Synthesis of selenium-linked neoglycoconjugates and pseudodisaccharides

Article abstract of DOI:10.1016/j.tet.2012.08.075

The introduction of organoselenium moieties within the structure of carbohydrates has received attention recently. Herein, we report on the synthesis of selenium-containing neoglycoconjugates and pseudodisaccharides by the reaction of nucleophilic selenium species, generated from sugar diselenides, with chiral N-Boc aziridines and sugar tosylates. The reaction proceeds with moderate to good yields for various substrates. The introduction of organoselenium moieties within the framework of various sugars, with increased levels of complexity, thus allowing the synthesis of disaccharide and glycoconjugate mimetics.

Full text of DOI:10.1016/j.tet.2012.08.075

Tetrahedron 68 (2012) 10470e10475
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of selenium-linked neoglycoconjugates and pseudodisaccharides
a
b
a
a,b,
Ricardo F. Affeldt , Hugo C. Braga , Lucas L. Baldassari , Diogo S. L u€ dtke
*
a
Instituto de Quím
ˇ
ica, Universid
ˇ
ade Federal do Rio Grande do Sul, UFRGS, Av. Bento Gon c¸ alves 9500, 9150 1-970 Porto Alegre, RS, Brazil
b
Faculdade de Ciencias Farmaceuticas, Universidade de S a~ o Paulo, USP, S a~ o Paulo, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2012
Received in revised form 16 August 2012
Accepted 25 August 2012
Available online 1 September 2012
The introduction of organoselenium moieties within the structure of carbohydrates has received at-
tention recently. Herein, we report on the synthesis of selenium-containing neoglycoconjugates and
pseudodisaccharides by the reaction of nucleophilic selenium species, generated from sugar diselenides,
with chiral N-Boc aziridines and sugar tosylates. The reaction proceeds with moderate to good yields for
various substrates. The introduction of organoselenium moieties within the framework of various sugars,
with increased levels of complexity, thus allowing the synthesis of disaccharide and glycoconjugate
mimetics.
Keywords:
Selenocarbohydrates
Neoglycoconjugates
Pseudodisaccharides
Chiral selenium compounds
Ó 2012 Elsevier Ltd. All rights reserved.
1
. Introduction
glucose oligosaccharides in the intestine, and of protein tyrosine
14
phosphatases.
In addition, selenium has been incorporated within the sugar
The synthesis of small chiral molecules containing a selenium
atom has received growing attention, particularly due to the broad
range of interesting biological activities displayed by these com-
pounds. Organic selenium compounds have been described to have
important roles in biological redox processes, in cancer prevention,
15
moiety in nucleoside chemistry. Selenonucleosides have found
extensive application in high resolution determination of three-
16
dimensional structures of DNA and RNA.
In this context, our group has developed efficient strategies for
1
immunology and ageing.
the synthesis of selenium-containing carbohydrates with different
17
Despite the fact that recently selenium has been incorporated in
the scaffold of several different classes of molecules, the in-
troduction of selenium within the carbohydrate framework has
received less attention. The most commonly encountered modifi-
cation of carbohydrates with selenium has been the introduction of
structural features. In the present work, we report on the syn-
thesis of more complex selenocarbohydrate derivatives, namely
neoglycoconjugates and pseudodisaccharides, linked by a selenium
atom (Fig. 1).
2
an organoselenium group at the anomeric position, which has
been reported as intermediates for the synthesis of glyco-
3
4
5
6
conjugates, oligosaccharides, glycals and C-glycosides. In addi-
tion, the synthesis of sugars containing selenium in their structures
7
has also been pursued and selenoglycosides and selenodi-
saccharides8 have been reported. Seleno pseudodisaccharides, in
which the selenium is non-glycosidically linked were recently re-
ported by Cumpstey and co-workers.9 Moreover, the replacement
of endocyclic oxygen by selenium to result in selenosugars was also
reported.11 Selenocarbohydrates have already been reported to
have interesting biological properties, such as inhibition of melanin
,10
Fig.
1. General
structure
of
selenium-linked
neoglycoconjugates
and
pseudodisaccharides.
12
synthesis in melan-A cancer cells, inhibition of human maltase
glucoamylase (MGA),13 an enzyme involved in the breakdown of
2. Results and discussion
Our initial efforts were focused on the synthesis of selenium-
linked neoglycoconjugates, and the desired conjugation would be
*
Corresponding author. Tel./fax: þ55 51 3308 7201; e-mail address: dsludtke@
iq.ufrgs.br (D.S. L u€ dtke).
0
040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.075

R.F. Affeldt et al. / Tetrahedron 68 (2012) 10470e10475
10471
achieved through the nucleophilic ring-opening of chiral N-Boc
aziridines, derived from amino acids. First, the required aziridines
aee were prepared by an efficient synthetic sequence involving
O
O
Se
i. NaBH4, THF/EtOH Ph
ii.
Se
2
O
NH
O
Boc
HO
5a 78%
Me
2
HO
Me
Ph
O
O
18
N
reduction of the amino acid to the corresponding amino alcohol,
Me
Me
4
a
2a
Boc
followed by Boc protection of the amino group in good yields for
the two step sequence (60e70%). The resulting N-Boc amino alco-
hols 1 were converted to the N-Boc aziridines 2aee in 72e85%, by
Scheme 3. Synthesis of selenoglycoconjugate 5a.
19
reaction with TsCl under basic conditions (Scheme 1).
2 2
N-Boc aziridine 2a with Li Se in 81% yield. Reduction of the dis-
elenide bond under usual conditions, followed by a substitution
reaction of the tosylate group resulted in the product 5a in 60%
yield (Scheme 4).
O
R
R
R
i. NaBH4,
ii. Boc
0 - 70%
I
2
TsCl, KOH
THF, reflux
OH
OH
N
2
O
NH
NH
2
Boc
Boc
6
(
1
2
a-e
2 2
Li Se
Ph
Ph
Se
NHBoc
6
2 steps)
2
2
2
2
2
a: R = Bn - 78%
N
Boc
81%
b: R = i-Pr- 81%
c: R = i-Bu- 72%
d: R = s-Bu- 73%
2a
2
i. NaBH
ii.
4
2 2
e: R = (CH ) SMe - 85%
O
O
TsO
Ph
Boc
Se
Scheme 1. Synthesis of N-Boc aziridines 2aee.
O
O
NH
HO
Me
HO
Me
Me
Scheme 4. Reaction between tosylate 3a and diselenide 6.
O
O
3a
Me
In parallel, the sugar-based diselenides 4aec, derived from the
carbohydrates -xylose, -galactose and -ribose, respectively,
were prepared according to our previously reported methodol-
ogy. The desired sugar-based diselenides were cleanly obtained in
high yields (85e89%) by a nucleophilic substitution reaction of
a tosylate leaving group in the appropriate carbohydrate derivative
60%
5
a
D
D
D
17
Comparing this result with the reaction shown in Scheme 3, it
became clear that the best approach was the use of the sugar dis-
elenide as the nucleophilic partner and the N-Boc aziridine as the
electrophile, due to higher yield obtained. Therefore we decided to
further expand the scope of the reaction between sugar-based
diselenide and aziridines to a broader range of substrates in order
to prepare a series of selenium-linked neoglycoconjugates. The
scope of the reaction was investigated using sugar diselenides with
different scaffolds and aziridines 2aee with varied substituents.
The results of these studies are shown in Table 1.
20
with Li
2
Se
2
(Scheme 2).
The ring opening reaction of the N-Boc aziridines proceeded
under mild conditions and with complete regiocontrol, with ex-
clusive attack of the selenium nucleophile at the less hindered
21
carbon of the three membered ring. In general, the products were
isolated in moderate to good yields. Five different seleno-
neoglycoconjugates 5aee, with the xylofuranose structure were
prepared in yields ranging from 75 to 85% (entries 1e5). Moreover,
changing the carbohydrate diselenide to the
b that contains a pyranoside structure resulted in the syntheses of
seleno-neoglycoconjugates 5f and 5g in good yields (entries 6 and
). Finally, the ribofuranose derivative 5h was also prepared in 30%
yield, starting with diselenide 4c with the N-Boc aziridine derived
from -phenylalanine (entry 8). Surprisingly, reaction of the
D-galactose derivative
4
7
L
ribofuranose-derived selenium nucleophile with the leucine-
derived aziridine did not afford the desired product 5i (entry 9)
and the starting materials were partially recovered alongside with
decomposition by-products.
Scheme 2. Synthesis of sugar diselenides 4aec.
An analogous strategy was pursued for the synthesis of the non-
glycosidic selenium-linked pseudodisaccharides 7. The selenium
sugar nucleophile was generated under conventional conditions, by
the reduction of the diselenide bond in 4, followed by nucleophilic
displacement of a tosylate leaving group present in a second sugar
unit 3 (Scheme 5).
By this approach we were able to prepare selenium-containing
pseudodisaccharides with different structural and stereochemical
features (Fig. 2). For example, starting with sugar diselenide 4a,
with a xylofuranose backbone and reacting with tosylate 3c, de-
With both required starting materials in hands, we turned our
attention to the synthesis of the selenium-linked neo-
glycoconjugates. We started our studies using furanose-derived
diselenide 4a as the nucleophile, combined with N-Boc aziridine
2
a, derived from the amino acid
nucleophile was generated in situ by reduction of the diselenide
bond with NaBH , under our previously described conditions. The
L-phenylalanine. The selenide
4
nucleophilic ring opening of the N-Boc aziridine occurred effi-
ciently, delivering the corresponding Seeneoglycoconjugate 5a in
7
8% yield (Scheme 3).
rived from D-ribose, resulted in the Se-pseudodisaccharide 7a in
For comparison, we have also performed the reaction between
70% yield. The opposite combination of reactants (4cþ3a), in order
to achieve the same product resulted in 30% yield of compound 7a.
Combination of different scaffolds was also possible and reaction of
the
D-xylofuranoside tosylate 3a and a diselenide possessing the
amino group. The diselenide 6 was prepared by ring-opening of

10472
R.F. Affeldt et al. / Tetrahedron 68 (2012) 10470e10475
Table 1
Synthesis of seleno glycoconjugates 5aei
i. NaBH
THF, EtOH
4
R
O
Se
O
Se
NHBoc
2
ii. R
Scheme 5. General approach for the synthesis of selenium-containing
pseudodisaccharides.
n
OPG
n
OPG
N
2a-e
Boc
5a-i
Entrya
1
Product
Yield (%)
78
83
2
3
4
75
78
Fig. 2. Structures of selenium-containing pseudodisaccharides prepared.
the galactopyranose-derived diselenide 4b, with ribo- and xylo-
furanose tosylates resulted in the corresponding products 7b and
7c in 95% and 50% yield, respectively. In an attempt to improve the
yield for pseudodisaccharide 7c, we generated the selenium nu-
cleophile under different reaction conditions. Therefore, reductive
2
2
cleavage was performed with NaBH
4
using DMF as the solvent
ꢀ
and the reaction was heated at 80 C for 24 h. However the prod-
uct was isolated in a similar 44% yield. Besides, the use of the gal-
actopyranose tosylate 3b as the electrophile and xylofuranose
diselenide 4a as the nucleophile source proved fruitless and the
starting material were almost entirely recovered. This result is in
line with our previous observation that tosylate 3b is more resistant
to nucleophilic attack with hindered nucleophiles, probably caused
5
6
85
62
1
7c
by the axial group at C-4.
It is worth noting that when the ribofuranose diselenide 4c was
used as the precursor of the selenium nucleophile, the yields were
consistently lower for both neoglycoconjugates and pseudodi-
saccharides, in comparison with the yields obtained with the
xylofuranose and galactopyranose derivatives. While at the present
moment we still don’t have a definitive explanation for this be-
haviour, a plausible reason might be the lower stability of the sel-
enide anion under the reaction conditions. Further studies are
needed to confirm this hypothesis. Conversely, the best electrophile
for disaccharide synthesis was the tosylate 3c, with the ribofur-
anose framework (Fig. 2).
7
50
3. Conclusions
In summary, we have described herein the synthesis of
8
30
selenium-linked neoglycoconjugates and pseudodisaccharides. The
approach further extends the scope of our methodology for the
introduction of organoselenium moieties within the framework of
various sugars, by this time allowing the synthesis of molecules
with increased levels of complexity.
4
4
. Experimental
9
NR
.1. General procedures
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
a
Standard conditions: sugar diselenide 4 (0.3 mmol), NaBH
Boc aziridine (0.5 mmol). NR¼no reaction.
4
(0.75 mmol) and N-

R.F. Affeldt et al. / Tetrahedron 68 (2012) 10470e10475
10473
2
0
1
Micro-TOF instrument in ESI-mode. Column chromatography was
Yield: 83%; [
d
a]
D
ꢂ13 (c 1.1, CHCl
3
). H NMR (CDCl
3
, 300 MHz, ppm)
performed using Merck Silica Gel (230e400 mesh) following the
¼5.94 (d, J¼3.6 Hz, 1H, H-1), 4.71 (bs, 1H, NH), 4.56 (d, J¼3.7 Hz,
1H, H-2), 4.39e4.30 (m, 2H, H-3, H-4), 3.66e3.53 (m, 1H, NCH), 3.28
(bs, 1H, OH), 3.00e2.75 (m, 4H, 2ꢁ CH ), 1.97e1.84 (m, 1H, CH), 1.52
(s, 3H, CH ), 1.32 (s, 3H, CH ), 0.95 (d, J¼6.6, 3H,
), 1.45 (s, 9H, 3ꢁ CH
CH ); C NMR (CDCl , 75 MHz, ppm)
2
3
methods described by Still. 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 vapour, or acidic vanillin or phosphomolib-
dic acid. THF was dried over sodium benzophenone ketyl and dis-
tilled prior to use. DMF was dried over calcium hydride. All other
solvents were used as purchased unless otherwise noted.
2
3
3
3
13
3
), 0.88 (d, J¼6.7 Hz, 3H, CH
3
3
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,
þ
21.7, 19.8, 17.0; HRMS-ESI: m/z calcd for C18
H33NO
6
SeþNa :
462.1371, found: 462.1368.
4
.2. General procedure for the preparation of carbohydrate
4.3.3. 5-Se-((S)-2-N-(tert-butoxycarbonyl)-4-methylpentyl)-5-
deoxy-1,2-O-isopropylidene-5-seleno- -xylofuranose
diselenides (4aec)
a-D
2
0
1
(
5c). Colourless oil. Yield: 75%; [
a
]
D
ꢂ40 (c 1.2, AcOEt); H NMR
Under argon atmosphere lithium diselenide was generated by
reaction of elemental selenium (95 mg, 1.2 mmol) with lithium
triethylborohydride (1.2 mL, 1.2 mmole1 M solution in THF) at
room temperature. The suspension was stirred for 20 min. After this
time t-BuOH (0.2 mL) and THF (4 mL) were added at room tem-
perature, followed by dropwise addition of a solution of the re-
spective tosylate (0.5 mmol in 1 mL THF). After stirring for 24 h
under reflux, the reaction mixture was quenched with aqueous
(CDCl , 300 MHz, ppm)
3
d¼5.94 (d, J¼3.6 Hz, 1H, H-1), 4.70 (bs, 1H,
NH), 4.63 (d, J¼3.5 Hz, 1H, H-2), 4.36e4.32 (m, 2H, H-3, H-4),
3.61e3.57 (m, 1H, NCH), 3.44 (bs, 1H, OH), 2.97e2.75 (m, 4H, 2ꢁ
CH
2
), 1.93e1.87 (m, 1H, CH), 1.51 (s, 3H, CH
3
), 1.44 (s, 9H, 3ꢁ CH
3
),
1.31e1.24 (m, 5H, CH
2
, CH
3
), 0.94 (d, J¼6.5 Hz, 3H, CH
3
), 0.87 (d,
13
J¼6.7 Hz, 3H, CH
3
); C NMR (CDCl , 75 MHz, ppm)
3
d¼155.8, 111.6,
104.9, 85.5, 81.5, 80.0, 74.4, 50.1, 43.4, 32.2, 28.3, 26.8, 26.2, 25.0,
þ
23.3, 22.2, 21.8; HRMS-ESI: m/z calcd for C19
H35NO
6
SeþNa :
saturated NH
combined organic layers were dried with MgSO
4
Cl (10 mL) and extracted with CH
2
Cl
2
(3ꢁ15 mL). The
476.1522, found: 476.1519.
4
, filtered and
concentrated. The crude product was purified by flash chroma-
tography eluting with a mixture of hexanes/ethyl acetate (80:20).
Analytical data for carbohydrate diselenides 4a and 4b were
4.3.4. 5-Se-((2S,3R)-2-N-(tert-butoxycarbonyl)-3-methylpentyl)-5-
deoxy-1,2-O-isopropylidene-5-seleno- -xylofuranose
a-D
2
0
1
(5d). Colourless oil. Yield: 78%; [
(CDCl , 300 MHz, ppm)
a
]
D
ꢂ30 (c 1.0, AcOEt); H NMR
17b,c
reported in our previous work.
3
d
¼5.93 (d, J¼3.6 Hz, 1H, H-1), 4.72 (bs, 1H,
NH), 4.55 (d, J¼3.6 Hz, 1H, H-2), 4.36e4.31 (m, 2H, H-3, H-4),
4
.2.1. bis(Methyl 5-deoxy-2,3-O-isopropylidene-
a
-
D
-ribofuranos-5-
3.66e3.62 (m, 1H, NCH), 3.15 (bs, 1H, OH), 2.97e2.74 (m, 4H, 2ꢁ
2
0
13
yl) diselenide (4c). Yellow oil. Yield: 82%; [
a
]
D
ꢂ122 (c 1.2, AcOEt);
CH
2
), 1.68e0.88 (m, 21H, 7ꢁ CH
3
); C NMR (CDCl
, 75 MHz, ppm)
3
, 75 MHz, ppm)
1
13
H NMR (CDCl
3
, 300 MHz, ppm)
d
¼4.99 (s, 1H, H-1), 4.74 (d,
d¼
C NMR (CDCl
3
d
¼155.2, 111.6, 104.8, 85.3, 81.5,
J¼5.4 Hz, 1H, H-2), 4.61 (d, J¼6.0 Hz, 1H, H-4), 4.47e4.42 (m, 1H, H-
79.8, 74.6, 51.6, 43.4, 32.1, 28.4, 26.6, 26.2, 25.0, 21.8, 17.6, 13.3;
þ
3
5
), 3.35 (s, 3H, OCH
), 1.49 (s, 3H, CH
¼112.4, 109.6, 86.8, 85.4, 83.3, 55.0, 32.9, 26.4, 25.0; HRMS-
ESI: m/z calcd for C18 Se
þNa: 557.0163; found: 557.0164.
3
), 3.22e3.16 (m, 1H, H-5), 3.04e3.00 (m, 1H, H-
HRMS-ESI: m/z calcd for C19
H35NO
6
SeþNa : 476.1522, found:
13
3
); 1.33 (s, 3H, CH
3
); C NMR (CDCl
3
, 75 MHz,
476.1519.
ppm)
d
30
H O
8
2
4.3.5. 5-Se-((S)-2-N-(tert-butoxycarbonyl)-4-(methylthio)butyl)-5-
deoxy-1,2-O-isopropylidene-5-seleno- -xylofuranose
a-D
2
0
1
4
.3. General procedure for the preparation of seleno glyco-
(5e). Colourless oil. Yield: 85%; [
(CDCl , 300 MHz, ppm)
a
]
D
ꢂ45 (c 1.0, AcOEt); H NMR
conjugates 5
3
d
¼5.94 (d, J¼3.6 Hz, 1H, H-1), 4.70 (bs, 1H,
NH), 4.63 (d, J¼3.5 Hz, 1H, H-2), 4.36e4.32 (m, 2H, H-3, H-4),
3.61e3.57 (m, 1H, NCH), 3.44 (bs, 1H, OH), 2.98e2.52 (m, 6H, 3ꢁ
Under argon atmosphere, sodium borohydride (0.75 mmol) was
added to solution of the carbohydrate diselenide 4aec
0.30 mmol) in THF (3 mL). Ethanol (2 mL) was then dropwise
a
CH
5ꢁ CH
2
), 2.11 (s, 3H, SCH
3
), 1.96e1.92 (m, 2H, CH
, 75 MHz, ppm)
2
), 1.53e1.33 (m, 18H,
13
(
3
); C NMR (CDCl
3
d
¼155.8, 111.6, 104.8, 85.4,
added and the clear pale yellow solution formed was stirred at
room temperature for 10 min. After this time a solution of the N-
Boc aziridine 2 (0.5 mmol in 2 mL THF) was added dropwise. After
stirring for 24 h under reflux, the reaction mixture was quenched
81.1, 78.8, 74.8, 54.5, 35.5, 30.7, 30.1, 28.5, 26.8, 26.2, 22.0, 15.8.
þ
HRMS-ESI: m/z calcd for C18
H
33NO
6
SeþNa : 494.1091, found:
494.1090.
with aqueous saturated NH
4
Cl (10 mL) and extracted with CH
2
Cl
2
,
4.3.6. 6-Se-((S)-2-N-(tert-butoxycarbonyl)-3-phenylpropyl)-6-
deoxy-1,2:3,4-di-O-isopropylidene-6-seleno- -galactopy-ranose
(
3ꢁ15 mL). The combined organic layers were dried with MgSO
4
a-D
2
0
1
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).
(5f). Colourless oil. Yield: 62%; [
(CDCl , 300 MHz, ppm)
a
]
D
ꢂ37 (c 0.9, AcOEt); H NMR
3
d
¼7.31e7.18 (m, 5H, Ar), 5.53 (d, J¼4.8 Hz,
1H, H-1), 4.99 (bs, 1H, NH), 4.65e4.60 (m, 1H, H-3), 4.38 (dd,
J¼7.8 Hz,1.8 Hz, 1H, H-4), 4.33e4.29 (m, 1H, H-2), 4.00 (dt, J¼7.2 Hz,
1.8 Hz, 1H, H-5), 3.91e3.86 (m, 1H, NCH), 2.93e2.70 (m, 6H, 3ꢁ
4
.3.1. 5-Se-((S)-2-N-(tert-butoxycarbonyl)-3-phenylpropyl)-5-
deoxy-1,2-O-isopropylidene-5-seleno- -xylofuranose (5a). Yellow
a-D
CH
3H, CH
2
), 1.55 (s, 3H, CH
3
), 1.44 (s, 3H, CH
3
), 1.43 (s, 9H, 3ꢁ CH
3
), 1.35 (s,
¼155.1,
2
0
1
13
oil. Yield: 78%; [
a
]
D
ꢂ31 (c 1.0, AcOEt); H NMR (CDCl
¼7.33e7.19 (m, 5H, Ar), 5.95 (d, J¼3.6 Hz, 1H, H-1), 4.86 (bs,
H, NH), 4.56 (d, J¼3.7 Hz, 1H, H-2), 4.39e4.29 (m, 2H, H-3, H-4),
3
, 300 MHz,
3
), 1.32 (s, 3H, CH
3
); C NMR (CDCl , 75 MHz, ppm) d
3
ppm)
d
137.7, 129.4, 128.4, 126.4, 109.2, 108.6, 96.5, 79.2, 72.0, 71.9, 70.9,
1
4
70.4, 68.5, 67.7, 51.6, 40.5, 29.8, 28.3, 26.0, 25.9, 25.0, 24.8, 24.6,
þ
.06e3.97 (m, 1H, NCH), 3.34 (bs, 1H, OH), 2.98e2.80 (m, 6H, 3ꢁ
24.4, 15.2; HRMS-ESI: m/z calcd for C26
found: 580.1788.
H
39NO
7
SeþNa : 580.1784,
1
3
CH
2
),1.53 (s, 3H, CH
3
),1.42 (s, 9H, 3ꢁ CH
3
),1.33 (s, 3H, CH
3
); C NMR
(
CDCl
3
, 75 MHz, ppm)
d¼155.6,137.3,129.4,128.6,126.6,111.6,104.8,
8
5.5, 81.2, 79.9, 74.8, 52.3, 39.9, 30.1, 28.3, 26.8, 26.2, 22.0; HRMS-
4.3.7. 6-Se-((S)-2-N-(tert-butoxycarbonyl)-4-methylpentyl)-6-
deoxy-1.2:3,4-di-O-isopropylidene-6-seleno- -galactopy-ranose
þ
ESI: m/z calcd for C22
H33NO
6
SeþNa : 510.1365, found: 510.1365.
a-D
2
0
1
(
5g). Yellow oil. Yield: 50%; [
300 MHz, ppm)
¼5.53 (d, J¼5.1 Hz, 1H, H-1), 4.73 (bs, 1H, NH), 4.61
(dd, J¼7.8 Hz, 2.4 Hz, 1H, H-3), 4.33e4.29 (m, 3H, H-4, H-2, NCH),
a
]
D
ꢂ31 (c 1.3, AcOEt); H NMR (CDCl
3
,
4.3.2. 5-Se-((S)-2-N-(tert-butoxycarbonyl)-3-methylbutyl)-5-deoxy-
d
1,2-O-isopropylidene-5-seleno- -xylofuranose (5b). Yellow oil.
a-D

10474
R.F. Affeldt et al. / Tetrahedron 68 (2012) 10470e10475
2
0
ꢂ87 (c 1.0, AcOEt); 1H NMR
3
1
(
.90 (dt, J¼7.2 Hz, 1.8 Hz, 1H, H-5), 2.88e2.70 (m, 6H, 3ꢁ CH
.68e1.61 (m, 1H, CH), 1.54 (s, 6H, 2ꢁ CH ), 1.44 (s, 9H, 3ꢁ CH ), 1.34
s, 3H, CH ), 1.33 (s, 3H, CH ), 0.90 (d,
), 0.91 (d, J¼6.3 Hz, 3H, CH
); C NMR (CDCl , 75 MHz, ppm)
¼155.3, 109.2,
08.5, 96.6, 79.0, 71.9, 70.9, 70.4, 68.4, 48.4, 43.9, 31.7, 28.3, 26.0,
2
),
(7c). Colourless oil. Yield: 50%; [
(CDCl , 300 MHz, ppm)
a]
D
xyl
3
3
3
d
¼5.92 (d, J¼3.6 Hz, 1H, H-1 ), 5.53 (d,
Gal
Gal
3
3
3
J¼4.8 Hz, 1H, H-1 ), 4.62 (dd, J¼7.8 Hz, 2.4 Hz, 1H, H-3 ), 4.56 (d,
13
xyl xyl xyl Gal
J¼6.6 Hz, 3H, CH
3
3
d
J¼3.6 Hz, 1H, H-2 ), 4.35e4.26 (m, 4H, H-3 , H-4 , H-2 , H-
Gal Gal
1
2
C
4
), 3.98e3.93 (m, 1H, H-5 ), 3.07 (dd, J¼11.9 Hz, 4.5 Hz, 1H),
Gal
xyl
5.9, 24.8, 24.4, 22.9, 22.3; HRMS-ESI: m/z calcd for
2.97e2.79 (m, 4H, CH
2
, CH
2
), 1.55 (s, 3H, CH
3
), 1.50 (s, 3H, CH
), 1.31 (s, 3H, CH ); C NMR
3
),
þ
13
23
H
41NO
7
SeþNa : 546.1940, found: 546.1940.
1.44 (s, 3H, CH
3
), 1.34 (s, 6H, 2ꢁ CH
3 3
(
CDCl , 75 MHz, ppm)
3
d
¼111.5, 109.4, 108.9, 104.8, 96.4, 85.0, 80.5,
4
5
.3.8. Methyl 5-Se-((S)-2-N-(tert-butoxycarbonyl)-3-phenylpro-pyl)-
-deoxy-2,3-O-isopropylidene-5-seleno- -ribofuranose
74.6, 72.3, 70.9, 70.5, 69.7, 26.7, 26.1, 26.0, 25.9, 24.9, 24.4, 24.0, 21.2;
þ
b
-
D
HRMS-ESI: m/z calcd for
C
20
H
32
O
9
SeþNa : 519.1104; found:
ꢀ
20
1
(
5h). White solid. Yield: 30%; mp 64 C; [
NMR (CDCl , 300 MHz, ppm)
¼7.32e7.18 (m, 5H, Ar), 4.98 (d,
J¼4.2 Hz, 1H, H-1), 4.74 (d, J¼5.1 Hz, 1H, H-2), 4.67e4.59 (m, 2H, H-
a
]
D
ꢂ45 (c 1.0, AcOEt); H
519.1109.
3
d
Acknowledgements
4
1
3
7
8
2
5
, H-3), 3.35 (s, 3H, OCH
H, H-5), 2.89e2.80 (m, 2H, CH
H, CH ), 1.32 (s, 3H, CH
), 1.41 (s, 9H, 3ꢁ CH
5 MHz, ppm)
6.7, 85.5, 85.4, 83.7, 83.3, 55.0, 33.0, 29.7, 29.3, 28.3, 26.5, 26.4,
5.0. HRMS-ESI: m/z calcd for C23
3
), 3.22e3.16 (m, 1H, H-5), 3.04e2.97 (m,
), 2.74e2.55 (m, 2H, CH ), 1.48 (s,
); C NMR (CDCl
2
2
We are grateful for the following agencies for financial support
and fellowships: CNPq, FAPERGS, CAPES and FAPESP.
13
3
3
3
3
,
d¼155.1, 137.5, 129.4, 128.5, 126.6, 112.4, 109.6, 86.9,
þ
References and notes
H35NO
6
SeþNa : 524.1527, found:
24.1515.
1
. (a) Mugesh, G.; Singh, H. B. Chem. Soc. Rev. 2000, 29, 347; (b) Mugesh, G.; du
Mont, W. W. Chem.dEur. J. 2001, 7, 1365; (c) Mugesh, G.; du Mont, W. W.; Sies,
H. Chem. Rev. 2001, 101, 2125; (d) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem.
Rev. 2004, 104, 6255; (e) Alberto, E. E.; Nascimento, V.; Braga, A. L. J. Braz. Chem.
Soc. 2010, 21, 2032; (f) Nogueira, C. W.; Rocha, J. B. T. J. Braz. Chem. Soc. 2010, 21,
4
.4. General procedure for the preparation of seleno di-
saccharides 7
2055; (g) Bhabak, K. P.; Mugesh, G. Acc. Chem. Res. 2010, 43, 1408; (h) Nogueira,
Under argon atmosphere, sodium borohydride (0.75 mmol) was
added to a solution of the appropriate carbohydrate diselenide 4
0.30 mmol) in THF (3 mL). Ethanol (2 mL) was then dropwise
added and the clear solution formed was stirred at room temper-
C. W.; Rocha, J. B. T. Arch. Toxicol. 2011, 85, 1313.
2
3
4
. (a) Mukherjee, C.; Tiwari, P.; Misra, A. K. Tetrahedron Lett. 2006, 47, 441; (b)
Tiwari, P.; Misra, A. K. Tetrahedron Lett. 2006, 47, 2345; (c) Valerio, S.;
Iadonisi, A.; Adinolfi, A.; Ravid aꢀ , A. J. Org. Chem. 2007, 72, 6097; (d) Di
(
Bussolo, V.; Fiasella, A.; Balzano, F.; Barretta, G. U.; Crotti, P. J. Org. Chem.
2
010, 75, 4284.
. (a) Jiaang, W.-T.; Chang, M.-Y.; Tseng, P.-H.; Chen, S.-T. Tetrahedron Lett. 2000, 41,
127; (b) Boutureira, O.; Bernardes, G. J. L.; Fernandez-Gonzalez, M.; Anthony,
ature for 10 min. After this time a solution of the tosylate 3
(
0.50 mmol in 2 mL THF) was slowly added. After stirring for 24 h
under reflux, the reaction mixture was quenched with aqueous
saturated NH Cl (10 mL) and extracted with CH Cl
(3ꢁ15 mL). The
combined organic layers were dried with MgSO , filtered and
3
D. C.; Davis, B. G. Angew. Chem., Int. Ed. 2012, 51, 1432; (c) Gamblin, D. P.;
Garnier, P.; van Kasteren, S.; Oldham, N. J.; Fairbanks, A. J.; Davis, B. G. Angew.
Chem., Int. Ed. 2004, 43, 828.
. (a) Yamago, S.; Yamada, T.; Hara, O.; Ito, H.; Mino, Y.; Yoshida, J.-I. Org. Lett.
2001, 3, 3867; (b) Yamago, S.; Yamada, T.; Hara, O.; Ito, H.; Hara, O.; Mino, Y.;
Yoshida, J.-I. Chem.dEur. J. 2005, 11, 6159; (c) France, R. R.; Compton, R. G.;
Davis, B. G.; Fairbanks, A. J.; Rees, N. V.; Wadhawan, J. D. Org. Biomol. Chem.
4
2
2
4
concentrated. The crude product was purified by flash chroma-
tography first eluting with hexanes and then with a mixture of
hexanes/ethyl acetate (70:30).
2004, 2, 2195; (d) Mehta, S.; Pinto, B. M. J. Org. Chem. 1993, 58, 3269; (e)
Johnston, B. D.; Pinto, B. M. Carbohydr. Res. 1998, 305, 289.
5
6
. Chambers, D. J.; Evans, G. R.; Fairbanks, A. J. Tetrahedron 2004, 60, 8411.
. Grant, L.; Liu, Y.; Walsh, K. E.; Walter, D. S.; Gallagher, T. Org. Lett. 2002, 4, 4623.
4
.4.1. (5-Deoxy-1,2-O-isopropylidene- -xylofuranosyd-5-yl)
a
-
D
(
(
methyl 5-deoxy-2,3-O-isopropylidene-b-D-ribofuranos-5-yl) selenide
7. (a) Kawai, Y.; Ando, H.; Ozeki, H.; Koketsu, M.; Ishihara, H. Org. Lett. 2005, 5,
ꢀ
20
7a). White solid. Yield: 70%; mp 122 C; [
a]
D
ꢂ64 (c 1.0, AcOEt);
4653; (b) Nanami, M.; Ando, H.; Kawai, Y.; Koketsu, M.; Ishihara, H. Tetrahedron
Lett. 2007, 48, 1113.
1
xyl
H NMR (CDCl
3
, 300 MHz, ppm)
d
¼5.92 (d, J¼3.7 Hz, 1H, H-1 ),
Rib
Rib
8. (a) Czernecki, S.; Randriamandimby, D. J. Carbohydr. Chem. 1996, 15, 183; (b)
Mehta, S.; Andrews, J. S.; Johnson, B. D.; Svensson, B.; Pinto, B. M. J. Am. Chem.
Soc. 1995, 117, 9783.
4
1
.99 (s, 1H, H-1 ), 4.72 (d, J¼5.9 Hz, 1H, H-2 ), 4.61 (d, J¼5.9 Hz,
Rib xyl Rib
H, H-4 ), 4.53 (d, J¼3.7 Hz, 1H, H-2 ), 4.38e4.28 (m, 3H, H-3
Rib
,
xyl
xyl
eꢀ re, V.; Cumpstey, I. Tetrahedron Lett. 2010, 51, 2127; (b) Cumpstey,
I.; Ramstadius, C.; Akhtar, T.; Goldstein, I. J.; Winter, H. C. Eur. J. Org. Chem.
2
H-3 , H-4 ), 3.35 (s, 3H, OCH
2
CH
3
), 3.02e2.92 (m, 2H, H-5 ),
9. (a) Fourni
xyl
xyl
.84e2.76 (m, 1H, H-5 ), 2.68e2.60 (m, 1H, H-5 ), 1.50 (s, 3H,
010, 1951.
0. For a review on non-glycosidically linked pseudodisaccharides, see: Cumpstey,
I. C. R. Chim. 2011, 14, 274.
1. (a) Merino-Montiel, P.; L oꢁ pez, O. L.; Fernandez-Bola n~ os, J. G. Tetrahedron 2012,
8, 3591; (b) Mohan, S.; Jayakanthan, K.; Nasi, R.; Kuntz, D. A.; Rose, D. R.; Pinto,
13
3
), 1.48 (s, 3H, CH
3 3 3
), 1.32 (s, 3H, CH ), 1.31 (s, 3H, CH ); C NMR
1
(
CDCl , 75 MHz, ppm)
3
d
¼129.8, 112.6, 111.7, 109.5, 104.9, 86.6, 85.3,
1
8
3.3, 80.4, 74.9, 55.1, 27.9, 26.8, 26.5, 26.2, 25.0, 19.9; HRMS-ESI: m/z
6
þ
calcd for C17
28
H O
8
SeþNa : 463.0842, found: 463.0849.
B. M. Org. Lett. 2010, 12, 1088; (c) Nasi, R.; Sim, L.; Rose, D. R.; Pinto, B. M. J. Org.
Chem. 2007, 72, 180; (d) Szczepina, M. G.; Johnston, B. D.; Yuan, Y.; Svensson, B.;
Pinto, B. M. J. Am. Chem. Soc. 2004, 126, 12458; (e) Johnston, B. D.; Ghavami, A.;
Jensen, M. T.; Svensson, B.; Pinto, B. M. J. Am. Chem. Soc. 2002, 124, 8245.
4.4.2. (6-Deoxy-1,2:3,4-di-O-isopropylidene-
a
-
b
D
-galactopyrano-sid-
-ribofuranos-5-yl)
6-yl) (methyl 5-deoxy-2,3-O-isopropylidene-
-
D
12. Ahn, S. J.; Koketsu, M.; Ishihara, H.; Lee, S. M.; Ha, S. K.; Lee, K. H.; Kang, T. H.;
2
0
1
selenide (7b). Yellow oil. Yield: 95%; [
NMR (CDCl
a
]
D
ꢂ71 (c 1.0, AcOEt);
H
Kim, S. Y. Chem. Pharm. Bull. 2006, 54, 281.
Gal
13. (a) Liu, H.; Nasi, R.; Jayakanthan, K.; Sim, L.; Heipel, H.; Rose, D. R.; Pinto, B. M. J.
3
, 300 MHz, ppm)
d
¼5.53 (d, J¼5.1 Hz, 1H, H-1 ), 4.97
Rib
Rib
Org. Chem. 2007, 72, 6562; (b) Liu, H.; Pinto, B. M. J. Org. Chem. 2005, 70, 753.
(
2
s, 1H, H-1 ), 4.72 (d, J¼6.0 Hz, 1H, H-2 ), 4.61 (dd, J¼10.2 Hz,
14. (a) Abdo, M.; Knapp, S. J. Am. Chem. Soc. 2008, 130, 9234; (b) Abdo, M.; Liu, S.;
Gal
Rib
.4 Hz, 1H, H-3 ), 4.61 (s, 1H, H-4 ), 4.36 (dd, J¼7.8 Hz, 1.5 Hz, 1H,
Gal Gal
Zhou, B.; Walls, C. D.; Wu, L.; Knapp, S.; Zhang, Z. Y. J. Am. Chem. Soc. 2008, 130,
1
3196.
15. (a) Adiwidjaja, G.; Schulze, O.; Voss, J.; Wirsching, J. Carbohydr. Res. 2000, 325,
07; (b) Jeong, L. S.; Tosh, D. K.; Kim, H. O.; Wang, T.; Hou, X.; Yun, H. S.; Kwon,
H-4 ), 4.31e4.29 (m, 1H, H-2 ), 3.91 (dt, J¼6.9 Hz, 1.5 Hz, 1H, H-
Gal
Gal
Rib
5
CH
CH
), 3.34 (s, 3H, OCH
3
), 2.94e2.66 (m, 5H, CH
), 1.45 (s, 3H, CH ), 1.35 (s, 3H, CH
); C NMR (CDCl
2
, CH
2
), 1.54 (s, 3H,
), 1.33 (s, 3H,
1
3
), 1.47 (s, 3H, CH
), 1.32 (s, 3H, CH
3
3
3
Y.; Lee, S. K.; Choi, J.; Zhao, L. X. Org. Lett. 2008, 10, 209; (c) Goudgaeon, N. M.;
Schinazi, R. F. J. Med. Chem. 1991, 34, 3305; (d) Chu, C. K.; Ma, L.; Olgen, S.;
Pierra, C.; Du, J.; Gumina, G.; Gullen, E.; Cheng, Y.-C.; Schinazi, R. F. J. Med. Chem.
13
3
3
3
, 75 MHz, ppm)
d¼112.2,
109.5, 109.1, 108.5, 96.6, 86.5, 85.3, 83.5, 71.6, 70.9, 70.4, 68.5, 54.8,
2
(
000, 43, 3906; (e) Cosford, N. D. P.; Schinazi, R. F. J. Org. Chem. 1991, 56, 2161;
2
C
9.6, 28.0, 26.4, 26.0, 25.9, 24.9, 24.3, 23.2; HRMS-ESI: m/z calcd for
f) Diaz, Y.; El-Laghdach, A.; Matheu, M. I.; Castillon, S. J. Org. Chem. 1997, 62,
ꢁ
þ
21
34
H O
9
SeþNa : 533.1260, found: 533.1260.
1501; (g) Diaz, Y.; El-Laghdach, A.; Castill oꢁ n, S. Tetrahedron 1997, 53, 10921; (h)
Review: Wnuk, S. F. Tetrahedron 1993, 49, 9877.
1
6. (a) Du, Q.; Carrasco, N.; Teplova, M.; Wilds, C. J.; Egli, M.; Huang, Z. J. Am. Chem.
4.4.3. (6-Deoxy-1,2:3,4-di-O-isopropylidene-
a-D-galactopyrano-sid-
Soc. 2002, 124, 24; (b) H o€ bartner, C.; Micura, R. J. Am. Chem. Soc. 2004, 126,
6
-yl) (5-deoxy-1,2-O-isopropylidene- -xylofuranosyd-5-yl) selenide
a
-
D
1141; (c) Buzin, Y.; Carrasco, N.; Huang, Z. Org. Lett. 2004, 6, 1099; (d) Salon, J.;

R.F. Affeldt et al. / Tetrahedron 68 (2012) 10470e10475
10475
Chen, G.; Portilla, Y.; Germann, M. W.; Huang, Z. Org. Lett. 2005, 7, 5645; (e)
Jiang, J.; Sheng, J.; Carrasco, N.; Huang, Z. Nucleic Acids Res. 2007, 35, 477; (f)
Caton-Williams, J.; Huang, Z. Chem. Biodiversity 2008, 5, 396; (g) Sheng, J.;
Huang, Z. Chem. Biodiversity 2010, 7, 753.
7. (a) Braga, A. L.; Severo-Filho, W. A.; Schwab, R. S.; Rodrigues, O. E. D.; Dornelles,
L.; Braga, H. C.; L u€ dtke, D. S. Tetrahedron Lett. 2009, 50, 3005; (b) Braga, H. C.;
Stefani, H. A.; Paix a~ o, M. W.; Santos, F. W.; L u€ dtke, D. S. Tetrahedron 2010, 66,
19. Braga, A. L.; Paix a~ o, M. W.; L u€ dtke, D. S.; Silveira, C. C.; Rodrigues, O. E. D. Org.
Lett. 2003, 5, 2635.
20. Gladysz, J. A.; Hornby, J. L.; Garbe, J. E. J. Org. Chem. 1978, 43, 1204.
21. For selected examples of regioselective aziridine ring-opening with selenium
nucleophiles. (a) Braga, A. L.; L u€ dtke, D. S.; Paix ~a o, M. W.; Alberto, E. E.; Stefani,
1
H. A.; Juliano, L. Eur. J. Org. Chem. 2005, 4260; (b) Braga, A. L.; Bottega, D. P.;
Paix a~ o, M. W.; Deobald, A. M.; Peppe, C.; Schneider, P. H. J. Org. Chem. 2006, 71,
3
2
441; (c) Braga, H. C.; Wouters, A. D.; Zerillo, F. B.; L u€ dtke, D. S. Carbohydr. Res.
010, 345, 2328.
4305; (c) Sureshkumar, D.; Gunasundari, T.; Saravanan, V.; Chandrasekaran, S.
Tetrahedron Lett. 2007, 48, 623.
18. McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org. Chem. 1993,
22. Bhuyan, B. J.; Mugesh, G. Org. Biomol. Chem. 2011, 9, 1356.
5
8, 3568.
23. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.