Short and general procedure for synthesizing cis-1,2-fused 1,3-oxathiolan-, 1,3-oxaselenolan-, and 1,3-oxazolidin-2-imine carbohydrate derivatives

Article abstract of DOI:10.1021/jo9023649

(Chemical Equation Presented) Novel cis-1,2-fused 1,3-oxathiolan-, 1,3-oxaselenolan-, and 1,3-oxazolidin-2-imine carbohydrate derivatives have been prepared by treatment of the corresponding 1,2-anhydrosugars with potassium thiocyanate, potassium selenocy

Full text of DOI:10.1021/jo9023649

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Short and General Procedure for Synthesizing
Cis-1,2-Fused 1,3-Oxathiolan-, 1,3-Oxaselenolan-,
and 1,3-Oxazolidin-2-imine Carbohydrate Derivatives
Javier Castilla, Irene Marın, M. Isabel Matheu,
ꢀ
Yolanda Dıaz,* and Sergio Castillon*
´
´
´
ꢁ
Departament de Quımica Analıtica i Quımica Organica,
´
Universitat Rovira i Virgili, C/ Marcel•lı Domingo s/n, 43007
Tarragona, Spain
yolanda.diaz@urv.cat; sergio.castillon@urv.cat
Received November 4, 2009
Novel cis-1,2-fused 1,3-oxathiolan-, 1,3-oxaselenolan-, and
1,3-oxazolidin-2-imine carbohydrate derivatives have been
prepared by treatment of the corresponding 1,2-anhydrosu-
gars with potassium thiocyanate, potassium selenocyanate,
and sodium cyanamide, respectively. The procedure is com-
patible with several protecting groups such as acyl, benzyl,
and silyl and also with sugars of different configurations.
FIGURE 1. Sugars containing 1,2-fused five-membered hetero-
cycles saturated (a) and unsaturated (b), previously reported, as
well as those described in this work (c).
the synthesis of new and more potent analogous com-
pounds.5 In addition, heterocycles can be useful as simulta-
neous protecting groups of anomeric and C-2 substituents6
and as precursors for glycoside and nucleoside asymmetric
syntheses7 as well as potential glycosidating agents.8
Figure 1 shows the main structures of carbohydrates
incorporating saturated (a) or unsaturated (b) 1,2-fused
five-membered heterocyclic rings previously reported in the
literature. The first syntheses of carbohydrates with satu-
rated five-membered heterocycles fused at the 1,2 positions
containing carbamates, thiocarbamates, and related func-
tions (I-IV, Figure 1a) consisted of the treatment of
unprotected reducing sugars with potassium cyanate or
thiocyanate in acidic media.9 Fused glycofuranosyl and
glycopyranosyl derivatives are also usually prepared by the
treatment of unprotected sugars with carbonylating agents
Carbohydrate-fused heterocycles form a diverse family of
compounds that exhibit interesting biological effects, includ-
ing fructose transport inhibition,1 as well as antitumor2 and
clinically useful antibacterial activity.3 Since the heterocyclic
moiety is directly involved in the binding process in the
enzyme pocket,4 much effort in recent years has focused on
€
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2004, 14, 3139–3142. (c) Wang, G. Anti-Infect. Agents Med. Chem. 2008, 7,
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Published on Web 12/15/2009
DOI: 10.1021/jo9023649
r
2009 American Chemical Society

Castilla et al.
JOCNote
similar process by treating the corresponding glycopyranosyl
azides with triphenylphosphine and then with carbon diox-
ide.11 In addition, bicyclic oxazolines and thiazolines (V, VI,
Figure 1b) can be prepared by cyclization of 1,2-trans-2-
deoxy-2-iodoglycopyranosyl derivatives12 and from 2-deoxy-
2-amidoglycosides.13
TABLE 1. Reaction of 1,2-Anhydroglucopyranose 1 with KSCN in the
Presence of Lewis Acids as Catalystsa
Herein, we show a general, short and efficient procedure
for synthesizing a new family of carbohydrate derivatives
with fused heterocycles of general formula VII (Figure 1c).
In the framework of developing new methodologies for the
synthesis of thiosugars, we explored the reaction of 1,2-
anhydrocarbohydrates with reagents typically used for
transforming epoxides into episulfides. Initially, the reaction
of 1,2-anhydro-3,4,6-tri-O-benzyl-R-D-glucopyranose14 (1)
with thiourea was tested but afforded a complex mixture of
products. When 1 was treated with KSCN (3 equiv) in dry
acetonitrile, the reaction also afforded a complex mixture
(Table 1, entry 1). Then, different Lewis acid catalysts were
entry
[cat.]
conversionb (%)
selectivityb (%)
1
2
3
4
5
6
100
100
100
40
100
100
mixture
mixture
40
95
95
BF3 OEt2
3
TMSOTf
Ti(OCH(CH3)2)4
TiCl4
TiO(CF3CO2)2
99
aConditions: 1 (1 mmol), KSCN (3 mmol), TiO(CF3CO2)2 (2% mol),
CH3CN (5 mL), reaction time (3 h), reflux. bConversion and selectivity
were determined by integration of H-1 protons in the reaction crude.
tested; however, when BF3 OEt2 was used (Table 1, entry 2)
oxathiolane cycle is fused cis with the carbohydrate. A
trans fusion would provide larger coupling constants
(∼9 Hz).5c,11a,b Vicinal coupling constants J2,3 (3.2 Hz) and
J3,4 (3.2 Hz) have unexpected small values, which suggests a
distorted pyranose ring with a preferential 0S2 pyranose
conformation, as previously reported for structurally related
bicyclic structures in solution.10,12a,13
A proposed mechanism for this transformation is shown
in Scheme 1. The reaction is presumably initiated by the
coordination of titanium catalyst to epoxide 1 with conco-
mitant opening of the epoxide by KSCN to give 3. Alter-
natively, the generation of oxocarbenium 4 could lead to the
formation of either 3 or 5. Since substituents at positions 1,2
in compound 3 have a cis relationship, compound 2 must
isomerize to 5 through cation 4. Further attack of the
alcoholate to the thiocyanate group in 5 would render the
final product. It has been reported that stoichiometric reac-
tions with organometallic reagents (Zr, Zn or Al) afforded
compounds of cis opening. Intermediates type 40, which have
been postulated in these cases, can not be discarded.17 There
are few examples of epoxides present in natural products
where their opening proceeds in a cis fashion.18
The reaction is compatible with other protecting groups
such as acetates. Thus, 1,2-anhydro-3,4,6-tri-O-acetyl-R-D-
glucopyranose (6)14 was reacted following the optimized
conditions to afford 7 in 66% yield (Table 2, entry 1). The
reaction was then extended to other 1,2-anhydropyranoses,
such as the galacto derivative 8,14 which afforded compound
9 in excellent yield when it was treated with KSCN under the
optimized conditions (Table 2, entry 2). With the aim of
investigating the possibility of obtaining compounds with
opposite configuration at the 1,2-positions, the altro deriva-
tive 1019 was also treated with KSCN in the presence of
TiO(CF3COO)2 to afford the expected product 11 in 75%
yield (Table 2, entry 3).
3
the results did not improve. When the reaction was con-
ducted in the presence of trimetylsilyl triflate, no thiirane was
detected; instead, compound 2 was isolated in 40% yield
(Table 1, entry 3). The use of titanium catalysts, such as
titanium isopropoxide, afforded 2 with low conversion but
with almost complete selectivity (Table 1, entry 4). The
highest conversions and selectivities were obtained when
TiCl4 and TiO(CF3CO2)2 were used as catalysts (Table 1,
entries 5 and 6) and with TiO(CF3CO2)2 the yield was
quantitative.15 A strong oxophile catalyst is necessary in this
case in order to activate the epoxide without interacting with
the soft thiocyanate reagent.16
The structure of compound 2, incorporating a 1,3-ox-
athiolan-2-imine moiety, was determined by NMR and IR
spectroscopy, as well as by exact mass spectrometry. The
presence of the imidoyl group was determined by 13C NMR
(CdNH at roughly 189 ppm) and by the presence of two
strong signals at 1495 and 1453 cm-1 in the IR spectrum,
which are characteristic of the imidoyl functional group. The
presence of a broad singlet at 8 ppm in the 1H NMR
spectrum is assigned to an imine hydrogen, which completes
the characterization of this group. Furthermore, the 1H
NMR spectrum showed a doublet at 5.66 ppm (J1,2 = 6.4
Hz) that correlated with a carbon at 82.2 ppm (C-1), which
was assigned to an unshielded anomeric hydrogen. The
chemical shift for C-1 indicated that it is bonded to sulfur
and oxygen and not to two oxygens (δ ∼100 ppm). The
coupling constant J1,2 ∼6-7 Hz is characteristic for H-1 in
an equatorial position,5a,d,9e,10,11a,12a indicating that the
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nian, M. P.; Siddiqui, Y. M.; Youssef, D. A.; Al-Hussain, K.; Al-Ahdal, M.
N; Al-Khodairy, F. J. Nat. Med. 2007, 61, 154–158. (b) El-Sayed, K. A.;
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SCHEME 1. Possible Mechanism for Product 2 Formation
SCHEME 2. Synthesis of Compound 13 from 12
SCHEME 3. Synthesis of Compounds 13 and 14
TABLE 2. Reaction of 1,2-Anhydroglucopyranoses 6, 8, and 10 with
KSCN in the Presence of TiO(CF3CO2)2
a
In summary, 1,3-oxathiolan-2-imine heterocycles fused to
the 1,2 positions of different pyranoses have been efficiently
prepared by the reaction of 1,2-anhydrosugars with KSCN
using TiO(CF3COO)2 as catalyst. The reaction is general and
1,2-anhydrosugars of gluco, galacto, and altro configura-
tions afforded compounds with the same relative configura-
tions, although the configuration of the anomeric position
for the two first cases was R and for the altro derivative was β.
The procedure can also be extended to the preparation of
seleno and amino derivatives, such as compounds 14 and 15,
respectively, which demonstrates the generality of the pro-
cedure. Although fully deprotected sulfur derivative can be
obtained in a one-pot process starting from triethylsilyl
protected 1,2-anhydrosugars, more research is being carried
out in order to generalize this deprotection to another
cyanide reagents.
aAll reactions were carried out at reflux under argon with 1.0 equiv of
substrate, 3.0 equiv of KSCN, 1 mol % of TiO(CF3COO)2, and CH3CN.
We then studied the reaction of the tri-O-silyl derivative 12
with KSCN/TiO(CF3COO)2 in the optimized conditions. To
our delight, the unprotected 1,3-oxathiolan-2-imine deriva-
tive 13 was directly recovered from the aqueous solution in a
85% yield. The silylated product was not present in the
organic phase, indicating that the deprotection was com-
plete. TLC control indicated that deprotection takes place
during the reaction and not in the workup. Deprotec-
tion tests of compound 7 (Zemplen conditions) were unsuc-
cessful.
Deprotection of the silyl groups in the presence of a strong
oxophile catalyst can explain the direct synthesis of the
unprotected compound 13 (Scheme 2).
Finally, we studied the generality of the reaction using
different cyanate reagents. The reaction of 1 with potassium
selenocyanate gave the selenocarboimidate derivative 14 in
very good yield after 3 h (Scheme 3a). The corresponding
imino-oxazolidine derivative 15 was also obtained in excel-
lent yield when 1 was reacted with sodium cyanamide
(Scheme 3b).
Experimental Section
General Procedure for Glycal Epoxydation.14 The glycal
(1.00 mmol) was dissolved in an ice bath cooled biphasic
solution of CH2Cl2 (4 mL), acetone (0.4 mL), and saturated
aqueous NaHCO3 (6.5 mL). The mixture was vigorously stirred
and a solution of Oxone (1.23 g, 2.00 mmol) in H2O (5 mL) was
added dropwise over 15 min. The crude reaction was vigorously
stirred at 0 °C for 30 min and was then allowed to warm to room
temperature until TLC indicated complete consumption of the
glycal. The organic phase was separated, and the aqueous phase
was extracted with CH2Cl2 (2 ꢀ 4 mL). The combined organic
phases were dried over MgSO4, filtered, and concentrated to
afford the 1,2-anhydropyranoses in the yields shown. The crude
could not be purified due the decomposition of the 1,2-anhydro
sugar.
General Procedure for the Synthesis of Cis-1,2-Fused 1,3-
Oxathiolan-, 1,3-Oxaselenolan-, and 1,3-Oxazolidin-2-imine
Carbohydrate Derivatives. To a stirred solution of the 1,2-
anhydro sugar (1.00 mmol) and XCN (X = KS, KSe, NaNH)
(3.00 mmol) in dry CH3CN (5 mL) was added finely powdered
TiO(CF3COO)2 (0.02 mmol) under an argon atmosphere, and
the mixture was heated to boiling for an appropriate time. After
completion of the reaction, followed by TLC, the mixture was
cooled to room temperature, H2O (10 mL) was added, and the
resultant mixture was extracted with EtOAc. The combined
In order to obtain the deprotected seleno and amino deri-
vatives, the silyl derivative 12 was also treated with potas-
sium selenocyanate and sodium cyanamide under similar
reactions conditions, but in these cases the reaction pro-
ceeded with the decomposition of the products.
516 J. Org. Chem. Vol. 75, No. 2, 2010

Castilla et al.
JOCNote
organic extracts were dried over MgSO4, filtered, and concen-
trated. Flash chromatography on silica gel gave the products in
the yields shown.
acknowledged. We are also grateful to the Servei de Recursos
Cientifics (URV) for its technical assistance.
Supporting Information Available: General experimental
methods, experimental procedures, compound characterization
data, and NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We acknowledge the financial sup-
port from DGESIC CTQ-2008-01569/BQU (Ministerio de
ꢀ
Educacion y Ciencia, Spain) and by a grant to J.C. is
J. Org. Chem. Vol. 75, No. 2, 2010 517