Synthesis of the first selenium-containing acyclic nucleosides and anomeric spironucleosides from carbohydrate precursors

Article abstract of DOI:10.1002/ejoc.200900793

We report the synthesis of acyclic and spiranic imidazole-derived C-selenonucleosides. 5-Hydroxy-4-tetrahydroxybutyl imidazolidine-2-selones, a novel class of acyclic selenonucleosides, were transformed into (tetrahydroxybutylimidazol2-yl)diselenide, by a

Full text of DOI:10.1002/ejoc.200900793

FULL PAPER
DOI: 10.1002/ejoc.200900793
Synthesis of the First Selenium-Containing Acyclic Nucleosides and Anomeric
Spironucleosides from Carbohydrate Precursors
Susana Maza,[a] Óscar López,[a] Sergio Martos,[a] Inés Maya,[a] and
José G. Fernández-Bolaños*[a]
Keywords: Selenium / Carbohydrates / Spiro compounds / Nucleosides / Heterocycles
We report the synthesis of acyclic and spiranic imidazole-de-
rived C-selenonucleosides. 5-Hydroxy-4-tetrahydroxybutyl
imidazolidine-2-selones, a novel class of acyclic selenonu-
cleosides, were transformed into (tetrahydroxybutylimidazol-
2-yl)diselenide, by acetylation and chemoselective N-de-
acetylation with methanolic imidazole. Furthermore, the syn-
thesis of a new class of conformationally restricted arabino-
configured spironucleosides containing an imidazolidine-2-
selone unit around the glycosidic bond was achieved, start-
ing from N-fructosamines, via 4-hydroxy-4-tetrahydoxy-
butyl-imidazolidine-2-selones as the key intermediates.
Acetylation–deacetylation of these intermediates gave access
to stable aromatic imidazoline-2-selones.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
explored the access to chiral 2-seleno-1,3-N-heterocyclic
templates, an attractive challenge from both synthetic and
biological points of view.
Introduction
Nucleoside analogues have proved to exhibit important
pharmacological properties, especially as antiviral,[1] antitu-
mor,[2] and antifungal agents.[3] Recent modifications of the
nucleoside structure consist of the introduction of a sele-
nium atom, an essential trace element,[4] either by replacing
the endocyclic oxygen atom of the carbohydrate residue[5]
or as part of the nucleobase.[6–8] The incorporation of 6-
selenoguanosine[9] and 4-selenothymidine[10] into DNA to
study nucleic acid base pairing by X-ray and for DNA visu-
alization, respectively, has also been described. Further-
more, a series of selenium-containing nucleosides and oligo-
nucleotides have been used for convenient phasing of X-ray
crystallographic data.[11–13] Some methylseleno nucleosides
were found to inhibit prostatic cancer cells growth.[14] Sele-
nium has not been found in DNA, although its presence in
natural uridines from tRNAs has been documented.[15]
Although the synthesis of acyclic nucleosides[1b,16] has
generated much interest due to their potent biological ac-
tivities, no selenium-containing acyclic nucleosides have
been reported up to now. The chemistry of organoselenium
compounds has been developed to a significant small extent
because of the intrinsic instability[17] of some of these com-
pounds. We have devoted our efforts in developing strate-
gies to reach, from carbohydrates, stable and versatile or-
ganoselenium templates.[18] In this communication we have
Results and Discussion
Reaction of phenyl isoselenocyanate[18] with -glucosa-
mine hydrochloride in aqueous ethanol in the presence of
NaHCO3 afforded 5-hydroxy-4-polyhydroxyalkylimid-
azolidine-2-selone 3 in a high yield of 99% after column
chromatography (Scheme 1). This reaction must be carried
out in the dark, as many selenium-containing compounds
undergo UV-induced decomposition.[19]
The reaction might proceed via nondetected selenourea
2, which could undergo spontaneous cyclization through
the carbonyl group of the open chain form to give imid-
azolidine-2-selone by a 5-exo-trig cyclization, according to
Baldwin’s[20] rules. NMR spectroscopic data showed 3 to
exist as a nonresolved mixture of 5R/5S diastereoisomers,
1
in a 90:10 ratio, measured by H NMR spectroscopy. The
assignment of the 5R configuration for the major dia-
stereoisomer was based on the J4,5 coupling constant
(3.1 Hz), indicating that both protons are in a trans ar-
rangement, whereas for the 5S derivatives the J value was
7.4 Hz, with 4-H and 5-H in a cis relationship.
Acid-catalyzed dehydration of 3 with AcOH in a re-
fluxing EtOH/water mixture afforded bicyclic glucofuran-
osoimidazolidine-2-selone 4 in 89% yield (Scheme 1). The
synthesis of 4 was previously reported,[21] but without the
isolation of parent selone 3. Attempts to convert bicyclic
derivative 4 into corresponding aromatic imidazoline-2-
selone 5 by dehydration under strong acid conditions were
[a] Departamento de Química Orgánica, Facultad de Química,
Universidad de Sevilla,
Apartado 1203, 41071 Seville, Spain
Fax: +34-95-4624960
E-mail: bolanos@us.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900793.
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FULL PAPER
Scheme 1.
unsuccessful, and precipitation of elemental selenium was coupling of -glucosamine hydrochloride 1 and p-meth-
observed. It has been reported that acidic treatment of a ylphenyl isoselenocyanate (84% yield), following the same
series of selenocarbamates leads to decomposition with the conditions as those used to prepare compound 3. We ob-
release of elemental selenium.[22]
served that at 30 °C for 24 h, the acetylation reaction took
The same reactions were carried out with the use of - place at both the hydroxy groups and the NH group of the
mannosamine hydrochloride and phenyl isoselenocyanate heterocyclic moiety to furnish 10 in 83% yield. Moreover,
(Scheme 2). In this case, 5-hydroxyimidazolidine-2-selone 7 when the acetylation reaction was carried out at 80 °C for
was obtained in a 90% yield, after chromatographic purifi- 48 h, we obtained a separable mixture of 10 (33%) and
cation. As indicated above for the -gluco-configured epi- imidazole 11 (40%). Imidazoline-2-selone 15 (Scheme 4)
1
mer, the H NMR spectrum showed the existence of two was not detected in the mixture.
diastereoisomers at the 5-position in a 5R/5S ratio of 4:96.
Scheme 2.
Acyclic C-pseudonucleoside 7 was subjected, in a one-
pot fashion, to acidic treatment to give corresponding bicy-
clic mannofuranosoimidazolidine-2-selone 8 in 68% yield
for the two steps (Scheme 2). The furanoid structure of 8
was evidenced by the observed J1,2 and J2,3 coupling con-
stants (6.9 and 6.6 Hz, respectively), which are in agreement
with the data reported for the only example of a manno-
Scheme 3.
configured glycofuranosoimidazolidine-2-one.[23]
We studied the acetylation of the polyhydroxyalkylimid-
Imidazole 11 could be formed as indicated in Scheme 4,
azolidine-2-selone template; reactions were conducted in a by air oxidation of 15 to give the corresponding transient
1:1 Ac2O/Py mixture at different temperatures and reaction diselenide 16, followed by loss of selenium as the key steps.
times, leading to different products, as depicted in Spontaneous oxidation of imidazoline-2-selone to diselen-
Scheme 3. We chose 9 as a model compound, obtained by ide has been reported.[24] Imidazole-based compounds are
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Acyclic and Spiranic Imidazole-Derived C-Selenonucleosides
attractive targets[25] because of their roles in several bio- as a mild base furnished not the expected pentaacetylated
logical processes,[26] applications in coordination chemis- derivative 12 but diselenide 16 in a 66% yield (Scheme 5).
try,[27] and also as an extracellular pH indicator for 1H In compound 12, the delocalization of the lone pair on N-
NMR spectroscopic imaging.[28] Imidazolyl alditols have 3 to the selone moiety allows N-1 to contribute more ef-
also been used for the preparation of imidazolo sugars, ficiently to the loss of the acetoxy group at C-5. Therefore,
studied as potential glycosidase inhibitors.[29]
we postulate that methanolic imidazole allows conversion
of 10 into 12, which easily undergoes loss of acetic acid to
give transient imidazoline-2-selone 15 (Scheme 5). Sponta-
neous air-promoted oxidation of 15 affords symmetrical
diselenide 16 in acceptable yield (66%) after chromato-
graphic purification.
A series of dialkyl and diaryl diselenides were synthe-
sized and found to possess gluthatione-peroxidase-like ac-
tivity, and thus, are good candidates as antioxidants;[31] for
example, diphenyl diselenide is known to be an antioxidant,
anti-inflammatory, antinociceptive, and anxyolytic agent.[32]
Furthermore, 20,[24] the selenium isoster of methimazole 19,
one of the most widely used drugs for the treatment of hy-
perthyroidism, also shows antithyroid activity. Compound
20 is spontaneously oxidized to diselenide 21, which in turn
can be reduced again to selone 20, so acting as a reversible
inhibitor.[33] The inhibitory activity of 20 is due to the re-
duction of H2O2, needed for the first step of the biosynthe-
sis of the thyroid hormone.[34]
Scheme 4.
When the temperature of the acetylation reaction was de-
creased to –20 °C, and the acetylation was performed for
24 h (Scheme 3), we obtained a 30:70 mixture of compound
10 (5R/5S Ͼ 99:1) and penta-O-acetylated derivative 12
(5R/5S, 83:17).
Attempts to carry out the chromatographic separation of
compounds 10 and 12 on silica gel chromatography led to
extensive decomposition, and pure diselenide 16 was iso-
lated as a minor compound (8%). This result demonstrates
the higher stability of hexaacetylated derivative 10 in com-
parison with pentaactylated compound 12, as the former
does not undergo decomposition under chromatographic
purification.
We have recently reported a new procedure for the
chemoselective N-deacetylation of carbohydrate derivatives
In order to check the influence of bulky substituents on
based on the use of methanolic imidazole.[30] Treatment of the ortho positions of the aromatic ring in the acetylation
the crude mixture of 10 and 12 with methanolic imidazole reaction of 5-hydroxyimidazolidine-2-selones, at 80 °C we
Scheme 5.
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S. Maza, Ó. López, S. Martos, I. Maya, J. G. Fernández-Bolaños
FULL PAPER
acetylated 22 and 23, obtained from -glucosamine and the
corresponding
o,oЈ-dialkylphenyl
isoselenocyanates
(Scheme 6). Surprisingly, no imidazole-derived compounds
were obtained, but hexaacetylated imidazolidine-2-selones
24 and 25 (96 and 84%), as a mixture of the 5R/5S dia-
stereoisomers in a ratio higher than 99:1. Furthermore, the
existence of bulky substituents in the o,oЈ-positions of the
aromatic ring restricts the free rotation of the aromatic ring,
giving rise to the presence of atropisomers in the NMR
spectra (52:48 and 56:44, respectively for the 5R diastereo-
isomers of 24 and 25).
Scheme 7.
at 7.04 ppm (HC=) and 160.9–161.1 ppm (C=Se) are con-
sistent with imidazoline-2-selones motifs.[36] Subsequent de-
acylation gave stable 38 and 39, acyclic C-nucleosides of the
imidazoline-2-selone type, in 77 and 91% yield, respectively.
N,NЈ-Disubstituted imidazoline-2-selones, used in industry
as catalysts for the preparation of epoxy resins,[37] were pre-
pared by reaction of nucleophilic carbenes with elemental
selenium.[38] N,NЈ-Disubstituted imidazoline-2-selones 36–
39 showed higher stability than N-substituted analogue 15,
which is nondetected because of its fast oxidation to imid-
azol-2-yl diselenide 16.
4-Hydroxyimidazolidine-2-selones 30 and 31 underwent
dehydration under weak acidic conditions to give a separa-
ble mixture of imidazoline-2-selones 38 and 39 (39 and 31%
yield, respectively) as minor compounds (Scheme 9), to-
gether with the major spiranic derivatives 42 and 43 (60
and 54%, respectively), whose NMR showed signals for a
mixture of diastereoisomers on the spiranic carbon C-5 in
a 86:14 ratio for 42, and 89:11 ratio for 43.
Scheme 6.
The high steric hindrance in transition state 26 that
would furnish cation 27 avoids the loss of the acetoxy group
on C-5 (Figure 1), so the corresponding imidazole deriva-
tive is not formed; therefore, hexaacetylated derivatives 24
and 25 are obtained in good yields, in comparison with the
reaction undergone by N-tolyl derivative 9.
The key synthetic intermediates are stabilized cations 40
and 41 (Scheme 9), obtained by protonation of the hydroxy
group on C-4 and subsequent loss of a water molecule. Loss
of the proton on C-5 (pathway a) furnished imidazoline-2-
selones 38 and 39, whereas nucleophilic attack of the hy-
droxy group on C-3Ј of the polyhydroxyalkyl chain (path-
way b) yielded arabino-configured spiranic derivatives 42
and 43. These derivatives represent the first described sele-
nium-containing spironucleosides, with the additional inter-
est of containing an imidazoline-2-selone unit in a fixed
conformation around the glycosidic bond, quite resembling
the heterocyclic moiety of (+)-hydantocidin. Hydantocidin,
the first natural spironucleoside described,[39] was found to
be a plant growth regulator and a potent herbicide, without
exerting toxicity to mammals.[40] Since then, many structur-
ally related spiro compounds have been prepared.[41]
Figure 1. Transition states and intermediates that might be involved
in C-5 deacylation of 24 and 25.
We also investigated the reaction of N-arylfructosamines
28 and 29[35] with phenyl and p-tolyl isoselenocyanates,
respectively, in DMF at room temperature to afford the cor-
responding 4-hydroxy-4-polyhydroxyalkylimidazolidine-2-
selones 30 and 31 (Scheme 7) in excellent yields after chro-
matographic purification (98 and 85%, respectively). As
previously indicated for the synthesis of 5-hydroxyimid-
azolidine-2-selones, the reaction must involve a nondetected
selenourea that undergoes intramolecular cyclization to give
30 and 31 as a nonresolved mixture of diastereoisomers at
C-4 (96:4 and 91:9 ratio, respectively), a diastereoselectivity
similar to that found for the 5-hydroxy analogues described
above. We could not carry out the unequivocal assignment
of the C-4 configuration for compounds 30 and 31.
Acetylation of imidazolidine-2-selones 30 and 31 pro-
voked aromatization of the heterocyclic moiety ring to give
tetra-O-acetylated imidazolines 36 and 37 (98 and 83%,
respectively). The formation of these derivatives arises from
the loss of acetic acid, presumably through stabilized cat-
Acetylation of 42 and 43 afforded per-O-acetylated deriv-
1
ions 34 and 35 (Scheme 8). H and 13C NMR resonances atives 44 and 45 as a nonresolved mixture of diastereoiso-
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Acyclic and Spiranic Imidazole-Derived C-Selenonucleosides
Scheme 8.
Scheme 9.
mers on C-5, with the same chromatographic mobility = 7.1, 7.2 Hz) and the minor isomers (J2,3 = 7.9, 8.2 Hz; J3,4
(Scheme 9). Resonances of C-5 (98.7, 100.5 ppm) confirm = 8.1, 8.3 Hz) of acetylated derivatives 44 and 45 (Figure 2).
their spiranic structure.
NOESY experiments on the diastereoisomeric mixture of
The major diastereoisomer of nonacetylated derivatives 44 allowed the unequivocal assignment of the spiranic C-5
42 and 43 exhibit high vicinal coupling constants, indicating configuration. For the major S diastereoisomer, strong
an almost antiperiplanar disposition of the protons, and cross peak correlations were observed between 3-H, 9a-H,
3
thus, confirming the E conformation of the furanoid ring and 9b-H. The 5R configuration of the minor diastereoiso-
as the major one in solution (Figure 2). The same conclu- mer was confirmed by a strong cross peak correlation be-
sion can be reached for both, the major (J2,3 = 7.4 Hz; J3,4 tween 4-H and 9a-H.
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0.60 mmol), phenyl isoselenocyanate (136 mg, 0.75 mmol,
1.25 equiv.), and NaHCO3 (50 mg, 0.60 mmol) in EtOH/H2O
(8 mL, 2:1) was heated at reflux in the dark for 30 min. Then,
AcOH (0.8 mL) was added, and the corresponding solution was
heated at reflux for 50 min. The reaction mixture was concentrated
to dryness coevaporating with EtOH, and the residue was purified
by column chromatography (CH2Cl2ǞCH2Cl2/MeOH, 10:1) to
give 8. Yield: 142 mg, 68%, Rf = 0.5 (CH2Cl2/MeOH, 5:1). [α]2D6
=
–110 (c = 0.6, DMSO). IR: ν = 3416, 1647, 1507, 698 cm–1. 1H
˜
NMR [300 MHz, (CD3)2SO]: δ = 9.41 (s, 1 H, NH), 7.70–7.38 (m,
5 H, Ar-H), 5.83 (d, J1,2 = 6.9 Hz, 1 H, 1-H), 5.48 (d, JH,OH
=
5.1 Hz, 1 H, OH-3), 4.70 (d, JH,OH = 3.3 Hz, 1 H, OH-5), 4.46 (t,
JH,OH = 5.7 Hz, 1 H, OH-6), 4.42 (m, J2,3 = 6.6 Hz, 1 H, 3-H),
4.37 (t, 1 H, 2-H), 3.74 (m, 2 H, 4-H, 5-H), 3.52 (ddd, J5,6a
=
C
Figure 2. Conformational preferences for compounds 42–45.
4.8 Hz, J6a,6b = 11.1 Hz, 1 H, 6a-H), 3.32 (m, 1 H, 6b-H) ppm. 13
NMR [75.5 MHz, (CD3)2SO]: δ = 178.2 (C=Se), 139.4, 128.4,
126.7, 126.6 (Ar), 94.5 (C-1), 78.7 (C-4), 71.6 (C-3), 69.8 (C-5), 63.3
(C-6), 62.4 (C-2) ppm. MS (FAB): m/z (%) = 367 (23) [M + Na]+.
C13H16N2O4Se (343.24): calcd. C 45.49, H 4.70, N 8.16; found C
45.13, H 4.62, N 8.24.
Conclusions
In conclusion, the coupling of aryl isoselenocyanates
with reducing amino sugars gives access to 5-hydroxy-4-
polyhydroxyalkylimidazolidine-2-selones, the acetylation of
which allows the synthesis of (polyhydroxyalkylimidazol-2-
yl)diselenides, a novel type of acyclic C-selenonucleosides.
Furthermore, reaction of aryl isoselenocyanates with N-
arylfructosamines furnishes N,NЈ-disubstituted 4-hydroxy-
4-polyhydroxyalkylimidazolidine-2-selones, a key interme-
diate, which can be transformed into stable aromatic imid-
azoline-2-selones by acetylation or into arabino-configured
spiranic imidazole-C-selenonucleosides upon acid-catalyzed
dehydration.
1-(p-Methylphenyl)-4-(1,2,3,4-tetra-O-acetyl-D-arabino-tetritol-1-
yl)imidazole (11): A solution of 9 (75 mg, 0.20 mmol) in Ac2O/Py
(1:1, 2.0 mL) was kept in the dark at 80 °C for 48 h. Then, the
mixture was concentrated to dryness coevaporating with toluene
and EtOH, and the residue was purified by column chromatog-
raphy (CH2Cl2ǞCH2Cl2/MeOH, 40:1) to give compounds 10
(42 mg, 33%) and 11. The latter was crystallized from EtOH to
give a white solid. Yield: 35 mg, 40%. M.p. 126–128 °C. Rf = 0.38
(CH2Cl2/MeOH, 40:1). [α]2D0 = –25 (c = 1.1, CH Cl ). IR: ν = 1745,
˜
2
2
1520, 1221, 819 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.74 (d,
J2,5 = 1.2 Hz, 1 H, 2-H), 7.25 (m, 5 H, 5-H, Ar-H), 6.15 (d, J1Ј,2Ј
= 5.2 Hz, 1 H, 1Ј-H), 5.74 (dd, J2Ј,3Ј = 6.8 Hz, 1 H, 2Ј-H), 5.28 (td,
J3Ј,4aЈ = 3.0 Hz, J3Ј,4bЈ = 6.0 Hz, 1 H, 3Ј-H), 4.29 (dd, J4aЈ,4bЈ
=
12.3 Hz, 1 H, 4aЈ-H), 4.14 (dd, 1 H, 4bЈ-H), 2.39 (s, 3 H, CH3Ar),
2.10, 2.08, 2.07, 2.04 (4 s, 3 H each, 4 OAc) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 170.8, 170.2, 170.0, 169.7 (4 CO), 138.4
(C-4), 137.9 (Ar-C), 135.9 (C-2), 134.7 (Ar-C), 130.6, 121.5 (Ar-
CH), 117.4 (C-5), 71.3 (C-2Ј), 69.2 (C-3Ј), 67.8 (C-1Ј), 62.0 (C-4Ј),
21.1 (CH3Ar), 21.1, 20.9 (ϫ2), 20.8 (4 CH3CO) ppm. MS (CI): m/z
(%) = 447 (33) [M + H]+. HRMS (CI): calcd. for C22H27N2O8 [M
+ H]+ 447.1767; found 447.1774. C22H26N2O8 (446.45): calcd. C
59.19, H 5.87, N 6.27; found C 59.10, H 5.89, N 6.38.
Experimental Section
(4R,5R/5S)-5-Hydroxy-1-phenyl-4-(D-arabino-tetritol-1-yl)imidaz-
olidine-2-selone (3): A suspension of -glucosamine hydrochloride
(141 mg, 0.65 mmol), phenyl isoselenocyanate (143 mg, 0.78 mmol,
1.2 equiv.), and NaHCO3 (55 mg, 0.65 mmol) in EtOH/H2O (2:1,
9 mL) was heated at reflux in the dark for 30 min. Then, the mix-
ture was concentrated to dryness, and the residue was purified by
column chromatography (CH2Cl2ǞCH2Cl2/MeOH, 5:1) to afford
3 as a syrup. Yield: 221 mg, 99% (5R/5S, 90:10). Rf = 0.24 (CH2Cl2/
MeOH, 5:1). [α]2D6 = +17 (c = 0.8, CH3OH). Data for the major
Bis[1-(p-methylphenyl)-4-(1,2,3,4-tetra-O-acetyl-D-arabino-tetritol-
1-yl)imidazol-2-yl]diselenide (16)
Method A: A solution of 9 (248 mg, 0.66 mmol) in Ac2O/Py (1:1,
4 mL) was kept in the dark at –20 °C for 30 h. Then, the mixture
was poured over water–ice and diluted with CH2Cl2. The organic
layer was separated, washed with 1  HCl, saturated aqueous
NaHCO3 and H2O, dried with MgSO4, filtered, and concentrated
to dryness to give a 70:30 mixture (357 mg) of pentaacetylated de-
rivative 12 and hexaacetylated derivative 10. Chromatographic sep-
aration (CH2Cl2/MeOH, 80:1Ǟ40:1) led to extensive decomposi-
tion, and the title diselenide was isolated as a minor compound
(28 mg, 8%).
1
diastereoisomer: H NMR (300 MHz, CD3OD): δ = 7.47–7.36 (m,
5 H, Ar-H), 5.53 (d, J4,5 = 3.1 Hz, 1 H, 5-H), 3.95 (dd, J4,1Ј
6.1 Hz, J1Ј,2Ј = 1.6 Hz, 1 H, 1Ј-H), 3.89 (dd, 1 H, 4-H), 3.81 (dd,
J3Ј,4aЈ = 2.9 Hz, J4aЈ,4bЈ = 10.6 Hz, 1 H, 4aЈ-H), 3.72 (ddd, J2Ј,3Ј
=
=
8.3 Hz, J3Ј,4bЈ = 5.5 Hz, 1 H, 3Ј-H), 3.67 (dd, 1 H, 4bЈ-H), 3.59 (dd,
1 H, 2Ј-H) ppm. 13C NMR (75.5 MHz, CD3OD): δ = 178.9 (C=Se),
140.3, 129.7, 128.8 (Ar), 90.2 (C-5), 72.7 (C-3Ј), 72.3 (C-2Ј), 70.9
(C-1Ј), 68.4 (C-4), 64.8 (C-4Ј) ppm. Data for the minor dia-
stereoisomer: 1H NMR (300 MHz, CD3OD): δ = 5.60 (d, J4,5
=
7.3 Hz, 1 H, 5-H), 4.33 (d, J4,1Ј = 7.8 Hz, 1 H, 1Ј-H), 4.14 (t, 1 H,
4-H), 3.57 (m, 1 H, 2Ј-H) ppm. 13C NMR (75.5 MHz, CD3OD): δ
= 179.4 (C=Se), 87.3 (C-5) 73.1 (C-3Ј), 72.8 (C-2Ј), 68.8 (C-1Ј),
63.2 (C-4), 58.3 ppm. MS (FAB): m/z (%) = 385 (77) [M + Na]+.
HRMS (FAB): calcd. for C13H18N2NaO580Se [M + Na]+ 385.0279;
found 385.0277.
Method B: To the crude mixture of compounds 10/12 (30:70,
52 mg, 0.09 mmol overall) in MeOH (4 mL) was added imidazole
(6 mg, 0.09 mmol), and the corresponding mixture was kept in the
dark at 40 °C for 24 h. Then, the mixture was concentrated to dry-
ness, and the residue was purified by column chromatography
(CH2Cl2/MeOH, 80:1Ǟ40:1) to give 16 as a syrup. Yield: 30 mg,
66%. Rf = 0.26 (CH2Cl2/MeOH, 40:1). [α]2D0 = +10 (c = 1.2,
1-Phenyl-(1,2-dideoxy-α-D-mannofuranoso)[2,1-d]imidazolidine-2-se-
lone (8): A suspension of -mannosamine hydrochloride (129 mg,
CH Cl ). IR: ν = 1745, 1459, 1218 cm–1 1H NMR (500 MHz,
.
˜
2
2
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Acyclic and Spiranic Imidazole-Derived C-Selenonucleosides
CDCl3): δ = 7.12 (m, 3 H, 5-H, Ar-H), 6.91 (m, 2 H, Ar-H), 6.19
trated to dryness coevaporating with toluene and EtOH, and the
(d, J1Ј,2Ј = 4.3 Hz, 1 H, 1Ј-H), 5.65 (dd, J2Ј,3Ј = 7.5 Hz, 1 H, 2Ј-H), residue was purified by column chromatography (CH2Cl2) to give
5.25 (ddd, J3Ј,4aЈ = 2.9 Hz, J3Ј,4bЈ = 5.7 Hz, 1 H, 3Ј-H), 4.23 (dd,
J4aЈ,4bЈ = 12.4 Hz, 1 H, 4aЈ-H), 4.10 (dd, 1 H, 4bЈ-H), 2.38 (s, 3 H,
CH3Ar), 2.11, 2.07, 2.04, 2.03 (4 s, 3 H each, 4 Ac) ppm. 13C NMR
44. Yield: 50 mg, 99% (5R/5S, 14:86). Rf = 0.45 (CH2Cl2/MeOH,
40:1). IR: ν = 1749, 1598, 1507, 1229, 1047, 832 cm–1. Data for the
˜
major diastereoisomer: 1H NMR (300 MHz, CDCl3): δ = 7.52–7.38
(125.8 MHz, CDCl3): δ = 170.8, 170.1, 170.0, 169.6 (4 CO), 139.3 (m, 7 H, Ar-H), 6.95 (m, 2 H, Ar-H), 5.57 (d, J3,4 = 7.1 Hz, 1 H,
(C-4), 139.1 (C-2), 135.1, 133.4, 129.8, 126.5 (Ar), 123.9 (C-5), 71.0 4-H), 5.13 (t, J2,3 = 7.4 Hz, 1 H, 3-H), 4.40 (d, J9a,9b = 12.0 Hz, 1
(C-2Ј), 69.0 (C-3Ј), 67.4 (C-1Ј), 62.1 (C-4Ј), 21.3 (CH3Ar), 21.1, H, 9a-H), 4.23 (dd, J2, = 3.1 Hz, JHa,Hb = 12.3 Hz, 1 H, CHaH-
Ha
Hb
21.0, 20.9, 20.9 (4 CH3CO) ppm. MS (LSI): m/z (%) = 1051 (7)
bOAc), 4.10 (dd, 1 H, J2, = 4.4 Hz, CHaHbOAc), 4.06 (d, 1 H,
[M + H]+. HRMS (LSI): calcd. for C44H51N4O1680Se2 [M + H]+ 9b-H), 4.05 (q, 2 H, JH,H = 7.0 Hz, CH2CH3), 3.99 (ddd, 1 H, 2-
1051.1630; found 1051.1674.
H), 2.18, 2.10, 1.89 (3 s, 3 H each, 3 Ac), 1.42 (t, 3 H,
CH2CH3) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 183.1 (CSe),
170.4, 170.2, 169.2 (3 CO), 158.5, 137.0, 132.9 (Ar-C), 131.6, 129.6,
129.5, 127.9, 115.0 (Ar-CH), 99.1 (C-5), 77.0 (C-2), 75.7 (C-4), 74.0
(C-3), 63.9 (CH2CH3), 62.7 (CH2OAc), 60.3 (C-9), 20.9 (ϫ2), 20.6
(3 CH3CO), 15.0 (CH2CH3) ppm. Data for the minor diastereoiso-
mer: 1H NMR (300 MHz, CDCl3): δ = 5.51 (d, J3,4 = 8.1 Hz, 1 H,
4-H), 4.67 (t, J2,3 = 7.9 Hz, 1 H, 3-H), 4.41 (d, J9a,9b = 11.9 Hz, 1
H, 9a-H), 4.21 (d, 1 H, 9b-H), 4.12 (q, JH,H = 7.0 Hz, 2 H,
CH2CH3), 4.07 (m, 1 H, 2-H), 3.98 (m, 1 H, CHaHbOAc), 3.81
(4R/4S)-1-p-Ethoxyphenyl-4-hydroxy-3-phenyl-4-(D-arabino-tetritol-
1-yl)imidazolidine-2-selone (30): To a solution of phenyl isoseleno-
cyanate (100 mg, 0.55 mmol) in DMF (8 mL) was added 1-deoxy-
1-p-ethoxyphenylamino--fructose (28,[35] 164 mg, 0.55 mmol), and
the resulting mixture was kept in the dark at room temperature for
3 d. Then, the mixture was concentrated to dryness, and the residue
was purified by column chromatography (CH2Cl2/MeOH,
40:1Ǟ10:1) to give 30 as an amorphous solid. Yield: 260 mg, 98%
(4R/4S, 96:4). Rf = 0.20 (CH2Cl2/MeOH, 10:1). [α]2D0 = +1 (c = 0.8,
(dd, J2, = 7.4 Hz, JHa,Hb = 11.9 Hz, 1 H, CHaHbOAc), 2.18, 2.06,
Hb
MeOH). IR: ν = 3283, 1602, 1515, 1242, 1036 cm–1. Data for the
˜
2.01 (3 s, 3 H each, 3 Ac), 1.41 (t, 3 H, CH2CH3) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 132.2, 129.0, 128.1, 127.9, 115.0 (Ar-CH),
78.4 (C-4), 76.3 (C-2), 73.1 (C-3), 63.6 (CH2OAc), 63.0 (C-9), 20.8,
20.7, 20.6 (3 CH3CO), 14.6 (CH2CH3) ppm. MS (LSI): m/z (%) =
591 (48) [M + H]+. HRMS (LSI): calcd. for C27H31N2O880Se [M
+ H]+ 591.1246; found 591.1239.
major diastereoisomer: 1H NMR (300 MHz, CD3OD): δ = 7.44
(m, 2 H, Ar-H), 7.43 (m, 5 H, Ar-H), 6.95 (m, 2 H, Ar-H), 4.74
(d, J5a,5b = 12.4 Hz, 1 H, 5a-H), 4.07 (q, JH,H = 7.0 Hz, 2 H,
CH2CH3), 3.84 (d, 1 H, 5b-H), 3.81 (br. d, J2Ј,3Ј = 8.1 Hz, 1 H, 2Ј-
H), 3.80 (br. s, 1 H, 1Ј-H), 3.72 (dd, J3Ј,4aЈ = 3.7 Hz, J4aЈ,4bЈ
=
10.6 Hz, 1 H, 4aЈ-H), 3.58 (ddd, J3Ј,4bЈ = 5.8 Hz, 1 H, 3Ј-H), 3.53
(dd, 1 H, 4bЈ-H), 1.40 (t, 3 H, CH2CH3) ppm. 13C NMR
(75.5 MHz, CD3OD): δ = 180.7 (CSe), 159.5, 139.2, 135.3 (Ar-C),
132.4, 129.5, 129.3, 129.3, 115.7 (Ar-CH), 95.1 (C-4), 73.0 (C-3Ј),
71.6 (C-2Ј), 69.8 (C-1Ј), 64.9 (C-4Ј), 64.8 (CH2CH3), 61.7 (C-5),
15.1 (CH2CH3) ppm. Data for the minor diastereoisomer: 1H
NMR (300 MHz, CD3OD): δ = 4.97 (d, J5a,5b = 11.7 Hz, 1 H, 5a-
H) ppm. MS (LSI): m/z (%) = 483 (48) [M + H]+. HRMS (LSI):
calcd. for C21H27N2O680Se [M + H]+ 483.1034; found 483.1031.
Supporting Information (see footnote on the first page of this arti-
cle): General methods, syntheses, and structural characterization
1
for compounds 7, 9, 10, 12, 22–25, 31, 36, 37, 39, 42–44; H and
13C NMR spectra for all new compounds; NOESY spectrum of
compound 44.
Acknowledgments
We thank the Dirección General de Investigación of Spain and the
Junta de Andalucía (Grants CTQ2008-02813 and FQM 134).
1-p-Ethoxyphenyl-3-phenyl-4-(D-arabino-tetritol-1-yl)imidazoline-2-
selone (38): To a solution of 36 (176 mg, 0.28 mmol) in dry MeOH
(5 mL) was added NaOMe (15.1 mg, 0.28 mmol), and the reaction
mixture was kept in the dark at room temperature for 30 min.
Then, IR-120(H+) Amberlite resin was added up to neutral pH,
which was then washed with hot MeOH, and the solution was con-
centrated to dryness. The residue was purified by column
chromatography (CH2Cl2/MeOH, 20:1) to give 38 as an amorphous
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˜
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(2R,3S,4S,5R/5S)-3,4-Diacetoxy-2-acetoxymethyl-8-(p-ethoxyphen-
yl)-6-phenyl-7-selenoxo-1-oxa-6,8-diazaspiro[4.4]nonane (44):
A
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kept in the dark at 4 °C for 24 h. Then, the mixture was concen-
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Received: July 15, 2009
Published Online: September 10, 2009
5246
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Eur. J. Org. Chem. 2009, 5239–5246