The furan approach to thiacyclic compounds. Stereoselective synthesis of 2,3-disubstituted tetrahydrothiopyrans

Article abstract of DOI:10.1016/j.tetlet.2008.04.077

We describe an efficient new approach to the synthesis of thiacyclic compounds that extends the methodology we previously developed for oxacycles: oxidation of a furan ring with singlet oxygen, followed by intramolecular hetero Michael addition. The new a

Full text of DOI:10.1016/j.tetlet.2008.04.077

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Tetrahedron Letters 49 (2008) 4040–4042
The furan approach to thiacyclic compounds. Stereoselective
synthesis of 2,3-disubstituted tetrahydrothiopyrans
*
*
Seila Boullosa, Zoila G a´ ndara, Manuel P e´ rez, Generosa G o´ mez , Yagamare Fall
Departamento de Qu ı´ mica Org a´ nica, Facultad de Qu ı´ mica, Universidad de Vigo, 36200 Vigo, Spain
Received 4 March 2008; revised 7 April 2008; accepted 11 April 2008
Available online 15 April 2008
Abstract
We describe an efficient new approach to the synthesis of thiacyclic compounds that extends the methodology we previously devel-
oped for oxacycles: oxidation of a furan ring with singlet oxygen, followed by intramolecular hetero Michael addition. The new approach
provides a new entry to nucleoside analogues and a-glucosidase inhibitors.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Thiacyclic compounds; Thiopyrans; Singlet oxygen; a-Glucosidase; Stereoselective synthesis
Cyclic sulfides have been widely used as templates to
facilitate and control various chemical transformations,
In view of the challenging opportunities noted above, we
investigated whether the synthesis of thiacyclic compounds
might profitably be approached by adopting the methods
we have developed for the synthesis of oxacyclic com-
1
one of their advantages for this purpose being the relative
ease with which the sulfur atom can be removed from the
final product. In particular, scaffolds derived from thiopy-
ran have been exploited in the construction of a huge num-
5
pounds from methoxyallene or furan. This methodology
6
a
has given access to chiral butenolides, natural oxacyclic
2
6b
6c
6d
ber of synthetic targets. A decade ago, interest in cyclic
products, polyoxepanes and polytetrahydropyrans,
sulfides chemistry received new impetus from the finding
and has also been extended to the synthesis of carbocyclic
systems. Here we report its extension to the stereoselective
synthesis of the cis and trans 2,3-disubstituted tetrahydro-
thiopyrans 2 and 3 (Scheme 1).
7
that the natural products salacinol (4) and kotalanol (5),
3
shown in Figure 1, are potent a-glucosidase inhibitors.
The synthesis of these cyclic sulfonium salts and their syn-
thetic analogues such as 6 and 7 has attracted considerable
attention in the past few years.
We envisaged that compounds 2 and 3 could be pre-
pared as shown in Scheme 1 from furan 6, which is easily
4
OH
OH OH OH
Cl
OH
OH
I
S
S
S
S
OSO3
S
O
OH
HO
HO
HO
SO3
OH
5 Kotalanol
HO
HO
OH
OH
HO
HO
OH
Salacinol
6
7
4
Fig. 1. Structures of some natural (4, 5) and synthetic (6, 7) glucosidase inhibitors.
*
Corresponding authors. Fax: +34 986 81 22 62 (Y.F.).
E-mail addresses: ggomez@uvigo.es (G. G o´ mez), yagamare@uvigo.es (Y. Fall).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.077

S. Boullosa et al. / Tetrahedron Letters 49 (2008) 4040–4042
4041
i
ii
O
OH
O
1
O
CO2Et
O
H
4
5
iii
iv
OTs
O
v
OH
O
O
S
7
6
O
vi
vii
O
S
O
O
OMe
HO
8
9
H
H
S
S
viii
S
ix
O
HO
O
OMe
1
1
1
0
H
H
H
H
S
+
TBDPSO
TBDPSO
HO
TBDPSO
2
3
Scheme 1. Reagents and conditions: (i) Ph
3
P, BrCH
iv) pTsCl, pyr (97%); (v) MeCOSK, DMF (70%); (vi) (a) O
77%); (viii) LAH, BF (99%); (ix) TBDPSCl, Im, DMF, DMAP [45% (2); 52% (3)].
ÁOEt
2
CO
2
Et, LiOH, LiCl, H
2
O, reflux (99%); (ii) LiAlH
4
, Et
2
O (95%); (iii) H
2
, Pd/C, MeOH (98%);
1
(
(
2
, MeOH, rose Bengal, hm;(b) Ac O, py, DMAP (>99%, 2 steps); (vii) K CO , MeOH, 0 °C
2
2
3
3
2
5
d
obtained in 92% yield from the inexpensive furaldehyde 1
by a one-pot Wittig reaction followed by LAH reduction
and catalytic hydrogenation (for the synthesis of large
quantities of alcohol 6, this three-step route is much
cheaper than LAH reduction of commercial ethyl 3-
hydropyrans, these isomers could not be separated by
column chromatography. However, the reaction of 11 with
TBDPSCl for 1 h afforded the monoprotected tetrahydro-
8
1
1a
thiopyran 2
(45%) and the diprotected tetrahydrothio-
(52%), which were easily separated. A likely
1
1b
pyran 3
5
d
(
furan-2-yl)propanoate ). Alcohol 6 was easily converted
explanation of the selective protection of the cis-diastereo-
isomer of compound 11 could be that because of steric
hindrance one diastereoisomer reacts more rapidly than
the other. The control of reaction time is crucial. The
relative stereochemistry of 3 was confirmed by NOE
experiments (Fig. 2).
9
in 97% yield into tosylate 7, which upon reaction with
potassium thioacetate in DMF gave furan 8 (70%). Oxi-
dation of 8 with singlet oxygen, followed by treatment with
1
0
9
9
acetic anhydride in pyridine, then afforded butenolide 9
(
99%, two steps); and treatment of 9 with potassium car-
bonate in methanol at 0 °C gave a 77% yield of the bicyclic
In conclusion, we have shown that the furan approach
to oxacycles that we developed some years ago can be
extended to the synthesis of thiacyclic systems. Work is
now in progress on the use of this methodology to build
templates for important synthetic targets and to explore
the fascinating world of thiosugars.
9
lactone 10 through an intramolecular Michael reaction.
The lactone ring of 10 was then opened with LAH,
affording a mixture of the diastereoisomeric cis and trans
9
2
,3-tetrahydrothiopyran diols 11. Unlike related tetra-
11%
Acknowledgements
H
S
This work was supported by grants from the Xunta de
Galicia (PGIDIT04BTF301031PR) and the Spanish Minis-
try of Education and Science (CTQ2007-61788). The work
of the NMR and MS divisions of the research support
services of the University of Vigo (CACTI) is gratefully
acknowledged.
TBDPSO
TBDPSO
3
H
10%
Fig. 2. NOE correlations in 3.

4042
S. Boullosa et al. / Tetrahedron Letters 49 (2008) 4040–4042
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