Construction of C-nucleosides diversified by [3+2] cycloaddition from a sugar-based mesoionic ring

Article abstract of DOI:10.1016/j.tet.2006.04.093

A mesoionic acyclic C-nucleoside (4), serves as the starting chiron to construct highly functionalized 2-aza-7-thiabicyclo[2.2.1]heptanes and heptenes by means of a [3+2] cycloaddition with acetylenic and olefinic dipolarophiles. Further elimination of ei

Full text of DOI:10.1016/j.tet.2006.04.093

Tetrahedron 62 (2006) 6909–6917
Construction of C-nucleosides diversified by [3D2]
cycloaddition from a sugar-based mesoionic ring
a,
Marıa J. Arevalo, Martın Avalos, Reyes Babiano, Pedro Cintas,
a
a
a
´
´
Jose L. Jimenez, Mark E. Light and Juan C. Palacios
*
´
´
a
b
a
´
´
a
´
ꢀ
Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Extremadura, E-06071 Badajoz, Spain
bDepartment of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
Received 6 March 2006; revised 24 April 2006; accepted 27 April 2006
Available online 23 May 2006
Abstract—A mesoionic acyclic C-nucleoside (4), serves as the starting chiron to construct highly functionalized 2-aza-7-thiabicyclo[2.2.1]-
heptanes and heptenes by means of a [3+2] cycloaddition with acetylenic and olefinic dipolarophiles. Further elimination of either sulfur or
hydrogen sulfide leads to acyclic C-nucleosides bearing a heterocyclic moiety of 2-pyridone.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
as potential fluorescent and/or photochemical probes in
nucleic acids.8
The synthesis of modified nucleosides and glycoconjugates
has come of age.1,2 Construction of a heterocyclic aglycon or
spacer by means of cycloaddition reactions represents a
convenient atom-economy strategy. Of particular relevance
are stereocontrolled [3+2] cycloadditions, which can be
employed to access numerous natural products and pharma-
ceuticals.3 Renewed interest in [3+2] cycloadditions
emerges from a few reactions of orthogonal functionaliza-
tion, well suited for biological applications, such as in click
chemistry repertories.4 Our research group has been largely
involved in asymmetric [3+2] cycloadditions of 1,3-thiazo-
2. Results and discussion
As reported in a previous communication,6 the 1,3-thiazo-
lium-4-olate system 4 (Scheme 1), can easily be prepared
from N-methyl-d-thiogluconamide9 (3) in a few step se-
quence using d-gluconolactone (1) as raw material.
CH2OH
AcO
OAc
O
MeNH2
H2O
Ac2O
py
OH
NHMe
O
lium-4-olates (thioisomunchnones) using carbohydrates as
¨
AcO
HO
stereodifferentiating elements.5 In a recent study we were
able to synthesize a mesoionic nucleus with an acyclic car-
bohydrate chain as substituent and we explored the reactivity
of the heterocyclic moiety.6 The present work extends such
results to other unsaturated dipolarophiles to produce new
C-nucleosides containing highly functionalized and poly-
cyclic fragments derived from pyrid-2-ones. It has been
recently demonstrated that C-nucleosides bearing the pyrid-
2-one core serve as a non-disruptive pyrimidine analog in
DNA duplex.7 Moreover, the pyridone chromophore absorbs
in the near UV range (l>300 nm) where common nucleic
acid bases are transparent, and exhibit room temperature
fluorescence. These properties enabling selective excitation
inanoligonucleotide chain makethese compoundsinteresting
AcO
OAc O
OH
1
2
Lawesson's
reagent
C6H6
AcO
AcO
OAc
OAc
S
PhCHClCOCl
Et3N, CHCl3
NHMe
AcO
Ph
AcO
AcO
OAc
N
AcO
OAc S
Me
O
3
4
Scheme 1.
Despite 4 turned out to be air sensitive and slowly decom-
posed at room temperature, it underwent 1,3-dipolar cyclo-
additions in dry solvents with several types of acetylenic
and olefinic dipolarophiles.
Keywords: 1,3-Dipolar cycloaddition; Mesoionic heterocycle; C-nucleo-
side; Pyridone; Thioisomunchnone.
¨
* Corresponding author. Tel.: +34 924 289 380; fax: +34 924 271 149;
e-mail: arevalo@unex.es
Thioisomunchnones are known to react with acetylenic
¨
dipolarophiles to form either pyrid-2-ones or thiophenes,10
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.093

´
M. J. Arevalo et al. / Tetrahedron 62 (2006) 6909–6917
6910
H
H
by extrusion of sulfur or isocyanate, respectively, from the
initially generated cycloadducts, which to the best of our
knowledge have never been isolated. However, the thioiso-
S
Ph
Ph
O
N
COOMe
COMe
CN
H
O
O
+
H
H
COOMe
COMe
CN
N
Me
Me
Me
OMe
Me
Me
Me
Me
R*
R*
H
S
14b
munchnone 4 reacted with acetylenic dipolarophiles such
¨
11
14a
as dimethyl acetylenedicarboxylate (5) and methyl propio-
late (6) in refluxing toluene and CH2Cl2, respectively, to
afford single products, which were identified as cyclo-
adducts 7 and 8 (Scheme 2).
H
H
S
Ph
Ph
O
N
O
H
O
+
H
H
4
+
N
R*
R*
H
S
15b
12
15a
Ph
COOMe
Ph 4
COOMe
3
S
H
H
O
2
R*
O
COOMe
R
S
Ph
+
Ph
Ph
5
O
N
2 N
∆
H
4
O
3
+
1N
+
N
H
H
6 R
Me
N
Me
CN
1 S
5
R*
O
Me
6
R
R*
R*
R*
9, 10
H
S
16b
13
16a
R* = D-gluco-(CHOAc)4-CH2OAc
4
5, 6
7, 8
R* = D-gluco-(CHOAc)4-CH2OAc
5, 7, 9 R = COOMe
6, 8, 10 R = H
Scheme 3.
Scheme 2.
The structure of 16a could unequivocally be established by
single-crystal X-ray analysis,6 which shows the exo disposi-
tion of the cyano group. In the 1H NMR spectrum of 16a, the
resonances of H-5endo, H-6endo, and H-6exo appeared as
double doublets. The more deshielding signal centered
at d 3.56 ppm contains a trans coupling (J¼3.6 Hz) and a cis
The main structural features of these initial bicyclic systems
were established by NMR spectroscopy and combustion
analysis. Particularly, in the 13C NMR spectra of 7, the reso-
nances at d 83.3 and 69.4 ppm were attributed to the bridge-
head carbons C-4 and C-1, respectively. The (1R,4R)
configuration proposed for 7 was established on the basis
of its 1H NMR spectrum, having a close similarity to those
of 23b and 25b (see below). On the other hand, cycloadduct
8 was not stable enough when it was subjected to chromato-
graphic purification on SiO2 and spontaneously evolved into
10 after sulfur extrusion.
coupling (J¼8.0 Hz) and it is therefore assigned to H-5endo
.
The signal at d 2.85 ppm showed a trans coupling as above
and a geminal one (J¼12.7 Hz), consistent with the H-6exo
proton. Finally, the resonance at 2.74 ppm with cis and gemi-
nal couplings was attributed to H-6endo. Although H-5endo
,
H-6endo, and H-6exo of the cycloadduct 16b isolated from
the same reaction, resonated at slightly different chemical
shifts: d 3.51 ppm (H-5endo) and 2.80 ppm (H-6exo and
H-6endo), they showed a similar coupling pattern, thus allow-
ing us to suggest that 16b was obtained from the approach of
the dipolarophile to the opposite face of the dipole.
Moreover, the chemical shifts for C-5 and C-6 of 16a and
16b proved that the CN group is located at C-5 in both cases.
The regio- and stereochemistry of the cycloadducts 14 and
15, assigned by analogy with the NMR data of 16a and 16b
(Tables 1 and 2) was confirmed by the existence of NOEs
between the H-6endo proton and the N-CH3 groups in these
compounds. This evidence together with the cis coupling
observed for the signal of the H-6endo proton suggest that
the H-5 proton lies in an endo disposition in all cases.
Desulfuration of 7 and 8 by Hg(OAc)2 in acetic acid–acetone
at room temperature also afforded the C-nucleosides 9 and
10, respectively. 13C NMR data supported the pyrid-2-one
structure and NOE experiments on compound 10 confirmed
the regiochemistry suggested for the methyl propiolate reac-
tion. Both H-10 and H-20, located at the sugar moiety, showed
NOEs with H-5 (Fig. 1).
The bimolecular cycloaddition of 2-phenylthioisomunch-
¨
nones with electron-deficient olefins provides a series of bi-
cyclic adducts, which were further reacted with NaOCH3 to
yield pyrid-2-one derivatives.11 However, the 2-(N,N0-di-
alkylamino)thioisomunchnones showed a different behavior
¨
leading to 4,5-dihydrothiophenes by opening of the initial
Likewise, the optical rotatory power can be helpful for the
assignment of the configuration of the bridgehead carbon
atoms in these cycloadducts. Compound 16a showed an
optical rotation (+6.0ꢀ) as low as they were found for 14a
(ꢁ0.5ꢀ) and 15a (+4.0ꢀ). However, higher values were mea-
sured for the cycloadducts 14b–16b (+56.0<[a]D<+67.5).13
1:1 cycloadduct.12
Thioisomunchnone 4 was found to undergo dipolar cyclo-
¨
addition with asymmetric and symmetrically substituted
olefinic dipolarophiles. Stable cycloadducts (14–16) were
obtained after reaction with methyl acrylate (11), methyl
vinyl ketone (12), and acrylonitrile (13) (Scheme 3).
None of these reactions showed appreciable facial diastereo-
selectivity and diastereomeric mixtures (ca. 1:1 ratio) of
exo cycloadducts arose from the approach of the dipolaro-
phile to both faces of the dipole (Scheme 4). However, these
cycloadditions proceeded with complete regioselectivity,
which was in turn opposite to that observed in the case of
2.2
COOMe
1.3
OAc
H
Ph
AcO
H
H
H
3.4
N
Me
O
1.6
AcOCH2
2-(N,N0-dialkylamino)thioisomunchnones, largely explored
¨
OAc
OAc
H
by our research group.5,12,14 Although this distinctive behav-
ior could be attributed to the presence of an amino sub-
stituent in the latter mesoionics, exerting a profound
7.9
Figure 1. NOEs measured for compound 10.

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M. J. Arevalo et al. / Tetrahedron 62 (2006) 6909–6917
6911
Table 1. 1H NMR chemical shift (ppm) data of compounds 14–16 (CDCl3)
Compound
H-5endo
H-6exo
H-6endo
H-10
H-20
H-30
H-40
H-50
H-500
14a
14b
15a
15b
16a
16b
3.30
3.28
3.44
3.39
3.56
3.51
2.70
2.78
2.70
2.76
2.85
2.80
2.60
2.56
2.50
2.44
2.74
2.80
5.76
5.84
5.75
5.82
5.77
5.82
5.62
5.51
5.63
5.51
5.60
5.46
5.44
5.42
5.45
5.42
5.44
5.41
5.12
5.15
5.15
5.15
5.13
5.14
4.37
4.38
4.38
4.37
4.39
4.38
4.15
4.19
4.17
4.19
4.17
4.19
Table 2. 13C NMR chemical shift (ppm) data of compounds 14–16 (CDCl3)
Compound
C-1
C-3
C-4
C-5
C-6
C-10
C-20
C-30
C-40
C-50
14a
14b
15a
15b
16a
16b
70.63
70.91
70.16
70.50
69.90
70.24
174.73
174.48
174.79
174.55
173.12
172.72
79.40
78.21
79.53
78.22
80.09
78.79
50.39
49.31
56.95
55.59
69.41
69.22
40.69
40.72
39.68
39.76
42.45
42.45
67.50
67.57
67.24
67.53
66.84
67.05
68.26
67.66
68.12
67.53
67.93
67.42
69.56
69.42
69.57
69.35
69.65
69.22
69.11
69.42
69.03
69.35
69.15
69.22
61.66
61.47
61.71
61.45
61.73
61.43
stereodirecting effect, a satisfactory rationale has not yet
been provided and additional studies will be required.
Diastereomeric mixtures of cycloadducts 22–24 were ob-
tained when 4 was reacted with symmetrically substituted
cyclic olefins such as N-phenylmaleimide (19), 1,4-benzo-
quinone (20), and 1,4-naphthoquinone (21) (Scheme 6).
R1
R2
S
H
Ph
R1
Ph
Ph
S
O
O
O
+
H
O
Ph
S
O
O
N
Ph
O
N
∆
R2
H
R1
R2
+
N
O
Me
N
N
Ph
Me
Me
+
N
Ph
Me
R*
R*
N
R*
H
N
Ph
S
14-16b
Me
R*
R*
S
O
R1
R2
O
O
14-16a
19
22a, 22b
14 R1 = COOMe; R2 = H
15 R1 = COMe; R2 = H
16 R1 = CN; R2 = H
OH
O
S
Ph
OH
Ph
O
O
4
+
+
N
R*
N
Me
R* = D-gluco-(CHOAc)4-CH2OAc
Me
R*
OH
S
OH
O
20
Scheme 4.
23a
23b
Ph
O
O
O
O
S
Ph
Cycloadducts 14–16 were transformed into the correspond-
ing pyrid-2-one C-nucleosides 10, 17, and 18, by elimination
of hydrogen sulfide using mercury(II) acetate in acetic acid–
acetone (Scheme 5). The formation of 10, previously
obtained from 4 and methyl propiolate, evidences the regio-
chemical control of these cycloadditions. The structures for
pyrid-2-ones 17 and 18 were assigned on the basis of their
analytical data and by comparison of their NMR spectra
with those of 10 (Table 3).
O
O
N
+
Me
N
R*
Me
R*
O
S
O
21
24a, 24b
R* = D-gluco-(CHOAc)4-CH2OAc
Scheme 6.
Suitable crystals for X-ray diffraction analysis could also be
obtained in the case of 23a (Fig. 2).15 It is interesting to note
that the tricyclic aglycon of 23a, unlike 22 and 24, contains
only two stereogenic centers due to aromatization of the
quinone moiety. This structural simplification proves that
diastereomers 23a and 23b do not emerge from endo/exo
approaches of the dipolarophile to the same face of the
dipole, but rather by exo attack of the dipolarophile to
Ph
H
S
Ph
Hg(OAc)2
Ph
O
R
H
O
R
H
O
AcH, acetone
H
H
R
N
+
N
Me
N
H
Me
R*
R*
Me
H
S
R*
14-16b
14-16a
10 R = COOMe
17 R = COMe
18 R = CN
R* = D-gluco-(CHOAc)4-CH2OAc
both faces of the thioisomunchnone.
¨
Scheme 5.
Thenatureoftheringsfusedtothe2-aza-7-thiabicyclo[2.2.1]-
heptane system of 22 and 24 has a remarkable influence
on their spectroscopic data, and prevents the unequivocal
Table 3. Selected 13C NMR chemical shift (ppm) data of compounds 10, 17,
and 18 (CDCl3)
1
assignment of their configurations by means of H- and
Compound
C-2
C-3
C-4
C-5
C-6
13C-chemical shift correlations with those of 14–16. How-
ever, aromatization of the naphthoquinone system of 24a
and 24b, easily achieved by treatment of such a diastereo-
meric mixture with SiO2 (Scheme 7), led to a mixture of
10
17
18
162.41
162.48
160.93
134.88
134.41
132.62
142.67
146.40
144.31
105.11
104.57
105.73
138.57
142.73
137.31

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M. J. Arevalo et al. / Tetrahedron 62 (2006) 6909–6917
6912
3. Conclusions
In conclusion, this paper reports a rapid access to enantio-
merically pure acyclic C-nucleosides containing a pyrid-2-
one moiety based on the 1,3-dipolar cycloadditions of a
carbohydrate-derived 1,3-thiazolium-4-olate system with
acetylenic and olefinic dipolarophiles. To the best of our
knowledge, this is the first time stable cycloadducts have
been isolated in the reaction of activated triple bonds (e.g.,
dimethyl acetylenedicarboxylate) with thioisomunchnones.
¨
Despite these [3+2] cycloadditions processes were found
to be regiospecific, no appreciable facial selectivity was in-
duced by appended chiral carbohydrate substituent. Efforts
to understand this stereochemical outcome by theoretical
studies as well as further pursuits to improve the diastereo-
selection are currently under way in our laboratories.
Figure 2. Perspective view of the structure of 23a.
4. Experimental
4.1. General methods
25a and 25b, whose spectroscopic data were very similar to
those of 23a and 23b, respectively. Moreover, the 1H NMR
spectrum of 7, which also contains an endocyclic double
bond between C-5 and C-6 atoms, exhibits the same proton
pattern of H NMR of 23b and 25b. This fact points to
a (1R,4R) configuration for 7 (Table 4).
Melting points were determined on a capillary apparatus and
are uncorrected. Optical rotations were measured at the
sodium line at 18ꢂ2 ꢀC. Analytical and preparative TLC
were performed on silica gel with monitoring by means of
UV light at 254 and 360 nm and iodinevapors. Flash chroma-
tography was performed with silica gel (400–230 mesh).
IR spectra were recorded on KBr pellets. 1H and 13C NMR
spectra were obtained at 400 and 100 MHz, respectively,
in CDCl3 (Me4Si as internal standard) unless otherwise
specified. Compounds 2 and 3 were prepared according to
literature procedures.9
1
OH
S
Ph OH
Ph
O
O
SiO2
24a, 24b
+
N
N
R*
Me
Me
R*
OH
S
OH
25a
25b
R* = D-gluco-(CHOAc)4-CH2OAc
4.2. Synthesis and characterization
Scheme 7.
4.2.1. 2-(10,20,30,40,50-Penta-O-acetyl-D-gluco-pentitol-1-yl)-
3-methyl-5-phenyl-1,3-thiazolium-4-olate (4). To a solution
of N-methyl-D-thiogluconamide (3) (1.0 g, 2.3 mmol) in dry
chloroform (10 mL) was added dropwise a solution of
a-chlorophenylacetyl chloride (0.7 mL, 4.6 mmol) in dry
chloroform (5 mL). After stirring at room temperature for
15 min and refluxing for 30 min, the reaction mixture was
washed with water. The organic layer was dried (MgSO4)
and concentrated under reduced pressure. The residue was
washed with petroleum ether and treated with a mixture of
chloroform–diethyl ether–petroleum ether to give 4 (0.8 g,
63%) as a yellowish solid; mp 65–70 ꢀC (dec); [a]D +128 (c
0.5, chloroform); IR (KBr, cmꢁ1): nmax 1751, 1624, 1371,
1
Table 4. H NMR chemical shift (ppm) data of compounds 7, 23, and 25
(CDCl3)
Compound
H-10
H-20
H-30
H-40
H-50
H-500
7
6.14
6.51
6.27
6.62
6.47
5.54
5.89
5.61
5.82
5.58
5.37
5.33
5.41
5.59
5.49
5.20
5.64
5.27
5.33
5.30
4.41
4.99
4.43
4.76
4.40
4.14
4.01
4.14
4.30
4.18
23a
23b
25a
25b
1
1217; H NMR (CDCl3) d 7.90–7.16 (m, 5H), 6.30 (d, 1H,
As above, cycloadducts 22 and 23 gave rise to pyrid-2-one
C-nucleosides 26 and 27 upon treatment with Hg(OAc)2 in
acetic acid at room temperature. However, desulfuration of
24 to give 28 could only be carried out using Raney nickel
in refluxing 2-butanol.
J¼6.3 Hz), 5.69 (dd, 1H, J¼4.3 and 6.2 Hz), 5.34 (dd, 1H,
J¼4.3 and 6.6 Hz), 5.02 (m, 1H), 4.38 (dd, 1H, J¼2.5 and
12.7 Hz), 4.09 (dd, 1H, J¼5.6 and 12.7 Hz), 3.81 (s, 3H),
2.18 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H), 2.05 (s,
3H); 13C NMR (CDCl3) d 170.72, 169.72, 169.51, 169.26,
169.01, 159.78, 143.60, 132.60, 128.62, 125.66, 124.07,
99.87, 68.95, 68.50, 68.24, 67.06, 61.38, 33.08, 20.62,
20.49, 20.35, 20.25.
Ph
Ph
O
O
Ph
R*
O
O
O
O
N
Ph
N
N
N
Me
Me
Me
4.2.2. (1R,4R)-1-(10,20,30,40,50-Penta-O-acetyl-D-gluco-pen-
titol-1-yl)-2-aza-2-methyl-5,6-dimethoxycarbonyl-3-oxo-
4-phenyl-7-thiabicyclo[2.2.1]hept-5-ene (7). To a solution
of 4 (1.0 g, 1.8 mmol) in dry toluene (15 mL) dimethyl
O
R*
R*
O
O
26
27
R* = D-gluco-(CHOAc)4-CH2OAc
28

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M. J. Arevalo et al. / Tetrahedron 62 (2006) 6909–6917
6913
acetylenedicarboxylate (0.3 mL, 2.2 mmol) was added, and
the mixture was refluxed for 5 h. After removal of the solvent,
the crude product was purified by flash chromatography
(diethyl ether) to give 7 (0.5 g, 40%); mp 60–65 ꢀC (dec);
[a]D +66 (c 0.5, chloroform); IR (KBr, cmꢁ1): nmax 2959,
6H), 2.08 (s, 3H), 2.07 (s, 3H); 13C NMR (CDCl3)
d 170.63, 169.80, 169.49, 167.36, 162.41, 142.67, 138.57,
134.88, 131.62, 129.12, 128.10, 127.87, 105.11, 70.11,
69.19, 68.95, 68.41, 61.48, 52.31, 31.90, 20.65, 20.68,
20.62, 20.22. Anal. Calcd for C29H33NO13: C, 57.71; H,
5.51; N, 2.32. Found: C, 57.54; H, 5.53; N, 2.23. Method B:
A mixture of cycloadducts 14a and 14b (0.13 g, 0.2 mmol)
was poured into a suspension of Hg(OAc)2 (0.1 g, 0.3
mmol) in acetic acid (3 mL) at room temperature and
processed as described for 9 to give 10 (0.3 g, 35%).
1
1750, 1624, 1440, 1373, 1213, 1128, 1044, 976; H NMR
(CDCl3) d 7.66–7.37 (m, 5H), 6.14 (d, 1H, J¼2.9 Hz), 5.54
(dd, 1H, J¼5.9 and 5.4 Hz), 5.37 (t, 1H, J¼5.7 Hz), 5.20
(m, 1H), 4.41 (dd, 1H, J¼3.5 and 12.4 Hz), 4.14 (dd, 1H,
J¼5.3 and 12.4 Hz), 3.79 (s, 3H), 3.51 (s, 3H), 3.04 (s,
3H), 2.17 (s, 3H), 2.13 (s, 3H), 2.09 (s, 3H), 2.08 (s, 3H),
2.07 (s, 3H); 13C NMR (CDCl3) d 178.52, 170.49, 169.75,
169.69, 169.23, 169.12, 163.01, 162.50, 150.31, 149.80,
130.93, 128.96, 128.29, 128.11, 83.28, 69.36, 68.08, 67.81,
65.29, 52.94, 52.45, 33.08, 20.76, 20.59, 20.33. Anal.
Calcd for C31H35NO15S: C, 53.68; H, 5.08; N, 2.02; S,
4.62. Found: C, 53.96; H, 5.06; N, 1.82; S, 4.47.
4.2.5. (1S,4R,5R)-1-(10,20,30,40,50-Penta-O-acetyl-D-gluco-
pentitol-1-yl)-2-aza-5-methoxycarbonyl-2-methyl-3-oxo-
4-phenyl-7-thiabicyclo[2.2.1]heptane (14a) and
(1R,4S,5S)-1-(10,20,30,40,50-penta-O-acetyl-D-gluco-penti-
tol-1-yl)-2-aza-5-methoxycarbonyl-2-methyl-3-oxo-4-
phenyl-7-thiabicyclo[2.2.1]heptane (14b). To a solution of
4 (1.0 g, 1.8 mmol) in dry chloroform (15 mL) methyl acry-
late (0.2 mL, 2.2 mmol) was added, and the mixture was
refluxed for 12 h. After removal of the solvent, the crude
product was purified by flash chromatography (diethyl ether)
and the two diastereomeric cycloadducts 14a (0.2 g, 12%)
and 14b (0.2 g, 12%) were separated by thin layer prepara-
tive chromatography (diethyl ether). 14a: mp 83 ꢀC (dec);
[a]D ꢁ0.5 (c 0.5, chloroform); IR (KBr, cmꢁ1): nmax 2965,
4.2.3. 6-(10,20,30,40,50-Penta-O-acetyl-D-gluco-pentitol-1-
yl)-4,5-dimethoxycarbonyl-1-methyl-3-phenylpyrid-2-
one (9). To a suspension of Hg(OAc)2 (0.1 g, 0.3 mmol) in
acetic acid (3 mL) compound 7 (0.1 g, 0.2 mmol) was added
and the reaction mixture was stirred at room temperature.
Acetone (3 mL) was mixed with the resultant gel and the in-
soluble material was filtered off and washed with acetone.
The filtrate was diluted with water, filtered, adjusted to pH
5 with sodium hydrogen carbonate, and extracted with chlo-
roform. The organic layer was washed with sodium hydro-
gen carbonate solution (1 M) followed by water, dried
(MgSO4), and concentrated in vacuo. Purification of the
residue by thin layer preparative chromatography (diethyl
ether) afforded 9, which crystallized as a white solid from
diethyl ether–petroleum ether (0.02 g, 30%); mp 75 ꢀC (dec);
[a]D +74.5 (c 0.5, chloroform); IR nmax (KBr, cmꢁ1) 3418,
2955, 1751, 1655, 1541, 1439, 1371, 1304, 1219, 1045; 1H
NMR (CDCl3) d 7.41–7.22 (m, 5H), 6.49 (m, 1H), 5.91
(dd, 1H, J¼3.2 and 5.7 Hz), 5.31 (dd, 1H, J¼3.4 and
6.2 Hz), 5.09 (m, 1H), 4.29 (dd, 1H, J¼3.7 and 12.3 Hz),
4.10 (dd, 1H, J¼6.0 and 12.2 Hz), 3.78 (s, 3H), 2.72 (s,
3H), 3.46 (s, 3H), 2.09 (s, 9H), 2.02 (s, 3H), 1.98 (s, 3H);
13C NMR (CDCl3) d 169.30, 168.79, 168.58, 165.33,
164.99, 160.66, 143.13, 139.52, 133.83, 128.76, 127.71,
127.24, 110.79, 70.33, 69.70, 68.82, 68.32, 60.97, 52.23,
51.60, 33.73, 19.84, 19.68. Anal. Calcd for C31H35NO15:
C, 56.28; H, 5.33; N, 2.12. Found: C, 55.50; H, 5.20; N, 2.07.
1
1750, 1447, 1373, 1213, 1045; H NMR (CDCl3) d 7.42–
7.26 (m, 5H), 5.76 (d, 1H, J¼5.1 Hz), 5.62 (t, 1H,
J¼4.9 Hz), 5.44 (t, 1H, J¼4.9 Hz), 5.12 (m, 1H), 4.37 (dd,
1H, J¼3.3 and 12.4 Hz), 4.15 (dd, 1H, J¼5.3 and
12.4 Hz), 3.30 (m, 1H, J¼4.3 and 8.0 Hz), 3.25 (s, 3H),
2.84 (s, 3H), 2.70 (dd, 1H, J¼4.4 and 12.3 Hz), 2.60 (dd,
1H, J¼8.0 and 12.3 Hz), 2.19 (s, 3H), 2.15 (s, 3H), 2.12
(s, 3H), 2.08 (s, 3H), 2.02 (s, 3H); 13C NMR (CDCl3)
d 174.73, 170.57, 170.39, 169.80, 169.42, 169.27, 131.75,
128.39, 127.85, 79.40, 70.63, 69.56, 69.11, 68.26, 67.50,
61.66, 51.76, 50.39, 40.69, 28.75, 20.96, 20.65, 20.55.
Anal. Calcd for C29H35NO13S: C, 54.62; H, 5.53; N, 2.20;
S, 5.03. Found: C, 54.57; H, 5.58; N, 2.14; S, 5.07. 14b:
mp 80 ꢀC (dec); [a]D +56.0 (c 0.5, chloroform); IR (KBr,
1
cmꢁ1) nmax 2955, 1751, 1447, 1373, 1213, 1043; H NMR
(CDCl3) d 7.43–7.27 (m, 5H), 5.84 (d, 1H, J¼3.3 Hz),
5.51 (dd, 1H, J¼3.7 and 4.9 Hz), 5.42 (t, 1H, J¼4.9 Hz),
5.15 (m, 1H), 4.38 (dd, 1H, J¼2.9 and 12.5 Hz), 4.19 (dd,
1H, J¼5.8 and 12.4 Hz), 3.28 (m, 1H), 3.26 (s, 3H), 2.88
(s, 3H), 2.78 (dd, 1H, J¼4.4 and 12.8 Hz), 2.56 (dd, 1H,
J¼8.2 and 12.7 Hz), 2.25 (s, 3H), 2.17 (s, 3H), 2.13 (s,
3H), 2.10 (s, 3H), 2.09 (s, 3H); 13C NMR (CDCl3)
d 174.48, 170.78, 170.63, 169.96, 169.72, 169.39, 131.85,
128.52, 128.31, 127.93, 78.21, 70.91, 69.42, 67.66, 67.57,
61.47, 51.80, 49.31, 40.72, 28.22, 20.89, 20.71, 20.57.
Anal. Calcd for C29H35NO13S: C, 54.62; H, 5.53; N, 2.20;
S, 5.03. Found: C, 54.63; H, 5.47; N, 2.28; S, 4.84.
4.2.4. 6-(10,20,30,50-Penta-O-acetyl-D-gluco-pentitol-1-yl)-
4-methoxycarbonyl-2-methyl-3-phenylpyrid-2-one (10).
Method A: A solution of 4 (1.0 g, 1.81 mmol) and methyl
propiolate (0.2 mL, 2.17 mmol) in dry dichloromethane
(15 mL) was heated at reflux for 10 h. The solvent was
then evaporated under reduced pressure and the crude prod-
uct was purified by flash chromatography (diethyl ether) and
then poured into a suspension of Hg(OAc)2 (0.1 g,
0.3 mmol) in acetic acid (3 mL) at room temperature and
processed as described for 9 to give 10 (0.2 g, 19%) as
a white solid; mp 80 ꢀC; [a]D 56.5 (c 0.5, chloroform); IR
(KBr, cmꢁ1) nmax 3472, 2960, 1749, 1653, 1555, 1454,
4.2.6. (1S,4R,5R)-5-Acetyl-1-(10,20,30,40,50-penta-O-ace-
tyl-D-gluco-pentitol-1-yl)-2-aza-2-methyl-3-oxo-4-phe-
nyl-7-thiabicyclo[2.2.1]heptane (15a) and (1R,4S,5S)-5-
acetyl-1-(10,20,30,40,50-penta-O-acetyl-D-gluco-pentitol-1-
yl)-2-aza-2-methyl-3-oxo-4-phenyl-7-thiabicyclo[2.2.1]-
heptane (15b). To a solution of 4 (1.0 g, 1.8 mmol) in dry
chloroform (15 mL) methyl vinyl ketone (0.3 mL, 2.2 mmol)
was added, and the mixture was refluxed for 12 h. After
removal of the solvent, the crude product was purified by
flash chromatography (eluant: diethyl ether) and the two
1
1373, 1217, 1049; H NMR (CDCl3) d 7.40–7.27 (m, 5H),
6.41 (s, 1H), 6.07 (d, 1H, J¼4.6 Hz), 5.60 (t, 1H,
J¼4.7 Hz), 5.42 (t, 1H, J¼5.3 Hz), 5.07 (m, 1H), 4.36 (dd,
1H, J¼2.9 and 12.6 Hz), 4.10 (dd, 1H, J¼6.2 and
12.6 Hz), 3.75 (s, 3H), 3.54 (s, 3H), 2.20 (s, 3H), 2.13 (s,

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M. J. Arevalo et al. / Tetrahedron 62 (2006) 6909–6917
6914
diastereomeric cycloadducts 15a (0.2 g, 18%) and 15b
(0.2 g, 18%) were separated by preparative thin layer chro-
matography (diethyl ether). 15a: mp 100 ꢀC (dec); [a]D
+4.0 (c 0.5, chloroform); IR (KBr, cmꢁ1): nmax 2980, 1751,
1707, 1371, 1215, 1043; 1H NMR (CDCl3) d 7.51–7.27 (m,
5H), 5.75 (d, 1H, J¼5.3 Hz), 5.63 (t, 1H, J¼4.9 Hz), 5.45
(dd, 1H, J¼4.6 and 6.5 Hz,), 5.15 (m, 1H), 4.38 (dd, 1H,
J¼3.1 and 12.5 Hz), 4.17 (dd, 1H, J¼5.3 and 12.5 Hz),
3.44 (dd, 1H, J¼4.3 Hz), 2.85 (s, 3H), 2.70 (dd, 1H, J¼4.3
and 12.3 Hz), 2.50 (dd, 1H, J¼8.0 and 12.3 Hz), 2.20 (s,
3H), 2.18 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H),
1.68 (s, 3H); 13C NMR (CDCl3) d 204.02, 174.79, 170.60,
170.48, 169.82, 169.42, 169.34, 131.92, 128.76, 128.41,
79.53, 70.16, 69.57, 69.03, 68.12, 67.24, 61.71, 56.95,
39.68, 30.19, 28.62, 20.69, 20.55. Anal. Calcd for
C29H35NO12S: C, 56.03; H, 5.67; N, 2.25; S, 5.16. Found:
C, 55.85; H, 5.70; N, 2.49; S, 5.18. 15b: mp 80 ꢀC (dec);
[a]D +62.5 (c 0.5, chloroform); IR (KBr, cmꢁ1) nmax 2961,
5.14 (m, 1H), 4.38 (dd, 1H, J¼2.92 and 12.5 Hz, H-50),
4.19 (dd, 1H, J¼5.6 and 12.5 Hz), 3.51 (dd, 1H, J¼3.9
and 8.0 Hz), 2.85 (s, 3H), 2.80 (m, 2H), 2.25 (s, 3H), 2.18
(s, 3H), 2.15 (s, 3H), 2.09 (s, 6H); 13C NMR (CDCl3)
d 172.72, 170.62, 169.85, 169.66, 169.36, 130.78, 129.45,
128.77, 128.16, 118.19, 78.79, 70.24, 69.22, 67.42, 67.05,
61.43, 42.45, 37.87, 28.02, 20.99, 20.76, 20.67, 20.52.
Anal. Calcd for C28H32N2O11S: C, 55.62; H, 5.33; N, 4.63;
S, 5.30. Found: C, 55.33; H, 5.43; N, 4.77; S, 4.81.
4.2.8. 4-Acetyl-6-(10,20,30,40,50-penta-O-acetyl-D-gluco-
pentitol-1-yl)-1-methyl-3-phenylpyrid-2-one (17). A mix-
ture of cycloadducts 15a and 15b (0.12 g, 0.2 mmol) was
poured into a suspension of Hg(OAc)2 (0.1 g, 0.3 mmol) in
acetic acid (3 mL) at room temperature and processed as
described for 9 to give 17 (0.05 g, 53%); mp 72 ꢀC (dec);
[a]D +118.0 (c 0.5, chloroform); IR (KBr, cmꢁ1) nmax 3472,
2964, 1751, 1719, 1659, 1501, 1447, 1373, 1215, 1045; 1H
NMR (CDCl3) d 7.42–7.30 (m, 5H), 6.22 (s, 1H), 6.05 (d,
1H, J¼4.7 Hz), 5.61 (t, 1H, J¼4.5 Hz), 5.39 (t, 1H, J¼
5.1 Hz), 5.08 (m, 1H), 4.35 (dd, 1H, J¼2.8 and 12.4 Hz),
4.09 (dd, 1H, J¼6.1 and 12.4 Hz), 3.77 (s, 3H), 2.19 (s,
3H), 2.15 (s, 3H), 2.09 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H),
1.79 (s, 3H); 13C NMR (CDCl3) d 203.05, 170.58, 170.43,
169.76, 169.57, 169.52, 162.48, 146.40, 142.73, 134.41,
130.02, 129.15, 128.89, 128.41, 104.57, 70.36, 69.14,
68.87, 68.39, 61.47, 31.88, 29.72, 20.67, 20.25. Anal. Calcd
for C29H33NO12: C, 59.28; H, 5.66; N, 2.38. Found: C,
59.14; H, 5.61; N, 2.19.
1
1744, 1707, 1373, 1215, 1043; H NMR (CDCl3) d 7.49–
7.28 (m, 5H), 5.82 (d, 1H, J¼3.5 Hz), 5.51 (t, 1H,
J¼4.8 Hz), 5.42 (dd, 1H, J¼5.2 and 6.3 Hz), 5.15 (m, 1H),
4.37 (dd, 1H, J¼2.9 and 12.5 Hz), 4.19 (dd, 1H, J¼5.8 and
12.4 Hz), 3.39 (dd, 1H, J¼4.3 and 8.0), 2.87 (s, 3H), 2.76
(dd, 1H, J¼4.4 and 12.8 Hz), 2.44 (dd, 1H, J¼8.1 and
12.8 Hz), 2.25 (s, 3H), 2.17 (s, 3H), 2.14 (s, 3H), 2.10 (s,
3H), 2.09 (s, 3H), 1.69 (s, 3H); 13C NMR (CDCl3)
d 204.36, 174.55, 170.60, 169.89, 169.85, 169.75, 169.40,
131.97, 128.77, 128.44, 128.26, 78.22, 70.50, 69.35, 67.53,
61.45, 55.59, 39.76, 30.50, 28.15, 20.85, 20.65, 20.59.
Anal. Calcd for C29H35NO12S: C, 56.03; H, 5.67; N, 2.25;
S, 5.16. Found: C, 55.94; H, 5.83; N, 2.32; S, 5.18.
4.2.9. 6-(10,20,30,40,50-Penta-O-acetyl-D-gluco-pentitol-1-
yl)-4-cyano-1-methyl-3-phenylpyrid-2-one (18). A mix-
ture of cycloadducts 16a and 16b (0.12 g, 0.2 mmol) was
poured into a suspension of Hg(OAc)2 (0.1 g, 0.3 mmol) in
acetic acid (3 mL) at room temperature and processed as
described for 9 to give 18 (0.03 g, 33%); mp 86.5 ꢀC; [a]D
+114.0 (c 0.5, chloroform); IR (KBr, cmꢁ1) nmax 2353,
4.2.7. (1S,4R,5R)-1-(10,20,30,40,50-Penta-O-acetyl-D-gluco-
pentitol-1-yl)-2-aza-5-cyano-2-methyl-3-oxo-4-phenyl-7-
thiabicyclo[2.2.1]heptane (16a) and (1R,4S,5S)-1-
(10,20,30,40,50-penta-O-acetyl-D-gluco-pentitol-1-yl)-2-aza-
5-cyano-2-methyl-3-oxo-4-phenyl-7-thiabicyclo[2.2.1]-
heptane (16b). To a solution of 4 (1.0 g, 1.8 mmol) in dry
chloroform (15 mL) acrylonitrile (0.1 mL, 2.2 mmol) was
added, and the mixture was refluxed for 12 h. After removal
of the solvent, the crude product was purified by flash chro-
matography (diethyl ether) and the two diastereomeric
cycloadducts 16a (0.1 g, 9%) and 16b (0.1 g, 9%) were sep-
arated by preparative thin layer chromatography (diethyl
ether). 16a: mp 97 ꢀC (dec); [a]D +6.0 (c 0.5, chloroform);
IR (KBr, cmꢁ1) nmax 2949, 1753, 1715, 1448, 1373, 1215,
1
1732, 1695, 1454, 1373, 1217, 1049; H NMR (CDCl3)
d 7.55–7.44 (m, 5H), 6.34 (s, 1H), 6.06 (d, 1H, J¼4.0 Hz),
5.57 (t, 1H, J¼4.6 Hz), 5.45 (t, 1H, J¼5.5 Hz), 5.06 (m,
1H), 4.38 (dd, 1H, J¼2.8 and 12.5 Hz), 4.11 (dd, 1H,
J¼5.9 and 12.5 Hz), 3.76 (s, 3H), 2.23 (s, 3H), 2.14 (s,
6H), 2.08 (s, 6H), 2.06 (s, 3H); 13C NMR (CDCl3)
d 170.71, 169.81, 169.48, 160.93, 144.31, 137.31, 132.62,
129.62, 128.29, 119.18, 116.12, 105.73, 69.62, 69.24,
69.02, 68.20, 61.46, 32.14, 20.64, 20.22. Anal. Calcd for
C28H30N2O11: C, 58.94; H, 5.30; N, 4.91. Found: C, 58.93;
H, 5.27; N, 5.03.
1
1047; H NMR (CDCl3) d 7.47–7.43 (m, 5H), 5.77 (d, 1H,
J¼5.4 Hz), 5.60 (t, 1H, J¼4.8 Hz), 5.44 (dd, 1H, J¼4.6
and 6.5 Hz), 5.13 (m, 1H), 4.39 (dd, 1H, J¼3.0 and
12.6 Hz), 4.17 (dd, 1H, J¼5.1 and 12.6 Hz), 3.56 (dd, 1H,
J¼3.6 and 8.0 Hz), 2.85 (dd, 1H, J¼8.0 and 12.7 Hz), 2.83
(s, 3H), 2.74 (dd, 1H, J¼3.7 and 12.7 Hz), 2.22 (s, 3H),
2.18 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H), 2.09 (s, 3H); 13C
NMR (CDCl3) d 173.12, 171.15, 170.69, 170.55, 169.78,
169.32, 130.71, 129.44, 128.77, 128.26, 118.28, 80.09,
69.90, 69.65, 69.41, 69.15, 67.93, 66.84, 61.73, 42.45,
39.09, 28.54, 20.72, 20.60, 20.52, 20.46. Anal. Calcd for
C28H32N2O11S: C, 55.62; H, 5.33; N, 4.63; S, 5.30. Found:
C, 55.31; H, 5.28; N, 4.64; S, 5.48. 16b: mp 93.2 ꢀC (dec);
[a]D +67.5ꢀ (c 0.5, chloroform); IR (KBr, cmꢁ1): nmax
2976, 1755, 1719, 1448, 1373, 1213, 1047; 1H NMR
(CDCl3) d 7.48–7.43 (m, 5H), 5.82 (d, 1H, J¼3.8 Hz),
5.46 (t, 1H, J¼4.5 Hz), 5.41 (dd, 1H, J¼4.9 and 6.3 Hz),
4.2.10. (3aS,4S,7R,7aR and 3aR,4R,7S,7aS)-4-
(10,20,30,40,50-Penta-O-acetyl-D-gluco-pentitol-1-yl)-4,7-
epithio-2,3a,4,5,7,7a-hexahydro-5-methyl-2,7-diphenyl-
1H-pyrrolo[3,4-c]pyridine-1,3,6-trione (22a and 22b). To
a suspension of 4 (1.0 g, 1.8 mmol) in dry toluene (15 mL)
N-phenylmaleimide (0.4 g, 2.2 mmol) was added, and the
mixture was refluxed for 12 h. After removal of the solvent,
the crude product was purified by flash chromatography (di-
ethyl ether) and the two diastereomeric cycloadducts were
separated by preparative thin layer chromatography (diethyl
ether). Fast-moving diastereomer: 0.4 g (30%), mp 175–
6 ꢀC (dec); [a]D ꢁ33.5 (c 0.5, chloroform); IR (KBr,
1
cmꢁ1) nmax 2980, 1723, 1499, 1373, 1217, 1044, 955; H
NMR (CDCl3) d 7.43–7.19 (m, 10H), 6.35 (m, 1H), 6.10

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M. J. Arevalo et al. / Tetrahedron 62 (2006) 6909–6917
6915
(d, 1H, J¼2.0 Hz), 5.56 (t, 1H, J¼2.0 Hz), 5.10 (m, 1H),
4.50 (dd, 1H, J¼2.6 and 12.5 Hz), 4.19 (dd, 1H, J¼6.8
and 12.5 Hz), 4.03 (d, 1H, J¼6.8 Hz), 4.03 (d, 1H,
J¼6.8 Hz), 3.79 (d, 1H, J¼6.8 Hz), 3.10 (s, 3H), 2.20 (s,
3H), 2.18 (s, 3H), 2.10 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H);
13C NMR (CDCl3) d 174.58, 171.75, 170.53, 170.43,
169.99, 169.75, 169.55, 164.46, 131.19, 129.99, 128.99,
128.67, 128.17, 126.33, 80.67, 70.62, 69.55, 69.25, 68.51,
61.45, 55.91, 51.05, 30.69, 21.05, 20.73, 20.60. Anal.
Calcd for C35H36N2O13S: C, 58.00; H, 5.01; N, 3.87; S,
4.42. Found: C, 57.81; H, 4.81; N, 3.63; S, 4.01. Slow-
moving diastereomer: 0.4 g (30%), mp 120–1 ꢀC (dec);
[a]D +3.0 (c 0.5, chloroform); IR (KBr, cmꢁ1) nmax 2994,
4.2.12. (1S,4R,4aR,10aS and 1R,4S,4aS,10aR)-1-
(10,20,30,40,50-Penta-O-acetyl-D-gluco-pentitol-1-yl)-
1,4-epithio-1,2,4,4a,10a-pentahydro-2-methyl-4-phenyl-
benzo[h]isoquinolin-3,5,10-trione (24a and 24b). From
1,4-naphtoquinone (0.3 g, 2.2 mmol) compounds 24 were
obtained as white solids as described for 22. Fast-moving
diastereomer: 0.2 g (10%); mp 105–110 ꢀC; [a]D +47 (c
0.5, chloroform), IR (KBr, cmꢁ1): nmax 2955, 1750, 1686,
1
1449, 1371, 1215, 1049; H NMR (CDCl3) d 7.89–7.39
(m, 9H), 5.56 (dd, 1H, J¼1.2 and 8.2 Hz), 5.47 (dd, 1H,
J¼1.3 and 9.1 Hz), 5.24 (d, 1H, J¼8.2 Hz), 55.02 (m, 1H),
4.22 (dd, 1H, J¼2.6 and 12.5 Hz), 4.00 (m, 2H), 3.63 (d,
1H, J¼7.3 Hz), 3.11 (s, 3H), 2.30 (s, 3H), 2.23 (s, 3H),
2.12 (s, 3H), 1.98 (s, 3H), 1.97 (s, 3H); 13C NMR (CDCl3)
d 192.45, 191.92, 175.12, 170.60, 170.42, 169.87, 169.57,
168.15, 137.42, 137.12, 134.46, 129.87, 129.23, 128.84,
128.08, 126.89, 126.20, 79.43, 71.69, 69.11, 68.08, 67.14,
67.01, 61.68, 58.34, 56.79, 30.75, 20.82, 20.61, 20.47.
Anal. Calcd for C35H35NO13S: C, 59.23; H, 4.97; N, 1.97;
S, 4.52. Found: C, 58.76; H, 4.86; N, 1.64; S, 4.55. Slow-
moving diastereomer: 0.06 g (3%); mp 135 ꢀC; [a]D ꢁ32
(c 0.25, chloroform); IR (KBr, cmꢁ1) nmax 2930, 1760,
1
1719, 1499, 1373, 1215, 1051; H NMR (CDCl3) d 7.50–
7.21 (m, 10H), 5.71–5.63 (m, 3H), 5.10 (m, 1H), 4.28 (dd,
1H, J¼2.4 and 12.5 Hz), 4.17 (dd, 1H, J¼4.2 and
12.5 Hz), 3.92 (d, 1H, J¼6.7 Hz), 3.77 (d, 1H, J¼6.7 Hz),
3.09 (s, 3H), 2.26 (s, 3H), 2.17 (s, 3H), 2.12 (s, 3H), 2.08
(s, 3H), 2.05 (s, 3H); 13C NMR (CDCl3) d 175.05, 171.12,
170.85, 170.48, 169.87, 169.68, 167.27, 131.20, 129.84,
129.11, 128.96, 128.77, 128.26, 126.44, 79.06, 70.33,
68.96, 68.13, 66.80, 66.72, 61.66, 53.86, 51.04, 30.57,
20.83, 20.64, 20.45, 20.37. Anal. Calcd for C35H36N2O13S:
C, 58.00; H, 5.01; N, 3.87; S, 4.42. Found: C, 57.70; H,
4.85; N, 3.73; S, 4.21.
1
1684, 1446, 1371, 1213, 1045; H NMR (CDCl3) d 7.94–
7.36 (m, 9H), 5.93 (d, 1H, J¼2.9 Hz), 5.80 (t, 1H,
J¼3.1 Hz), 5.46 (dd, 1H, J¼4.9 and 6.2 Hz), 5.15 (m, 1H),
4.44 (dd, 1H, J¼3.1 and 12.4 Hz), 4.14 (dd, 1H, J¼5.6
and 12.4 Hz), 3.91 (d, 1H, J¼7.4 Hz), 3.66 (d, 1H,
J¼7.3 Hz), 3.11 (s, 1H), 2.13 (s, 6H), 2.08 (s, 6H), 2.03 (s,
3H); 13C NMR (CDCl3) d 192.30, 191.30, 175.42, 170.60,
170.09, 169.75, 169.15, 168.57, 137.41, 136.21, 134.60,
134.23, 130.26, 129.04, 128.90, 127.98, 126.73, 81.73,
69.91, 69.66, 69.18, 67.90, 67.72, 61.48, 58.93, 56.62,
30.53, 20.83, 20.70, 20.59.
4.2.11. (1S,4S)-1-(10,20,30,40,50-Penta-O-acetyl-D-gluco-
pentitol-1-yl)-1,4-epithio-1,2,4-trihydro-5,8-dihydroxy-
2-methyl-4-phenylisoquinolin-3-one (23a) and (1R,4R)-1-
(10,20,30,40,50-penta-O-acetyl-D-gluco-pentitol-1-yl)-1,4-
epithio-1,2,4-trihydro-5,8-dihydroxy-2-methyl-4-phenyl-
isoquinolin-3-one (23b). From 1,4-benzoquinone (0.2 g,
2.2 mmol) compounds 23 were obtained as white solids as
described for 22. 23a: 0.2 g (20%); mp 210 ꢀC (dec); [a]D
+1.0 (c 0.5, chloroform); IR (KBr, cmꢁ1) nmax 2920,
4.2.13. 1-(10,20,30,40,50-Penta-O-acetyl-D-gluco-pentitol-1-
yl)-1,4-epithio-1,2,4-trihydro-5,10-dihydroxy-2-methyl-
4-phenylbenzo[h]isoquinoline-3-one (25a) and
1-(10,20,30,40,50-penta-O-acetyl-D-gluco-pentitol-1-yl)-1,4-
epithio-1,2,4-trihydro-5,10-dihydroxy-2-methyl-4-phe-
nylbenzo[h]isoquinoline-3-one (25b). A mixture of dia-
stereomers 24a and 24b (0.1 g, 0.14 mmol) was treated with
silica gel (3.0 g) for 10 days. The reaction mixture was fil-
tered and after washing three times the silica gel with ethyl
acetate, combined solutions were concentrated in vacuo to
give a mixture of 25a and 25b, which were separated by
preparative thin layer chromatography (diethyl ether). 25a:
0.03 g (25%), mp 85 ꢀC (dec); [a]D ꢁ216 (c 0.25, chloro-
form); IR (KBr, cmꢁ1) nmax 1753, 1667, 1593, 1371, 1049;
1H NMR (CDCl3) d 8.12–7.42 (m, 10H), 6.62 (d, 1H,
J¼0.8 Hz), 5.82 (dd, 1H, J¼0.8 and 7.1 Hz), 5.59 (dd, 1H,
J¼4.3 and 7.1 Hz), 5.33 (m, 1H), 4.76 (dd, 1H, J¼2.7 and
12.4 Hz), 4.30 (dd, 1H, J¼7.9 and 12.5 Hz), 2.84 (s, 3H),
2.23 (s, 3H), 2.15 (s, 3H), 2.11 (s, 3H), 2.08 (s, 3H), 2.07
(s, 3H); 13C NMR (CDCl3) d 183.04, 179.04, 177.70,
170.75, 170.32, 170.03, 169.70, 169.45, 156.75, 153.07,
134.69, 134.11, 132.25, 131.50, 131.02, 128.93, 128.68,
128.32, 127.98, 126.89, 126.73, 82.57, 70.45, 69.93,
69.08, 65.80, 66.04, 61.44, 32.57, 21.39, 20.78, 20.55.
Anal. Calcd for C35H35NO13S: C, 59.23; H, 4.97; N, 1.97;
S, 4.52. Found: C, 59.45; H, 4.82; N, 1.82; S, 4.48. 25b:
0.04 g (40%), [a]D +45 (c 0.25, chloroform); IR (KBr,
cmꢁ1) nmax 1755, 1666, 1593, 1371, 1049; 1H NMR
(CDCl3) d 8.03–7.26 (m, 10H), 6.47 (d, 1H, J¼3.8 Hz),
1
1744, 1696, 1493, 1435, 1375, 1287, 1213, 1065, 955; H
NMR (CDCl3) d 8.09–7.43 (m, 5H), 7.23 (s, 1H), 6.58 (d,
1H, J¼8.9 Hz), 6.51 (s, 1H), 6.42 (d, 1H, J¼8.9 Hz), 5.88
(d, 1H, J¼8.5 Hz), 5.64 (dd, 1H, J¼2.2 and 7.7 Hz), 5.33
(dd, 1H, J¼2.2 and 8.5 Hz), 4.99 (dd, 1H, J¼2.5 and
12.4 Hz), 4.38 (s, 1H), 4.01 (dd, 1H, J¼10.0 and 12.4 Hz),
2.62 (s, 3H), 2.27 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 2.08
(s, 3H), 2.05 (s, 3H); 13C NMR (CDCl3) d 192.45, 191.92,
177.91, 172.77, 171.03, 170.04, 169.63, 169.21, 145.34,
141.67, 132.77, 130.38, 129.51, 128.57, 128.27, 119.40,
118.82, 81.80, 70.54, 68.96, 68.17, 66.26, 63.71, 62.16,
30.84, 21.31, 21.07, 20.83, 20.46. Anal. Calcd for
C31H33NO13S: C, 56.44; H, 5.04; N, 2.12; S, 4.86. Found:
C, 56.29; H, 5.16; N, 2.03; S, 4.65. 23b: 0.09 g (7%); mp
115 ꢀC; [a]D +4.5 (c 0.5, chloroform); IR (KBr, cmꢁ1):
1
nmax 3430, 1753, 1493, 1371, 1217, 1047, 955; H NMR
(CDCl3) d 8.13–7.46 (m, 5H), 6.56 (d, 1H, J¼8.9 Hz),
6.43 (d, 1H, J¼8.9 Hz), 6.27 (d, 1H, J¼2.4 Hz), 5.61
(dd, 1H, J¼2.4 and 5.8 Hz), 5.41 (dd, 1H, J¼5.8 Hz), 5.27
(m, 1H), 4.43 (dd, 1H, J¼3.8 and 12.3 Hz), 4.14 (dd,
1H, J¼5.5 and 12.3 Hz), 2.78 (s, 3H), 2.14 (s, 3H), 2.12
(s, 6H), 2.10 (s, 3H), 2.02 (s, 3H); 13C NMR (CDCl3)
d
170.69, 170.08, 169.87, 169.08, 145.25, 143.02,
132.00, 129.74, 129.56, 128.62, 127.44, 119.31, 119.13,
81.51, 69.58, 68.73, 63.44, 61.42, 30.47, 21.00, 20.85,
20.66. Anal. Calcd for C31H33NO13S: C, 56.44; H,
5.04; N, 2.12; S, 4.86. Found: C, 56.22; H, 5.25; N, 2.05;
S, 4.58.

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M. J. Arevalo et al. / Tetrahedron 62 (2006) 6909–6917
6916
5.58 (t, 1H, J¼4.2 Hz), 5.49 (dd, 1H, J¼4.8 and 6.1 Hz),
5.30 (m, 1H), 4.40 (dd, 1H, J¼3.4 and 12.4 Hz), 4.18 (dd,
1H, J¼5.2 and 12.4 Hz), 2.97 (s, 3H), 2.22 (s, 3H), 2.09
(s, 9H), 2.05 (s, 3H); 13C NMR (CDCl3) d 181.79, 179.03,
178.74, 170.54, 170.27, 169.75, 169.36, 168.90, 156.81,
153.50, 134.45, 134.08, 132.25, 131.70, 131.08, 128.98,
128.75, 128.02, 126.77, 126.35, 82.49, 69.50, 68.99,
68.69, 65.60, 61.51, 30.89, 21.01, 20.75, 20.68, 20.49.
1H NMR (CDCl3) d 8.08–6.88 (m, 9H), 8.17 (d, 1H, J¼
4.0 Hz), 629.55 (t, 1H, J¼4.5 Hz), 6.07 (t, 1H, J¼5.7 Hz),
5.59 (m, 1H), 4.83 (d, 1H, J¼12.3 Hz), 4.48 (dd, 1H,
J¼6.5 and 12.3 Hz), 3.84 (s, 3H), 1.74 (s, 6H), 1.68 (s,
3H), 1.60 (s, 3H); 13C NMR (CDCl3) d 183.31, 182.61,
170.61, 170.02, 169.66, 169.27, 150.79, 136.81, 135.75,
135.23, 134.51, 133.93, 133.78, 128.32, 127.83, 127.36,
126.67, 113.40, 70.61, 69.97, 69.50, 69.33, 61.67, 37.65,
21.01, 20.78. Anal. Calcd for C35H33NO13: C, 62.22; H,
4.92; N, 2.07. Found: C, 61.85; H, 4.98; N, 2.19.
4.2.14. 4-(10,20,30,40,50-Penta-O-acetyl-D-gluco-pentitol-1-
yl)-2,5-dihydro-5-methyl-2,7-diphenyl-1H-pyrrolo [3,4-
c]pyridine-1,3,6-trione (26). A mixture of cycloadducts
22a and 22b (0.1 g, 0.2 mmol) was poured into a suspension
of Hg(OAc)2 (0.1 g, 0.3 mmol) in acetic acid (3 mL) at room
temperature and processed as described for 9 to give 26
(0.03 g, 30%) as a white solid; mp 95 ꢀC (dec); [a]D +47.0
(c 0.5, chloroform); IR (KBr, cmꢁ1) nmax 3472, 2964,
1751, 1719, 1659, 1501, 1447, 1373, 1215, 1045; 1H NMR
(CDCl3) d 7.52–7.35 (m, 5H), 7.59 (d, 1H, J¼8.6 Hz),
6.00 (dd, 1H, J¼2.3 and 8.7 Hz), 5.19 (dd, 1H, J¼2.5 and
7.6 Hz), 5.08 (m, 1H), 4.25 (dd, 1H, J¼3.0 and 12.6 Hz),
4.03 (dd, 1H, J¼5.6 and 12.6 Hz), 3.88 (s, 3H), 2.16 (s,
6H), 2.08 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H); 13C NMR
(CDCl3) d 170.48, 170.24, 169.99, 169.63, 168.66, 164.56,
163.81, 163.69, 142.97, 132.78, 131.50, 131.08, 130.15,
129.95, 129.53, 128.86, 128.59, 127.71, 126.89, 126.50,
108.09, 68.70, 68.60, 67.44, 66.96, 61.35, 35.38, 21.01,
20.73, 20.62, 20.46. Anal. Calcd for C35H34N2O13: C,
60.13; H, 4.96; N, 4.06. Found: C, 60.11; H, 5.02; N, 4.09.
Acknowledgements
Financial support from the Ministry of Science and Tech-
nology (Projects BQU2003-05946 and CTQ2005-07676)
is gratefully acknowledged. M.J.A. thanks the Ministry of
Education for a doctoral fellowship.
References and notes
1. Vorbruggen, H.; Ruh-Pohlenz, C. The Handbook of Nucleoside
¨
Synthesis; Wiley: New York, NY, 2001.
2. Allen, H. J.; Kisailus, E. C. Glycoconjugates: Composition,
Structure and Function; Marcel Dekker: New York, NY, 1992.
3. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Towards Heterocycles and Natural Products; Padwa, A.,
Pearson, W. H., Eds.; Wiley: New York, NY, 2002.
4. For some recent applications of click chemistry: (a) Lober, S.;
´
Rodrıguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5, 1753–
4.2.15. 1-(10,20,30,40,50-Penta-O-acetyl-D-gluco-pentitol-1-
yl)-2-methyl-4-phenyl-2H-isoquinoline-3,5,6-trione (27).
A mixture of cycloadducts 23a and 23b (0.1 g, 0.2 mmol)
was poured into a suspension of Hg(OAc)2 (0.1 g,
0.3 mmol) in acetic acid (3 mL) at room temperature and pro-
cessed as described for 9 to give 27 (0.02 g, 20%) as a yellow-
ish solid; mp 85 ꢀC (dec); [a]D ꢁ17.0 (c 0.25, chloroform);
IR (KBr, cmꢁ1) nmax 3480, 2980, 1751, 1643, 1510, 1447,
1755; (b) Ryu, E.-H.; Zhao, Y. Org. Lett. 2005, 7, 1035–
1037; (c) Xu, G.-L.; Ren, T. Organometallics 2005, 24,
2564–2566; (d) Krasinski, A.; Radic, Z.; Manetsch, R.;
Raushel, J.; Taylor, P.; Sharpless, K. B.; Kolb, H. C. J. Am.
Chem. Soc. 2005, 127, 6686–6692; (e) Hotha, S.; Kashyap, S.
J. Org. Chem. 2006, 71, 364–367; (f) Taniguchi, A.; Sohma,
Y.; Kimura, M.; Okada, T.; Ikeda, K.; Hayashi, Y.; Kimura,
T.; Hirota, S.; Matsuzaki, K.; Kiso, Y. J. Am. Chem. Soc.
2006, 128, 696–697.
1
1373, 1217, 1074; H NMR (CDCl3) d 7.46–7.75 (m, 5H),
7.53 (d, 1H, J¼4.1 Hz), 6.01 (t, 1H, J¼4.5 Hz), 5.62 (t, 1H,
J¼5.6 Hz), 5.19 (m, 1H), 4.53 (dd, 1H, J¼2.4 and
12.5 Hz), 4.32 (dd, 1H, J¼6.7 and 12.5 Hz), 3.81 (s, 3H),
2.71 (s, 3H), 2.14 (s, 3H), 2.09 (s, 3H), 2.08 (s, 6H); 13C
NMR (CDCl3) d 184.22, 183.71, 170.64, 170.02, 169.69,
169.30, 169.21, 163.45, 150.44, 141.72, 138.18, 134.87,
134.75, 133.44, 111.88, 70.07, 69.73, 69.32, 69.24, 61.56,
37.20, 20.77, 20.55. Anal. Calcd for C31H31NO13: C,
59.52; H, 4.99; N, 2.24. Found: C, 59.14; H, 4.91; N, 2.19.
´
´
5. Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios,
J. C. Acc. Chem. Res. 2005, 38, 460–468.
´
6. Arevalo, M. J.; Avalos, M.; Babiano, R.; Cintas, P.; Hursthouse,
´
M. B.; Jimenez, J. L.; Light, M. E.; Palacios, J. C. Tetrahedron:
´
Asymmetry 2002, 13, 223–226.
7. Obika, S.; Hari, Y.; Sekiguchi, M.; Imanishi, T. Angew. Chem.,
Int. Ed. 2001, 40, 2079–2081.
8. Wenska, G.; Skalski, B.; Gdaniec, Z.; Adamiak, R. W.;
Matulic-Adamic, J.; Beigelman, L. J. Photochem. Photobiol.,
A 2003, 133, 169–176.
4.2.16. 1-(10,20,30,40,50-Penta-O-acetyl-D-gluco-pentitol-1-
yl)-2-ethoxy-5-(1,2-diethoxycarbonyl hydrazine)-5-
phenyl-3-methylthiazolidin-4-one (28). A suspension of
Raney nickel (0.03 g) in acetone (5 mL) was refluxed for
2 h. After cooling at room temperature and decanting the
solvent, a solution of cycloadducts 24a and 24b (0.1 g,
0.1 mmol) in 2-butanol was added and the reaction mixture
was heated at reflux for 2 h. After three washings of the cat-
alyst with 2-butanol, the combined solutions were filtered
and the solvent was concentrated in vacuo. The crude mix-
ture was purified by preparative thin layer chromatography
(acetonitrile–chloroform 1:9 as eluent) to give 28 (0.03 g,
32%); mp 95 ꢀC; [a]D ꢁ9.5 (c 0.25, chloroform); IR (KBr,
cmꢁ1) nmax 2970, 1751, 1641, 1447, 1371, 1217, 1049;
´
´
9. Arevalo, M. J.; Avalos, M.; Babiano, R.; Cabanillas, A.; Cintas,
P.; Jimenez, J. L.; Palacios, J. C. Tetrahedron: Asymmetry 2000,
´
11, 1985–1995.
10. Potts, K. T.; Houghton, E.; Singh, U. P. J. Org. Chem. 1974, 25,
3627–3631.
11. (a) Potts, K. T.; Baum, J.; Houghton, E. J. Org. Chem. 1974, 25,
3631–3641; (b) Robert, A.; Baudy, M.; Foucaud, A.; Golic, L.;
Stanovnik, B. Tetrahedron 1978, 34, 3525–3530.
´
12. (a) Avalos, M.; Babiano, R.; Cabanillas, A.; Cintas, P.; Higes,
´
F. J.; Jimenez, J. L.; Palacios, J. C. J. Org. Chem. 1996,
61, 3738–3748; (b) Avalos, M.; Babiano, R.; Cintas, P.;
´
´
Clemente, F. R.; Gordillo, R.; Jimenez, J. L.; Palacios, J. C.;
Raithby, P. R. J. Org. Chem. 2000, 65, 5089–5097;

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M. J. Arevalo et al. / Tetrahedron 62 (2006) 6909–6917
6917
´
(c) Areces, P.; Avalos, M.; Babiano, R.; Cintas, P.; Gonzalez,
´
15. Crystal data for compound 23a: monoclinic, space group P21,
3
˚
˚
´
L.; Hursthouse, M. B.; Jimenez, J. L.; Light, M. E.; Lopez,
I.; Palacios, J. C.; Silvero, G. Eur. J. Org. Chem. 2001, 2135–
´
a¼13.137(2), b¼7.9233(8), c¼15.190(2) A, V¼1580.9(4) A ,
Z¼2, dcalcd¼1.382 Mg/m3, q range for data collection¼3.00–
25.02ꢀ, index ranges¼ꢁ15ꢃhꢃ15, ꢁ9ꢃkꢃ9, ꢁ14ꢃlꢃ17,
(Mo Ka)¼0.171 mmꢁ1. For a total of 5779 collected reflec-
tions, 4481 were independent reflections [Rint¼0.0755]. The
final R indices were R1¼0.0697, wR2¼0.1330 [F2>2s(F2)],
R1¼0.1312, wR2¼0.1624 (all data). The final difference elec-
tron density map contains maximum and minimum peak
´
2144; (d) Avalos, M.; Babiano, R.; Cintas, P.; Clemente,
´
F. R.; Gordillo, R.; Jimenez, J. L.; Palacios, J. C. J. Org.
Chem. 2001, 66, 5139–5145.
13. (a) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley: New York, NY, 1994; pp 1081–
1082 and references therein; (b) Hudson, C. S. J. Am. Chem.
Soc. 1909, 31, 66–86; (c) Ferrier, R. J. The Carbohydrates.
Chemistry and Biochemistry; Pigman, W., Horton, D.,
Wander, J. D., Eds.; Academic: New York, NY, 1980; Vol.
IB, pp 1356–1362.
3
˚
heights of 0.303 and ꢁ0.387 e/A . These data have been depos-
ited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 146528. Copies
of the data can be obtained, free of charge, on applica-
tion to CCDC, 12 Union Road, Cambridge CB12 1EZ,
UK [fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.
ac.uk].
´
´
14. Arevalo, M. J.; Avalos, M.; Babiano, R.; Cintas, P.; Hursthouse,
M. B.; Jimenez, J. L.; Light, M. E.; Lopez, I.; Palacios, J. C.
´
´
Tetrahedron 2000, 56, 1247–1256.