Stereoselective synthesis of 2,3,4-trisubstituted tetrahydrothiophenes

Article abstract of DOI:10.1016/j.tetlet.2009.09.104

We describe an efficient new approach for the synthesis of highly substituted chiral tetrahydrothiophenes, based on the oxidation of a chiral furan substrate with singlet oxygen, followed by intramolecular hetero Michael addition.

Full text of DOI:10.1016/j.tetlet.2009.09.104

Tetrahedron Letters 50 (2009) 6941–6943
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of 2,3,4-trisubstituted tetrahydrothiophenes
*
*
Pedro Besada , Manuel Pérez, Generosa Gómez, Yagamare Fall
Departamento de Química Orgánica, Facultade de Química, Universidade de Vigo, 36310 Vigo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2009
Revised 15 September 2009
Accepted 18 September 2009
Available online 24 September 2009
We describe an efficient new approach for the synthesis of highly substituted chiral tetrahydrothioph-
enes, based on the oxidation of a chiral furan substrate with singlet oxygen, followed by intramolecular
hetero Michael addition.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Furan
Singlet oxygen
Tetrahydrothiophenes
Stereoselective synthesis
Substituted tetrahydrothiophenes, some of which are shown in
Figure 1, have received considerable attention because of their
wide spectrum of biological activities. The natural products sala-
cinol (1) and kotalanol (2), isolated from Salacia reticulata, Salacia
compounds.12 In order to enlarge the scope of our methodology,
we have focused our attention on the synthesis of thiacyclic com-
pounds. Recently, we have reported the preparation of six-mem-
bered thiacyclic compounds.13 The challenge to obtain the more
constrained five-membered ring and the chemical and biological
importance of tetrahydrothiophenes prompted us to extend our
methodology to the synthesis of this class of compounds. Herein,
we report the stereoselective synthesis of chiral 2,3,4-trisubsti-
tuted tetrahydrothiophenes 21.
oblonga, and Salacia chinesis, are potent
a
-glucosidase inhibitors.1
Significant efforts to prepare these cyclic sulfonium salts and syn-
thetic analogues, such as 3 and 4, have been made in the past few
years.2 Recently, the related compounds salaprinol (5) and ponkor-
anol (6) were also isolated from the same plant species.3 Biotin (7)
is involved in important biological functions.4 The adenosine ana-
logues LJ-568 (8) and LJ-1251 (9) are potent and selective A3 ago-
nist and antagonist, respectively.5 The chiral dihydrothiophene 10
inhibits copper amine oxidases.6 Furthermore, tetrahydrothioph-
enes have been used as templates to facilitate and control various
chemical transformations, as in asymmetric metal catalysis hydro-
genation, catalytic asymmetric epoxidation, and catalytic intramo-
lecular cyclopropanation.7 In nanochemistry, the study of
adsorption and properties of thiophenes, tetrahydrothiophenes,
and chiral sulfur compounds, as cysteine, on gold surfaces have ac-
quired importance lately.8 The substituted thiophene 11 has also
been used for size control synthesis of gold nanoparticles.9
For these reasons, the development of new synthetic ap-
proaches to tetrahydrothiophenes is of interest for organic chem-
ists. Previously, we have described a new methodology for the
synthesis of oxacyclic compounds from methoxyallene or furan.10
We have prepared chiral butenolides, natural oxacyclic products,
polyoxepanes, and polytetrahydropyrans.11 This methodology has
also been extended to the synthesis of carbocyclic and azacyclic
The chiral furan 16 is the key intermediate in our synthesis and
it was prepared as shown in Scheme 1. Diol 13 was obtained from
the commercially available tri-O-acetyl-D-glucal as previously re-
ported.11a Selective protection of the primary alcohol of compound
13 by treatment with tosyl chloride in the presence of dibutyltin
oxide14 followed by protection of the secondary hydroxyl group
of the rather unstable tosylate 14 provided compounds 1515 in
good yield. We have used TBDPS and the less bulky TBS as protect-
ing groups in order to study the influence of the steric hindrance in
the process. Treatment of 15a and 15b with potassium thioacetate
in DMF16 gave the chiral furans 16a (94%) and 16b (92%).15
Oxidation of 16a with singlet oxygen in MeOH–CH2Cl2 1:1 in
the presence of diisopropylethylamine afforded the 4-hydroxybut-
enolide 17a15 as a 1.6:1 diastereomeric mixture in 71% yield
(Scheme 2). Reduction of compound 17a with sodium borohydride
under Luche’s conditions followed by in situ acid-catalyzed lacton-
ization gave enantiomerically pure butenolide 18a15 in very good
yield (84%). At this stage the stereochemistry at C4 was unknown;
however, the influence of the vicinal O-silylprotected group
observed previously for related compounds11a allowed us to
anticipate that the absolute configuration would be 4S. This result
will be unambiguously confirmed later. Treatment of 18a with
* Corresponding authors. Tel.: +34 986 81 23 20; fax: +34 986 81 22 62.
E-mail addresses: pbes@uvigo.es (P. Besada), yagamare@uvigo.es (Y. Fall).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.104

6942
P. Besada et al. / Tetrahedron Letters 50 (2009) 6941–6943
OH
OH OH
R
R
OH
I-
Cl-
-
S
OSO3
S
S
S
S
OH
-
HO
HO
HO
OSO3
OH
HO
OH
HO
OH
HO
OH
HO
salacinol (1), R = CH2OH
salaprinol (5), R = H
kotalanol (2), R = OH
ponkoranol (6), R = H
3
4
HN
O
S
COOH
N
I
S
S
N
OEt
H
H
O
N
S
R
N
Cl
HN NH
H2N
OH
O
11
10
HO
OH
biotin (7)
LJ-568 (8), R = CONHCH3
LJ-1251 (9), R = H
Figure 1. Substituted tetrahydrothiophenes with important biological and chemical applications.
OAc
AcO
i, ii
iii
OAc
OAc
S
9.8%
OH
OTs
H
AcO
O
O
O
OH
v
OH
14
OTBDPS
5.6%
O
H
H
10.9%
12
13
6.7%
21a
iv
OTs
S
O
O
Figure 2. NOe correlations for 21a.
OR
OR
15a, R = TBDPS
15b, R = TBS
16a, R = TBDPS
16b, R = TBS
provided 68% yield of the bicyclic lactone 19b, which was unevent-
fully converted into target compound 21b.
In conclusion, a new and efficient method for the stereoselec-
tive synthesis of highly substituted chiral tetrahydrothiophenes
Scheme 1. Reagents and conditions: (i) K2CO3, MeOH, rt; (ii) InCl3ꢀ4H2O, CH3CN, rt,
77% from 12; (iii) p-TsCl, Bu2SnO, Et3N, CH2Cl2, rt; (iv) TBDPSCl or TBSCl, Im, DMAP,
DMF, rt, 69% (15a from 13), 61% (15b from 13); and (v) KSCOCH3, DMF, 70 °C, 94%
(16a), 92% (16b).
from the commercially available tri-O-acetyl-D-glucal is described.
The use of this methodology for the synthesis of natural products
and synthetic analogues with pharmacological activity is now in
progress in our laboratories.
O
O
i
ii
iii
16a
16b
O
O
S
S
O
O
OH
OR
OR
Acknowledgments
17a, R = TBDPS
17b, R = TBS
18a, R = TBDPS
18b, R = TBS
This work was financially supported by the Spanish Ministry of
Education and Science (CTQ2007-61788) and the Xunta de Galicia
(INCITE08PXIB314253PR, INCITE08ENA314019ES, and INCITE08P-
XIB314255PR). The work of the NMR and MS divisions of the re-
search support services of the University of Vigo (CACTI) is also
gratefully acknowledged. Pedro Besada and Manuel Pérez thank
the Xunta de Galicia for an Isidro Parga Pondal and an Angeles Al-
variño contract, respectively.
H
H
S
S
S
HO
iv
AcO
v
O
O
HO
OR
AcO
OR
OR
20a, R = TBDPS
20b, R = TBS
21a, R = TBDPS
21b, R = TBS
19a, R = TBDPS
19b, R = TBS
Scheme 2. Reagents and conditions: (i) (a) 1O2, hv, rose bengal, MeOH, CH2Cl2,
DIPEA, ꢁ78 °C; (b) H2C2O4 0.12 M, CH2Cl2, rt, 71% (17a), 69% (17b); (ii) (a)
CeCl3ꢀ7H2O, NaBH4, MeOH, 0 °C; (b) MeOH, HCl, rt, 84% (18a), 73% (18b); (iii) K2CO3,
MeOH, 0 °C, 53% (19a), 68% (19b) (iv) BF3ꢀOEt2, LiAlH4, Et2O, rt; and (v) Ac2O, DMAP,
Py, rt, 84% (21a from 19a), 88% (21b from 19b).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.104.
References and notes
potassium carbonate in methanol at 0 °C gave a 53% yield of the
bicyclic lactone 19a15 through an intramolecular Michael reaction.
The lactone ring of 19a was then opened with lithium aluminium
hydride to afford diol 20a15 which was acetylated without further
purification to give tetrahydrothiophene 21a17a (84%, two steps).
The stereochemistry of compound 21a was established
unequivocally using nOe experiments (Fig. 2), these results also
confirmed the stereochemistry for compound 18a anticipated by
us. Tetrahydrothiophene 21b17b was obtained from furan 16b fol-
lowing the same sequence of reactions (Scheme 2). The intramo-
lecular Michael reaction for the less bulky compound 18b
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a
]
D ꢁ48.67 (c 0.35, CHCl3); 1H NMR (CDCl3) d
7.69 (4H, m, H-Ph), 7.44 (6H, m, H-Ph), 5.26 (1H, m, H3), 4.44 (1H, m, H4), 4.14
(2H, m, H20), 3.93 (1H, m, H2), 2.93 (1H, dd, J = 11.3 and 4.2 Hz, 1H5), 2.69 (1H,
dd, J = 11.3 and 1.6 Hz, 1H5), 2.07 (3H, s, COCH3), 2.06 (1H, m, 1H10), 2.01 (3H,
s, COCH3), 1.82 (1H, m, 1H10), 1.11 (9H, s, C(CH3)3); 13C NMR (CDCl3) d 170.9,
169.9, 135.7, 135.6, 133.3, 132.8, 130.0, 129.9, 127.8, 127.7, 80.3, 77.4, 63.2,
44.6, 36.3, 29.3, 26.8, 20.9, 20.8, 19.1; HRMS m/z calcd for C26H34NaO5SSi
509.17884, found 509.17874 (M+Na)+; (b) Selected data for compound 21b: [
a]
D
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4.12 (2H, m, H20), 3.78 (1H, m, H2), 3.14 (1H, m, 1H5), 2.73 (1H, m, 1H5), 2.10
(3H, s, COCH3), 2.07 (1H, m, 1H10), 2.05 (3H, s, COCH3), 1.86 (1H, m, 1H10), 0.90
(9H, s, C(CH3)3), 0.12 (3H, s, SiCH3), 0.11 (3H, s, SiCH3); 13C NMR (CDCl3) d
170.9, 170.1, 80.7, 76.6, 63.3, 44.4, 36.7, 29.2, 25.6, 20.9, 17.9, ꢁ4.9, ꢁ5.0;
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