Synthesis of seleno-carbohydrates derived from d-galactose

Article abstract of DOI:10.1016/j.carres.2010.08.019

The synthesis of seleno-galactopyranosides in a short and efficient manner is described, starting from the parent carbohydrate d-galactose. The approach described allows the synthesis of small libraries of compounds with a number of structural variations at the group attached to selenium. Compounds with aryl, propargyl, allyl, acyl, and alkyl substituents are described.

Full text of DOI:10.1016/j.carres.2010.08.019

Carbohydrate Research 345 (2010) 2328–2333
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of seleno-carbohydrates derived from D-galactose
⇑
Hugo C. Braga, Ana D. Wouters, Felipe B. Zerillo, Diogo S. Lüdtke
Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, USP, CEP, 05508-900 São Paulo, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2010
Received in revised form 26 August 2010
Accepted 29 August 2010
Available online 21 September 2010
The synthesis of seleno-galactopyranosides in a short and efficient manner is described, starting from the
parent carbohydrate D-galactose. The approach described allows the synthesis of small libraries of com-
pounds with a number of structural variations at the group attached to selenium. Compounds with aryl,
propargyl, allyl, acyl, and alkyl substituents are described.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Galactopyranosides
Selenium
Seleno-carbohydrates
Carbohydrates
1. Introduction
HBV (hepatitis B virus) 2.25,26 Moreover, the replacement of an oxy-
gen atom by selenium, in the nucleoside framework served as an
Selenium is an essential biological element and it is present in
several enzymes, such as glutathione peroxidase (GPx), thioredoxin
reductase (TrxR), and formate dehydrogenase.1–5 It is known that
the selenium atom plays a key role in the mode of action of such pro-
teins, which cannot be played by its closest relative, sulfur.6 Sele-
nium has been shown to be involved in a number of important
biological processes ranging from cancer prevention,7,8 redox regu-
lation,9 aging,10 and immunology to male reproduction.11–13
In light of the important biological activities of selenium com-
pounds, the incorporation of selenium into small organic molecules
has received much attention in recent years. The toxicology and
pharmacology of these compounds, as well as their ability to mimic
the catalytic behavior of natural enzymes, have been widely stud-
ied.14–17 Nevertheless, efficient methods for the incorporation of
selenium atoms into carbohydrate frameworks are still limited, de-
spite the interesting synthetic and biological potential of carbohy-
drates containing selenium in their structures.18–22 Examples
already reported in the literature show that seleno-carbohydrates
are effective depigmenting compounds, inhibiting melanin synthe-
sis in melan-A cells, in similar levels to phenylthiourea, which is a
well-known inhibitor of such a process.23 In addition, selenosugars
have also been detected in human urine as a metabolite for the
excretion of selenium.24 The incorporation of selenium into nucleo-
sides has also been accomplished and the seleno-nucleosides have
been found to display important biological profiles, including activ-
ities against HIV-1 (human immunodeficiency virus type-1) and
anomalous scattering center, thus facilitating the 3-dimensional
structure determination of nucleic acids by X-ray crystallography
experiments.27–31
From the synthetic point of view, carbohydrates presenting an
organoselenium group at the anomeric position have been described
to act as selective glycosylatingagentsinthesynthesisofoligosaccha-
rides,32–34 and as useful intermediates for the synthesis of functional-
ized glycals,35 C-glycosides,36 and glycoconjugates.37 In this context,
we recently described an easy, straightforward synthetic route for
the preparation of a series of chiral seleno-xylofuranosides, starting
from the readily available carbohydrate D
-xylose.38 Among the sele-
no-furanosides prepared, diselenide 2 significantly reduced the
in vitro activity of the d-aminolevulinate dehydratase (d-ALA-D) en-
zyme, whereas the phenyl-substituted selenide 1 increased the activ-
ity of the enzyme, showing promising anti-oxidant activity.
In connection with our recent interest in the chemistry of car-
bohydrate derivatives,38–41 we decided to expand the scope of
our previous work to the synthesis of galactopyranoside deriva-
tives containing a selenium moiety in their structures. Keeping in
mind the importance of the synthesis of small libraries of com-
pounds with different structural motifs for biological screening,
the work described herein provides a useful extension of our meth-
odology to substrates with a different, more hindered, carbohy-
drate scaffold (Fig. 1).42
2. Results and discussion
Initially, the synthesis of an appropriate precursor for the intro-
duction of the selenium atom was needed. This was conveniently
⇑
Corresponding author. Tel.: +55 11 3091 3687; fax: +55 11 3815 4418.
E-mail address: dsludtke@usp.br (D.S. Lüdtke).
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.08.019

H. C. Braga et al. / Carbohydrate Research 345 (2010) 2328–2333
2329
this work
OH
ref . 38
HO
O
HO
HO
O
HO
OH
OH
D-xylose
OH
OH
D-galactose
PhSe
Se
SeR1
O
OH
OH
Me
Se
O
Me
O
O
O
Me
Me
O
Me
Me
Me
Me
O
O
O
O
O
O
O
O
O
3
1
O
2
2
4
Me
Me
Me
Me
2
Figure 1. Structures of selenium-containing carbohydrates.
achieved in a short synthetic sequence involving protection of
D
-
with the phenylselenide nucleophile, clean substitution occurred
and the desired product was isolated in excellent yield (entry 8).
Again, introduction of an excess NaBH4 after 12 and 18 h was nec-
essary to achieve full conversion and high yield of the product.
With this optimal condition in hand, we extended the protocol
to additional selenium nucleophiles and high yields of the desired
products were achieved (Table 2, entries 1–5). The developed pro-
tocol allowed the synthesis of arylseleno-carbohydrates with
chloro (3b) and methoxy (3c) substituents, as well as with the 2-
thienyl (3d) and benzyl (3e) groups. The reaction is also efficient
with a sulfur nucleophile,45 which results in the thio-galactopyran-
oside 7 in very high yield (entry 6).
galactose as a bis-acetonide by treatment with acetone, in the pres-
ence of catalytic amounts of iodine.43 The primary hydroxyl group
was then converted to the corresponding tosylate 5 and mesylate 6
in good yield, by reaction with the corresponding sulfonyl chloride
in the presence of pyridine as base (Scheme 1).
The tosylate 5 was then subjected to a reaction with phenylsele-
nide nucleophile to introduce the selenium atom in the carbohy-
drate framework (Table 1). The conditions initially studied were
those successfully applied in the xylofuranoside synthesis.38 Thus,
the phenylselenide nucleophile was generated in situ from the cor-
responding diphenyl diselenide, by reduction with NaBH4, in a 3:1
mixture of THF and ethanol, and the substitution was carried out un-
der reflux. Surprisingly, under these standard conditions, the desired
seleno-carbohydrate 3a was formed in only 25% yield (Table 1, entry
1), and most of the starting material was recovered unchanged.
Experiments conducted using ethanol alone, did not result in any
formation of the desired product (entry 2). We then tried to conduct
the nucleophilic substitution reaction under more forcing condi-
tions, by increasing the amount of the selenium nucleophile in the
reaction mixture. The use of 0.8 equiv of diphenyl diselenide
(1.6 equiv of PhSeꢀ) resulted in an increase in the yield to 56% (entry
3). Changing the co-solvent from ethanol to t-butanol or methanol
did not result in improvements in the yield of the product (entries
4 and 5). The use of a more powerful PhSeNa nucleophile, generated
from the reaction of (PhSe)2 with metallic sodium in THF–HMPA, re-
sulted in very low conversion.44 In all reactions, after prolonged
heating, a yellow color was observed in the solution, indicating the
reoxidation of the selenide anion back to the diphenyl diselenide.
Thus, using the standard conditions followed by addition of an ex-
cess of NaBH4 after 12 h, furnished the best results using the tosylate
as leaving group, and the seleno-carbohydrate 3a was obtained in a
moderate 68% yield (entry 7).
The reaction of tosylate 5 with lithium diselenide,46,47 was also
performed. In this case, the tosylate was found to be a good leaving
group, and the reaction occurred smoothly to afford the galactopy-
ranoside diselenide in 87% yield (Scheme 2). The high yield achieved
for this reaction contrasts with the low yields observed for the reac-
tion of tosylate 5 with the phenylselenide nucleophile (see Table 1,
entries 1–5). The easier reaction with Li2Se2 might be attributed to
the smaller size of the nucleophile when compared with the PhSeꢀ,
thus minimizing steric interactions during the nucleophilic attack.
To furtherexpandthescope of seleno-carbohydrates prepared, the
diselenide 4 was treated with sodium borohydride, and the resulting
selenideanionwastrappedwithseveralelectrophilesleadingtofunc-
tionalized seleno-pyranosides (Scheme 3). The reaction with propar-
gyl and allyl bromide proceeded smoothly and the corresponding
products 8 and 9 were isolated in 75% and 76% yield, respectively.
When the electrophile used was benzoyl chloride, the corresponding
selenolester10wasobtainedin86%isolatedyield.Selenolestershave
recently found interest in the investigation of new molecular materi-
als with liquid crystalline and fluorescent properties.48 Finally, the
conjugate addition of the soft selenide nucleophile to methyl acrylate
was pursued.49,50 Unexpectedly, the product isolated from this reac-
tion was the primary alcohol instead of the Michael adduct. Presum-
ably, the conjugate addition of selenide occurred and the resulting
product was reduced by the excess of sodium borohydride.51 Thus,
the seleno-carbohydrate 11containingafreeprimaryalcoholwasiso-
lated in 83% yield. It is worth mentioning that the seleno-carbohy-
The resistance of the tosylate 5 to undergo nucleophilic substi-
tution prompted us to investigate the behavior of the analogous
mesylate as the precursor for the synthesis of the desired seleno-
galactopyranosides. Gratifyingly, when mesylate 6 was treated
drates 8–11 can be used as
a synthetic handle for further
X
Me
Me
OH
functionalization through, for example, metal-catalyzed reactions
such as the Sonogashira52 and Heck53 reactions or dipolar cycloaddi-
tions with organic azides (click chemistry).54
O
HO
HO
i. acetone, I2 (cat)
reflux, 3 h, 63%
O
O
O
O
ii. TsCl, py, CH2Cl2, r.t., 65%
or
MsCl, py, CH2Cl2, r.t., 70%
OH
OH
O
Me
3. Conclusions
Me
5: X=OTs
6: X=OMs
In summary, we have described herein a short and efficient syn-
thesis of selenium-containing carbohydrates, derived from D-gal-
Scheme 1.

2330
H. C. Braga et al. / Carbohydrate Research 345 (2010) 2328–2333
Table 1
Optimization of the reaction conditions for the synthesis of seleno-carbohydrate 3a
X
Me
Me
SePh
O
Me
Me
O
O
O
O
0.6 equiv (PhSe)2, NaBH4
O
O
THF/EtOH (3:1)
reflux, 24 h
O
O
3a
O
Me
Me
Me
Me
5: X=OTs
6: X=OMs
Entry
Substrate
Variation from standard conditions
Yielda (%)
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
6
None
25
Only EtOH as solvent
0.8 equiv (PhSe)2
0.8 equiv (PhSe)2, t-BuOH instead of EtOH
0.8 equiv (PhSe)2, MeOH instead of EtOH
(PhSe)2/Na as nucleophile, THF/HMPA as solvent
Addition of 1 equiv of NaBH4 after 12 h and 18 h
Addition of 1 equiv of NaBH4 after 12 h and 18 h
No reaction
56
46
25
20
68
96
a
Isolated yields.
Table 2
Synthesis of seleno-galactopyranosides 3a–e and thio-galactopyranosides 7
Me
Me
O
O
O
OMs
Me
SeR
Me
O
O
i. 0.6 equiv (RSe)2, NaBH4
THF/EtOH (3:1), reflux, 12 h
Me
Me
Se
R
O
Me
O
Me
Me
O
i. NaBH4
O
Me
O
Se
O
O
ii.electrophile
O
O
ii. addition of 1 equiv NaBH4,
reflux, 12 h
iii. addition of 1 equiv NaBH4,
reflux, 2 h
O
Se
Me
6
O
4
O
O
3a-d, 7
O
O
Me
O
O
O
Me
Me
O
Me
Me
Me
Me
O
Entry
RSe
Yielda (%)
Me
Me
1
2
3
4
PhSe (3a)
96
93
91
93
98
95
p-ClPhSe (3b)
p-MeOPhSe (3c)
2-thienylSe (3d)
BnSe (3e)
Se
5
Me
Se
Me
Me
O
O
O
6b
PhS (7)
Me
O
O
O
a
O
Isolated yields.
Reaction performed with (PhS)2 instead of (PhSe)2.
b
O
9
8
O
O
75% yield
76% yield
Me
Me
Ph
Se
Me
Me
OH
O
Me
Me
Seo + LiEt3BH
Li2Se2
Me
O
Se
Me
Me
O
O
Me
O
O
O
O
OTs
Me
O
O
O
Me
Me
Me
O
O
O
O
11
83% yield
O
O
O
O
10
Se
O
O
Me
83% yield
Me
THF, t-BuOH
Me
O
Se
Me
Me
Me
5
4
87%
Me
O
Me
O
Scheme 3. Synthesis of functionalized seleno-galactopyranosides 8–11.
O
O
Me
Me
carbohydrates and also for biological screenings, particularly con-
cerning their anti-oxidant properties and inhibition of melanin
synthesis.
Scheme 2. Synthesis of diselenide 4.
4. Experimental
actose, which broadens the scope of our methodology previously
described for the synthesis of seleno-xylofuranosides. The exten-
sion of our methodology to a broader range of carbohydrates per-
4.1. General procedures
mits
a straightforward access to seleno-carbohydrates with
1H and 13C NMR spectra were recorded at 300 and 75 MHz
respectively with tetramethylsilane as internal standard. Low res-
different structural motifs. We believe that this approach may have
significant importance in the design of new selenium-containing

H. C. Braga et al. / Carbohydrate Research 345 (2010) 2328–2333
2331
olution mass spectra were recorded on a Shimadzu GCMS-QP5050
instrument in EI-mode. High resolution mass spectra were re-
corded 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.55 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. CH2Cl2 was distilled from phosphorus
pentoxide. All other solvents were used as purchased unless other-
wise noted. Tosylate 5 and mesylate 6 were prepared according to
literature procedures.43,56 Yields refer to chromatographically and
spectroscopically homogeneous materials with purity of >95%, as
judged by 1H NMR spectroscopy.
5.53 (d, J = 5.0 Hz, 1H, H-1), 4.61 (dd, J = 7.8 Hz, 2.3 Hz, 1H, H-3),
4.36–4.33 (m, 2H, H-4, H-2), 3.90 (td, J = 7.3 Hz, 1.3 Hz, 1H, H-5),
3.79 (s, 3H, OCH3), 2.72–2.69 (m, 2H, CH2), 1.54 (s, 3H, CH3), 1.52
(s, 3H, CH3), 1.34 (s, 3H, CH3), 1.33 (s, 3H, CH3).13C NMR (CDCl3,
75 MHz) d: 158.4, 131.3, 129.9, 113.9, 109.1, 108.5, 96.6, 71.9,
71.0, 70.5, 68.4, 55.2, 27.1, 26.1, 26.0, 24.8, 24.4. GC-MS (70 eV)
m/z (%): 43 (20), 59 (5), 77 (3), 91 (2), 121 (100). HRMS-ESI: m/z
calcd for C19H26O6Se + Na+: 453.0787; found: 453.0791.
4.2.4. 6-Deoxy-1,2:3,4-di-O-isopropylidene-6-(2-
thienylselenyl)-a-D-galactopyranose (3d)
Orange oil, yield: 93%, ½a D20
ꢂ
ꢀ55.6 (c 1, CHCl3). 1H NMR (CDCl3,
300 MHz) d: 7.33 (dd, J = 5.2 Hz, 1.1 Hz, 1H, Ar), 7.26 (dd,
J = 3.5 Hz, 1.1 Hz, 1H, Ar), 6.90 (dd, J = 5.3 Hz, 3.5 Hz, 1H, Ar), 5.51
(d, J = 5.0 Hz, 1H, H-1), 4.61 (dd, J = 7.8 Hz, 2.4 Hz, 1H, H-3), 4.42
(dd, J = 7.8 Hz, 1.8 Hz, 1H, H-4), 4.28 (dd, J = 5.0 Hz, 2.4 Hz, 1H, H-
2), 3.87 (td, J = 7.1 Hz, 1.8 Hz, 1H, H-5), 3.06–2.92 (m, 2H, CH2),
1.44 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.29 (s, 3H,
CH3). 13C NMR (CDCl3, 75 MHz) d: 135.8, 130.7, 127.9, 123.3,
109.2, 108.5, 96.6, 71.5, 71.0, 70.5, 66.9, 30.6, 25.9, 25.7, 24.9,
24.4. GC–MS (70 eV) m/z (%): 43 (100), 59 (45), 71 (34), 85 (64),
100 (24), 113 (21), 127 (24), 406 (17). HRMS-ESI: m/z calcd for
4.2. General procedure for the preparation of seleno-
carbohydrates 3a–e and 7
Under an argon atmosphere, sodium borohydride was added to
a solution of the diorganoildiselenide (0.18 mmol) in THF (1 mL).
MeOH (1 mL) was then dropwise added and the clear solution
formed was stirred at room temperature for 10 min. After this time
a solution of the mesylate 6 (0.3 mmol in 2 mL THF) was added
dropwise. After stirring for 12 h under reflux, NaBH4 (1 equiv)
was added and the reaction was stirred under reflux for 6 h. After
this time, a second portion of NaBH4 (1 equiv) was added and the
reaction mixture was heated at reflux for 2 h, and quenched by
the addition of aq satd NH4Cl (10 mL), and extracted with CH2Cl2
(3 ꢁ 15 mL). The combined organic layers were dried with MgSO4,
filtered, and concentrated. The crude product was purified by flash
chromatography eluting with a mixture of hexanes–EtOAc (90:10).
C
16H22O5SSe + Na+: 429.0245; found: 429.0254.
4.2.5. 6-(Benzylselenyl)-6-deoxy-1,2:3,4-di-O-isopropylidene-
a-
D
-galactopyranose (3e)
Orange solid, yield: 98%, ½a D20
ꢂ
ꢀ67.1 (c 1, CHCl3). 1H NMR (CDCl3,
300 MHz) d: 7.29–7.25 (m, 5H, Ar), 5.53 (d, J = 5.0 Hz, 1H, H-1),
4.62–4.59 (m, 1H, H-3), 4.32–4.29 (m, 2H, H-4, H-2), 3.90–3.85
(m, 3H, H-5, CH2), 2.78–2.67 (m, 2H, CH2), 1.52 (s, 3H, CH3), 1.45
(s, 3H, CH3), 1.34 (s, 3H, CH3), 1.33 (s, 3H, CH3). 13C NMR (CDCl3,
75 MHz) d: 139.3, 128.8, 128.4, 126.6, 109.2, 108.5, 96.6, 71.9,
71.0, 70.5, 68.4, 27.6, 26.1, 25.9, 24.8, 24.4, 23.0. GC–MS (70 eV)
m/z (%): 43 (63), 59 (29), 71 (19), 91 (100), 100 (15), 113 (15).
4.2.1. 6-Deoxy-1,2:3,4-di-O-isopropylidene-6-phenylselenyl-a-
HRMS-ESI: m/z calcd for
C
19H26O5Se + Na+: 437.0838; found:
D
-galactopyranose (3a)
Yellow solid, yield: 96%, ½a D20
ꢂ
ꢀ73.5 (c 1, CHCl3), 1H NMR (CDCl3,
437.0850.
300 MHz) d: 7.56–7.50 (m, 2H, Ar), 7.26–7.20 (m, 3H, Ar), 5.52 (d,
J = 5.0 Hz, 1H, H-1), 4.59 (dd, J = 7.8 Hz, 2.3 Hz, 1H, H-3), 4.42 (dd,
J = 7.9 Hz, 1.7 Hz, 1H, H-4), 4.22 (dd, J = 5.0 Hz, 2.4 Hz, 1H, H-2),
3.86 (td, J = 8.1 Hz, 1.7 Hz, 1H, H-5), 3.13–3.10 (m, 2H, CH2), 1.45
(s, 3H, CH3), 1.33 (s, 3H, CH3), 1.27 (s, 3H, CH3), 1.24 (s, 3H, CH3).
13C NMR (CDCl3, 75 MHz) d: 132.4, 129.4, 128.8, 126.6, 108.8,
108.2, 96.4, 71.2, 70.7, 70.2, 66.7, 26.5, 25.7, 25.4, 24.6, 24.1. GC–
MS (70 eV) m/z (%): 43 (100), 59 (44), 71 (40), 85 (41), 100 (50),
113 (32), 127 (15), 400 (32). HRMS-ESI: m/z calcd for C18H24O5S-
e + Na+: 423.0681; found: 423.0680.
4.2.6. 6-Deoxy-1,2:3,4-di-O-isopropylidene-6-phenylthio-a-D-
galactopyranose (7)
Yellow oil, yield: 95%, ½a D20
ꢂ
ꢀ97.8 (c 1, CHCl3). 1H NMR (CDCl3,
300 MHz) d: 7.40–7.37 (m, 2H, Ar), 7.28–7.23 (m, 2H, Ar), 7.18–
7.13 (m, 1H, Ar), 5.51 (d, J = 5.0 Hz, 1H, H-1), 4.59 (dd, J = 7.9 Hz,
2.4 Hz, 1H, H-3), 4.37 (dd, J = 7.9 Hz, 1.8 Hz, 1H, H-4), 4.28 (dd,
J = 5.0 Hz, 2.4 Hz, 1H, H-2), 3.84 (td, J = 6.9 Hz, 1.7 Hz, 1H, H-5),
3.17–3.15 (m, 2H, CH2), 1.45 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.27
(s, 3H, CH3), 1.23 (s, 3H, CH3). 13C NMR (CDCl3, 75 MHz) d: 135.7,
129.4, 128.9, 126.1, 109.3, 108.5, 96.6, 71.2, 70.8, 70.5, 66.1, 33.2,
25.9, 25.6, 24.8, 24.4. GC–MS (70 eV) m/z (%): 43 (83), 59 (46), 71
(100), 85 (22), 100 (21), 109 (12), 123 (44), 352 (21). HRMS-ESI:
m/z calcd for C18H24O5S + Na+: 375.1237; found: 375.1241.
4.2.2. 6-(p-Chloro-phenylselenyl)-6-deoxy-1,2:3,4-di-O-
isopropylidene-a-D-galactopyranose (3b)
Yellow oil, yield: 93%, ½a D20
ꢂ
ꢀ68.4 (c 1, CHCl3). 1H NMR (CDCl3,
300 MHz) d: 7.47–7.44 (m, 2H, Ar), 7.23–7.20 (m, 2H, Ar), 5.52
(d, J = 5.0 Hz, 1H, H-1), 4.59 (dd, J = 7.8 Hz, 1.7 Hz, 1H, H-3), 4.37
(dd, J = 7.8 Hz, 0.8 Hz, 1H, H-4), 4.27–4.24 (m, 1H, H-2), 3.81 (t,
J = 6.7 Hz, 1H, H-5), 3.14–4.11 (m, 2H, CH2), 1.45 (s, 3H, CH3),
1.33 (s, 3H, CH3), 1.28 (s, 6H, 2 ꢁ CH3). 13C NMR (CDCl3, 75 MHz)
d: 134.1, 133.2, 129.1, 128.0, 109.3, 108.5, 96.7, 71.6, 71.0, 70.5,
67.1, 27.3, 25.9, 25.6, 24.8, 24.4. GC-MS (70 eV) m/z (%): 43 (100),
59 (42), 71 (34), 85 (37), 100 (47), 113 (30), 127 (15), 434 (13).
HRMS-ESI: m/z calcd for C18H23ClO5Se + Na+: 457.0291; found:
457.0294.
4.3. Procedure for the synthesis of diselenide (4)
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 solu-
tion of tosylate 5 (0.5 mmol) in THF (1 mL). The resulting solution
was stirred for 24 h at room temperature. The mixture was
quenched by the addition of a satd NH4Cl solution (20 mL), ex-
tracted with CH2Cl2, and the combined organic fractions were col-
lected, dried over MgSO4, and filtered, the solvent was removed in
vacuo. The crude product was purified by flash chromatography
(hexane–EtOAc 50:50) to afford the diselenide 4.
4.2.3. 6-Deoxy-1,2:3,4-di-O-isopropylidene-6-(p-methoxy-
phenylselenyl)-a-D-galactopyranose (3c)
Yellow oil, yield: 91%, ½a D20
ꢂ
ꢀ55.3 (c 1, CHCl3). 1H NMR (CDCl3,
300 MHz) d: 7.23 (d, J = 8.6 Hz, 2H, Ar), 6.75 (d, J = 8.0 Hz, 2H, Ar),

2332
H. C. Braga et al. / Carbohydrate Research 345 (2010) 2328–2333
4.3.1. Bis-(6-deoxy-1,2:3,4-di-O-isopropylidene-
a
-
D
-
25.3, 24.8, 24.2. GC-MS (70 eV) m/z (%): 43 (17), 59 (5), 77 (13),
85 (2), 105 (100), 113 (2). HRMS-ESI: m/z calcd for C19H24O6Se + -
Na+: 451.0630; found: 451.0629.
galactopyranos-6-yl) diselenide (4)
Orange solid, yield: 87%, ½a D20
ꢂ
ꢀ62.1 (c 1, CHCl3). 1H NMR (CDCl3,
300 MHz) d: 5.52 (d, J = 4.9 Hz, 2H, H-1), 4.63 (dd, J = 7.8 Hz, 2.3 Hz,
2H, H-3), 4.37 (dd, J = 7.9 Hz, 1.7 Hz, 2H, H-4), 4.31 (dd, J = 5.0 Hz,
2.3 Hz, 2H, H-2), 4.04 (td, J = 6.8 Hz, 1.6, 2H, H-5), 3.21–3.09 (m,
4H, CH2), 1.56 (s, 6H, CH3), 1.44 (s, 6H, CH3), 1.34 (s, 6H, CH3),
1.32 (s, 6H, 2 ꢁ CH3). 13C NMR (CDCl3, 75 MHz) d: 109.2, 108.7,
96.6, 71.7, 71.0, 70.5, 68.1, 29.6, 29.1, 26.0, 24.9, 24.4. GC–MS
(70 eV) m/z (%): 43 (100), 59 (38), 71 (4), 85 (44), 100 (5), 113
(5), 127 (26), 185 (4). HRMS-ESI: m/z calcd for C24H38O10Se2 + Na+:
669.0688; found: 669.0676.
4.4.4. 6-Deoxy-6-(3-hydroxypropylselenyl)-1,2:3,4-di-O-
isopropylidene-a-D-galactopyranose (11)
Yellow oil, yield: 83%. ½a D20
ꢂ
ꢀ58.0 (c 1, CHCl3). 1H NMR (CDCl3,
300 MHz) d: 5.53 (d, J = 4.8 Hz, 1H, H-1), 4.61 (dd, J = 7.9 Hz,
2.7 Hz, 1H, H-3), 4.35 (dd, J = 7.9 Hz, 1.8 Hz, 1H, H-4), 4.29 (dd,
J = 5.0 Hz, 2.3 Hz, 1H, H-2), 3.93 (td, J = 6.9 Hz, 1.8 Hz, 1H, H-5),
3.74 (t, J = 6.0 Hz, 2H, CH2O), 2.79–2.73 (m, 4H, 2 ꢁ CH2), 1.95
(qui, J = 6.6 Hz, 2H, CH2), 1.53 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.34
(s, 3H, CH3), 1.33 (s, 3H, CH3). 13C NMR (CDCl3, 75 MHz) d: 109.2,
108.5, 96.6, 71.9, 70.9, 70.4, 68.6, 62.0, 32.0, 26.0, 25.9, 24.8, 24.4,
23.0, 20.8. GC–MS (70 eV) m/z (%): 43 (100), 59 (43), 71 (33), 85
(20), 100 (34), 113 (23), 127 (12), 382 (8). HRMS-ESI: m/z calcd
for C15H26O6Se + Na+: 405.0787; found: 405.0792.
4.4. General procedure for the synthesis of functionalized
seleno-pyranosides 8–11
Under an argon atmosphere, sodium borohydride was added to
a solution of diselenide 4 (0.1 mmol) in THF (3 mL). MeOH (1 mL)
was then dropwise added and the clear solution formed was stirred
at room temperature for 10 min. After this time a solution of the
appropriate electrophile (2 equiv) was added dropwise. After stir-
ring for 24 h at room temperature, the reaction mixture was
quenched by the addition of aq satd NH4Cl (5 mL) and the solution
was extracted with CH2Cl2 (3 ꢁ 10 mL). The combined organic lay-
ers were dried with MgSO4, filtered, and concentrated. The crude
product was purified by flash chromatography eluting with a mix-
ture of hexanes–EtOAc (90:10) and (60:40) in the case of 11.
Acknowledgements
The authors are indebted to FAPESP (Grant 07/02382-7 and fel-
lowships to H.C.B. and F.B.Z.), CAPES (fellowship to A.D.W) and
CNPq (Grant 472064/2008-8, and research fellowship to D.S.L.)
for financial support.
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ꢀ59.8 (c 1, CHCl3). 1H NMR (CDCl3,
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ꢂ
ꢀ62.4 (c 1, CHCl3). 1H NMR (CDCl3,
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