Synthesis of new iso-C-nucleoside analogues from 2-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-α-D-altropyranosid-3-yl)ethanal

Article abstract of DOI:10.1016/j.carres.2005.01.003

Treatment of 2-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-α-d- altropyranosid-3-yl)ethanal with malononitrile, cyanoacetamide and 2-cyano-N-(4-methoxyphenyl)acetamide, respectively, in the presence of aluminium oxide yielded 2-cyano-4-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-α-d- altropyranosid-3-yl)crotonic acid derivatives. Cyclization with sulfur and triethylamine was performed to synthesize the 2-amino-5-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-α-d-altropyranosid-3-yl) thiophene-3-carbonic acid derivatives, which were treated with triethyl orthoformate/ammonia and triethyl orthoformate, respectively, to furnish 6-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-α-d-altropyranosid-3-yl) thieno[2.3-d]pyrimidine derivatives. Deprotection in two steps afforded 2-amino-5-(1,6-anhydro-3-deoxy-β-d-altropyranos-3-yl)thiophene-3- carbonitrile and 6-(1,6-anhydro-3-deoxy-β-d-altropyranos-3-yl)thieno[2.3-d] pyrimidine derivatives, respectively.

Full text of DOI:10.1016/j.carres.2005.01.003

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005)547–555
Synthesis of new iso-C-nucleoside analogues from
2-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-a-D-
altropyranosid-3-yl)ethanal
Iran Otero,a,b Holger Feist,a Lidcay Herrera,a Manfred Michalik,c
d
Jose Quincoces and Klaus Peseke
a,
*
´
aInstitut fu¨r Chemie, Universita¨t Rostock, D-18051 Rostock, Germany
b
´
´
Facultad de Quımica y Farmacia, Universidad Central de Las Villas, Carretera a Camajuanı, km 5.5. Santa Clara, Cuba
cLeibniz-Institut fu¨r Organische Katalyse an der Universita¨t Rostock, Buchbinderstraße 5-6, D-18055 Rostock, Germany
dUniversidade Bandeirante de Sa˜o Paulo, Rua Maria Candida, 1813, Vila Guilherme, Sao Paulo, CEP: 02071-013, Brazil
Received 16 February 2004; received in revised form 25 November 2004; accepted 3 January 2005
Available online 20 January 2005
In memory of Professor Dr. Christian Pedersen
Abstract—Treatment of 2-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-a-D-altropyranosid-3-yl)ethanal with malononitrile, cyano-
acetamide and 2-cyano-N-(4-methoxyphenyl)acetamide, respectively, in the presence of aluminium oxide yielded 2-cyano-4-
(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-a-D-altropyranosid-3-yl)crotonic acid derivatives. Cyclization with sulfur and trieth-
ylamine was performed to synthesize the 2-amino-5-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-a-D-altropyranosid-3-yl)thio-
phene-3-carbonic acid derivatives, which were treated with triethyl orthoformate/ammonia and triethyl orthoformate,
respectively, to furnish 6-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-a-D-altropyranosid-3-yl)thieno[2.3-d]pyrimidine deriva-
tives. Deprotection in two steps afforded 2-amino-5-(1,6-anhydro-3-deoxy-b-D-altropyranos-3-yl)thiophene-3-carbonitrile and 6-
(1,6-anhydro-3-deoxy-b-D-altropyranos-3-yl)thieno[2.3-d]pyrimidine derivatives, respectively.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: Nucleoside analogues; Iso-C-nucleosides; Branched-chain monosaccharides; Thiophenecarbonic acid derivatives; Thieno[2.3-d]-
pyrimidines
1. Introduction
nucleosides are known.8–11 In order to obtain potentially
less toxic and more active compounds, which might also
be less susceptible to resistance many synthetic strategies
have been developed for the formation of C-nucleosides
in the last years.12 Furthermore, iso-C-nucleosides in
which the nucleobase is linked by a carbon–carbon bond
to the sugar moiety as a carbon other than C-1 are of
growing interest.13–15
Gewald et al.16 described the synthesis of thiophene
derivatives with biological activity by the reaction of
Knoevenagel compounds with elemental sulfur mostly
in N,N-dimethylformamide using amines as bases. The
reaction of 1,6-anhydro-2-(dicyanomethylene)-2,3-
dideoxy-4-S-ethyl-4-thio-b-D-erythro-hexopyranose with
Representatives of 2-amino-thiophene-3-carboxylates
have significant analgesic activity.1 The correspon-
ding 5-carboxamido-4-hydroxy-3-(b-D-ribofuranosyl)thio-
phene-2-carbonic acid derivatives were investigated as
virucides and virostatic agents.2 Furthermore, thieno[2,3-
d]pyrimidine derivatives3 showed interesting biological
properties including antihypertensive,4 antiallergenic,5
antitumour,6 antiviral,6 anti-HIV-16 and analgesic7
activities. A few examples of thieno[2,3-d]pyrimidine
*
Corresponding author. Tel.: +49 381 498 6410; fax: +49 381 498
6412; e-mail: klaus. peseke@uni-rostock.de
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.01.003

548
I. Otero et al. / Carbohydrate Research 340 (2005) 547–555
sulfur and triethylamine yielded the corresponding
monosaccharidic anellated thiophene-3-carbonitrile.17
Similarly, C-nucleosides and iso-C-nucleosides of 2-ami-
nothiophene-3-carbonitriles with a-D-glycopyranosyl
and a-D-altropyranosid-2-yl, respectively, units at C-5
were prepared.18,19 These compounds were converted
to 6-(a-D-glycopyranosyl and a-D-altropyranosid-2-yl,
respectively)thieno[2,3-d]pyrimidines.
In the present paper we describe the synthesis of the
hitherto unknown iso-C-nucleosides with a 3-deoxy-
a-D-altropyranosid-3-yl unit in order to use these
compounds later in various biological tests.
sid-3-yl)ethanal 4 in 75% yield. The branched-chain
monosaccharidic aldehyde 4 was subsequently used
as a versatile starting material for the preparation of
iso-C-nucleosides.
Firstly, compound 4 was treated with malononitrile,
cyanoacetamide and 2-cyano-N-(4-methoxyphenyl)acet-
amide, respectively, to give the corresponding products
5a–c resulting from the Knoevenagel reaction (Scheme
2). These reactions were carried out by using an excess
of the CH-acidic compounds and basic aluminium oxide
in toluene.26,27 The conversion of 5a was complete after
1 h at room temperature providing 6a in a yield of 90%.
In order to drive the condensation of aldehyde 4 with
cyanoacetamide and 2-cyano-N-(4-methoxyphenyl)acet-
amide to completion, it was required to heat the reaction
mixtures to reflux for 24 h and 2 h, respectively. How-
ever, isolated yields were still lower than in the case of
5a, because decomposition occurred under these reac-
tion conditions. The structures 5a–c were confirmed by
the IR and NMR spectra. The appearance of cyano
and carboxamide bands, respectively, in the IR spectra
and the absence of the aldehyde signal and the occur-
rence of the typical cyano and carbonyl resonances in
the 13C NMR spectra clearly demonstrated the success-
ful course of the Knoevenagel reaction. The values for
the coupling constants JH3-CN and JH3-C@O (13 Hz and
6 Hz, respectively)determined from a coupled 13C
NMR spectrum confirmed the (E)-configuration of the
structures 5b and 5c.
2. Results and discussion
4,6-O-Benzylidene-3-deoxy-3-(prop-2-enyl)-a-D-altropyr-
anoside (2)was prepared in 80% yield by treatment of
methyl 2,3-anhydro-4,6-O-benzylidene-a-D-mannopyr-
anoside (1)with allylmagnesium bromide ( Scheme
1).20,21 Benzylation of the 2-hydroxy group in THF with
benzyl bromide and sodium hydride in the presence of
tetrabutylammonium iodide22,23 gave the branched-
chain sugar 3. Postema et al. have described the oxida-
tion of similar unsaturated compounds with ozone in
CH2Cl2 followed by reduction with Zn/acetic acid to
give the corresponding aldehydes.24 We decided for the
oxidation with osmium tetroxide and sodium periodate
in 1,4-dioxane/water (10:1)25 and isolated the (pyrano-
6'
1
6'
O
OH
OBn
O
OBn
O
O
O
O
O
1
Ph
Ph
Ph
Ref. [18,19]
OMe
5'
Ph
5'
O
i
ii
O
O
O
4'
O
O
4'
1'
1'
2'
3'
2'
3'
2
OMe
OMe
OMe
2
3
2
1
O
4
3
Scheme 1. Synthesis of 2-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-a-D-altropyranosid-3-yl)ethanal (4). Reagents and conditions: (i) BnBr,
NaH, tetrabutylammonium iodide, THF, 22 ꢁC; (ii)NaIO 4, OsO4, dioxane/H2O (10:1), 22 ꢁC.
6'
6'
OBn
O
O
OBn
O
O
Ph
ii
5'
Ph
5'
O
i
O
4'
3
4'
3'
1'
+
4
1'
2'
R
CN
2'
1
3'
5
4
OMe
3
2
OMe
4
S
CN
1
2
R
R
NH2
5a: R = CN
5b: R = CONH2
5c: R = CONHC6H4OMe-p
6a: R = CN
6b: R = CONH2
6c: R = CONHC6H4OMe-p
Scheme 2. Syntheses of 2-amino-5-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-a-D-altropyranosid-3-yl)thiophene-3-carbonic acid derivatives 6.
Reagents and conditions: (i)Al 2O3, toluene, 22 ꢁC; (ii)S 8, Et3N, DMF, 22 ꢁC.

I. Otero et al. / Carbohydrate Research 340 (2005) 547–555
549
6'
In order to prepare thiophene iso-C-nucleosides, com-
O
5
OBn
O
pounds 5a–c were treated according to this procedure
with elemental sulfur in the presence of triethylamine
in N,N-dimethylformamide to give the aminothiophene
derivatives 6a–c as light yellow solids in 85%, 45% and
65% yields, respectively (Scheme 2). The reaction of 5a
with elemental sulfur was completed in 15 min. For
the generation of thiophene carbonic acid derivatives
6b and 6c a reaction time of 12 h was necessary. The
structures of compounds 6a–c were investigated by spec-
troscopic methods. In the IR spectra absorption bands
for the amino groups were present. The DEPT spectra
showed the absence of the former C-4 methylene group.
Most characteristic in the 1H NMR spectra of 6a–c were
the H-4 doublets at d = 6.79, 6.75 and 6.88, respectively,
due to long-range couplings of H-4 of the thiophene ring
with H-30 in the sugar moiety probably caused by a
ÔWÕ-arrangement. The mass spectra of 6a–c gave peaks
corresponding to their molecular masses.
Ph
5'
O
4'
1'
2'
7
3'
6
i
OMe
6a
S
4a
7a
N
4
1
H2N
N
2
3
7
6'
OBn
O
O
5
Ph
5'
O
4'
1'
2'
3'
6
ii
OMe
6b, 6c
7
S
7a
4a
Starting from 1,2-enaminonitriles pyrimidine deriva-
tives can be prepared.28 In this manner 6a was reacted
with triethyl orthoformate under reflux. Without any
further purification the syrupy formimidic acid ester ob-
tained was converted into the corresponding 4-amino-6-
(pyranosid-3-yl)thieno[2.3-d]pyrimidine 7 in 50% yield
by treatment with a saturated ethanolic ammonia solu-
tion (Scheme 3). The mass spectrum of compound 7
showed the expected molecular peak and in the IR spec-
trum no absorption band for CN was visible anymore.
In the 1H NMR spectrum a new singlet at d = 8.41
appeared, which was assigned to the H-2 of the
thieno[2.3-d]pyrimidine ring.
The 6-(pyranosid-3-yl)thieno[2.3-d]pyrimidin-4-ones
8a,b could be obtained as white crystals in 56% and
65% yields, respectively, by reaction of the thiophene-
carboxamides 6b and 6c with triethyl orthoformate in
N,N-dimethylformamide (Scheme 3). The absence of
an absorption band for NH2 and the appearance of
the carbonyl signals at different positions in the IR spec-
trum confirmed ring closure. In the 1H NMR spectra of
8a,b the characteristic singlets at d = 7.99 and 8.01,
respectively, were in accordance with the expected value
for H-2. Generally, two tautomeric forms can be formu-
lated for compound 8a. The NMR spectra showed the
existence of only one compound in solution. However,
we conclude from a carbonyl signal at 1668 cmÀ1 in
the IR spectrum that compound 8a predominantly exists
as the oxo tautomer.
1
N
O
4
N
3
R
2
8a: R = H
8b: R = C6H4OMe-p
Scheme 3. Syntheses of 6-(methyl 2-O-benzyl-4,6-O-benzylidene-3-
deoxy-a-D-altropyranosid-3-yl)thieno[2.3-d]pyrimidine derivatives 7, 8.
Reagents and conditions: (i)(a)(EtO) 3CH, reflux (b)NH 3, EtOH,
reflux; (ii)(EtO) 3CH, reflux.
can only be explained by the fact that exists an axial–
axial position of protons H-20 and H-30, which confirms
also the preferred conformation 1C4. This conformation
was also verified by a correlation between H-10 and H-
60a,b in the NOESY spectrum.
Iodotrimethylsilane (TMSI)is known as an useful re-
agent for the cleavage of benzylic and alkylic ethers.29,30
According to this procedure the splitting of the 2-O-benz-
yl group was tried with iodotrimethysilane in chloro-
form at room temperature. After 24 h of reaction and
followed by hydrolysis with methanol a new compound
could be isolated in all cases. The NMR spectra showed
that not only the benzyl, but also the glycosidic methyl
group was cleaved under reacetalization. The cleavage
of acetals in the presence of halotrimethylsilane and
the introduction of halogenide at the anomeric carbon
has already been reported.31–33 In order to determine
the structure of 10a–c several measurements were made.
The products were assigned as 1,6-anhydro-b-D-altro-
pyranosides based on NOESY and HMBC experiments.
In each case the NOESY spectra showed a characteristic
correlation between the H-30 and H-60a protons and the
HMBC spectra verified the connectivity through three
bonds between H-10 and C-60 and between C-10 and
H-60a, which are only possible in the postulated
The deprotection of compounds 6a, 7 and 8a was car-
ried out in two steps. In the first step the benzylidene
group was completely removed by treatment with acetic
acid/water at 70 ꢁC. Compounds 9a–c were obtained in
medium yields due to the formation of elimination prod-
ucts, which were not completely characterized (Scheme
0
3
4). The value for the coupling constant J2 ,3
0
(ꢀ 10.0 Hz)in comparison to compounds 6a, 7 and 8a

550
I. Otero et al. / Carbohydrate Research 340 (2005) 547–555
OH
6'
3'
6'
5'
O
1'
1'
OH
5'
ii
i
O
O
OMe
OBn
6a, 7, 8a
4'
4'
3'
2'
Het
OH
2'
Het
OH
9
10
NC
H2N
9a, 10a: Het =
9b, 10b: Het =
9c, 10c: Het =
S
NH2
N
S
S
N
O
HN
N
Scheme 4. Deprotection of 6a, 7, 8a. Reagents and conditions: (i)HOAc–H 2O 9:1, 70 ꢁC; (ii)(a)TMSI, CHCl 3, 22 ꢁC; (b)MeOH.
1,6-anhydrosugar structure. The mass spectra confirmed
the proposed structures. In addition, the 1H,1H coupling
constants and carbon chemical shifts determined for 10
were quite similar to the values reported for 1,6-anhy-
dro-b-D-altropyranosides.34–36
were performed on a Leco CHNS-932 instrument. For
chromatography Merck silica gel 60 (230–400 mesh)
was used. Solvents and liquid reagents were purified
and dried according to recommended procedures.
3.1. Methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-3-
(prop-2-enyl)-a-D-altropyranoside (3)
H
H
Sodium hydride (9.0 mmol)was added to a solution of
methyl 4,6-O-benzylidene-3-deoxy-3-(prop-2-enyl)-a-D-
altropyranoside (2, 1.58 g, 6.0 mmol)in tetrahydrofuran
(50 mL). After stirring the mixture at room temperature
for 30 min tetrabutylammonium iodide (0.185 g,
0.5 mmol)and benzyl bromide (0.72 mL, 6 mmol)were
added. Stirring was continued for 3 h and then the solu-
tion was poured in water (30 mL)and extracted with
dichloromethane. The combined organic phases were
dried over Na2SO4, filtered and concentrated under
reduced pressure. The syrup obtained was purified by
column chromatography (toluene/EtOAc 10:1)to yield
O
6'
5'
1'
*
H
H
O
OH
4'
3'
2'
Het
OH
Characteristic NOESY* and HMBC correlations
3. Experimental
TLC was carried out on silica gel 60 GF254 (Merck)with
detection by UV light (k = 254 nm)and/or by charring
with 5% sulfuric acid in ethanol. Silica gel 60 (63–200
mesh)(Merck)was used for column chromatography.
Melting points were determined by using a Boetius melt-
ing point apparatus and are corrected. Specific rotations
were determined with a Polar LlP (IBZ Messtechnik).
IR spectra were recorded with a Nicolet 205 FT-IR
spectrometer. 1H NMR spectra (500.13 and
2.26 g (95%)of 3 as a white solid; TLC: toluene/EtOAc
22
D
10:1, Rf: 0.45; mp 44–46 ꢁC; ½aꢁ +50.4 (c 0.5, CHCl3);
1
IR (KBr), m (cmÀ1): 1641 (C@C); H NMR (250 MHz,
CDCl3): d 7.51–7.27 (m, 10H, 2 · Ph); 5.81–5.65 (m,
1H, H-2); 5.59 (s, 1H, CHPh); 5.10–4.98 (m, 2H, H-3);
3
0
0
0
4.66 (br s, 1H, J1 2 ꢀ 1.2 Hz, H-1 ); 4.55 (q(AB),
2H, 2JA,B ꢀ 12.0 Hz, CH2Ph); 4.27 (dd, 1H,
2
3
J6 ax,6 eq ꢀ 10.0 Hz, J5 ,6 eq ꢀ 4.9 Hz, H-60eq); 4.13
0
0
0
0
3
3
(dd, 1H, J4 ,5 ꢀ 10.0 Hz, J3 ,4 ꢀ 5.2 Hz, H-40); 3.95
0
0
0
0
3
250.13 MHz, respectively)and
13C NMR spectra
(dt, 1H, J5 ,6 ax ꢀ 10.0 Hz, H-50); 3.79 (t, 1H, H-60ax);
0
0
3
3.61 (dd, 1H, J2 ,3 ꢀ 1.8 Hz, H-20); 3.35 (s, 3H,
OMe); 2.53–2.46 (m, 2H, H-1); 2.41–2.31 (m, 1H, H-
30); 13C NMR (75.5 MHz, CDCl3): d 137.9, 137.8
(2 · ipso-Ph); 137.1 (C-2); 128.9, 128.8, 128.4, 128.3,
127.8, 126.2 (o-, m-Ph); 116.7 (C-3); 101.9 (CHPh);
100.6 (C-10); 76.3 (C-20); 75.8 (C-40); 71.7 (CH2Ph);
69.6 (C-60); 59.3 (C-50); 55.1 (OMe); 39.2 (C-30);
28.5 (C-1); MS,FAB+ (m/z): 397 [M+H]+; Anal. Calcd
for C24H28O5: C, 72.71; H, 7.12. Found: C, 72.90; H,
7.24.
0
0
(125.8 MHz, 75.5 MHz and 62.9 MHz, respectively)
spectra were recorded on Bruker instruments AVANCE
500, ARX 300 and AC 250, respectively, with CDCl3 or
DMSO-d6 as solvents. The calibration of spectra was
carried out on TMS (internal, 1H)and solvent ( 13C)sig-
1
13
C
1
nals (d HTMS = 0; d
= 77.0). The H and 13C
CDCl3
NMR signals were assigned by DEPT and two-dimen-
sional 1H,1H COSY and 1H,13C correlation spectra.
The mass spectra were recorded on an AMD 402/3 spec-
trometer (AMD Intectra GmbH). Elemental analysis

I. Otero et al. / Carbohydrate Research 340 (2005) 547–555
551
3.2. 2-(Methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-
a-D-altropyranosid-3-yl)ethanal (4)
(C-30); 29.9 (C-4); MS, EI (m/z): 446 [M]+; Anal. Calcd
for C26H26N2O5: C, 69.94; H, 5.87; N, 6.27. Found:
C, 69.98; H, 5.98; N, 6.31.
Compound 3 (1.98 g, 5 mmol)was dissolved in 1,4-diox-
ane/water 10:1 (50 mL). An OsO4-solution (0.4 mg in
1,4-dioxane, 0.4 mL)was added, and the resulting mix-
ture was stirred by room temperature for 1 h. Then,
NaIO4 (3.2 g, 15 mmol)as a saturated solution in water
was given to the mixture and stirring was continued for
12 h. After filtration the solvent was completely removed
in vacuo. The residue was purified by column chroma-
tography (toluene/EtOAc 10:1)to yield 1.49 g (75%)of
3.4. (2E)-2-Cyano-4-(methyl 2-O-benzyl-4,6-O-benzylid-
ene-3-deoxy-a-D-altropyranosid-3-yl)crotonamide (5b)
To a solution of 4 (0.398 g, 1 mmol)in dried toluene
(30 mL), cyanoacetamide (0.168 g, 2 mmol) and Al2O3
(0.1 g, aluminium oxide 90, active basic, Merck)were
added and the mixture was stirred under reflux for
24 h. After filtration the solvent was evaporated and
the residue purified by column chromatography (tolu-
ene/EtOAc 1:1)to yield 0.350 g (75%)of 5b as a white
4 as a colourless syrup; TLC: toluene/EtOAc 10:1, Rf
24
D
0.30; ½aꢁ +52.7 (c 1.0, CHCl3); IR (capillary), m
(cmÀ1): 1721 (CO); 1H NMR (250 MHz, CDCl3): d
9.75 (s, 1H, H-1); 7.45–7.25 (m, 10H, 2 · Ph); 5.59 (s,
solid; TLC: toluene/EtOAc 1:2, Rf 0.45; mp 62–64 ꢁC;
23
½aꢁ +29.7 (c 1.0, CHCl3); IR (KBr), m (cmÀ1): 3194,
D
2
1H, CHPh); 4.69 (q(AB), 2H, JA,B ꢀ 12.0 Hz, CH2Ph);
3343 (NH2); 2222 (CN); 1696 (CO); 1H NMR
3
3
4.63 (br s, 1H, J1 ,2 ꢀ 1.2 Hz, H-10); 4.27 (dd, 1H,
(250 MHz, CDCl3): d 7.61 (dd, 1H, J3,4a ꢀ 6.7 Hz,
0
0
2
3
J6 ax,6 eq ꢀ 10.0 Hz, J5 ,6 eq ꢀ 4.0 Hz, H-60eq); 4.16
3J3,4b ꢀ 9.2 Hz, H-3); 7.50–7.30 (m, 10H, 2 · Ph); 5.95
0
0
0
0
3
3
(dd, 1H, J4 ,5 ꢀ 10.0 Hz, J3 ,4 ꢀ 5.2 Hz, H-40); 3.89
(br d, NH2); 5.59 (s, 1H, CHPh); 4.68 (br s, 1H,
J1 ,2 ꢀ 1.2 Hz, H-10); 4.58 (s, 2H, CH2Ph); 4.30 (dd,
0
0
0
0
3
3
(dt, 1H, J5 ,6 ax ꢀ 10.0 Hz, H-50); 3.80 (t, 1H, H-60ax);
0
0
0
0
3
2
3
3.56 (dd, 1H, J2 ,3 ꢀ 2.1 Hz, H-20); 3.33 (s, 3H, OMe);
3.12–3.04 (m, 1H, H-30); 2.98–2.93 (m, 2H, H-2); 13C
NMR (62.9 MHz, CDCl3): d 201.4 (C-1); 137.8, 137.5
(2 · ipso-Ph); 129.1, 128.4, 128.3, 127.9, 127.8, 126.1 (o-,
m-, p-Ph); 101.8 (CHPh); 100.5 (C-10); 76.7 (C-20); 75.1
(C-40); 71.8 (CH2Ph); 69.4 (C-60); 59.6 (C-50); 55.1
(OMe); 39.7 (C-2); 32.9 (C-30); HRMS: Anal. Calcd for
C23H26O6 398.17294; Found: [M]+ m/z 398.17045.
1H, J6 ax,6 eq ꢀ 10.1 Hz, J5 ,6 eq ꢀ 4.9 Hz, H-60eq);
0
0
0
0
0
0
3
3
4.19 (dd, 1H, J4 ,5 ꢀ 10.1 Hz, J3 ,4 ꢀ 5.2 Hz, H-40);
0
0
0
0
3
4.01 (dt, 1H, J5 ,6 ax ꢀ 10.1 Hz, H-50); 3.81 (t, 1H, H-
60ax); 3.42–3.39 (m, 1H, H-20); 3.40 (s, 3H, OMe);
3.11–2.89 (m, 2H, H-4); 2.62–2.54 (m, 1H, H-30); 13C
NMR (62.9 MHz, CDCl3): d 161.1 (C-3); 160.9 (C-1);
137.4, 137.2 (2 · ipso-Ph); 129.1, 128.9, 128.2, 128.0,
127.9, 126.1 (o-, m-, p-Ph); 114.9 (CN); 110.8 (C-2);
101.9 (CHPh); 99.6 (C-10); 76.6 (C-20); 75.5 (C-40);
72.1 (CH2Ph); 69.3 (C-60); 59.3 (C-50); 55.0 (OMe);
38.9 (C-30); 28.7 (C-4); MS, EI (m/z): 464 [M]+; Anal.
Calcd for C26H28N2O6: C, 67.23; H, 6.08; N, 6.03.
Found: C, 67.75; H, 6.32; N, 5.88.
0
0
3.3. 2-Cyano-4-(methyl 2-O-benzyl-4,6-O-benzylidene-
3-deoxy-a-D-altropyranosid-3-yl)crotononitrile (5a)
To a solution of 4 (0.398 g, 1 mmol)in dried toluene
(10 mL), malononitrile (0.165 g, 2.5 mmol) and Al2O3
(0.1 g, aluminium oxide 90, active basic, Merck)were
added and the mixture was stirred at room temperature
for 1 h. After filtration the solvent was evaporated and
theresiduewaspurifiedbycolumnchromatography(tolu-
3.5. (2E)-2-Cyano-N-(4-methoxyphenyl)-4-(methyl 2-O-
benzyl-4,6-O-benzylidene-3-deoxy-a-D-altropyranosid-3-
yl)crotonamide (5c)
ene/EtOAc 10:1)to yield 0.400 g (90%)of 5a as a colour-
To a solution of 4 (0.398 g, 1 mmol)in dried tolu-
ene (30 mL), 2-cyano-N-(4-methoxyphenyl)acetamide
(0.376 g, 2 mmol)and Al 2O3 (0.1 g, aluminium oxide
90, active basic, Merck)were added and the mixture
was stirred under reflux for 2 h. After filtration the sol-
vent was evaporated and the residue purified by column
chromatography (toluene/EtOAc 7:1)to yield 0.400 g
25
D
less syrup; TLC: toluene/EtOAc 10:1, Rf 0.42; ½aꢁ +8.2
1
(c 1.0, CHCl3); IR (capillary), m (cmÀ1): 2235 (CN); H
NMR (250 MHz, CDCl3): d 7.43–7.31 (m, 10H,
3
3
2 · Ph); 7.03 (dd, 1H, J3,4a ꢀ 7.0 Hz, J3,4b ꢀ 8.6 Hz,
H-3); 5.56 (s, 1H, CHPh); 4.68 (br s, 1H, 3J1 ,2 ꢀ 1.2 Hz,
0
0
2
H-10); 4.60 (q(AB), 2H, JA,B ꢀ 12.0 Hz, CH2Ph); 4.29
2
3
(dd, 1H, J6 ax,6 eq ꢀ 9.8 Hz, J5 ,6 eq ꢀ 4.6 Hz, H-60eq);
(70%)of 5c as a white solid; TLC: toluene/EtOAc 7:1,
0
0
3
0
0
23
D
3
4.17 (dd, 1H, J4 ,5 ꢀ 9.8 Hz, J3 ,4 ꢀ 5.5 Hz, H-40);
Rf 0.38; mp 68–71 ꢁC; ½aꢁ +35.8 (c 1.0, CHCl3) ; IR
0
0
0
0
3
3.93 (dt, 1H, J5 ,6 ax ꢀ 9.8 Hz, H-50); 3.80 (t, 1H, H-
(KBr), m (cmÀ1): 3332 (NH); 2221 (CN); 1686 (CO);
0
0
3
60ax); 3.39 (s, 3H, OMe); 3.34 (dd, 1H, J2 ,3 ꢀ 2.1 Hz,
H-20); 3.06–2.85 (m, 2H, H-4); 2.48–2.41 (m, 1H, H-30);
13C NMR (75.5 MHz, CDCl3): d 168.9 (C-3); 137.1,
136.9 (2 · ipso-Ph); 129.2, 128.6, 128.2, 127.9, 127.2,
125.9 (o-, m-, p-Ph); 112.0, 110.5 (2 · CN); 102.1 (CHPh);
99.4 (C-10); 90.0 (C-2); 76.3 (C-20); 75.2 (C-40); 72.3
(CH2Ph); 69.2 (C-60); 59.2 (C-50); 55.0 (OMe); 39.1
1H NMR (250 MHz, CDCl3):
d
7.70 (dd, 1H,
0
0
3
3J3,4a ꢀ 6.4 Hz, J3,4b ꢀ 8.9 Hz, H-3); 7.65 (br s, NH);
7.47–7.41 (m, 2H, Ho-NHC6H4); 7.37–7.28 (m, 10H,
2 · Ph); 6.93–6.86 (m, 2H, Hm-NHC6H4); 5.59 (s, 1H,
3
CHPh); 4.69 (br s, 1H, J1 ,2 ꢀ 1.2 Hz, H-10); 4.59
0
0
2
0
0
(s, 2H, CH2Ph); 4.31 (dd, 1H, J6 ax,6 eq ꢀ 10.1 Hz,
3
J5 ,6 eq ꢀ 4.9 Hz,
H-60eq);
4.20
(dd,
1H,
0
0

552
3
I. Otero et al. / Carbohydrate Research 340 (2005) 547–555
3
J4 ,5 ꢀ 10.1 Hz, J3 ,4 ꢀ 5.5 Hz, H-40); 4.02 (dt, 1H,
(reaction time 12 h). Purification by column chromato-
graphy (EtOAc)gave 0.220 g (45%)of 6b as a light yellow
0
0
0
0
3
J5 ,6 ax ꢀ 10.1 Hz, H-50); 3.82 (t, 1H, H-60ax); 3.80 (s,
0
0
25
D
3H, p-OMe); 3.43–3.39 (m, 1H, H-20); 3.42 (s, 3H,
OMe); 3.11–2.92 (m, 2H, H-4); 2.64–2.59 (m, 1H, H-
30); 13C NMR (62.9 MHz, CDCl3): d 160.5 (C-3);
157.1, 157.07 (C-1, Cp-NHC6H4); 137.3, 137.2
(2 · ipso-Ph); 129.7 (Cipso-NHC6H4); 129.0, 128.6,
128.2, 128.1, 127.9, 126.1 (o-, m-, p-Ph); 122.3 (Co-
NHC6H4); 115.0 (CN); 114.2 (Cm-NHC6H4); 111.8 (C-
2); 101.9 (CHPh); 99.6 (C-10); 76.6 (C-20); 75.5 (C-40);
72.1 (CH2Ph); 69.3 (C-60); 59.4 (C-50); 55.4 (p-OMe);
54.9 (OMe); 38.9 (C-30); 28.7 (C-4); MS, EI (m/z): 570
[M]+; Anal. Calcd for C33H34N2O7: C, 69.46; H, 6.01;
N, 4.91. Found: C, 69.19; H, 6.06; N, 4.77.
solid; TLC: EtOAc, Rf 0.48; mp 88–91 ꢁC; ½aꢁ +92.6 (c
1.0, CHCl3); IR (KBr), m (cmÀ1): 3439, 3399, 3328
(NH2); 1642 (CO); 1H NMR (250 MHz, CDCl3): d
4
0
7.50–7.30 (m, 10H, 2 · Ph); 6.75 (d, 1H, J3 ,4 ꢀ 1.2
Hz, H-4); 6.05 (br s, NH2); 5.61 (s, 1H, CHPh); 5.39
(br s, NH2); 4.73 (s, 1H, H-10); 4.66 (q(AB), 2H,
2JA,B ꢀ 12.0 Hz,
CH2Ph);
0
4.28
(dd,
1H,
2
3
J6 ax,6 eq ꢀ 9.8 Hz, J5 ,6 eq ꢀ 5.2 Hz, H-60eq); 4.23 (dd,
0
0
0
3
3
1H, J4 ,5 ꢀ 9.8 Hz, J3 ,4 ꢀ 5.8 Hz, H-40); 4.07 (dt,
0
0
0
0
3
1H,
J5 ,6 ax ꢀ 9.8 Hz, H-50); 3.93 (dd, 1H,
0
0
3
3
J2 ,3 ꢀ 2.1 Hz, J1 ,2 ꢀ 0.9 Hz, H-20); 3.79 (t, 1H, H-
60ax); 3.71–3.66 (m, 1H, H-30); 3.33 (s, 3H, OMe); 13C
NMR (62.9 MHz, CDCl3): d 167.8 (CONH2); 161.8
(C-2); 137.8, 137.4 (2 · ipso-Ph); 129.0, 128.6, 128.2,
128.0, 127.8, 126.3 (o-, m-, p-Ph); 123.3 (C-4); 120.2
(C-5); 106.7 (C-3); 102.2 (CHPh); 99.7 (C-10); 78.6
(C-20); 75.6 (C-40); 72.3 (CH2Ph); 69.3 (C-60); 59.1 (C-
50); 54.8 (OMe); 41.2 (C-30); MS, EI (m/z): 496 [M]+;
Anal. Calcd for C26H28N2O6S: C, 62.89; H, 5.68; N,
5.64; S, 6.46. Found: C, 62.96; H, 5.98; N, 5.15; S,
5.92.
0
0
0
0
3.6. 2-Amino-5-(methyl 2-O-benzyl-4,6-O-benzylidene-
3-deoxy-a-D-altropyranosid-3-yl)thiophene-3-
carbonitrile (6a)
Compound 5a (0.446 g, 1 mmol)was dissolved in dry
N,N-dimethylformamide (5 mL). To this solution, sulfur
(0.048 g, 1.5 mmol)and triethylamine (0.21 mL)were
added, and the whole mixture was stirred at room tem-
perature for 15 min. Water (30 mL)was added, the mix-
ture was extracted with CH2Cl2 (3 · 50 mL), the organic
phase was washed with water (2 · 50 mL), dried
(Na2SO4)and evaporated under reduced pressure. The
residue was purified by column chromatography (tolu-
ene/EtOAc 5:1)to yield 0.406 g (85%)of 6a as a light
3.8. 2-Amino-N-(4-methoxyphenyl)-5-(methyl 2-O-
benzyl-4,6-O-benzylidene-3-deoxy-a-D-altropyranosid-
3-yl)thiophene-3-carboxamide (6c)
The reaction of 5c (0.446 g, 1 mmol)with sulfur was car-
ried out as described above for the preparation of 6a
(reaction time 12 h). Purification by column chromato-
graphy (toluene/EtOAc 4:1)gave 0.390 g (65%)of 6c as
yellow solid; TLC: toluene/EtOAc 5:1, Rf 0.38; mp
23
D
162–164 ꢁC; ½aꢁ +91.2 (c 1.0, CHCl3); IR (KBr), m
(cmÀ1): 3215, 3309 (NH2); 2214 (CN); 1H NMR
(250 MHz, CDCl3): d 7.50–7.30 (m, 10H, 2 · Ph); 6.79
a light yellow solid; TLC: toluene/EtOAc 4:1, Rf 0.30;
20
4
0
(d, 1H, J3 ,4 ꢀ 1.2 Hz, H-4); 5.60 (s, 1H, CHPh); 4.72
mp 95–98 ꢁC; ½aꢁ +92.9 (c = 0.5, CHCl3); IR (KBr), m
D
2
(s, 1H, H-10); 4.65 (q(AB), 2H, JA,B ꢀ 12.0 Hz,
(cmÀ1): 3436, 3322 (NH2); 1633 (CO); 1H NMR
(250 MHz, CDCl3): d 7.57–7.43 (m, 2H, Ho-NHC6H4);
7.40–7.34 (m, 10H, 2 · Ph); 6.91–6.84 (m, 3H, Hm-
NHC6H4, H-4); 6.03 (br s, NH2); 5.63 (s, 1H, CHPh);
CH2Ph); 4.61 (br s, NH2); 4.27 (dd, 1H,
0
2
3
J6 ax,6 eq ꢀ 10.0 Hz, J5 ,6 eq ꢀ 5.2 Hz, H-60eq); 4.22
0
0
0
3
3
(dd, 1H, J4 ,5 ꢀ 10.0 Hz, J3 ,4 ꢀ 5.4 Hz, H-40); 3.99
0
0
0
0
3
2
(dt, 1H, J5 ,6 ax ꢀ 10.0 Hz, H-50); 3.92 (dd, 1H,
4.76 (s, 1H, H-10); 4.69 (q(AB), 2H, JA,B ꢀ 12.0 Hz,
0
0
3
3
2
J2 ,3 ꢀ 2.1 Hz, J1 ,2 ꢀ 1.0 Hz, H-20); 3.78 (t, 1H, H-
CH2Ph);
0
4.30
J5 ,6 eq ꢀ 5.2 Hz,
(dd,
H-60eq);
1H,
J6 ax,6 eq ꢀ 10.0 Hz,
0
0
0
0
0
0
60ax); 3.68–3.62 (m, 1H, H-30); 3.33 (s, 3H, OMe); 13C
NMR (62.9 MHz, CDCl3): d 162.2 (C-2); 137.3, 137.2
(2 · ipso-Ph); 129.1, 129.0, 128.6, 128.3, 127.9, 126.3
(o-, m-, p-Ph); 125.3 (C-4); 123.5 (C-5); 115.9 (CN);
102.2 (CHPh); 99.6 (C-10); 87.1 (C-3); 78.2 (C-20); 75.4
(C-40); 72.4 (CH2Ph); 69.3 (C-60); 59.1 (C-50); 54.9
(OMe); 41.3 (C-30); MS, EI (m/z): 478 [M]+; Anal. Calcd
for C26H26N2O5S: C, 65.26; H, 5.48; N, 5.85; S, 6.70.
Found: C, 65.21; H, 5.73; N, 5.61; S, 6.01.
4.27
(dd,
1H,
3
0
3
3
3
3
J4 ,5 ꢀ 10.0 Hz, J3 ,4 ꢀ 5,8 Hz, H-40); 4.12 (dt, 1H,
0
0
0
0
3
J5 ,6 ax ꢀ 10.0 Hz, H-50); 3.96 (dd, 1H, J2 ,3 ꢀ 2.1 Hz
0
0
0
0
J1 ,2 ꢀ 0.9 Hz, H-20); 3.81 (t, 1H, H-60ax); 3.80 (s,
0
0
3H, p-OMe); 3.76–3.69 (m, 1H, H-30); 3.36 (s, 3H,
OMe); 13C NMR (62.9 MHz, CDCl3):
d 163.9
(CONH2); 161.2 (C-2); 156.3 (Cp-NHC6H4); 137.5,
137.4 (2 · ipso-Ph); 129.7 (Cipso-NHC6H4); 129.1,
128.6, 128.3, 128.1, 127.9, 126.3 (o-, m-, p-Ph); 122.5
(C-4); 122.3 (Co-NHC6H4); 120.7 (C-5); 114.2 (Cm-
NHC6H4); 107.9 (C-3); 102.2 (CHPh); 99.7 (C-10); 78.7
(C-20); 75.7 (C-40); 72.4 (CH2Ph); 69.3 (C-60); 59.2
(C-50); 55.4 (p-OMe); 54.9 (OMe); 41.3 (C-30); MS,
EI (m/z): 602 [M]+; Anal. Calcd for C33H34N2O7S: C,
65.76; H, 5.69; N, 4.65; S, 5.32. Found: C, 65.72; H,
5.96; N, 4.47; S, 5.01.
3.7. 2-Amino-5-(methyl 2-O-benzyl-4,6-O-benzylidene-
3-deoxy-a-D-altropyranosid-3-yl)thiophene-3-
carboxamide (6b)
The reaction of 5b (0.446 g, 1 mmol)with sulfur was car-
ried out as described above for the preparation of 6a

I. Otero et al. / Carbohydrate Research 340 (2005) 547–555
553
3.9. 4-Amino-6-(methyl 2-O-benzyl-4,6-O-benzylidene-3-
deoxy-a-D-altropyranosid-3-yl)thieno[2.3-d]pyrimidine (7)
(o-, m-, p-Ph); 124.0 (C-4a); 121.3 (C-5); 102.6 (CHPh);
99.7 (C-10); 78.6 (C-20); 75.4 (C-40); 72.5 (CH2Ph); 69.4
(C-60); 59.3 (C-50); 54.9 (OMe); 42.0 (C-30); MS, EI
(m/z): 506 [M]+; Anal. Calcd for C27H26N2O6S: C,
64.02; H, 5.17; N, 5.53; S, 6.33. Found: C, 63.84; H,
5.44; N, 5.32; S, 6.03.
Compound 6a (0.478 g, 1 mmol)was dissolved in trie-
thyl orthoformate (10 mL)and the mixture heated under
reflux for 1 h. After evaporation of the solvent under
reduced pressure the residue was dissolved in a saturated
solution of NH3 in abs ethanol (10 mL)and the mixture
again was heated under reflux for 2 h. Then the solvent
was removed in vacuo and the residue purified by col-
umn chromatography (EtOAc)to yield 0.255 g (50%)
3.11. 3,4-Dihydro-3-(4-methoxyphenyl)-6-(methyl 2-O-
benzyl-4,6-O-benzylidene-3-deoxy-a-D-altropyranosid-
3-yl)thieno[2,3-d]pyrimidin-4-one (8b)
of 7 as a white solid; TLC: EtOAc, Rf 0.32; mp 97–
The reaction of 6c (0.446 g, 1 mmol)with triethyl ortho-
formate was carried out as described above for the prep-
aration of 8a. Purification by column chromatography
(toluene/EtOAc 4:1)gave 0.200 g (65%)of 8b as a white
21
100 ꢁC; ½aꢁ +83.1 (c 1.0, CHCl3); IR (KBr), m (cmÀ1):
D
3385, 3191 (NH2); 1H NMR (250 MHz, CDCl3): d
8.41 (s, 1H, H-2); 7.49–7.31 (m, 11H, 2 · Ph, H-5);
5.65 (s, 1H, CHPh); 5.53 (br s, NH2); 4.77 (s, 1H, H-
solid; TLC: toluene/EtOAc 4:1, Rf 0.35; mp 94–97 ꢁC;
23
½aꢁ +139.9 (c 1.0, CHCl3); IR (KBr), m (cmÀ1) : 1688
2
10); 4.70 (q(AB), 2H, JA,B ꢀ 12.0 Hz, CH2Ph); 4.38
D
2
3
1
0
0
0
0
(dd, 1H,
J6 ax,6 eq ꢀ 10.0 Hz,
J5 ,6 eq ꢀ 5.2 Hz, H-
(CO); H NMR (250 MHz, CDCl3): d 8.01 (s, 1H, H-
3
3
2
60eq); 4.31 (dd, 1H, J4 ,5 ꢀ 10.0 Hz, J3 ,4 ꢀ 5.8 Hz,
2); 7.58 (d, 1H, J3 ,5 ꢀ 1.2 Hz, H-5); 7.52–7.49 (m,
0
0
0
0
0
3
H-40); 4.18 (dt, 1H, J5 ,6 ax ꢀ 10.0 Hz, H-50); 4.07 (dd,
2H, Ho-NHC6H4); 7.40–7.15 (m, 10H, 2 · Ph); 7.05–
6.99 (m, 2H, Hm-NHC6H4); 5.65 (s, 1H, CHPh); 4.77
0
0
3
3
1H, J2 ,3 ꢀ 2.1 Hz, J1 ,2 ꢀ 1.2 Hz, H-20); 3.98–3.92
(m, 1H, H-30); 3.83 (t, 1H, H-60ax); 3.30 (s, 3H, OMe);
13C NMR (62.9 MHz, CDCl3): d 167.4, 157.1 (C-4, C-
7a); 153.3 (C-2); 137.6 (C-6); 137.2, 137.1 (2 · ipso-Ph);
129.1, 128.6, 128.3, 128.2, 127.9, 126.2 (o-, m-, p-Ph);
117.0 (C-5); 115.9 (C-4a); 102.4 (CHPh); 99.5 (C-10);
78.7 (C-20); 75.4 (C-40); 72.4 (CH2Ph); 69.3 (C-60); 59.2
(C-50); 54.8 (OMe); 42.0 (C-30); MS, EI (m/z): 505
[M]+; Anal. Calcd for C27H27N3O5S: C, 64.14; H, 5.38;
N, 8.31; S, 6.34. Found: C, 64.18; H, 5.67; N, 7.97; S,
6.02.
0
0
0
0
(br s, 1H,3J1 ,2 ꢀ 1.2 Hz, H-10); 4.71 (q(AB), 2H,
0
0
2JA,B ꢀ 12.0 Hz,
CH2Ph);
0
4.36
(dd,
1H,
2
3
J6 ax,6 eq ꢀ 10.1 Hz, J5 ,6 eq ꢀ 5.2 Hz, H-60eq); 4.32
0
0
0
3
3
(dd, 1H, J4 ,5 ꢀ 10.1 Hz, J3 ,4 ꢀ 5.8 Hz, H-40); 4.19
0
0
0
0
3
(dt, 1H, J5 ,6 ax ꢀ 10.1 Hz, H-50); 4.09 (dd, 1H,
0
0
3
J2 ,3 ꢀ 2.1 Hz, H-20); 3.97–3.91 (m, 1H, H-30); 3.86 (s,
3H, p-OMe); 3.83 (t, 1H, H-60ax); 3.32 (s, 3H, OMe);
13C NMR (62.9 MHz, CDCl3): 163.2 (C-4); 159.9 (C-
7a); 157.3 (Cp-NHC6H4); 145.9 (C-2); 138.1 (C-6);
137.2, 137.1 (2 · ipso-Ph); 129.9 (Cipso-NHC6H4);
129.1, 128.9, 128.6, 128.3, 128.2, 127.9 (o-, m-, p-Ph);
125.3 (C-5); 123.9 (C-4a); 122.3 (Co-NHC6H4); 114.7
(Cm-NHC6H4); 102.7 (CHPh); 99.6 (C-10); 78.6 (C-20);
75.4 (C-40); 72.5 (CH2Ph); 69.4 (C-60); 59.2 (C-50); 55.6
(p-OMe); 54.9 (OMe); 41.9 (C-30); MS, CI (m/z): 613
[M]+; Anal. Calcd for C34H32N2O7S: C, 66.65; H, 5.26;
N, 4.57; S, 5.23. Found: C, 67.03; H, 5.48; N, 4.26; S,
4.84.
0
0
3.10. 3,4-Dihydro-6-(methyl 2-O-benzyl-4,6-O-benzylid-
ene-3-deoxy-a-D-altropyranosid-3-yl)thieno[2,3-d]pyrimi-
din-4-one (8a)
A solution of compound 6b (0.478 g, 1 mmol)and tri-
N,N-
ethyl orthoformate (300 lL, 3 mmol)in dry
dimethylformamide (10 mL)was heated under reflux
for 7 h. The solvent was evaporated under reduced pres-
sure and the residue purified by column chromatogra-
phy (EtOAc)to yield 0.140 g (56%)of 8a as a white
3.12. 2-Amino-5-(methyl 2-O-benzyl-3-deoxy-a-D-
altropyranosid-3-yl)thiophene-3-carbonitrile (9a)
solid; TLC: EtOAc, Rf 0.46; mp 109–112 ꢁC;
25
½aꢁ +86.2 (c 1.0, CHCl3); IR (KBr), m (cmÀ1): 3168
A solution of compound 6a (0.480 g, 1 mmol)in acetic
acid (5 mL)and water (0.5 mL)was heated at 70 ꢁC
D
1
(NH); 1668 (CO); H NMR (250 MHz, CDCl3): d 12.2
(br s, NH); 7.99 (s, 1H, H-2); 7.57 (d, 1H,
for 2 h. Water (10 mL)and NaHCO were added until
3
2
0
J5,3 ꢀ 1.2 Hz, H-5); 7.52–7.34 (m, 10H, 2 · Ph); 5.66
neutralization of the solution. The mixture was ex-
tracted with EtOAc (3 · 50 mL), the organic phase was
washed with water (2 · 50 mL), dried (Na2SO4)and
evaporated under reduced pressure. The residue was
purified by column chromatography (CHCl3/MeOH
(s, 1H, CHPh); 4.77 (s, 1H, H-10); 4.71 (q(AB), 2H,
2JA,B ꢀ 12.0 Hz,
CH2Ph);
3
4.37
(dd,
1H,
2
J6 ax,6 eq ꢀ 10.1 Hz, J5 ,6 eq ꢀ 5.5 Hz, H-60eq); 4.32
0
0
0
0
3
3
(dd, 1H, J4 ,5 ꢀ 10.4 Hz, J3 ,4 ꢀ 5.2 Hz, H-40); 4.16
0
0
0
0
(m, 1H, H-50); 4.11 (br s, 1H, H-20); 3.98–3.92 (m, 1H,
10:1)to yield 0.187 g (48%)of
9a as a white solid;
3
H-30); 3.84 (t, 1H, J5 ,6 ax ꢀ 10.1 Hz, H-60ax); 3.33 (s,
3H, OMe); 13C NMR (62.9 MHz, CDCl3): d 165.3 (C-
4); 159.5 (C-7a); 143.1 (C-2); 138.1 (C-6); 137.2, 137.1
(2 · ipso-Ph); 129.1, 128.7, 128.3, 128.2, 127.9, 126.9
TLC: CHCl3/MeOH 10:1, Rf 0.49; mp 128–130 ꢁC;
0
0
22
½aꢁ À33.0 (c 1.0, acetone); IR (KBr), m (cmÀ1): 3208,
D
3304, 3408, 3428 (NH2, OH); 2215 (CN); 1H NMR
(250 MHz, acetone-d6): d 7.31–7.16 (m, 5H, Ph); 6.56

554
I. Otero et al. / Carbohydrate Research 340 (2005) 547–555
4
0
(d, 1H, J3 ,4 ꢀ 1.0 Hz, H-4); 6.22 (br s, NH2); 4.69 (d,
3.89–3.70 (m, 4H, H-20, H-50, H-60); 3.46 (ddd, 1H,
3
3
3
J1 ,2 ꢀ 4.0 Hz, H-10); 4.52 (q(AB), 2H,
J2 ,3 ꢀ 10.0 Hz, J3 ,5 ꢀ 1.0 Hz, H-30); 3.43 (s, 3H,
0
0
0
0
0
1H,
2JA,B ꢀ 11.5 Hz, CH2Ph); 4.24 (br s, OH); 4.03–3.95
OMe); 13C NMR (62.9 MHz, acetone-d6): d 164.9 (C-
4); 157.7 (C-7a); 144.8 (C-2); 140.4, 139.1 (C-6, ipso-
Ph); 128.5, 128.2, 127.8 (o-, m-, p-Ph); 124.9 (C-4a);
121.3 (C-5); 103.4 (C-10); 79.1 (C-20); 76.4 (C-50); 72.9
(CH2Ph); 68.9 (C-40); 62.9 (C-60); 54.9 (OMe); 45.2 (C-
30); MS, EI (m/z): 419 [M+H]+; Anal. Calcd for
C20H22N2O6S: C, 57.40; H, 5.30; N, 6.69; S, 7.66.
Found: C, 57.77; H, 5.54; N, 5.93; S, 7.79.
(m, 1H, H-40); 3.81–3.67 (m, 3H, H-50, H-60); 3.63 (dd,
3
1H, J2 ,3 ꢀ 10.0 Hz, H-20); 3.40 (s, 3H, OMe); 3.13
0
0
(ddd, 1H, J3 ,4 ꢀ 4.0 Hz, H-30); 13C NMR (75.5 MHz,
acetone-d6): d 164.5 (C-2); 139.0 (ipso-Ph); 128.3,
127.9, 127.6 (o-, m-, p-Ph); 124.9 (C-5); 124.5 (C-4);
116.1 (CN); 103.7 (C-10); 84.6 (C-3); 78.7 (C-20);
76.2 (C-50); 72.7 (CH2Ph); 68.6 (C-40); 62.7 (C-60);
54.7 (OMe); 44.3 (C-30); MS, EI (m/z): 390 [M]+;
Anal. Calcd for C19H22N2O5S: C, 58.45; H, 5.68; N,
7.17; S, 8.21. Found: C, 58.61; H, 5.89; N, 6.46; S,
8.79.
3
0
0
3.15. 2-Amino-5-(1,6-anhydro-3-deoxy-b-D-altropyranos-
3-yl)thiophene-3-carbonitrile (10a)
Compound 9a (0.390 g, 1 mmol)was dissolved in chlo-
roform (10 mL). To this solution trimethylsilyliodide
(0.05 mL, 3.7 mmol)was added, and the whole mixture
was stirred under argon at room temperature for 12 h.
After disappearance of 9a, MeOH (10 mL)was added
and the mixture stirred for 4 h. The solution was concen-
trated under reduced pressure and the residue was puri-
fied by column chromatography (CHCl3/MeOH 10:1)to
3.13. 4-Amino-6-(methyl 2-O-benzyl-3-deoxy-a-D-
altropyranosid-3-yl)thieno[2.3-d]pyrimidine (9b)
The deprotection of compound 7 (0.500 g, 1 mmol)was
carried out as described above for the preparation of 9a
(reaction time 6 h). Purification by column chromato-
graphy (EtOAc/MeOH 10:1)gave 0.265 g (63%)of 9b
as a white solid; TLC: EtOAc/MeOH 10:1, Rf 0.31;
yield 0.160 g (53%)of 10a as a white solid; TLC: CHCl3/
25
D
21
D
mp 210–212 ꢁC; ½aꢁ À1.4 (c 0.5, MeOH); IR (KBr), m
MeOH 10:1, Rf 0.28; mp 78–81 ꢁC; ½aꢁ À201.7 (c 1.0,
1
(cmÀ1): 3410, 3372, 3331, 3233 (NH2, OH); H NMR
acetone); IR (KBr), m (cmÀ1): 3408, 3332, 3212 (NH2,
(250 MHz, DMSO-d6): d 8.18 (s, 1H, H-2); 7.39 (d,
OH); 2203 (CN); 1H NMR (500 MHz, DMSO-d6): d
6.84 (br s, 2H, NH2); 6.46 (s, 1H, H-4); 5.15 (s, 1H,
2
0
1H, J5,3 ꢀ 1.0 Hz, H-5); 7.31 (br s, NH2); 7.18–6.99
3
3
(m, 5H, Ph); 5.32 (d, 1H, J4 ,OH-4 ꢀ 5.5 Hz, OH-40);
H-10); 5.14 (d, 1H, J4 ,OH-4 ꢀ 7.0 Hz, OH-40); 4.92 (d,
0
0
0
0
3
3
4.86 (t, 1H, J6 ,OH-6 ꢀ 5.8 Hz, OH-60); 4.68 (d, 1H,
1H,
0
J2 ,OH-2 ꢀ 7.0 Hz, OH-20); 4.38 (dd, 1H,
0
0
0
0
3
2
3
3
J1 ,2 ꢀ 4.5 Hz, H-10); 4.46 (q(AB), 2H, JA,B ꢀ 11.6 Hz,
J5 ,6 b ꢀ 5.5 Hz, J4 ,5 ꢀ 2.5 Hz, H-50); 3.79 (d, 1H,
0
0
0
0
0
2
CH2Ph); 3.93–3.85 (m, 1H, H-40); 3.75–3.52 (m, 4H, H-
20, H-50, H-60); 3.37 (s, 3H, OMe); 3.37–3.32 (m, 1H, H-
30); 13C NMR (75.5 MHz, DMSO-d6): d 166.5, 157.9
(C-4, C-7a); 153.5 (C-2); 138.5, 138.1 (C-6, ipso-Ph);
128.1, 127.6, 127.5 (o-, m-, p-Ph); 118.7 (C-5); 115.4
(C-4a); 103.1 (C-10); 78.3 (C-20); 76.7 (C-50); 72.5
(CH2Ph); 67.8 (C-40); 61.6 (C-60); 55.0 (OMe); 44.9
(C-30); MS, EI (m/z): 417 [M]+; Anal. Calcd for
C20H23N3O5S: C, 57.54; H, 5.55; N, 10.07; S, 7.68.
Found: C, 57.78; H, 5.69; N, 9.88; S, 7.96.
J6 a,6 b ꢀ 7.5 Hz, H-60a); 3.61–3.56 (m, 1H, H-40, H-
0
0
3
3
60b); 3.47 (ddd, 1H, J1 ,2 ꢀ 1.0 Hz, J2 ,3 ꢀ 10.2 Hz,
0
0
0
0
H-20); 2.86 (dd, 1H, J3 ,4 ꢀ 4.0 Hz, H-30); 13C NMR
(125.8 MHz, DMSO-d6): d 164.9 (C-2); 124.5 (C-5);
123.4 (C-4), 117.1 (CN); 102.3 (C-10); 81.8 (C-3); 77.4
(C-50); 70.5 (C-20); 69.4 (C-40); 65.4 (C-60); 43.1 (C-30);
MS, EI (m/z): 268 [M]+; Anal. Calcd for C11H12N2O4S:
C, 49.24; H, 4.51; N, 10.44; S, 11.95. Found: C, 48.79;
H, 4.59; N, 9.57; S, 12.27.
3
0
0
3.16. 4-Amino-6-(1,6-anhydro-3-deoxy-b-D-altropyranos-
3-yl)thieno[2.3-d]pyrimidine (10b)
3.14. 3,4-Dihydro-6-(methyl 2-O-benzyl-3-deoxy-a-D-
altropyranosid-3-yl)thieno[2,3-d]pyrimidin-4-one (9c)
The reaction of compound 9b (0.210 g, 0.5 mmol)with
trimethylsilyliodide was carried out as described above
for the preparation of 10a. Purification by column chro-
matography (EtOAc/MeOH 5:1)gave 0.140 g (85%)of
The deprotection of compound 8a (0.250 g, 0.5 mmol)
was carried out as described above for the preparation
of 9a (reaction time 2 h). Purification by column chro-
matography (EtOAc/MeOH 10:1)gave 0.145 g (69%)
10b as a white solid; TLC: EtOAc/MeOH 5:1, Rf 0.22;
22
D
of 9c as a white solid; TLC: EtOAc/MeOH 10:1, Rf
mp 195–198 ꢁC; ½aꢁ À104.5 (c 1.0, MeOH); IR (KBr),
22
D
0.48; mp 75–78 ꢁC; ½aꢁ +0.8 (c 1.0, acetone); IR
m (cmÀ1): 3416, 3348, 3233 (NH2, OH); 1H NMR
(500 MHz, DMSO-d6): d 8.18 (s, 1H, H-2); 7.34 (s,
(KBr), m (cmÀ1): 3415 (OH); 1669 (CO); 1H NMR
(250 MHz, acetone-d6): d 11.3 (br s, NH); 8.05 (s, 1H,
1H, H-5); 7.29 (br s, 2H, NH2); 5.23 (s, 1H, H-10);
4
3
0
0
0
H-2); 7.32 (d, 1H, J3 ,5 ꢀ 1.0 Hz, H-5); 7.24–7.11 (m,
5.22 (d, 1H, J4 ,OH-4 ꢀ 6.0 Hz, OH-40); 5.08 (d,
3
3
0
0
0
0
0
5H, Ph); 4.77 (d, 1H, J1 ,2 ꢀ 4.0 Hz, H-1 ); 4.56
1H,
0
J2 ,OH-2 ꢀ 6.6 Hz, OH-20), 4.46 (dd, 1H,
2
3
3
0
0
0
(q(AB), 2H, JA,B ꢀ 12.0 Hz, CH2Ph); 4.52–4.36 (br s,
J5 ,6 b ꢀ 5.0 Hz, J4 ,5 ꢀ 2.0 Hz, H-50); 3.89 (d, 1H,
3
3
2
OH); 4.14 (t, 1H, J3 ,4 ꢀ J4 ,5 ꢀ 4.0 Hz, H-40);
J6 a,6 b ꢀ 7.9 Hz, H-60a); 3.77–3.69 (m, 2H, H-20, H-
0
0
0
0
0
0

I. Otero et al. / Carbohydrate Research 340 (2005) 547–555
555
3
40); 3.64 (dd, 1H, H-60b); 3.15 (dd, 1H, J2 ,3 ꢀ 10.1 Hz,
0
0
6. Shehata, I. A.; El-Subbagh, H. I.; Abdelal, A. M.; El-
Sherbeny, M. A.; Al-Obaid, A. A. Med. Chem. Res. 1996,
6, 148–163.
7. Pathak, U. S.; Singh, S.; Padh Indian J. Chem., Sect. B
1991, 30B, 618–619.
8. El-Barbary, A. A.; El-Brollosy, N. R.; Pedersen, E. B.;
Nielsen, C. Monatsh. Chem. 1995, 126, 593–600.
9. El-Barbary, A. A.; El-Brollosy, R.; Pedersen, E. B.;
Nielsen, C. Sulfur Lett. 1996, 20, 31–42.
J3 ,4 ꢀ 3.5 Hz, H-30); 13C NMR (125.8 MHz, DMSO-
d6): d 166.3, 157.8 (C-4, C-7a); 153.2 (C-2); 138.9 (C-6);
118.2 (C-5); 115.5 (C-4a); 102.3 (C-10); 77.5 (C-50);
70.6, 69.4 (C-20, C-40); 65.6 (C-60); 44.3 (C-30); MS,
FAB+ (m/z): 295 [M]+; HRMS: Anal. Calcd for
C12H13N3O4S 295.06268; Found: [M]+ m/z: 295.06148.
3
0
0
10. El-Barbary, A. A.; El-Brollosy, N. R.; Abdel-Bary, H. M.;
Pedersen, E. B.; Stein, P.; Nielsen, C. Liebigs Ann. Chem.
1995, 1371–1375.
3.17. 3,4-Dihydro-6-(1,6-anhydro-3-deoxy-b-D-altropyr-
anos-3-yl)thieno[2,3-d]pyrimidin-4-one (10c)
11. Patil, V. D.; Wise, D. S.; Wotring, L. L.; Bloomer, L. C.;
Townsend, L. B. J. Med. Chem. 1985, 28, 423–427.
12. Simons, C. C-Nucleosides. In Nucleoside Mimetics: Their
Chemistry and Biological Properties; Simons, C., Ed.;
Harwood Academic: Amsterdam, 2001; pp 117–135.
13. Yu, H. W.; Zhang, H. Y.; Yang, Z. J.; Min, J. M.; Ma, L.
T.; Zhang, L. H. Pure Appl. Chem. 1998, 70, 435–438.
14. Zhang, M.; Zhang, H.; Yang, Z.; Ma, L.; Min, J.; Zhang,
L. Carbohydr. Res. 1999, 318, 157–161.
15. Casiraghi, G.; Cornia, M.; Rassu, G.; Sante, C. D.; Spanu,
P. Tetrahedron 1992, 48, 5619–5628.
16. Gewald, K.; Kleinert, M.; Thiele, B.; Hentschel, M.
J. Prakt. Chem. 1972, 314, 303–314.
The reaction of compound 9c (0.210 g, 0.5 mmol)with
trimethylsilyliodide was carried out as described above
for the preparation of 10a. Purification by column chro-
matography (EtOAc/MeOH 5:1)gave 0.115 g (74%)of
10c as a white solid; TLC: EtOAc/MeOH 5:1, Rf 0.35;
24
D
mp decomposition at 220 ꢁC; ½aꢁ À72.3 (c 1.0, MeOH);
1
IR (KBr), m (cmÀ1): 3431 (NH, OH); 1686 (CO); H
NMR (500 MHz, DMSO-d6): d 12.3 (br s, NH); 8.03
3
(s, 1H, H-2); 7.21 (s, 1H, H-5); 5.23 (d, 1H, J4 ,OH-4
0
0
ꢀ 6.6 Hz, OH-40); 5.21 (s, 1H, H-10); 5.09 (d, 1H,
3
J2 ,OH-2 ꢀ 7.0 Hz,
OH-20);
4.45
(dd,
1H,
´
17. Gomez, M.; Quincoces, J.; Peseke, K.; Michalik, M.;
0
0
Reinke, H. J. J. Carbohydr. Chem. 1999, 18, 851–865.
18. Garcia, I.; Feist, H.; Cao, R.; Michalik, M.; Peseke, K.
J. Carbohydr. Chem. 2001, 20, 681–687.
19. Herrera, L.; Feist, H.; Quincoces, J.; Michalik, M.; Peseke,
K. J. Carbohydr. Chem. 2003, 22, 171–178.
3
3
J5 ,6 b ꢀ 5.7 Hz, J4 ,5 ꢀ 2.2 Hz, H-50); 3.91 (d, 1H,
0
0
0
0
2
J6 a,6 b ꢀ 7.9 Hz, H-60a); 3.76–3.60 (m, 3H, H-20, H-40,
0
0
3
3
H-60b); 3.20 (dd, 1H, J2 ,3 ꢀ 10.1 Hz, J3 ,4 ꢀ 3.8 Hz,
H-30); 13C NMR (125.8 MHz, DMSO-d6): d 163.8 (C-
4); 157.3 (C-7a); 144.8 (C-2); 140.5 (C-6); 123.9 (C-4a);
120.2 (C-5); 102.2 (C-10); 77.4 (C-50); 70.7, 69.3 (C-20,
C-40); 65.5 (C-60); 43.7 (C-30); MS, EI (m/z): 296 [M]+;
HRMS: Anal. Calcd for C12H12N2O5S 296.04669;
Found: [M]+ m/z 296.04474.
0
0
0
0
20. Hughes, A. B.; Stick, R. V.; Tilbrook, D. M. Aust. J.
Chem. 1990, 43, 1681–1695.
´
21. Wood, A. J.; Holt, D. J.; Domınguez, M.; Jenkins, P. R.
J. Org. Chem. 1998, 63, 8522–8529.
22. Furstner, A.; Baumgartner, J. Tetrahedron 1993, 49, 8541–
¨
8560.
23. Nakata, M.; Toshima, K.; Kai, T.; Kinoshita, M. Bull.
Chem. Soc. Jpn. 1985, 58, 3457–3464.
24. Postema, M. H. D.; Piper, J. L.; Liu, L.; Shen, J.; Faust,
M.; Andreana, P. J. Org. Chem. 2003, 68, 4748–4754.
Acknowledgements
´
25. Tronchet, J. M. J.; Zsely, M.; Geoffroy, M. Carbohydr.
Res. 1995, 275, 245–258.
26. Peseke, K.; Feist, H.; Hanefeld, W.; Kopf, J.; Schulz, H.
J. Carbohydr. Chem. 1995, 14, 317–325.
27. Texier-Boullet, F.; Focaud, A. Tetrahedron Lett. 1982, 23,
4727–4728.
The authors would like to thank the Deutsche Fors-
chungsgemeinschaft and the Fonds der Chemischen
Industrie for financial support. I.O. is grateful to the
Deutscher Akademischer Austauschdienst for
scholarship.
a
28. Taylor, E. C.; Berger, J. J. Org. Chem. 1967, 32, 2376–
2378.
29. Jung, M. E.; Lyster, M. A. J. Org. Chem. 1977, 42, 3761–
3764.
30. Olah, G. A.; Narang, S. C.; Gupta, B. G.; Malhotra, R.
J. Org. Chem. 1979, 44, 1247–1251.
References
1. Pathak, U. S.; Patel, R. S.; Singh, S. Ind. J. Pharm. Sci.
1991, 53, 85–87.
31. Chan, T. H.; Lee, S. D. Tetrahedron Lett. 1983, 24, 1225–
1228.
2. Huybrechts, L.; Buffel, D.; Freyne, E.; Hoornaert, G.
Tetrahedron 1984, 40, 2479–2485.
32. Millar, A.; Kim, K.; Minster, D.; Ohgi, T.; Hecht, S.
J. Org. Chem. 1986, 51, 189–196.
3. Ibrahim, Y. A.; Elwahy, A. H. M.; Kadry, A. M. Adv.
Heterocycl. Chem. 1996, 65, 235–281.
33. Yamazaki, F.; Sato, S.; Nukada, T.; Ito, Y.; Ogawa, T.
Carbohydr. Res. 1990, 201, 31–50.
4. Russell, R. K.; Press, J. B.; Rampulla, R. A.; McNally, J.
J.; Falotico, R.; Keiser, J. A.; Bright, D. A.; Tobia, A.
J. Med. Chem. 1988, 31, 1786–1793.
5. Temple, D. L.; Yevich, J. P.; Covington, R. R.; Hanning,
C. A.; Seidehamel, R. J.; Mackey, H. K.; Bartek, M. J.
J. Med. Chem. 1979, 22, 505–510.
34. Cruzado, C.; Martin-Lomas, M. Carbohydr. Res. 1988,
175, 193–199.
35. Rijsbergen, R.; Anteunis, M.; De Bruyn, A. J. Carbohydr.
Chem. 1992, 11, 463–470.
36. Paulsen, H.; Sinnwell, V.; Greve, W. Carbohydr. Res.
1976, 49, 27–35.