Synthesis of 5′-seleno-xylofuranosides

Article abstract of DOI:10.1016/j.tet.2010.03.033

The synthesis of selenium derivatives of naturally occurring chiral molecules is becoming increasingly important in recent years. In this context, we describe herein an easy, straightforward synthetic route for the preparation of a series of chiral seleno-furanosides, starting from the readily available carbohydrate d-xylose. In addition, selected compounds were screened as inhibitors of the δ-aminolevulinate dehydratase (δ-ALA-D) enzyme. Diselenide 4 was found to reduce significantly the enzymatic activity, while seleno-furanoside 1a increased δ-ALA-D activity.

Full text of DOI:10.1016/j.tet.2010.03.033

Tetrahedron 66 (2010) 3441–3446
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Tetrahedron
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Synthesis of 50-seleno-xylofuranosides
a
a
b
c
a,
*
´
´
˜
¨
Hugo C. Braga , Helio A. Stefani , Marcio W. Paixao , Francielli W. Santos , Diogo S. Ludtke
a Faculdade de Cieˆncias Farmaceˆuticas, Universidade de S˜ao Paulo, 05508-900 S˜ao Paulo, SP, Brazil
b Departamento de Qu´ımica, Universidade Federal de S˜ao Carlos,13565-905, S˜ao Carlos, SP, Brazil
c Universidade Federal do Pampa, Uruguaiana, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of selenium derivatives of naturally occurring chiral molecules is becoming increasingly
important in recent years. In this context, we describe herein an easy, straightforward synthetic route for
the preparation of a series of chiral seleno-furanosides, starting from the readily available carbohydrate
Received 12 February 2010
Received in revised form 6 March 2010
Accepted 8 March 2010
D
-xylose. In addition, selected compounds were screened as inhibitors of the
dratase ( -ALA-D) enzyme. Diselenide 4 was found to reduce significantly the enzymatic activity, while
seleno-furanoside 1a increased -ALA-D activity.
d-aminolevulinate dehy-
Available online 12 March 2010
d
d
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
In this context, by reviewing the current literature we found that
studies are mainly focused on the introduction of the organo-
selenium moiety at the anomeric position of pyranoside sugars.
More specifically, Misra and co-workers described the preparation
of several selenoglycosides by the reaction between glycosyl
bromides and organic diselenides, mediated by powdered zinc, in
the presence of catalytic amounts of ZnCl2, delivering preferentially
Organoselenium chemistry has continued to attract consider-
able attention due to its pivotal role in the synthesis of a large
number of biological compounds (e.g., seleno-carbohydrates,
selenoamino acids, and selenopeptides).1,2 Dietary selenium is an
essential element in human nutrition, playing important roles in
cancer prevention, immunology, aging, male reproduction, and
other physiological processes.3 Indeed, organoselenium com-
pounds have also emerged as an exceptional class of structures,
which exemplify a role in biochemical processes, serving as
important therapeutic compounds ranging from antiviral and
anticancer agents to naturally occurring food supplements.4
However, despite to the growing importance of this field,
methods for the incorporation of the selenium atom in carbohy-
drates and derivatives are limited, compared to the its closest
relative sulfur,5 and there is still a need for further developments
toward the synthesis of carbohydrate-derived chiral selenium-
compounds, potentially candidates for biological evaluation.6 In
particular, recently seleno-carbohydrates have been described to
be effective depigmenting compounds on a mushroom tyrosinase
inhibitory assay and some compounds inhibited melanin synthesis
in the melan-A cells, in similar levels to phenylthiourea, which is
a well-known inhibitor of such process.7 Besides, carbohydrates
presenting an organoselenium group at the anomeric position
have also been described to act as selective glycosylating agents in
the synthesis of oligosaccharides,8 and as useful intermediates
for the synthesis of functionalized glycals,9 C-glycosides10 and
glycoconjugates.11
the
b
-selenoglycoside.12 The same authors have discovered that
changing the Zn/ZnCl2 promoter to indium (I) iodide, the
a anomer
could be obtained preferentially.13 Additionally, selenoglycosides
have also been obtained in high yields by reaction of glycosyl
chlorides or bromides and p-methylselenobenzoate.14
It is worth to note that the development of methods for the
synthesis of furanoside-based seleno-carbohydrates is scarcely
studied. Thus, we describe herein a short synthetic route for the
preparation of a series of chiral 50-seleno-furanosides 1, starting
from the readily available carbohydrate D
-xylose (Fig. 1).15
Figure 1. General structure of 50-seleno-xylofuranosides.
An attractive feature related to the structure of seleno-
xylofuranosides 1, is the presence of a free hydroxyl group near
to the selenium atom, in a cis relationship. This is relevant, since it
* Corresponding author. Tel.: þ55 11 3091 3687; fax: þ55 11 3815 4418; e-mail
address: dsludtke@usp.br.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.033

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H.C. Braga et al. / Tetrahedron 66 (2010) 3441–3446
is known that intramolecular non-bonding interaction between
selenium and other heteroatoms, such O and N, has a beneficial
effect to the glutathione peroxidase (GPx) like activity of numerous
simple, synthetic organoselenium compounds.1,16
Next, we extended our studies to a broader range of selenium
nucleophiles, in order to prepare a small library of compounds,
which would be highly desirable for biological evaluation of such
compounds. Thus, we extended the optimal conditions to a wide
range of selenium nucleophiles, as depicted in Table 1. The reaction
is tolerant to a variety of substituents at the aromatic ring of the
organoselenium moiety, allowing the preparation of a series of
seleno-carbohydrates.
2. Results and discussion
For the introduction of the selenium moiety in the carbohydrate
framework, we decided to use the known tosylate 2 as the pre-
cursor. Thus, this compound was straightforwardly obtained by
a short synthetic sequence, as outlined in Scheme 1.
We could successfully perform the reaction starting with aro-
matic diselenides possessing electron-withdrawing groups, such as
4-ClPh (entry 2, 84% yield), 4-CF3Ph (entry 3, 79% yield) and the
electron-donating groups, 4-MeOPh (entry 4, 84% yield) and
4-MePh (entry 5, 83% yield). Moreover, the introduction of heter-
oaromatic (2-thienyl, entry 7, 81% yield) and aliphatic groups (Bn,
entry 6, 72% yield; and n-Bu, entry 8, 88% yield) were also achieved
in very good yields. It is noteworthy that all reactions proceeded
smoothly, with very little by-product formation. Due to the success
obtained with the preparation of the seleno-carbohydrates, we
decided to extend our studies to sulfur and tellurium analogues, in
order to prepare some different chalcogen carbohydrate de-
rivatives, based on the xylose-derived framework. In fact, reduction
of diphenyl disulfide or p-toluyl ditelluride with NaBH4, under the
same conditions used for the diselenides, followed by reaction with
2, delivered the corresponding thio-carbohydrate 1i and telluro-
carbohydrate 1j in moderate yields (Table 1, entries 10 and 11).
Additionally, the seleno-furanoside 1a, which presents the iso-
propylidene protecting group, was converted into methyl seleno-
xylofuranoside in a straightforward manner (Scheme 2). First,
treatment with aqueous trifluoroacetic acid lead to deprotection of
the cis diol, and the crude product was immediately converted into
the corresponding methyl glycoside by reaction with MeOH, in the
presence of a catalytic amount of acid. The desired product 3 was
Scheme 1. Synthesis of tosylate 2.
First, the treatment of
catalytic amounts of I2 furnished the corresponding di-iso-
propylidene-
-xylofuranose,17 which was selectively hydrolyzed
D-xylose with acetone, in the presence of
D
with HCl 0.12 M, to the corresponding diol in 69% yield. Important
to mention is that the concentration of the HCl solution had to be
carefully optimized, since more concentrated solutions hydrolyzed
both isopropylidene groups, while more diluted ones did not fur-
nish the desired product. Reaction of the primary hydroxyl group
with p-TsCl in pyridine as described by Lu and Just18 delivered the
desired tosylate 2 in 81% yield (Scheme 1).
With tosylate 2 in hands, we turned our attention to the in-
corporation of the organoselenium moiety in the furanoside
backbone, through the nucleophilic substitution of the OTs leaving
group (Table 1). Studies toward the optimization of this step were
performed using phenylselenide nucleophile, which was generated
in situ from the corresponding diphenyl diselenide, by reduction
with NaBH4, according to our previous work.19 After screening
several reaction parameters, in particular temperature and solvent,
we found that the best results were achieved in a 3:1 mixture of
THF and ethanol, under reflux. Under these conditions, tosylate 2
was cleanly converted into seleno-carbohydrate 1a and the product
was isolated in 83% yield (Table 1, entry 1). Experiments conducted
using either ethanol or THF alone, did not result in any formation of
the desired product. Also, when the reaction was carried out at
room temperature, the isolated yield of selenide 1a dropped to 55%.
obtained in 95% yield (two steps), as a 1.7:1(
a:b) mixture of
anomers, as determined by 1H NMR analysis.
Scheme 2. Synthesis of methyl seleno-furanoside 3.
Furthermore, we have also performed the reaction of tosylate 2
with lithium diselenide, prepared by reaction of elemental sele-
nium with LiEt3BH.20 Using THF/t-BuOH as solvent, the tosylate 2
underwent smooth substitution and we were able to prepare
carbohydrate-derived diselenide 4 in 89% yield. It is worth men-
tioning that this compound was already described several years ago
by Van Es and co-workers, en route to the synthesis of 5-deoxy-5-
Table 1
Syntheses of seleno-xylofuranoses 1
seleno-D
-xylose.21 In their synthesis, the authors employed a two
step procedure, starting from tosylate 2, with an overall yield of
42%. By our protocol, the diselenide 4 was directly obtained in
higher yield, in a single reaction. Besides, changing the stoichi-
ometry between the elemental selenium and LiEt3BH,22 lithium
selenide was generated and its reaction with tosylate 2 furnished
the selenide 5 in 73% yield (Scheme 3).
In order to highlight the synthetic utility of diselenide 4,
selected transformations to functionalized seleno-furanosides were
performed and are depicted in Scheme 4. For example, cleavage of
diselenide 4 with sodium borohydride, followed by trapping of the
resulting selenide anion with several electrophiles leads to in-
teresting selenium derivatives possessing the seleno-furanoside
nucleus. Thus, the selenide was alkylated with propargyl and allyl
Entry
R1YYR1
R1Y
Yielda (%)
1
2
3
4
5
6
7
8
9
(PhSe)2
PhSe (1a)
83
84
79
84
83
81
72
88
64
54
(4-ClPhSe)2
(4-CF3PhSe)2
(4-OMePhSe)2
(4-MePhSe)2
(2-thienylSe)2
(BnSe)2
(n-BuSe)2
(PhS)2
(4-MePhTe)2
4-ClPhSe (1b)
4-CF3PhSe (1c)
4-OMePhSe (1d)
4-MePhSe (1e)
2-thienylSe (1f)
BnSe (1g)
n-BuSe (1h)
PhS (1i)
4-MePhTe (1j)
10
a
Isolated yields.

H.C. Braga et al. / Tetrahedron 66 (2010) 3441–3446
3443
Scheme 3. Syntheses of 4 and 5.
bromide and the corresponding products 6 and 7 were isolated in
92 and 94% yield, respectively. When the electrophile used was
benzoyl chloride, the corresponding selenol ester 8 could be cleanly
prepared in 95% isolated yield. Selenol esters are important in-
termediates in organic synthesis and also the investigation of new
molecular material, in particular, liquid crystals.23 Finally, ring-
opening of an aziridine, derived from the enantiopure amino acid
around 90% of the enzyme activity. The inhibitory potency of
compound 1g (thiophene derivative) was lower than compound 4
because 50
compound 1b demonstrated a significant inhibitory effect only at
high 400 M concentrations, indicating an advantage about the
mM reduced the enzyme activity about 16%. Similarly,
m
possible toxicological properties of these compounds. Thereby, the
inhibition caused by these compounds followed the order of
4>1g>1b. Compound 4, a carbohydrate-derived diselenide, dem-
L-valine, was accomplished in a mild and selective manner, leading
to the seleno-glycoconjugate 9 in 83% yield.
onstrated the strongest potential inhibitory in
d-ALA-D activity
Scheme 4. Synthesis of functionalized seleno-furanosides.
Although selenium-compounds generally hold promise as po-
tent antioxidant compounds, they are generally poisonous to
mammalian systems.24 Some investigators believe that selenium-
compounds exert their toxic effects through interference with
certain enzyme systems in the living organism, particularly
through mercaptide formation with important sulphydryl enzymes
with physiological importance in biological systems.1b Thus, we
selected seleno-furanosides (1a, 1b, 1g) and the carbohydrate-
(Fig. 2). This enzyme is an important indicator of toxicity since
enzyme inhibition may impair heme biosynthesis and can result in
the accumulation of ALA substrate, which has some pro-oxidant
4
1g
1a
1b
180
144
108
72
*
*
derived diselenide (4) to evaluate their effect on
dehydratase ( -ALA-D) activity of rat liver in vitro.
-ALA-D catalyzes the asymmetric condensation of two mole-
cules of -aminolevulinic acid ( -ALA) to porphobilinogen in the
initial steps of heme biosynthesis.25
-ALA-D is a sulfhydryl con-
d-aminolevulinate
d
d
d
d
*
d
taining enzyme and compounds that oxidize sulfhydryl groups
modified its activity.26 Of particular importance, organoselenium
compounds like ebselen and diphenyl diselenide demonstrated an
inhibitory effect on this enzyme activity in vitro.24,27 On the other
hand, diphenyl diselenide demonstrated many pharmacological
properties;1b in particular, this compound was able in restoring
oxidative parameters changed after cadmium exposure.28
*
*
*
*
36
*
*
*
0
0
10
50
100
200
400
1000
5'-Seleno-xylofuranosides [µM]
Thus, we verified that the compound 4 (carbohydrate-derived
Figure 2. Effect of 50-seleno-xylofuranosides (1a, 1b, 1g, and 4) on hepatic
d-ALA-D
activity of rat in vitro. *Denoted p<0.05 as compared to control group (ANOVA/
Duncan).
diselenide) significantly inhibited the
all tested concentrations. In fact, 50
d
-ALA-D activity of rat liver in
m
M of this compound reduced

3444
H.C. Braga et al. / Tetrahedron 66 (2010) 3441–3446
activity.29 On the other hand, compound 1a (seleno-furanoside) did
not reduce -ALA-D activity and it increased enzyme activity in the
concentration of 400 M (Fig. 2). Considering that -ALA-D is
85.1, 80.0, 74.8, 26.6, 26.2, 24.3; HRMS-ESI: m/z calcd for
C
d
14H18O4SeþNaþ: 353.0263; found: 353.0269.
m
d
extremely sensitive to the presence of pro-oxidants elements,
which can oxidize its –SH groups during oxidative stress, we can
infer that compound 1a presents a very low toxicity.
4.2.2. (3aR,5S,6R,6aR)-5-((4-Chlorophenylselanyl)methyl)-2,2-dime-
20
thyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (1b). Yield: 84%;
[a]
D
¼7.48
ꢁ52.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz, ppm)
d
(d, J¼8.0 Hz, 2H), 7.25 (d, J¼8.0 Hz, 2H), 5.91 (d, J¼3.6 Hz, 1H), 4.50
(d, J¼3.6 Hz, 1H), 4.31–4.22 (m, 2H), 3.20–3.08 (m, 2H), 1.42 (s, 3H),
3. Conclusions
1.26 (s, 3H); 13C NMR (CDCl3, 75 MHz, ppm)
d
¼134.6, 133.8, 129.4,
127.4, 111.8, 104.8, 85.2, 79.7, 74.9, 26.7, 26.2, 24.7; HRMS-ESI:
In summary, the present work describes the preparation of
chiral selenium-containing carbohydrates in an easy and efficient
strategy. We believe that approach may have significant impor-
tance in the design of new selenium-containing carbohydrates for
biological screenings. Initial studies in this area reveal that the
properties of organoselenium compounds may be related in parts
to their observed in vitro anti-oxidative activity making them
promising candidates as medicaments in the management of
a number of diseases in which oxidative stress have been impli-
cated in their etiology.1b Taking into account our results we can
suggest that the compound 1a could be a potential candidate for
further studies of antioxidant potential as well as toxicological and
pharmacological effects. Studies to further evaluate the potential of
these compounds are currently underway.
m/z calcd for C14H17ClO4SeþNaþ: 386.9879; found: 386.9870.
4.2.3. (3aR,5S,6R,6aR)-2,2-Dimethyl-5-((4-(trifluoromethyl) phe-
nylselanyl)methyl)tetrahydrofuro[2,3-d][1,3]dioxol-6-ol
20
(1c). Yield: 79%; [
300 MHz, ppm)
a
]
D
ꢁ48.0 (c 1.0, CHCl3); 1H NMR (CDCl3,
d
¼7.54 (dd, J1¼8.5 Hz; J2¼5.5 Hz, 2H), 6.96
(t, J¼8.5 Hz, 2H), 5.90 (d, J¼3.6 Hz, 1H), 4.50 (d, J¼3.6 Hz, 1H), 4.27–
4.22 (m, 2H), 3.14–3.0 (m, 2H), 1.40 (s, 3H), 1.27 (s, 3H); 13C NMR
(CDCl3, 75 MHz, ppm)
d
¼164.3, 161.0, 136.0, 135.9, 123.5, 116.6,
116.3, 111.7, 104.7, 85.2, 79.8, 74.9, 26.6, 26.2, 24.7; HRMS-ESI: m/z
calcd for C15H17F3O4SeþNaþ: 421.0132; found: 421.0139.
4.2.4. (3aR,5S,6R,6aR)-5-((4-Methoxyphenylselanyl)methyl)-2,2-di-
20
methyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (1d). Yield: 84%; [a]
D
ꢁ56.4 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz, ppm)
d
¼7.53
4. Experimental
(d, J¼8.1 Hz, 2H), 6.81 (d, J¼8.1 Hz, 2H), 5.88 (d, J¼3.6 Hz,1H), 4.47 (d,
J¼3.6 Hz,1H), 4.30–4.20 (m, 2H), 3.78 (s, 3H), 3.11–2.95 (m, 2H),1.42
(s, 3H), 1.28 (s, 3H); 13C NMR (CDCl3, 75 MHz, ppm)
d
¼159.3, 135.8,
4.1. General procedures
118.1,114.6,111.7,104.2, 84.6, 79.8, 74.8, 54.9; 26.2, 25.8, 24.8; HRMS-
1H and 13C NMR spectra were recorded at 300 and 75 MHz,
respectively with tetramethylsilane as internal standard. High
resolution mass spectra were recorded on a Bruker Daltonics
Micro-TOF instrument in ESI-mode. Column chromatography was
performed using Merck Silica Gel (230–400 mesh) following the
methods described by Still.30 Thin layer chromatography (TLC) was
performed using Merck Silica Gel GF254, 0.25 mm thickness. For
visualization, TLC plates were either placed under ultraviolet light,
or stained with iodine vapor, or acidic vanillin. THF was dried over
sodium benzophenone ketyl and distilled prior to use. Dichloro-
methane was distilled from phosphorus pentoxide. All other sol-
vents were used as purchased unless otherwise noted. Tosylate 2
was prepared according to literature procedures.18 Yields refer to
chromatographically and spectroscopically homogeneous mate-
rials with purity of >95%, as judged by 1H NMR spectroscopy.
ESI: m/z calcd for C15H20O5SeþNaþ: 383.0374; found: 383.0373.
4.2.5. (3aR,5S,6R,6aR)-2,2-Dimethyl-5-(p-tolylselanyl-methyl) tetra-
20
hydrofuro[2,3-d][1,3]dioxol-6-ol (1e). Yield: 83%; [
a
]
ꢁ30.0 (c 1.0,
D
CHCl3); 1H NMR (CDCl3, 300 MHz, ppm)
d
¼7.54 (d, J¼7.6 Hz, 2H), 7.15
(d, J¼7.6 Hz, 2H), 5.96 (d, J¼3.5 Hz, 1H), 4.55 (d, J¼3.5 Hz, 1H), 4.40–
4.34 (m, 1H), 4.28 (s, 1H), 3.24–3.11 (m, 2H), 2.38 (s, 3H), 1.49 (s, 3H),
1.32 (s, 3H); 13C NMR (CDCl3, 75 MHz, ppm)
d
¼137.9, 133.8, 130.1;
125.1; 111.6; 104.7; 85.1; 80.2; 74.9; 26.6; 26.2; 24.7; 21.1; HRMS-ESI:
m/z calcd for C15H20O4SeþNaþ: 367.0425; found: 367.0421.
4.2.6. (3aR,5S,6R,6aR)-2,2-Dimethyl-5-((thiophen-2-ylselanyl)
20
methyl)tetrahydrofuro[2,3-d][1,3]dioxol-6-ol (1f). Yield: 81%; [a]
D
ꢁ31.6 (c 1.1, CHCl3); 1H NMR (CDCl3, 300 MHz, ppm)
d
¼7.42
(d, J¼5.3 Hz, 1H), 7.28 (d, J¼3.7 Hz, 1H), 7.01 (dd, J1¼5.3 Hz;
J2¼3.7 Hz, 1H), 5.92 (d, J¼3.6 Hz, 1H), 4.52 (d, J¼3.6 Hz, 1H), 4.35–
4.32 (m, 2H), 3.13–2.97 (m, 2H), 1.47 (s, 3H), 1.32 (s, 3H); 13C NMR
4.2. General procedure for the preparation of seleno-
carbohydrates 1
(CDCl3, 75 MHz, ppm)
d
¼136.4; 131.5; 130.7; 128.2; 111.7; 104.6;
85.1; 79.9; 74.9; 27.5; 26.6; 26.2; HRMS-ESI: m/z calcd for
C12H16O4SSeþNaþ: 358.9833; found: 358.9840.
Under an argon atmosphere, sodium borohydride was added to
a solution of the diorganoil diselenide (0.55 mmol) in THF (4 mL).
Ethanol (2 mL) was then added dropwise and the clear solution
formed was stirred at room temperature for 10 min. After this time
a solution of the tosylate 2 (1 mmol in 1 mL THF) was added
dropwise. After stirring for 24 h under reflux, the reaction mixture
was quenched with aqueous saturated NH4Cl (10 mL) and extracted
with CH2Cl2 (3ꢀ15 mL). The combined organic layers were dried
with MgSO4, filtered, and concentrated. The crude product was
purified by flash chromatography first eluting with hexanes and
then with a mixture of hexanes/ethyl acetate (70:30).
4.2.7. (3aR,5S,6R,6aR)-5-(Benzylselanylmethyl)-2,2-dimethyltetrahy-
20
drofuro[2,3-d][1,3]dioxol-6-ol (1g). Yield: 72%; [
a
]
ꢁ55.8 (c 1.0,
D
CHCl3); 1H NMR (CDCl3, 300 MHz, ppm)
d
¼7.38–7.23 (m, 5H), 5.90
(d, J¼3.6 Hz, 1H), 4.51 (d, J¼3.6 Hz, 1H), 4.33–4.22 (m, 2H), 3.80
(s, 2H), 2.85 (dd, J1¼12.0 Hz; J2¼5.3 Hz, 1H), 2.70 (dd, J1¼12.0 Hz;
J2¼9.5 Hz, 1H), 2.0 (d, J¼4.7 Hz, 1H), 1.47 (s, 3H), 1.30 (s, 3H); 13C
NMR (CDCl3, 75 MHz, ppm)
d
¼139.1, 128.9, 128.7, 127.0, 111.7, 104.8,
85.1, 80.1, 75.2, 28.4, 26.8, 26.2, 20.3; HRMS-ESI: m/z calcd for
C15H20O4SeþNaþ: 367.0425; found: 367.0424.
4.2.1. (3aR,5S,6R,6aR)-2,2-Dimethyl-5-(phenylselanylmethyl)tetra-
4.2.8. (3aR,5S,6R,6aR)-5-(Butylselanylmethyl)-2,2-dimethyltetrahy-
20
20
hydrofuro[2,3-d][1,3]dioxol-6-ol (1a). Yield: 83%; [
a
]
ꢁ45.4 (c 1.3,
drofuro[2,3-d][1,3]dioxol-6-ol (1h). Yield: 88%; [
a
]
ꢁ48.3 (c 1.0,
D
D
CHCl3); 1H NMR (CDCl3, 300 MHz, ppm)
d
¼7.59–7.56 (m, 2H), 7.28–
CHCl3); 1H NMR (CDCl3, 300 MHz, ppm)
d
¼5.99 (d, J¼3.6 Hz, 1H),
7.26 (m, 3H), 5.91 (d, J¼3.7 Hz, 1H), 4.50 (d, J¼3.7 Hz, 1H), 4.35–4.29
4.60 (d, J¼3.6 Hz, 1H), 4.40–4.34 (m, 2H), 2.97–280 (m, 2H), 2.09
(m, 1H), 1.77–1.72 (m, 2H), 1.56 (s, 3H), 1.47 (qui, J¼7.3 Hz, 2H), 1.37
(m, 1H), 4.24 (s, 1H), 3.23–3.10 (m, 2H), 1.42 (s, 3H), 1.29 (s, 3H); 13C
NMR (CDCl3, 75 MHz, ppm)
d
¼133.3, 129.3, 128.0, 127.6, 111.7, 104.7,
(s, 3H), 0.97 (s, 3H); 13C NMR (CDCl3, 75 MHz, ppm)
d¼111.6, 104.8,

H.C. Braga et al. / Tetrahedron 66 (2010) 3441–3446
3445
85.2, 80.2, 75.3, 32.6, 26.7, 26.2, 24.7, 22.9, 20.1, 13.5; HRMS-ESI: m/z
calcd for C12H22O4SeþNaþ: 333.0581; found: 333.0575.
74.8, 26.7, 26.5, 26.2; HRMS-ESI: m/z calcd for C16H26O8Se2þNaþ:
528.9856; found: 528.9860.
4.2.9. (3aR,5S,6R,6aR)-2,2-Dimethyl-5-(phenylthiomethyl)-
4.5. General procedure for the synthesis of functionalized
seleno-furanosides 6–9
20
tetrahydrofuro[2,3-d][1,3]dioxol-6-ol (1i). Yield: 64%; [
a
]
ꢁ44.7
D
(c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz, ppm)
d
¼7.51–7.48 (m, 2H),
7.22–7,20 (m, 3H), 5.90 (d, J¼3.6 Hz, 1H), 4.48 (d, J¼3.6 Hz, 1H),
Under an argon atmosphere, sodium borohydride was added to
a solution of diselenide 4 (0.03 mmol,15 mg) in THF (1 mL). Ethanol
(0.3 mL) was then dropwise added and the clear solution formed
was stirred at room temperature for 10 min. After this time a solu-
tion of the appropriate electrophile (0.12 mmol in 0.3 mL THF) was
added dropwise. After stirring for 24 h at room temperature, the
reaction mixture was quenched with aqueous saturated NH4Cl
(5 mL) and extracted with CH2Cl2 (3ꢀ10 mL). The combined organic
layers were dried with MgSO4, filtered, and concentrated. The crude
product was purified by flash chromatography first eluting with
hexanes and then with a mixture of hexanes/ethyl acetate.
4.30–4.27 (m, 1H), 4.23 (s, 1H), 3.19–3.11 (m, 2H), 1.40 (s, 3H), 1.27
(s, 3H); 13C NMR (CDCl3, 75 MHz, ppm)
d
¼135.2, 130.1, 129.8, 129.1,
126.8, 111.8, 104.7, 85.1, 79.3, 74.6, 31.4, 26.7, 26.2; HRMS-ESI: m/z
calcd for C14H18O4SþNaþ: 305.0824; found: 305.0825.
4.2.10. (3aR,5S,6R,6aR)-2,2-Dimethyl-5-((p-tolyltellanyl-selanyl)
20
methyl)tetrahydrofuro[2,3-d][1,3]dioxol-6-ol (1j). Yield: 54%; [a]
D
ꢁ40.0 (c 1.1, CHCl3); 1H NMR (CDCl3, 300 MHz, ppm)
d
¼7.67
(d, J¼7.9 Hz, 2H), 7.0 (d, J¼7.6 Hz, 2H), 5.87 (d, J¼3.7 Hz, 1H), 4.42
(d, J¼3.7 Hz, 1H), 4.38–4.35 (m, 1H), 4.21–4.19 (m, 1H), 3.07
(dd, J1¼11.9 Hz; J2¼5.1 Hz,1H), 2.95 (dd, J1¼11.9 Hz; J2¼10.2 Hz,1H),
2.29 (s, 3H), 1.51 (s, 3H), 1.24 (s, 3H); 13C NMR (CDCl3, 75 MHz, ppm)
4.5.1. (3aR,5S,6R,6aR)-2,2-Dimethyl-5-((prop-2-ynylselanyl)-methyl)-
20
d
¼139.4, 138.5, 130.4; 111.6; 106.7, 104.9, 85.3, 81.8, 75.5, 26.7, 26.3,
tetrahydrofuro[2,3-d][1,3]dioxol-6-ol (6). Yield: 92%; [
a
]
ꢁ36.4 (c 1.1,
D
21.2, 4,6; HRMS-ESI: m/z calcd for C15H20O4TeþNaþ: 417.0322;
CHCl3); 1H NMR (CDCl3, 250 MHz, ppm)
d
¼5.88 (d, J¼3.7 Hz,1H), 4.47
found: 417.0309.
(d, J¼3.7 Hz, 1H), 4.41–4.32 (m, 1H), 4.24 (d, J¼2.3 Hz, 1H), 3.23–3.20
(m, 2H), 3.07 (dd, J1¼12.5 Hz; J2¼5.7 Hz, 1H), 2.89 (dd, J1¼12.5 Hz;
J2¼9.3 Hz,1H), 2.23 (t, J¼2.3 Hz,1H),1.44 (s, 3H),1.25 (s, 3H); 13C NMR
4.3. Procedure for the synthesis of (3R,4R,5S)-2-methoxy-
5-(phenylselanylmethyl)tetrahydrofuran-3,4-diol (3)
(CDCl3, 75 MHz, ppm)
d
¼111.5, 104.6, 85.0, 80.7, 79.8, 75.2, 71.4, 29.4,
26.5, 26.0, 20.9; HRMS-ESI: m/z calcd for C11H16O4SeþNaþ: 315.0112;
In a round bottomed flask, seleno-carbohydrate 1a (165 mg,
0.5 mmol) was stirred in an aqueous solution of trifluoracetic acid
(50%) for 1 h at room temperature. After this time, the reaction
mixture was concentrated in vacuum, co-evaporated with toluene
(3ꢀ15 mL) and the residue dissolved in a MeOH (10 mL), in the
presence of a catalytic amount of sulfuric acid, and stirred for ad-
ditional 24 h, at room temperature. Following this time, the mix-
ture was neutralized by the addition of sodium bicarbonate. The
mixture was filtered and the solvents evaporated to afford the
product 3 as a 1.7:1 mixture of anomers. Yield: 95%; 1H NMR (CDCl3,
found: 315.0108.
4.5.2. (3aR,5S,6R,6aR)-5-(Allylselanylmethyl)-2,2-dimethyltetrahy-
20
drofuro[2,3-d][1,3]dioxol-6-ol (7). Yield: 94%; [
a
]
ꢁ41.4 (c 1.1,
D
CHCl3); 1H NMR (CDCl3, 250 MHz, ppm)
d
¼5.92–5.74 (m, 2H), 5.01
(dd, J1¼16.8 Hz; J2¼1.3 Hz, 1H), 4.97 (dd, J1¼9.8 Hz; J2¼0.8 Hz, 1H),
4.46 (d, J¼3.8 Hz,1H), 4.27 (ddd, J1¼9.3 Hz; J2¼5.5 Hz; J3¼2.8 Hz,1H),
4.23–4.17 (m, 1H), 3.18 (d, J¼7.8 Hz, 2H), 2.79 (dd, J1¼12.0 Hz;
J2¼5.3 Hz, 1H), 2.65 (dd, J1¼12.0 Hz; J2¼9.3 Hz, 1H), 1.92 (d, J¼5.3 Hz,
1H),1.43 (s, 3H),1.25 (s, 3H); 13C NMR (CDCl3, 75 MHz, ppm)
d¼134.5,
250 MHz, ppm)
d
¼7.57–7.50 (m, 2H), 7.29–7.20 (m, 3H), 4.96
116.7,111.5,104.6, 84.9, 79.7, 75.1, 29.5, 26.6, 26.0,19.4; HRMS-ESI: m/z
calcd for C11H18O4SeþNaþ: 317.0268; found: 317.0260.
(d, J¼4.3 Hz, 0.37H), 4.82 (s, 0.63H), 4.52 (td, J1¼7.3 Hz; J2¼4.0 Hz,
0.63H), 4.35 (td, J1¼7.0 Hz; J2¼5.0 Hz, 0.37H), 4.24–4.17 (m, 1H),
4.14–4.04 (m, 1H), 3.44 (s, 1.1H), 3.34 (s, 1.9H), 3.20–3.00 (m, 3H);
4.5.3. Se-((3aR,5S,6R,6aR)-6-Hydroxy-2,2-dimethyl-tetrahydro-
furo[2,3-d][1,3]dioxol-5-yl)methyl benzoselenoate (8). Yield: 95%;
13C NMR (CDCl3, 62.5 MHz, ppm)
129.0, 127.2, 127.0, 108.5, 101.6, 86.5, 79.6, 78.4, 78.1, 76.8, 76.2, 55.8,
55.1, 27.1, 26.5; HRMS-ESI: m/z calcd for C12H16O4SeþNaþ:
327.0112; found: 327.0110.
d¼132.8, 132.6, 130.0, 129.7, 129.1,
20
[a
]
ꢁ40.1 (c 1.0, CHCl3); 1H NMR (CDCl3, 250 MHz, ppm)
¼7.92
d
D
(d, J¼8.5 Hz, 2H), 7.64 (tt, J1¼7.3 Hz; J2¼1.3 Hz, 1H), 7.52–7.43 (m,
2H), 5.97 (d, J¼3.5 Hz, 1H), 4.59 (d, J¼3.8 Hz, 1H), 4.33 (ddd,
J1¼10.3 Hz; J2¼4.5 Hz; J3¼2.3 Hz, 1H), 4.14 (d, J¼2.0 Hz,1H), 3.59 (br
s, 1H), 3.44 (dd, J1¼13.0 Hz; J2¼10.3 Hz, 1H), 3.25 (dd, J1¼13.0 Hz;
J2¼4.5 Hz, 1H), 1.50 (s, 3H), 1.32 (s, 3H); 13C NMR (CDCl3, 62.5 MHz,
4.4. Procedure for the synthesis of
(3aR,3a0R,5S,50S,6R,6aR,60R,6a0R)-5,50-diselanediylbis-
(methylene)bis(2,2-dimethyltetrahydrofuro[2,3-d]
[1,3]-dioxol-6-ol) (4)
ppm)
d
¼197.2, 138.3, 134.4, 129.0, 127.4, 111.7, 105.0, 84.8, 81.4, 74.2,
26.7, 26.1, 21.1; HRMS-ESI: m/z calcd for C15H18O5SeþNaþ:
381.0217; found: 381.0218.
Under an argon atmosphere, dithium diselenide was generated
by reaction of gray elemental selenium (95 mg, 1.2 mmol) with
lithium triethylborohydride (1.2 mL,1.2 mmol). The suspension was
allowed to stir for at least 20 min, and t-BuOH (0.2 mL) and THF
(4 mL) were added, followed by dropwise addition of a solution of
tosylate 2 (172 mg, 0.5 mmol) in THF (1 mL). The resulting solution
was stirred for 24 h under reflux. The mixture was quenched with
a saturated NH4Cl solution (20 mL), extracted with CH2Cl2 and the
combined organic fractions were collected, dried over MgSO4 and
filtered, the solvent was removed in vacuo. The crude product was
4.5.4. tert-Butyl (S)-1-(((3aR,5S,6R,6aR)-6-hydroxy-2,2-dimethylte-
trahydrofuro[2,3-d][1,3]dioxol-5-yl)methyl-selanyl)-3-methylbutan-
20
2-ylcarbamate (9). Yield: 83%; [
(CDCl3, 300 MHz, ppm)
a]
ꢁ12.7 (c 1.1, CHCl3); 1H NMR
D
d
¼5.94 (d, J¼3.6 Hz,1H), 4.71 (br s,1H), 4.56
(d, J¼3.7 Hz, 1H), 4.39–4.30 (m, 2H), 3.66–3.53 (m, 1H), 3.28 (s, 1H),
3.00–2.75 (m, 4H), 1.97–1.84 (m, 1H), 1.52 (s, 3H), 1.45 (s, 9H), 1.32
(s, 3H), 0.95 (d, J¼6.6, 3H), 0.88 (d, J¼6.7, 3H); 13C NMR (CDCl3,
75 MHz, ppm)
d
¼156.1, 111.6, 104.8, 85.4, 81.1, 79.7, 74.7, 56.3, 29.0,
28.4, 26.8, 26.2, 21.7, 19.8, 17.0; HRMS-ESI: m/z calcd for
C18H33NO6SeþNaþ: 462.1371; found: 462.1368.
purified by flash chromatography (hexane/ethyl acetate 50:50) to
20
afford the diselenide 4. Analytical data for 4: Yield: 89%; [
a]
þ8.1
D
(c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz, ppm)
d
¼5.93 (d, J¼3.7 Hz,
4.6. Biological activity
1H), 4.55 (d, J¼3,7 Hz, 1H), 4.41 (td, J¼7.0 Hz, J¼2.5 Hz, 1H),
4.30–4.29 (m, 1H), 3.30–3.27 (m, 2H), 2.38–2.36 (m, 1H), 1.51 (s, 3H),
1. Animals: male adult albino Wistar rats (150–200 g) from our
own breeding colony were used. The animals were kept in
1.31 (s, 3H); 13C NMR (CDCl3, 75 MHz, ppm)
d
¼111.8,104.5, 85.2, 80.9,

3446
H.C. Braga et al. / Tetrahedron 66 (2010) 3441–3446
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and 1000
m
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incubated for 1 h at 37 ꢂC.
d-ALA-D activity is reported as % of the
control value (100%). Data are reported as mean ꢃ SD, n¼3–5.
3. Statistical analysis: statistical significance was assessed by
analysis of variance (Anova) followed by Duncan’s test when
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The authors are indebted to FAPESP (Grant 07/02382-7 and
fellowships to M.W.P. and H.C.B.) and CNPq (Grant 472064/2008-8,
and research fellowship to D.S.L. and F.W.S) for financial support.
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