanyl-4-penten-2-ol de-
rivatives as a way of preparing cyclic sulfides. The reaction
is completely chemoselective and always proceeds by activa-
tion of the sulfur centre. The reaction of 2-sulfanyl-4-penten-
selenyltetrahydrothiophene 12 or the sulfanyl acetate 13, de-
pending on the selenium reagent used. On the other hand,
electrophile-induced cyclization of 1-sulfanyl-4-penten-2-ol
derivatives 23−25 depends on the electrophile used. Iodo-
thioetherification of benzyl sulfide 25 followed by oxidation
1-ol derivatives proceeds by a 5-endo mode. Unsaturated affords unsaturated sulfone 26 as a result of 6-endo-cycliza-
thiol 6 undergoes iodine-promoted cyclothioetherification to
give the tetrahydrothiophene 9 in moderate yields and with
tion, dehydroiodination and oxidation. In contrast, seleno-
thiocyclization of 24 with PhSeX results in the formation of
excellent regio- and stereoselectivity. However, when the re- the 5-exo tetrahydrothiophenes 29/30 and/or 31/32.
action starts from the benzyl sulfide 7, a diastereomeric mix-
ture of 9 and 10 is obtained in good yields. Selenium-pro- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
moted cyclization of unsaturated thioacetate 5 provides the
Germany, 2003)
Introduction
more, sulfur cyclizations are known to be highly reversible
and to give products that can further isomerize.[5,9,13,20]
The most widely accepted mechanistic interpretation of
sulfur cyclization involves initial generation of a source of a
positive sulfur atom (pathway a, Scheme 1), such as sulfanyl
halide, followed by intramolecular electrophilic addition of
the S atom to the alkene to form episulfonium species. Nu-
cleophilic (SN2) opening of the episulfonium ion produces
the final ring.[3Ϫ13] Only a few examples describe the cyc-
lization in the form of an addition of a nucleophilic sulfur
group to an electrophilically activated alkene (pathway
b).[14Ϫ16]
Electrophile-promoted cyclization of acyclic alkenes with
internal nucleophiles is an important synthetic tool for the
construction of a wide range of heterocyclic structures. This
strategy has been extensively studied in substrates in which
the heteroatom is O or NH,[1] and has been used to synthes-
ise products with interesting biological properties.[2] Less at-
tention has been paid to the synthesis of sulfur analogues
by this approach,[3Ϫ16] even though replacement of O by S
is a well-known strategy in the search for interesting new
compounds.
Mechanistically, the overall reaction is believed to pro-
ceed as a stepwise addition/dealkylation sequence through
a cationic intermediate. Oxygen and nitrogen cyclizations
are considered to be kinetically controlled and the regiose-
lectivity can be predicted by use of Baldwin’s rules;[17Ϫ19]
sulfur cyclizations, however, often afford products with dif-
ferent regiochemical outcomes. This difference can be ac-
counted for by the fact that sulfur, which is a third-row
element of larger atomic size, greater polarizability and
higher nucleophilicity, may allow transition states that are
not possible for the smaller second-row elements, and so
Baldwin’s rules cannot be applied to these systems. Further-
Scheme 1. Proposed mechanisms for the electrophilically induced
cyclization of sulfanylalkenes
Turos et al.[3,14] have carried out a systematic study of
electrophilic and nucleophilic sulfur cyclizations from un-
saturated sulfanyl halides and sulfides, respectively, by
modifying the tether between the reactive sites and the type
of unsaturated group. On treatment with iodine, thiols Ϫ
which are prone to oxidation and dimerization Ϫ generate
the sulfanyl iodide, which undergoes intramolecular addi-
tion to the alkene moiety present in the molecule. However,
[a]
´
´
´ `
i Quımica Organica,
Departament de Quımica Analıtica
Universitat Rovira i Virgili
Pl. Imperial Tarraco 1, 43005 Tarragona, Spain
Fax: (internat.) ϩ 34-977/559563
E-mail: castillon@quimica.urv.es
ydiaz@quimica.urv.es
Eur. J. Org. Chem. 2003, 209Ϫ216  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0101Ϫ0209 $ 20.00ϩ.50/0
209

´
´
G. Jana, A. Viso, Y. Dıaz, S. Castillon
FULL PAPER
benzyl sulfides are quite resistant to dimerization and ox- cyanocuprate afforded homoallylic alcohol 3 in an excellent
idation and seem to add to activated alkenes and therefore yield.[22] Activation of the hydroxy group as a tosylate 4
to react through a nucleophilic pathway (Scheme 1, path- and displacement with potassium thioacetate under typical
way b).
SN2 conditions gave thioacetate 5 in a 85% yield, which was
We have recently shown that the electrophile-promoted subjected to oxygen-free hydrolysis to afford labile thiol 6
cyclization of alkenediols and -triols can be regioselectively in a 96% yield. The corresponding benzyl sulfide 7 was also
controlled, depending on the electrophile (Scheme 2).[22,23] prepared in a 62% yield, together with the elimination prod-
With iodine as an electrophile, 5-exo cyclization takes place uct 8 (18%), by displacement of tosylate 4 with sodium
exclusively by involvement of the primary hydroxy group benzylsulfide.
(path a) even when it is protected. If selenium electrophiles
are used, however, the 5-endo product (path b) is obtained.
Scheme 2. Chemo- and regioselectivity in the electrophilically in-
duced cyclization of 4-pentene-1,2-diols
We decided to extend our study to electrophilically in-
Scheme 3. Synthesis of 2-sulfanyl-4-penten-1-ol derivatives
duced cyclization reactions by replacing the hydroxy groups
The study of the cyclization started with treatment of
by sulfur functionalities. In this paper we report cyclizations
thiol 6 with iodine in the presence of K2CO3 in dichlorome-
of differently protected unsaturated sulfanyl alcohol deriv-
thane at Ϫ78 °C for 12 h, to afford the 5-endo cyclization
product 9 in a 41% yield as a single stereoisomer, along
with disulfide 11 (Entry 1, Table 1, Scheme 4). The config-
uration of the product was elucidated by NOE experi-
ments (Figure 1).
atives such as 2-sulfanyl-4-pentenols (Scheme 2; X ϭ OR,
Y ϭ SR, Z ϭ H) and 1-sulfanyl-4-penten-2-ols (Scheme 2;
X ϭ SR, Y ϭ OR, Z ϭ H) induced by iodine and selenium
electrophiles as a procedure for obtaining chiral sulfur-con-
taining heterocycles.
Results and Discussion
We first explored the synthesis and cyclization of 2-sul-
fanyl-4-penten-1-ol derivatives. Thioacetate 5, thiol 6 and
benzyl sulfide 7 were synthesized and subjected to thiocy-
clization in order to study the chemo-, regio- and stereo-
selectivity of the reaction.
Scheme 4. Iodine-induced cyclization of 2-sulfanyl-4-penten-1-ol
derivatives
Compounds 5, 6 and 7 were prepared from enantiopure
glycidol (1) by a straightforward sequence (Scheme 3). Pro-
tection of 1 as a tert-butyldiphenylsilyl ether 2 and nucleo-
philic regioselective ring opening with a higher-order vinyl- Figure 1. Observed NOE effects in compound 9
Table 1. Iodine-promoted thiocyclization of compounds 6 and 7
Entry
Substrate
Reagents
Product
Ratio 9/10
Yield
1
2
3
4
5
6
7
8
9
6
6
6
6
6
7
7
7
7
7
I2, K2CO3, CH2Cl2, Ϫ78 °C
I2, K2CO3, CH2Cl2, Ϫ20 °C
I2, NaHCO3, MeCN
NIS, K2CO3, CH2Cl2, Ϫ20 °C
NIS, CH2Cl2, Ϫ20 °C
I2, CH2Cl2, 0 °C Ǟ room temp.
I2, NaHCO3, CH2Cl2, 0 °C Ǟ room temp.
I2, NaHCO3, MeCN
Br2, CH2Cl2
NIS, CH2Cl2, 0 °C Ǟ room temp.
9/10
100:0
80:20
100:0
90:10
90:10
60:40
58:42
63:37
41%[a]
40%[a]
4%[a]
45%[a]
40%[a]
77%
9/10
9/10
9/10
9/10
9/10
9/10
75%
70%
9/10
complex mixture
10
9/10
85:15
40%[a]
[a]
Variable amounts of disulfide 11 (not quantified) were also recovered.
210
Eur. J. Org. Chem. 2003, 209Ϫ216

Stereoselective Synthesis of Homochiral Substituted Tetrahydrothiophenes
FULL PAPER
Carrying out the reaction at Ϫ20 °C did not improve the
As shown above, the thiocyclization reactions were all
yield and gave a lower stereoselectivity (Entry 2). Replace- chemo- and regiospecific, and they all provided the 5-endo
ment of the base (Entry 3) or the electrophilic reagent (Ent-
ries 4 and 5) did not cause any significant changes in the
yield or 9/10 isomer ratio. The cis compound 9 was always
the major isomer, and variable amounts of disulfide 11 were
always obtained as a secondary product. In the iodocycliz-
ation of similar diol and triol systems (Scheme 2) we ob-
served that the counter-ion had a decisive role in the cyc-
lization process.[22] Thus, 5-exo cyclizations took place in
the presence of a nucleophilic counter-ion such as IϪ, but
there was no reaction when non-nucleophilic counter-ions
were used. In contrast, cyclizations from sulfur derivatives 6
and 7 proceeded even in the presence of a non-nucleophilic
counter-ion (Entries 4 and 5) and exhibited complete
chemoselectivity through involvement of the sulfur atom.
Thiocyclization of benzyl sulfide 7 with iodine afforded
the 5-endo product as a diastereomeric mixture of tetrahy-
drothiophenes 9 and 10 (Table 1, Entries 6Ϫ8). Under these
conditions the yield increased to around 75% but the stereo-
selectivity decreased (ca. 60:40). Neither base nor solvent
seemed to have any influence on the stereochemical out-
come of the reaction. The use of bromine as electrophilic
reagent (Entry 9) resulted in a complex mixture. Treatment
of compound 7 with N-iodosuccinimide (NIS) (Entry 10)
gave a mixture of diastereomeric tetrahydrothiophenes 9
and 10 in a lower yield (40%) but with a higher stereoselect-
ivity (85:15).
Treatment of thioacetate 5 with iodine gave compound 9
in very low yield (4%). This may be because of its lower
nucleophilicity relative to benzyl sulfide 7. We then decided
to explore the selenium-promoted cyclization of 5 (Table 2,
Scheme 5). Thus, when PhSeCl/AgOTf was used as an elec-
trophilic system, the 5-endo cyclization product 12 was ob-
tained in a 9% yield (Entry 1). Treatment of thioacetate 5
with PhSeCl in dichloromethane increased the yield of 12
to 38%, but compound 13 (10% yield) was also isolated
(Entry 2). Use of N-phenylselenophthalimide (N-PSP) and
camphorsulfonic acid (CSA)[23] in dichloromethane af-
forded no cyclization product but increased the amount of
compound 13 obtained (56%, Entry 3). Formation of 13 is
believed to proceed by nucleophilic attack of the thioacetate
oxygen atom on the intermediate seleniranium ion.
product by involvement of the sulfur atom; no traces of the
4-exo product, or of the 5-exo product by involvement of
the oxygen atom[22,24] were detected. Both the yield and the
stereochemical outcome appeared to depend on the group
attached to the sulfur atom.
In contrast to iodocyclization from benzyl sulfide 7, sel-
enium-promoted thiocyclization of 5 is highly stereoselec-
tive. This may be because the congestion of the seleniran-
ium ion is greater than in the alkeneϪiodine π complex.
Nicolaou et al.[7] explained the stereospecificity of an ana-
logous selenium-promoted thiocyclization in terms of the
complexation of both the olefin and the sulfur group by
selenium prior to seleniranium ion formation. In addition,
cyclization from 5 involves initial sulfonium ion formation
and subsequent deacylation. Like benzyl sulfide cycliza-
tions, deacylation requires a nucleophilic anion if it is to
proceed. This may explain the improved yield in compound
12 when changing from PhSeOTf to PhSeCl, as ClϪ is more
nucleophilic than TfOϪ and therefore facilitates deacyl-
ation. On the other hand, N-PSP/CSA gave no cyclization
product, perhaps because of the absence of nucleophiles in
the medium.
In the light of the results obtained with 2-sulfanyl-4-pen-
tenol derivatives, we decided to explore the preparation and
cyclization of primary sulfanyl derivatives, that is, 1-sul-
fanyl-4-pentenols. Benzyl sulfides 23/25 and thioacetate 24
were prepared from enantiopure (S)-glycidol and subjected
to thiocyclization. Treatment of diol 20 with tosyl chloride
in pyridine gave the monotosylated compound 21 in 78%
yield. Displacement of the sulfonate group with sodium
benzylsulfide or potassium thioacetate afforded the thio de-
rivatives 23 and 25, respectively, in quantitative yields.
Benzyl sulfide 23 was also prepared through the cyclic
sulfite derivative 22 and nucleophilic ring opening with
sodium benzylsulfide.
Scheme 5. Selenium-induced cyclization of sulfanylpentenol 5
Table 2. Selenium-promoted thiocyclization of compound 5
Scheme 6. Synthesis of 1-sulfanyl-4-pentene-2-ol derivatives
Entry
Substrate
Reagents
Product
Ratio 12/13
Yield
1
2
3
5
5
5
PhSeCl, AgOTf, MeCN
PhSeCl, CH2Cl2, Ϫ78 °C
N-PSP, CSA, CH2Cl2
12/13
12/13
12/13
100:0
80:20
0:100
9%
38%:10%
56%
Eur. J. Org. Chem. 2003, 209Ϫ216
211

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G. Jana, A. Viso, Y. Dıaz, S. Castillon
FULL PAPER
In the light of the results obtained from the cyclization
promoted by different iodine electrophiles, we decided to
explore the selenothioetherification of thioacetate 24. Treat-
ment of 24 with 1.1 equiv. of phenylselenyl chloride in
dichloromethane (Table 4, Entry 1) provided a 57:43 dia-
stereomeric mixture of tetrahydrothiophenes 29 and 30 in
67% yield. This reaction is thought to proceed through 5-
exo cyclization followed by acetylation of the hydroxy
group by acetyl chloride generated in the course of the reac-
tion. In order to prevent acetylation, the reaction was car-
ried out in methanol (Entry 2), so that compounds 31 and
32 were obtained with better stereoselectivity but in a lower
yield (38%). Acid-mediated selenothioetherification with N-
phenylselenophthalimide and camphorsulfonic acid in
dichloromethane (Entry 3) resulted in a 64:36 mixture of
acetylated products 29 and 30 in 32% yield. The use of this
reagent system in methanol gave the free hydroxy derivat-
ives 31 and 32 with higher stereoselectivity (76:24) and in a
higher yield (47%). In summary, selenothioetherification of
thioacetate 24 is completely regioselective, and only the 5-
exo product is formed.
Table 3. Iodocyclization of thioalkenols 23؊25
Entry Sub- Reagent
strate
Reaction conditions[a] Product (yield)
1
2
3
4
5
6
7
8
23
23
23
25
24
24
24
24
I2
A
A
4 h at 25 °C
4 h at 25 °C
decomposition
complex mixture
decomposition
Br2
NIS
I2
I2
I2
I2
NIS
Ϫ 4 h at 0 °C
A
A
B
B
B
ϩ oxidation mCPBA 26 (66%)
24 h, 0 to 25 °C
6 h, Ϫ78 to 0 °C
16 h, Ϫ78 to 25 °C
1 h at Ϫ78 °C
27 (53%)
28 (35%)
complex mixture
28 (78%)
[a]
A: 1.0 equiv. of I2 or Br2 in CH2Cl2. B: CH3OH, 3.0 equiv.
of NaHCO3.
Treatment of benzyl sulfide 23 with iodine under a vari-
ety of conditions gave either unchanged starting material or
complex mixtures. When bromine or NIS were used, the
reaction mixtures were again complex (Entries 2 and 3).
Cyclizations of tert-butylsilyl-protected compound 25, in-
duced by iodine or NIS, also gave decomposition products.
Nevertheless, when the reaction was followed by oxidation
with mCPBA to prevent decomposition, unsaturated sul-
fone 26 was isolated as a major product (Entry 4). Com-
pound 26 is believed to be formed by 6-endo cyclization,
dehydroiodination and oxidation of the sulfide to the sul-
fone.
Table 4. [Seϩ]-promoted thiocyclization of thioacetate 24
Entry Substrate Reagents
Product Ratio Yield
1
2
3
4
24
24
24
24
PhSeCl, CH2Cl2,
room temp.
PhSeCl, MeOH,
room temp.
N-PSP, CSA, CH2Cl2, 29/30
room temp.
29/30
31/32
57:43 67%
70:30 38%
64:36 32%
76:24 47%
N-PSP, CSA, MeOH, 31/32
room temp.
Conclusion
In conclusion, unlike the electrophile-promoted cyclo-
etherification of pentene-1,2-diols, electrophile-induced cyc-
Scheme 7. Iodine-induced cyclization of 1-sulfanyl-4-pentene-2-ol lization of 1-sulfanyl- and 2-sulfanylpentenol derivatives al-
derivatives 24 and 25
ways proceeds with complete chemoselectivity, by involve-
ment of the sulfur centre (Scheme 9). Iodine-promoted thio-
When thioacetate 24 was treated with iodine (Entry 5),
cyclization always undergoes an endo cyclization
diiodide 27 was formed as a crystalline solid in a 53% yield.
independently of the relative position of the sulfur atom.
This compound is thought to form by 6-endo cyclization,
acetylation of the hydroxy group, and acetate displacement
by iodide generated in situ. When dry deoxygenated meth-
anol was used as a solvent in the treatment of 24 with iod-
ine or NIS, acetate 28 was obtained as a result of an intra-
molecular transesterification process.
Scheme 8. Selenium-induced cyclization of 1-sulfanyl-4-pentene-2-
ol derivative 24
Scheme 9. Summary of the reactivity of 1-sulfanyl- and 2-sulfanyl-
pentenol derivatives towards iodo- and selenothioetherification
212
Eur. J. Org. Chem. 2003, 209Ϫ216

Stereoselective Synthesis of Homochiral Substituted Tetrahydrothiophenes
FULL PAPER
gummy liquid. [α]2D5 ϭ Ϫ15.1, (c ϭ 1.07, CHCl3). IR: ν˜ ϭ 1692
When the sulfur atom is present at position 2, the cycliza-
tion is always 5-endo, independently of the electrophile.
When the sulfur atom is present at position 1, it is possible
to control the regioselectivity depending on the electrophile
and the sulfur protecting group; thus, iodine provides the
6-endo product while selenium provides the 5-exo product.
The stereoselectivity and the yield of the iodine-pro-
moted thiocyclization of derivatives 5Ϫ7 depend on the
group attached to the sulfur atom. Thus, iodocyclization of
cmϪ1 1H NMR (CDCl3): δ ϭ 7.71Ϫ7.33 (m, 10 H, Ph), 5.74
.
(dddd, 1 H, J ϭ 7.0, 7.0, 10.1, 17.1 Hz, 4-H), 5.20Ϫ5.04 (m, 2 H,
5-H), 3.79 (dd, J ϭ 3.7, 9.2 Hz, 1 H, 1-H), 3.76Ϫ3.68 (m, 1 H, 2-
H), 3.67 (dd, J ϭ 5.3, 9.2 Hz, 1 H, 1-H), 2.66Ϫ2.53 (m, 1 H, 3-H),
2.46Ϫ2.35 (m, 1 H, 3-H), 2.29 (s, 3 H, Me). 1.06 (s, 9 H, Me) ppm.
13C NMR (CDCl3): δ ϭ 195.6 (CO), 135.7, 135.6 (Ph), 134.9 (C-
4), 133.3, 129.7, 127.7, 127.6 (Ph), 117.6 (C-5), 64.9 (C-1), 45.6 (C-
2), 35.4 (C-3), 30.7 (Me), 26.6 (Me), 19.3 (CSi) ppm. C23H30O2SSi
(398.63): calcd. C 69.30, H 7.58, S 8.04; found C 69.52, H 7.60,
thiol 6 is highly stereoselective and provides compound 9 in S 8.01.
a moderate yield, whereas benzyl sulfide 7 affords a mixture
(S)-1-O-(tert-Butyldiphenylsilyl)-2-sulfanyl-4-penten-1-ol (6): Com-
of compounds 9 and 10 with low stereoselectivity and in
good yields. Selenium-mediated cyclization of thioacetate 5
affords 5-endo selenotetrahydrothiophene 12 in a moderate
yield but with excellent stereoselectivity.
pound 5 (0.199 g, 0.5 mmol) was dissolved in dry methanol (5 mL)
and the solution was degassed with argon for 30 min. Sodium me-
thoxide (0.135 g, 2.5 mmol) was added in one portion, and the re-
action mixture was stirred under an inert gas. Once the reaction
was complete, the mixture was diluted with water (5 mL) and the
basic solution was acidified to pH ϭ 4 by addition of 1  oxalic
acid. The aqueous solution was extracted with diethyl ether (2 ϫ
25 mL) and the organic layer was washed with brine and dried with
MgSO4. Evaporation of the solvent under reduced pressure gave
0.177 g (96%) of spectroscopically pure, labile thiol 6 as a colorless
oil, which was used in the next reaction without further purifica-
tion. 1H NMR (CDCl3): δ ϭ 7.66Ϫ7.22 (m, 10 H, Ph), 5.69 (dddd,
1 H, J ϭ 7.0, 7.0, 10.1, 17.0 Hz, 4-H), 5.07Ϫ4.98 (m, 2 H, 5-H),
3.62 (dd, J ϭ 6.0, 10.1 Hz, 1 H, 1-H), 3.58 (dd, J ϭ 6.1, 10.1 Hz,
1 H, 1-H), 2.92 (ddddd, J ϭ 1.4, 1.4, 5.3, 7.0, 14.2 Hz, 1 H, 2-H),
2.24 (ddddd, J ϭ 1.4, 1.4, 5.3, 7.0, 14.2 Hz, 1 H, 3-H), 2.21 (ddddd,
J ϭ 1.2, 1.2. 7.0 .8.3, 14.2 Hz, 1 H, 3-H), 1.75 (d, J ϭ 7.5 Hz, 1 H,
SH), 1.00 (s, 9 H, Me) ppm. 13C NMR (CDCl3): δ ϭ 135.7, 135.7
(Ph), 135.0 (C-4), 133.4, 129.6, 127.6 (Ph), 117.2(C-5), 64.9(C-1),
41.7(C-2), 38.5(C-3), 26.7(Me), 19.2(CSi) ppm.
Experimental Section
General Remarks: Melting points are uncorrected. Optical rotations
1
were measured at 25 °C in 10-cm cells. H and 13C NMR spectra
were recorded with 300 and 400 MHz (75.4 and 100.5 MHz) instru-
ments. Coupling constants are given in Hz. Elemental analyses
´
were determined at the Servei de Recursos Cientıfics (Universitat
Rovira i Virgili). TLC was carried out on aluminium sheets pre-
coated with silica gel 60 F254. Flash column chromatography was
performed with Kieselgel 60 (40Ϫ63 microns). Radial chromato-
graphy was performed on 1-, 2- or 4-mm silica gel plates, depending
on the amount of product. Band separation was monitored by UV.
Medium pressure chromatography (MPLC) was performed with
silica gel 60 A CC (6Ϫ35 microns). All chromatographic solvents
were distilled at atmospheric pressure prior to use. Dry solvents
were obtained by conventional methods.
(S)-2-(Benzylsulfanyl)-1-O-(tert-butyldiphenylsilyl)-4-penten-1-ol
(7): Benzylhydrosulfide (0.744 g, 6 mmol) was added at 0 °C to a
suspension of sodium metal (0.161 g, 7 mmol) in dry DMF
(10 mL). The cooling bath was removed and the mixture was stirred
for 1 h at room temperature. A solution of compound 4 (2.5 g,
5 mmol) in dry DMF (10 mL) was added dropwise over 5 min, and
stirring was continued at room temperature for a further 2 h. The
reaction mixture was poured into water (100 mL) and extracted
with diethyl ether (2 ϫ 50 mL). The solvent of the combined or-
ganic layers was removed and the resulting crude product was puri-
fied by column chromatography on silica gel in hexane/ethyl acetate
(95:5) to afford compounds 7 (1.39 g, 62%) and 8 (0.270 g, 18%)
as colorless oils. 7: [α]2D5 ϭ Ϫ20.7, (c ϭ 1.03, CHCl3). 1H NMR
(CDCl3): δ ϭ 7.60Ϫ7.13 (m, 15 H, Ph), 5.73Ϫ5.64 (m, 1 H, 4-H),
5.01Ϫ4.92 (m, 2 H, 5-H), 3.67 (dd, J ϭ 5.1, 10.5 Hz, 1 H, 1-H),
3.57Ϫ3.47 (m, 3 H, SCH2, 1-H), 2.62 (ddd, J ϭ 5.7, 7.2, 12.9 Hz,
1 H, 2-H), 2.47 (ddd, J ϭ 6.3, 7.2, 13.5 Hz, 1 H, 3-H), 2.35 (ddd,
J ϭ 6.3, 7.2, 13.5 Hz, 1 H, 3-H) ppm. 13C NMR (CDCl3): δ ϭ
135.6(Ph), 135.2(C-4), 133.5, 133.4, 129.6, 128.7, 128.4, 127.6,
126.8 (Ph), 116.9 (C-5), 65.9 (C-1), 46.3 (C-2), 35.6 (C-3,SCH2Ph),
26.8 (CH3), 19.2(CSi) ppm. C28H34OSSi (446.72): calcd. C 75.35,
H 7.62, S 7.17, found C 75.36, H 7.63, S 7.20. 8: 1H NMR (CDCl3):
δ ϭ 7.70Ϫ7.38 (m, 10 H, Ph), 6.42Ϫ6.27 (m, 1 H), 5.83Ϫ5.75 (m,
2 H), 5.21Ϫ5.05 (m, 2 H), 4.25 (m, 2 H), 1.05 (s, 9 H) ppm. 13C
NMR (CDCl3): δ ϭ 126.6, 135.5, 133.5, 132.8, 130.2, 129.6, 127.6,
116.6, 63.9, 26.7, 19.2 ppm.
(R)-1-O-(tert-Butyldiphenylsilyl)-2-O-(p-tolylsulfonyl)-4-pentene-
1,2-diol (4): p-Toluenesulfonyl chloride (2.35 g, 12.38 mmol) was
added at 0 °C to alcohol 3 (1.40 g, 4.13 mmol) in anhydrous pyrid-
ine (25 mL) and the mixture was kept at 4 °C (refrigerator) for 4
d. The reaction mixture was poured into cold water (100 mL) and
extracted with diethyl ether (2 ϫ 50 mL). The combined organic
layers were washed with NaHCO3 and brine, and dried with
MgSO4. The solvent was removed and the crude product was puri-
fied by column chromatography on silica gel in hexane/ethyl acetate
(95:5) to afford pure product 4 (1.84 g, 90%) as a viscous liquid.
[α]2D5 ϭ ϩ8.0 (c ϭ 1.32, CHCl3). 1H NMR (CDCl3): δ ϭ 7.75Ϫ7.20
(m, 14 H, Ph), 5.58 (dddd, J ϭ 7.1, 7.1, 10.1, 17.1 Hz, 1 H, 4-H),
5.08Ϫ4.97 (m, 2 H, 5-H), 4.55 (tt, J ϭ 4.7, 4.7 Hz, 6.2, 6.2 Hz, 1
H, 2-H), 3.62 (dd, J ϭ 4.7, 11.1 Hz, 2 H, 1-H), 2.61Ϫ2.42 (m, 2 H,
3-H), 2.40 (s, 3 H), 1.01 (s, 9 H) ppm. 13C NMR (CDCl3): δ ϭ
144.4, 135.5, 135.4, 132.8 (Ph), 132.0 (C-4), 129.7, 129.6, 127.7,
127.6 (Ph), 118.8 (C-5), 81.9(C-2), 63.8 (C-1), 35.5 (C-3), 26.6 (Me),
21.6 (Me), 19.1 (CSi) ppm. C28H34O4SSi (494.72): calcd. C 67.98,
H 6.93, S 6.48; found C 68.22, H 6.94, S 6.46.
(S)-2-(Acetylsulfanyl)-1-O-(tert-butyldiphenylsilyl)-4-penten-1-ol
(5): Solid potassium thioacetate (1.42 g, 12.5 mmol) was added to
substrate 4 (1.23 g, 2.5 mmol) in anhydrous DMF (15 mL), and the
mixture was stirred for 12 h at 45 °C. It was then cooled, diluted
with water (75 mL) and extracted with diethyl ether (2 ϫ 25 mL).
The combined organic layers were washed with saturated aqueous
NaHCO3 and brine, and dried with MgSO4. Removal of the sol-
vent and column chromatography on silica gel in hexane/ethyl acet-
ate (95:5) yielded 0.84 g (85%) of pure product of 5 as a colorless,
Representative Procedure for the Halocyclization of 6 and 7: Potas-
sium carbonate (0.138 g, 1 mmol) and iodine (0.152 g, 0.6 mmol)
were added at Ϫ78 °C to a solution of homoallylic thiol 6 (0.073 g,
0.2 mmol) in anhydrous CH2Cl2 (10 mL), and the reaction mixture
Eur. J. Org. Chem. 2003, 209Ϫ216
213

´
´
G. Jana, A. Viso, Y. Dıaz, S. Castillon
FULL PAPER
was stirred for 12 h at room temperature, washed with a 10% aq.
Na2S2O3 solution (10 mL) and brine, and dried with MgSO4. The
solvent was evaporated and the resulting crude mass was subjected
to radial chromatography on silica gel in hexane to give pure prod-
uct 9 (0.040 g, 41%) as a colorless oil.
1 H, 4-H), 5.10Ϫ5.01 (m, 2 H, 5-H, 5Ј-H), 3.88 (br. s, 2 H, OH),
3.68 (dtd, J ϭ 7.5, 6.5, 6.5, J1,2 ϭ 2.8 Hz, 1 H, 2-H), 3.56 (dd, J ϭ
11.5, 2.8 Hz, 1 H, 1-H), 3.37 (dd, J ϭ 11.5, 7.5 Hz, 1 H, 1Ј-H),
2.18Ϫ2.12 (m,
2
H, 3-H, 3Ј-H) ppm. 13C NMR (CDCl3,
75.4 MHz): δ ϭ 134.2(C-4), 117.8 (C-5), 71.4 (C-2), 66.0 (C-1), 37.6
(C-3) ppm. C5H10O2 (102.13): calcd. C 58.80; H 9.87; found. C,
59.15; H 9.90.
(2S,4S)-[(2-tert-Butyldiphenylsilyloxy)methyl]-4-iodo-tetrahydro-
thiophene (9): [α]2D5 ϭ ϩ1.3, (c ϭ 1.10, CHCl3). 1H NMR (CDCl3):
δ ϭ 7.65Ϫ7.25 (m, 10 H), 4.04 (dddd, J ϭ 6.1, 6.1, 10.9, 12.4 Hz, (R)-1-(Tosyloxy)-4-penten-2-ol (21): Tosyl chloride (1.87 g,
1 H, 4-H), 3.65 (d, J ϭ 6.1 Hz, 2 H, 6-H), 3.45 (dddd, J ϭ 6.1, 6.1, 9.80 mmol) was added to a cold solution (Ϫ10 °C) of compound
6.1, 9.4 Hz, 1 H, 2-H), 3.15 (dd, J ϭ 6.1, 10.9 Hz, 1 H, 4-H), 3.07 20 (1.00 g, 9.80 mmol) in dry pyridine (20 mL). The mixture was
(dd, 1 H, J2 ϭ 10.9, 10.9 Hz, 5Ј-H), 2.70 (ddd, J ϭ 6.1, 6.1, 12.4 Hz,
allowed to react at Ϫ10 °C for 15 h, and then poured into an aque-
1 H, 3-H), 1.82 (ddd, J ϭ 9.4, 12.4, 12.4 Hz, 1 H, 3Ј-H), 0.99 (s, 9 ous HCl solution and extracted with dichloromethane. The com-
H) ppm. 13C NMR (CDCl3): δ ϭ 135.7, 133.4, 133.3, 129.8, 127.8 bined organic layers were dried with magnesium sulfate and con-
(Ph), 67.8 (C-6), 48.9 (C-2), 45.7 (C-3), 41.6 (C-5), 26.7 (Me), 20.2
(C-4), 19.1 (CSi) ppm. C21H27IOSSi (482.49): calcd. C 52.28, H
5.60, S 6.64 found C 52.47, H 5.59, S, 6.65.
centrated. Purification of the crude product by column chromato-
graphy in hexane-hexane/ethyl acetate (3:1) gave 1.96 g (78%) of
1
compound 21. [α]2D5 ϭ Ϫ9.8 (c ϭ 0.94, CHCl3). H NMR (CDCl3,
400 MHz): δ ϭ 7.79 (d, J ϭ 8.4 Hz, 2 H, Ph), 7.35 (d, J ϭ 8.4 Hz,
2 H, Ph), 5.79Ϫ5.69 (m, 1 H, 4-H), 5.12Ϫ5.07 (m, 2 H, 5-H, 5Ј-
H), 4.06Ϫ4.00 (m, 1 H, 2-H), 3.94Ϫ3.90 (m, 2 H, 1-H, 1Ј-H), 2.63
(br. s, 1 H, OH), 2.45 (s, 3 H, CH3), 2.26Ϫ2.22 (m, 2 H, 3-H, 3Ј-
H) ppm. 13C NMR (CDCl3, 100.5 MHz): δ ϭ 145.0, 132.8 (C-4),
132.2, 129.8, 127.8 (Ph), 118.6 (C-5), 72.9 (C-1), 68.4 (C-2), 37.2
(C-3), 21.5 (CH3) ppm. C12H16OS (256.32): calcd. C 56.80, H 5.71,
S 12.50; found C 56.56, H 5.70, S 12.56.
(2S,4S)-[(2-tert-Butyldiphenylsilyloxy)methyl]-4-(phenylselenyl)-
tetrahydrothiophene (12) and 1,4-Diol Derivative 13: Solid PhSeCl
(0.100 g, 0.52 mmol) was added to a cold solution (Ϫ78 °C) of
homoallylic thioacetate 5 (0.199 g, 0.5 mmol) in anhydrous CH2Cl2
(15 mL). The mixture was allowed to warm to room temperature
while stirring for 16 h. The reaction mixture was washed with satur-
ated NaHCO3 and brine, and dried with MgSO4. The solvent was
removed and the resulting crude mass was purified by column chro-
matography on silica gel in hexane/ethyl acetate (98:2) to afford
products 12 (0.100 g, 38%) and 13 (0.022 g, 10%) (2:1 diastereom-
(3R)-4-Allyl-1,3,2-dioxathiolane 2-Oxide (22): An ice/water-cooled
solution of diol 20 (0.143 g, 1.40 mmol) and triethylamine
eric mixture) as colorless oils. 12: [α]2D5 ϭ Ϫ8.6, (c ϭ 0.85, CHCl3). (0.780 mL, 5.61 mmol) in dry dichloromethane (6 mL) was added
1H NMR (CDCl3): δ ϭ 7.65Ϫ7.16 (m, 15 H, Ph), 3.63 (dd, J ϭ dropwise over a period of 10 min to a solution of thionyl chloride
7.0, 9.9 Hz, 1 H, 6-H), 3.59 (dd, J ϭ 6.0, 9.9 Hz, 1 H, 6Ј-H), (0.150 mL) in dichloromethane (4 mL). The mixture was stirred at
3.56Ϫ3.48 (m, 2 H, 4-H, and 2-H), 2.99 (dd, J ϭ 6.1, 10.6 Hz, 1
0 °C for 1 h, monitored by TLC in hexane/ethyl acetate (1:5). The
H, 5-H), 2.82 (dd, J ϭ 10.6, 10.6 Hz, 1 H, 5Ј-H), 2.51 (ddd, J ϭ mixture was then diluted with dichloromethane and washed with
5.2, 6.1, 12.6 Hz, 1 H, 3-H), 1.52 (ddd, J ϭ 9.3, 12.5, 12.5 Hz, 1 water (2 ϫ 50 mL) and brine (100 mL). The organic layer was dried
H, 3Ј-H), 0.97 (s, 9 H) ppm. 13C NMR (CDCl3): δ ϭ 135.6, 135.1,
with sodium sulfate, filtered and concentrated in vacuo. The crude
133.3, 129.7, 127.1, 127.9, 127.7 (Ph), 68.1 (C-6), 49.3 (C-4), 43.1 residue was filtered through a small pad of silica gel to give 0.195 g
(C-2), 40.5 (C-3), 38.1 (C-5), 26.8 (Me), 19.1 (CSi) ppm. C27H32OS- (94%) of a diastereomeric mixture of compound 22 as an orange
SeSi (511.65): calcd. C 63.40, H 6.26, S 6.26; found C 63.51, H syrup. H NMR (CDCl3, 400 MHz): δ ϭ 5.78Ϫ5.64 (m, 1 H, 2Ј-
1
6.25, S 6.24. 13: Data obtained from the spectra of the diastereo-
H), 5.17Ϫ5.11 (m, 2 H, 3Ј-Ha, 3Ј-Hb), 4.97 (q, J ϭ 6.4 Hz, 1 H, 4-
1
meric mixture: IR: ν˜ ϭ 1738 cmϪ1(νCO). Major diastereomer: H H), 4.62 (dd, J ϭ 8.4, 6.4 Hz, 1 H, 5-Ha), 3.97 (dd, J ϭ 8.4, 6.4 Hz,
NMR (CDCl3): δ ϭ 7.66Ϫ7.19 (m, 15 H, Ph), 5.14Ϫ5.12 (m,1 H, 1 H, 5-Hb), 2.69Ϫ2.34 (m, 2 H, 1Ј-Ha, 1Ј-Hb) ppm. 13C NMR
4-H), 3.74 (dd, J ϭ 10.5, 5.4 Hz, 1 H, 1-H), 3.62 (dd, J ϭ 10.4,
(CDCl3, 100.5 MHz): δ ϭ δ ϭ 131.6 (C-2Ј), 119.2 (C-3Ј), 79.1 (C-
1
6.6 Hz, 1 H, 1Ј-H), 3.04 (dd, J ϭ 12.9, 5.7 Hz, 1 H, 5-H), 2.96 (dd, 4), 70.6 (C-5), 37.5 (C-1Ј) ppm. H NMR (CDCl3, 400 MHz): δ ϭ
J ϭ 12.9, 6.0 Hz, 1 H, 5Ј-H), 2.86Ϫ2.82 (m,1 H, 2-H), 2.36 (dt, 5.78Ϫ5.64 (m, 1 H, 2Ј-H), 5.17Ϫ5.11 (m, 2 H, 3Ј-Ha, 3Ј-Hb),
J ϭ 14.7, 5.7, 5.7 Hz, 1 H, 3-H), 1.92 (ddd, J3Ј,3 ϭ 14.7, 7.2, 7.2 Hz,
1 H, 3Ј-H), 1.79 (s, 3 H, Me), 1.04 (s, 9 H, Me) ppm. 13C NMR ppm. 13C NMR (CDCl3, 100.5 MHz): δ ϭ 131.2 (C-2Ј), 119.5 (C-
4.50Ϫ4.29 (m, 2 H, 5-Ha, 5-Hb), 2.69Ϫ2.34 (m, 2 H, 1Ј-Ha, 1Ј-Hb)
(CDCl3): δ ϭ 170.4 (CO), 135.6Ϫ127.1 (CAr), 71.4 (C-4), 66.0 (C-
1), 49.3 (C-2), 35.4, (C-5), 31.1 (C-3), 27.6 [Si(Me)3], 20.7 (Me),
19.1 (CSiMe3) ppm. Minor diastereomer: NMR (CDCl3): δ ϭ
170.4 (CO), 135.6Ϫ127.1 (CAr), 70.8 (C-4), 66.9 (C-1), 48.8 (C-2),
35.3 (C-5), 31.5 (C-3), 27.6 [Si(Me)3], 20.6 (Me), 19.1 (CSiMe3)
ppm.
3Ј), 82.5 (C-4), 69.9 (C-5), 36.5 (C-1Ј) ppm.
(R)-1-(Benzylsulfanyl)-4-penten-2-ol (23). Method A (from 22): So-
dium benzylsulfide (0.120 g, 0.81 mmol, prepared by treatment of
benzylhydrosulfide with 1 equiv. of NaH in diethyl ether for 16 h,
filtration and drying under vacuum) and 15-crown-5 (0.160 mL,
0.54 mmol) were added under an inert gas to a solution of 22
(0.80 g, 0.54 mmol) in dry DMF (2 mL). The reaction was mon-
itored by TLC (hexane/ethyl acetate, 2:1). The mixture was diluted
(R)-4-Pentene-1,2-diol (20): A tetrabutylammonium fluoride solu-
tion in THF (1 , 28 mL, 28.00 mmol) was added to a cold solution
(0 °C) of 3 (8.59 g, 25.26 mmol) in 258 mL of dry THF, and the with water/ice, and extracted thoroughly with dichloromethane.
mixture was stirred at 0 °C for 2 h. The cooling bath was then
removed and the mixture was allowed to warm to room temper-
ature and then poured into water/ice. The aqueous solution was
extracted with ethyl acetate, and the combined organic layers were
dried with magnesium sulfate. The solvent was removed in vacuo
and the crude product was chromatographed (diethyl ether/petro-
leum ether, 20:1) to give compound 20 (2.51 g, 98%) as a pure
The combined organic layers were dried with sodium sulfate and
concentrated. The resulting crude product was filtered through a
small pad of silica gel and then purified by radial chromatography
with hexane/dichloromethane (1:1) to give 0.084 g (75%) of com-
pound 23 as a syrup. Method B (from Tosylate 21): Sodium benzyl-
sulfide (0.390 g, 2.64 mmol) was added to a solution of tosylate 21
(0.450 g, 1.76 mmol) in dry acetonitrile (14 mL). The mixture was
syrup. [α]2D5 ϭ ϩ3.3 (c ϭ 0.25, CHCl3). 1H NMR (CDCl3, stirred at room temperature for 2 h, filtered through silica gel and
300 MHz): δ ϭ 5.79 (ddt, J4,5;trans ϭ 17.1 Hz, J ϭ 10.2, 5.7, 5.7 Hz, concentrated. The resulting residue was purified by column chro-
214
Eur. J. Org. Chem. 2003, 209Ϫ216

Stereoselective Synthesis of Homochiral Substituted Tetrahydrothiophenes
FULL PAPER
matography with an elution gradient (hexane, hexane/CH2Cl2, 10:1,
CH2Cl2) to give 0.363 g (99%) of alkenol 23 as a colorless syrup. (dtt, J ϭ 5.6, 5.6, 19.2 Hz, 1 H, 4-H), 2.35 (ddt, J ϭ 19.2, 9.2,
[α]2D5 ϭ Ϫ51.4 (c ϭ 0.85, CHCl3). 1H NMR (CDCl3, 400 MHz): 2.8 Hz, 1 H, 2.8 Hz, 4Ј-H), 1.10 [s, 9 H, (CH3)3] ppm. 13C NMR
δ ϭ 7.38Ϫ7.35 (m, 5 H, Ph), 5.84Ϫ5.73 (m, 1 H, 4-H), 5.14Ϫ5.09 (CDCl3, 100.5 MHz): δ ϭ 133.7, 135.6 (Ph), 134.2 (C-5), 130.4,
13.2 Hz, 1 H, 2-H), 3.15 (dd, J ϭ 11.2, 13.2 Hz, 1 H, 2Ј-H), 2.54
(m, 2 H, 5-H, 5Ј-H), 3.74 (s, 2 H, CH2Bn), 3.72Ϫ3.66 (m, 1 H, 2-
H), 2.61 (dd, J ϭ 13.6, 3.6 Hz, 1 H, 1-H), 2.48 (br. s, 1 H, OH),
130.2 (Ph), 129.4 (C-6), 128.0, 127.9 (Ph), 65.4 (C-3), 57.9 (C-2),
34.9 (C-4), 26.8 [(CH3)3CSi], 19.0 [(CH3)3CSi] ppm. C21H26O3SSi
2.43 (dd, J ϭ 14.0, 8.4 Hz, 1 H, 1Ј-H), 2.30Ϫ2.24 (m, 2 H, 3-H, (386.58): calcd. C 65.25, H 6.78, S 8.29; found C 65.00, H 6.80,
3Ј-H) ppm. 13C NMR (CDCl3, 100.5 MHz): δ ϭ 137.9, 134.0 (C-
4), 128.9, 128.6, 127.2 (Ph), 118.1 (C-5), 68.6 (C-2), 40.5 (C-3), 38.3
(C-1), 36.2 (CH2Bn) ppm. C12H16OS (208.32): calcd. C 69.23, H
7.69, S 15.38; found C 69.45, H 7.70; S 15.43.
S 8.31.
3,5-Diiodo-tetrahydrothiopyran (27): Iodine (0.088 g, 0.34 mmol)
was added at 0 °C to a solution of compound 24 (0.053 g,
0.33 mmol) in dry dichloromethane (1 mL). The mixture was
(R)-1-(Acetylsulfanyl)-4-penten-2-ol (24): Potassium thioacetate stirred for 24 h and then decolourized with 5% aq. Na2SO3. The
(780 g, 6.68 mmol) and 18-crown-6 (1.77 g, 6.68 mmol) were added aqueous layer was extracted with dichloromethane (3 ϫ 50 mL)
under an inert gas to a solution of tosylate 21 (1.14 g, 4.45 mmol)
in CH3CN (18 mL). The mixture was stirred for 2.5 h (TLC: hex-
ane/ethyl acetate, 2:1), filtered through silica gel and concentrated.
The crude product was purified by radial chromatography with
and the combined organic layers were dried with anhydrous
MgSO4, filtered and concentrated in vacuo. The resulting residue
was purified by radial chromatography with an elution gradient
(hexane, hexane/dichloromethane, 1:1) to afford 0.062 g (53%) of
compound 27 as a solid. M.p. 115Ϫ117 °C. EM: m/z ϭ 354, 227,
CH2Cl2 to give compound 24 in a quantitative yield. [α]2D5 ϭ Ϫ32.8
1
(c ϭ 1.06, CHCl3). H NMR (CDCl3, 400 MHz): δ ϭ 5.86Ϫ5.77 127, 99, 67, 46. 1H NMR (C6D6, 400 MHz): δ ϭ 3.68Ϫ3.60 (dddd,
(m, 1 H, 4-H), 5.19Ϫ5.14 (m, 2 H, 5-H, 5Ј-H), 3.84Ϫ3.78 (m, 1 H, 2 H, J ϭ 12.4, 11.0, 3.6, 4.0 Hz, 3-H, 5-H), 2.61Ϫ2.56 (dddd, 1 H,
2-H), 3.14 (dd, J ϭ 14.0, 4.0 Hz, 1 H, 1-H), 2.93 (dd, J ϭ 14.0,
7.2 Hz, 1 H, 1Ј-H), 2.45 (br. s, 1 H, OH), 2.38 (s, 3 H, CH3), 4 H, 2-H, 6-H), 2.03 (q, J ϭ 12.4 Hz, 1 H, 4-H) ppm. 13C NMR
2.36Ϫ2.23 (m, (CDCl3, 100.5 MHz): δ ϭ 52.1 (C-4), 37.6 (C-2, C-6), 24.5 (C-3,
H, 3-H, 3Ј-H) ppm. 13C NMR (CDCl3,
J ϭ 12.4, J ϭ 5.2, 3.2, J 4Ј,2 ϭ 1.6 Hz, 4Ј-H), 2.47 (d, J ϭ 11.0 Hz,
2
100.5 MHz): δ ϭ 196.3 (CO), 133.7 (C-4), 118.5 (C-5), 69.8 (C-2), C-5) ppm.
40.6 (C-3), 35.4 (C-1), 30.5 (CH3) ppm. C7H12O2S (160.23): calcd.
C 52.50, H 7.50, S 20.00; found C 52.70, H 7.52, S 19.94.
(R)-4-Penten-2-ol Derivative 28: NaHCO3 (0.129 g, 1.54 mmol) and
NIS (0.125 g, 0.54 mmol) were added under argon to a cold solu-
tion (Ϫ78 °C) of compound 24 (0.082 g, 0.51 mmol) in dry and
deoxygenated CH3OH (3 mL). The reaction mixture was stirred at
(R)-Penten-2-ol Derivative 25: A solution of alkenol 23 (0.198 g,
0.95 mmol), imidazole (0.136 mg, 2.00 mmol) and tert-butyldi-
phenylsilyl chloride (0.370 mL) in DMF (2 mL) was heated at 55 Ϫ78 °C for 1 h (TLC: hexane/ethyl acetate, 2:1) and decolourized
°C for 16 h (TLC: hexane/ethyl acetate, 5:1). The mixture was di- with Na2SO3 (5%), the aqueous layer was extracted with dichloro-
luted with CH2Cl2 (75 mL) and washed with water (5 ϫ 50 mL) methane (3 ϫ 50 mL), and the combined organic layers were dried
and brine (50 mL). The combined organic layers were dried with
magnesium sulfate, filtered and concentrated in vacuo. The re-
sulting residue was filtered through a pad of silica gel and then
purified by radial chromatography with hexane to afford 0.344 g
with anhydrous MgSO4, filtered and concentrated. The crude prod-
uct was chromatographed on silica gel (hexane/ethyl acetate, 5:1)
to give acetate 28 (0.064 g, 78%). 1H NMR (CDCl3, 400 MHz):
δ ϭ 5.79Ϫ5.67 (m, 1 H, 4-H), 5.17Ϫ5.08 (m, 3 H, 5-H, 5Ј-H, 2-
(81%) of compound 25. [α]2D5 ϭ ϩ7.1 (c ϭ 0.63, CHCl3). 1H NMR H), 2.89 (dd, J ϭ 14, 6.0 Hz, 1 H, 1-H), 2.85 (dd, J ϭ 14, 6.8 Hz,
(CDCl3, 400 MHz): δ ϭ 7.60Ϫ7.56 (m, 4 H, Ph), 7.34Ϫ7.24 (m, 6
1 H, 1Ј-H), 2.52Ϫ2.30 (m, 2 H, 3-H, 3Ј-H), 2.05 (s, 3 H, CH3) ppm.
H, Ph), 7.23Ϫ7.00 (m, 5 H, Ph), 5.66Ϫ5.56 (m, 1 H, 4-H), 13C NMR (CDCl3, 100.5 MHz): δ ϭ 170.4 (CO), 132.7 (C-4), 118.5
4.90Ϫ4.83 (m, 2 H, 5-H, 5Ј-H), 3.80Ϫ3.74 (m, 1 H, 2-H), 3.34 (d, (C-5), 72.3 (C-2), 42.2 (C-3), 37.3 (C-1), 21.0 (CH3) ppm.
J ϭ 13.2 Hz, 1 H, CH2Bn), 3.28 (d, J ϭ 13.2 Hz, 1 H, CH2Bn),
Selenothioetherification of 24 under Basic Conditions. (3S,5S)-Tetra-
2.45 (dd, J ϭ 13.2, 7.2 Hz, 1 H, 1-H), 2.35 (dd, J ϭ 13.6, 4.8 Hz,
hydrothiophen-3-ol Derivative 29 and (3S,5R)-Tetrahydrothiophen-3-
1 H, 1Ј-H), 2.31Ϫ2.25 (m, 1 H, 3-H), 2.19Ϫ2.13 (m, 1 H, 3Ј-H),
ol Derivative 30: Phenylselenyl chloride (0.075 g, 0.38 mmol) was
0.96 [s, 9 H, (CH3)3] ppm. 13C NMR (CDCl3, 100.5 MHz): δ ϭ
added to a cold solution (Ϫ78 °C) of alkenol 24 (0.058 g,
0.36 mmol) in 11 mL of dry dichloromethane. The course of the
138.4, 135.9 (C-4), 134.0, 133.9, 133.8, 129.6, 129.6, 128.7, 128.3,
127.5, 127.4, 126.7 (Ph), 117.7 (C-5), 71.9 (C-2), 39.8 (C-3), 37.4
reaction was monitored by TLC. The reaction mixture was then
(C-1), 36.7 (CH2Bn), 26.9 (CH3), 19.3 ppm. C28H34OSSi (446.72):
washed with saturated NaHCO3 solution and brine. The organic
calcd. C 75.34, H 7.62, S 7.17; found C 75.46, H 7.59, S 7.20.
layer was dried with anhydrous MgSO4 and the solvent was re-
3-O-(tert-Butyldiphenylsilyl)-1,1-dioxo-3,4-dihydro-2H-thiopyran-3-
ol (26): Iodine (0.033 g, 0.13 mmol) was added under argon to a tion gradient: hexane/ethyl acetate, 20:1, hexane/ethyl acetate,
cold solution (Ϫ78 °C) of compound 25 (0.052 g, 0.12 mmol) in 10:1), to afford a 10:13 diastereomeric mixture of tetrahydrothioph-
dry dichloromethane (1 mL). The mixture was allowed to warm to enes 29 and 30 (0.083 g 67%). The single diastereoisomers were
moved in vacuo. The resulting residue was purified by MPLC (elu-
room temperature, and mCPBA (0.074 g, 0.30 mmol) was then ad-
ded. After 2 h, aqueous Na2SO3 (5%, 25 mL) was added. The aque-
ous layer was extracted with dichloromethane (3 ϫ 50 mL) and the
combined organic layers were dried with anhydrous MgSO4 and
concentrated. The resulting residue was purified by radial chroma-
separated by radial chromatography with cyclohexane/ethyl acetate
1
(25:1). 29 (higher Rf): [α]2D5 ϭ ϩ18.8 (c ϭ 1.00, CHCl3). H NMR
(CDCl3, 400 MHz): δ ϭ 7.54Ϫ7.51 (m, 2 H, Ph), 7.32Ϫ7.26 (m, 3
H, Ph), 5.38 (q, 1 H, J4.8 Hz, 3-H), 3.60 (ddt, J ϭ 7.2, 5.2, 8.8 Hz,
1 H, 8.8 Hz, 5-H), 3.20 (d, J ϭ 7.2 Hz, 2 H, 6-H), 3.17 (dd, J ϭ
tography with an elution gradient (hexane/dichloromethane, 1:1, 11.6, 5.2 Hz, 1 H, 2-H), 3.00 (ddd, J ϭ 11.6, 4.4, 0.6 Hz, 1 H, 2Ј-
dichloromethane) to afford 0.037 g (66%) of compound 26 as a
H), 2.32 (ddd, 1 H, J ϭ 13.6, J ϭ 7.6, 5.2 Hz, 4-H), 2.14 (dt, J ϭ
syrup. IR: ν˜ ϭ 908 cmϪ1, 735 cmϪ1. 1H NMR (CDCl3, 400 MHz):
13.6, 5.2 Hz, 1 H, 5.2 Hz, 4Ј-H), 2.03 (s, 3 H, CH3) ppm. 13C NMR
δ ϭ 7.67Ϫ7.62 (m, 4 H, Ph), 7.50Ϫ7.35 (m, 6 H, Ph), 6.33 (ddd, 1 (CDCl3, 100.5 MHz): δ ϭ 135.0, 133.4, 129.2, 127.3 (Ph), 76.8 (C-
H, J ϭ 10.8, J ϭ 4.4, 2.8 Hz, 6-H), 6.25 (ddd, J ϭ 10.8, 5.6, 2.8 Hz, 3), 45.5 (C-5), 40.3 (C-4), 36.9 (C-2), 35.7 (C-6), 21.2 (CH3) ppm.
1 H, 5-H), 4.45 (m, 1 H, 3-H), 3.31 (dddd, J ϭ 1.2, 2.4, 3.2, C13H16O2SSe (315.29): calcd. C 49.52, H 5.08, S 10.16; found C
Eur. J. Org. Chem. 2003, 209Ϫ216
215

´
´
G. Jana, A. Viso, Y. Dıaz, S. Castillon
FULL PAPER
49.38, H 5.06, S 10.13. 30 (lower Rf): [α]2D5 ϭ ϩ17.0 (c ϭ 0.350, were added to a solution of thioacetate 24 (0.043 g, 0.27 mmol) in
CHCl3). 1H NMR (CDCl3, 400 MHz): δ ϭ 7.55Ϫ7.52 (m, 2 H, 1.5 mL of dichloromethane. The mixture was stirred for 2 h, filtered
Ph), 7.29Ϫ7.26 (m, 3 H, Ph), 5.49 (m, 1 H, 3-H), 3.81 (dddd, J ϭ
through a small pad of silica gel and concentrated in vacuo. The
8.4, 6.4, 6.4, 9.6 Hz, 1 H, 5-H), 2.28 (dd, J ϭ 12.0, 4.4 Hz, 1 H, 2- residue was purified by radial chromatography (elution gradient:
H), 3.18 (dd, J ϭ 12.0, 6.4 Hz, 1 H, 6-H), 3.14 (dd, J ϭ 12.4, hexane, hexane/ethyl acetate, 3:1) to give a 24:76 mixture of com-
8.0 Hz, 1 H, 6Ј-H), 2.94 (ddd, J ϭ 12.0, 2.4, 1.6 Hz, 1 H, 2Ј-H), pounds 31 and 32 (0.034 g, 47%).
2.40 (dddd, J ϭ 13.6, 5.6, 3.2, 1.6 Hz, 1 H, 4-H), 2.05 (s, 3 H,
CH3), 1.79 (ddd, J ϭ 13.6, 9.6, 4.0 Hz, 1 H, 4Ј-H) ppm. 13C NMR
Acknowledgments
We thank the DGESIC (Ministerio de Educacion y Cultura, Spain)
for financial support and for awarding a post-doctoral fellowship
to G. J. We thank the Servei de Recursos Cientıfics (URV) for sup-
(CDCl3, 100.5 MHz): δ ϭ 133.2, 129.2, 127.3 (Ph), 77.1 (C-3), 46.7
(C-5), 42.0 (C-4), 37.7 (C-2), 33.9 (C-6), 21.2 (CH3) ppm.
C13H16O2SSe (315.29): calcd. C 49.52, H 5.08, S 10.16; found C
49.61, H 5.10, S 10.15.
´
´
port.
Selenothioetherification of 24 under Basic Conditions in Methanol.
(3S,5S)-5-[(Phenylselenyl)methyl]-tetrahydrothiophen-3-ol (31) and
[1]
(3S,5R)-5-[(Phenylselenyl)methyl]-tetrahydrothiophen-3-ol
(32):
P. A. Bartlett, ‘‘Olefin Cyclization Processes that Form Car-
Phenylselenyl chloride (68 mg, 0.35 mmol) was added to a cold so-
lution (Ϫ78 °C) of alkenol 24 (0.058 g, 0.36 mmol) in 11 mL of dry
methanol. The reaction mixture was allowed to warm and stirred
for 6 h, and then washed with saturated NaHCO3 solution and
brine. The organic layer was dried with anhydrous MgSO4 and the
solvent was removed in vacuo. The resulting residue was purified
by radial chromatography (elution gradient: hexane, hexane/ethyl
acetate, 3:1), to give a 70:30 diastereomeric mixture of tetrahy-
drothiophenes 31 and 32 (0.034 g, 38%). 31: 1H NMR (CDCl3,
400 MHz): δ ϭ 7.44Ϫ7.41 (m, 2 H, Ph), 7.18Ϫ7.15 (m, 3 H, Ph),
4.42 (m, 1 H, 3-H), 3.51 (m, 1 H, 5-H), 2.94 (dd, J ϭ 12.2, 5.2 Hz,
1 H, 2-H), 3.12Ϫ3.03 (m, 2 H, 6-H, 6Ј-H), 2.81 (ddd, J ϭ 12.2,
5.2, 1.2 Hz, 1 H, 2Ј-H), 2.34 (br. s, 1 H, OH), 2.23 (ddd, J ϭ 13.2,
7.2, 5.2 Hz, 1 H, 4-H), 1.58 (ddd, J ϭ 13.2, 5.6, 1.2 Hz, 1 H, 4Ј-H)
ppm. 13C NMR (CDCl3, 100.5 MHz) 132.9, 129.2, 128.9, 127.0
(Ph), 75.1 (C-3), 45.4 (C-5), 43.2 (C-4), 40.1 (C-2), 36.0 (C-6) ppm.
32: 1H NMR (CDCl3, 400 MHz): δ ϭ 7.44Ϫ7.41 (m, 2 H, Ph),
7.18Ϫ7.15 (m, 3 H, Ph), 4.54 (m, 1 H, 3-H), 3.73 (m, 1 H, 5-H),
3.19 (dd, J ϭ 12.0, 8.4 Hz, 1 H, 2-H), 3.12Ϫ3.03 (m, 2 H, 6-H, 6Ј-
H), 2.75 (ddd, J ϭ 12.0, 1.6, 1.6 Hz, 1 H, 2Ј-H), 2.27 (br. s, 1 H,
OH), 2.23 (dddd, 1 H, J ϭ 13.2, 6.4, 2.8, 1.6 Hz, 4-H), 1.58 (ddd,
J ϭ 13.2, 9.6, 3.6 Hz, 1 H, 4Ј-H) ppm. 13C NMR (CDCl3,
100.5 MHz): δ ϭ 132.8, 129.4, 128.9, 127.0 (Ph), 75.0 (C-3), 46.0
(C-5), 44.6 (C-4), 40.8 (C-2), 34.7 (C-6) ppm.
bon-Heteroatom Bonds’’ in Asymmetric Synthesis, vol. 3 (Ed.:
J. D. Morrison), Academic Press, New York, 1984.
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E. Vedejs, R. A. Buchanan, P. C. Conrad, G. P. Meier, M. J.
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E. Turos, M. Parvez, R. S. Garigipati, S. M. Weinreb, J. Org.
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[2]
[3]
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[7]
[8]
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[9]
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[10]
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[11]
M. Narisada, H. Onoue, M. Ohtani, F. Watanabe, T. Okada,
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P. N. Confalone, G. Pizzolato, E. G. Baggiolini, D. Lollar, M.
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[12]
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[14]
Chem. 1995, 60, 6468.
Selenothioetherification of 24 under Acidic Conditions. Synthesis of
29/30 and 31/32: N-Phenylselenophthalimide (N-PSP, 0.105 g,
0.29 mmol) and camphorsulfonic acid (0.047 g, 0.20 mmol) were
added to a solution of thioacetate 24 (0.046 g, 0.29 mmol) in
1.5 mL of dichloromethane. The mixture was stirred for 4 h, filtered
through a small pad of silica gel and concentrated in vacuo. The
residue was purified by radial chromatography (elution gradient:
hexane, hexane/ethyl acetate, 3:1) to give a 64.36 mixture of
acetylated products 29 and 30 (0.029 g, 32%) and a 26:74 mixture
of compounds 31 and 32 (23%).
[15]
X.-F. Ren, E. Turos, J. Org. Chem. 1994, 59, 5858.
[16]
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J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 736.
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[22]
´
F. Bravo, S. Castillon, Eur. J. Org. Chem. 2001, 507Ϫ516.
K. C. Nicolaou, D. A. Claremont, W. E. Barnette, S. P. Seitz,
[23]
J. Am. Chem. Soc. 1979, 101, 3704.
[24]
Selenothioetherification of 24 under Acidic Conditions in Methanol.
Synthesis of 31 and 32: N-Phenylselenophthalimide (N-PSP,
0.098 g, 0.32 mmol) and camphorsulfonic acid (0.044 g, 0.19 mmol)
´
´
Y. D ıaz, F. Bravo, S. Castillon, J. Org. Chem. 1999, 64, 6508.
Received July 8, 2002
[O02373]
216
Eur. J. Org. Chem. 2003, 209Ϫ216