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

Article abstract of DOI:10.1081/CAR-120021697

Treatment of 2-(methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-α-D-altropyranosid-2-yl)ethanal (3) with malononitrile in the presence of aluminium oxide provided 2-cyano-4-(methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-α-D-altropyranosid-2-yl) crotononitrile (

Full text of DOI:10.1081/CAR-120021697

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Synthesis of (Methyl
3‐O‐Benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐d‐altropyranosid‐
Derivatives as Precursors of New Iso‐C‐nucleoside
Analogues
Lidcay Herrera a , Holger Feist a , José Quincoces b , Manfred Michalik c & Klaus Peseke a
a Fachbereich Chemie, Universität Rostock, D‐18051, Rostock, Germany
b Universidade Bandeirante de São Paulo, Rua Maria Candida, 1813, Vila Guilherme, Sao
Paulo, CEP: 02071‐013, Brazil
c Institut für Organische Katalyseforschung, Buchbinderstraße 5‐6, D‐18055, Rostock,
Germany
Published online: 28 Oct 2011.
To cite this article: Lidcay Herrera , Holger Feist , José Quincoces , Manfred Michalik & Klaus Peseke (2003) Synthesis
of (Methyl 3‐O‐Benzyl‐4,6‐O‐benzylidene‐2‐deoxy‐α‐d‐altropyranosid‐2‐yl)thiophene Derivatives as Precursors of New
Iso‐C‐nucleoside Analogues, Journal of Carbohydrate Chemistry, 22:3-4, 171-178, DOI: 10.1081/CAR-120021697
To link to this article: http://dx.doi.org/10.1081/CAR-120021697
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 22, Nos. 3 & 4, pp. 171–178, 2003
Synthesis of (Methyl 3-O-Benzyl-4,6-O-benzylidene-2-
deoxy-a-D-altropyranosid-2-yl)thiophene Derivatives
as Precursors of New Iso-C-nucleoside Analogues
Lidcay Herrera,1 Holger Feist,1 Jose´ Quincoces,2
Manfred Michalik,3 and Klaus Peseke1,
*
1Fachbereich Chemie, Universita¨t Rostock, Rostock, Germany
2Universidade Bandeirante de Sa˜o Paulo, Vila Guilherme, Sao Paulo, Brazil
3Institut fu¨r Organische Katalyseforschung, Rostock, Germany
ABSTRACT
Treatment of 2-(methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-a-D-altropyranosid-
2-yl)ethanal (3) with malononitrile in the presence of aluminium oxide provided 2-
cyano-4-(methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-a-D-altropyranosid-2-
yl)crotononitrile (4). Starting from 4, cyclization with sulphur and triethylamine
yielded 2-amino-5-(methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-a-D-altropyrano-
sid-2-yl)thiophene-3-carbonitrile (5). Further cyclization could be achieved with
triethyl orthoformate/ammonia to furnish 4-amino-6-(methyl 3-O-benzyl-4,6-O-
benzylidene-2-deoxy-a-D-altropyranosid-2-yl)thieno[2.3-d]pyrimidine (8).
Key Words: Nucleoside analogues; Branched-chain sugars; Malononitrile;
Thiopene; Thieno[2.3-d]pyrimidine.
*
Correspondence: Klaus Peseke, Fachbereich Chemie, Universita¨t Rostock D-18051 Rostock,
Germany; Fax: 49-381-498-6412; E-mail: klaus.peseke@chemie.uni-rostock.de.
171
DOI: 10.1081/CAR-120021697
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2003 by Marcel Dekker, Inc.

172
Herrera et al.
INTRODUCTION
The synthesis of C-nucleoside analogues in the last years has been carried out in a
search for compounds having anticancer, antibacterial and antiviral activities.[1–4] Fur-
thermore, iso-C-nucleosides in which the nucleobase is linked by a carbon-carbon bond
to the sugar moiety at a carbon other than C-1 are a special type of C-nucleosides.
These substances may have an increased chemical and enzymatic stability under phy-
siological conditions.[5]
Several syntheses of iso-C-nucleosides have been reported.[4–6] Recently we de-
scribed a method for the preparation of C-nucleosides on the basis of (a-D-glycopy-
ranosyl) thiophene and thienopyrimidine derivatives[7] due to the wide spectrum of
interesting biological properties of thiophene derivatives such as serine protease in-
hibitions,[8] dihydrofolate reductase inhibitions,[9] analgesic,[10,11] and anti-inflammat-
ory[11] properties, among others. In the present paper we describe the synthesis of the
corresponding iso-C-nucleosides, the (methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-a-
D-altropyranosid-2-yl)thiophene and (methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-a-
D-altropyranosid-2-yl)thieno[2.3-d]pyrimidine.
RESULTS AND DISCUSSION
Methyl 2,3-anhydro-4,6-benzylidene-a-D-allopyranoside 1 was reacted in two steps
to furnish the known alkene derivative 2.[12,13] Oxidation of 2 with osmium tetroxide
and sodium periodate[14] afforded in two hours 2-(methyl 3-O-benzyl-4,6-O-benzyli-
1
dene-2-deoxy-a-D-altropyranosid-2-yl)ethanal 3 in 66% yield. The signals in the H and
13C NMR spectra found at d = 9.66 and 199.0, respectively, are typical of the alde-
hyde group in structure 3.
Starting from 3, the Knoevenagel reaction with excess malononitrile could be
performed to yield the crotononitrile derivative 4 (Scheme 1). The reaction was cata-
lyzed by aluminium oxide,[15,16] permitting complete transformation of the starting
material in only one hour. After isolation of the product by column chromatography,
the spectroscopic data of the product clearly verified the formation of compound 4. In
the IR spectrum both cyano groups appeared at 2242 cm–1 and the mass spectrum gave
the corresponding molecular peak.
The degree of acidity of the methylene group at the neighbouring position to the
dicyanomethylene moiety allowed the preparation of 2-amino-5-(methyl 3-O-benzyl-
4,6-O-benzylidene-2-deoxy-a-D-altropyranosid-2-yl)thiophene-3-carbonitrile (5) by
treatment of 4 with elementary sulphur and triethylamine.[17] In the original procedure
for the synthesis of such thiophenes, ethanol was used as solvent.[18] However, we
carried out the reaction in N,N-dimethylformamide and isolated the thiophene-3-
carbonitrile 5 as light yellow solid in 82% yield. As expected, in the IR spectrum of
5 only one CN band was found at a lower wave number 2204 cm–1 due to the
conjugation of the cyano group with the thiophene ring and the amino group. In the 13C
1
NMR spectrum of 5 only one CN signal at d = 115.2 was present and in the H NMR
spectrum the signals of H-4 of the thiophene ring and amino group appeared at
d = 6.51 and 4.71, respectively.

Synthesis of Thiophene Derivatives
173
Scheme 1.
For further cyclization the enaminonitrile unit located in the thiophene ring of 5
could be used.[19] Treatment of thiophene 5 with triethyl orthoformate under reflux
afforded a crude syrupy formimidic acid ester 6 which furnished, by reaction with a
saturated ethanolic ammonia solution at room temperature, the 2-[aminomethylenami-
no]thiophene-3-carbonitrile 7 in 41% yield. On the other hand, 6 reacted with a sa-
turated ethanolic ammonia solution under reflux gave the corresponding thieno[2.3-d]
pyrimidine-4-amine 8 in 64% yield (Scheme 2).
In the IR and 13C NMR spectra of compound 7 the expected CN peaks were
1
displayed and in the H NMR spectrum a broad singulet at d = 7.83 could be assigned
to the aminomethylenamino group of the thiophene ring. The absence of CN peaks
in the IR and in the 13C NMR spectra of the (a-D-altropyranosid-2-yl)thieno[2.3-d]
pyrimidine 8 proved the successful ring closure. Furthermore, in the H NMR spec-
1
trum a defined singlet appeared at d = 8.42 belonging to H-2 of the thieno[2.3-d]
pyrimidine ring.

174
Herrera et al.
Scheme 2.
EXPERIMENTAL
General procedures. Melting points were determined with a Boe¨tius melting
point apparatus and are corrected. Optical rotations were measured with a Polar LmP
(IBZ Meßtechnik) polarimeter. IR spectra were recorded with a Nicolet 205 FT-IR
1
spectrometer. H and 13C NMR spectra were recorded with a Bruker AC 250 (250.1
MHz and 62.9 MHz, respectively) and a Bruker ARX 300 (300.1 MHz and 75.5 MHz,
respectively). The calibration of spectra was carried out by means of solvent peaks
1
(CDCl3: d H 7.25; d 13C 77.0). The 13C NMR signals were assigned by DEPT and/or
1
two-dimensional H,13C correlation spectra. Mass spectra were obtained with an AMD
402/3 spectrometer (AMD Intectra GmbH). Elemental analyses were performed with a
Leco CHNS-932. Column chromatography was carried out on silica gel 60 (230–400
mm, Merck). Thin-layer chromatography (TLC) was performed on silica gel 60 GF254
foils (Merck) with detection by UV-light and by charring with sulphuric acid. Solvents
and liquid reagents were purified and dried according to recommended procedures.

Synthesis of Thiophene Derivatives
175
2-(Methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy- -D-altropyranosid-2-yl)etha-
nal (3). To methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-C-(prop-2-enyl)-a-D-
altropyranoside (2) (1.98 g, 5 mmol) dissolved in dioxane/water 10:1 (50 mL), was
added an OsO4-solution (0.4 mg in dioxane, 0.4 mL), and the resulting reaction mixture
was stirred at room temperature for 45 min. Then NaIO4 (2.14 g), as a saturated
solution in water was added, the mixture stirred for 2 h, filtered, and the solvent
completely removed in vacuo. Compound 3 was obtained as a white solid after column
chromatography (toluene/ethyl acetate 3:1): yield 1.31 g (66%); mp 95–97°C;
[a]D21 + 45.7 (c 1.0, CHCl3); Rf 0.35 (toluene/ethyl acetate 3:1). IR (KBr): 1717 cm–1
1
3
(CO). H NMR (250.1 MHz, CDCl3), d 9.66 (t, 1H, J1,2 = 1.2 Hz, H-1); 7.47–7.15
(m, 10H, ArH); 5.54 (s, 1H, CH-Ph); 4.82, 4.78 (q (AB), 2H, JA,B = 13.1 Hz, CH2-
2
3
Ph); 4.44 (m, 1H, H-5’); 4.41 (d, 1H, J1’,2’ = 0.5 Hz, H-1’); 4.31 (dd, 1H,
3
2J6’a,6’b = 10.3 Hz, J5’,6’a = 5.4 Hz, H-6’a); 3.75–3.64 (m, 3H, H-3’, H-4’, H-6’b);
2
3
3.41 (s, 3H, OMe); 2.90 (m, 1H, H-2’); 2.66 (ddd, 1H, J2a,2b = 18.2, Hz, J2a,2’ = 8.0
3
2
3
Hz, J1,2a = 1.2 Hz, H-2a); 2.47 (ddd, 1H, J2a,2b = 18.2, Hz, J2b,2’ = 6.3 Hz,
3J1,2b = 1.2 Hz, H-2b). 13C NMR (62.9 MHz, CDCl3), d 199.0 (C-1); 138.7, 137.5
(2 Â i-Ph); 129.0 (p-Ph), 128.2, 128.1, 127.5, 126.2 (o-,m-Ph); 127.2 (p-Ph); 102.2
(CH-Ph); 101.4 (C-1’); 77.2 (C-4’); 74.4 (C-3’); 72.1 (CH2-Ph); 69.4 (C-6’); 58.2 (C-5’);
55.7 (OMe); 44.7 (C-2); 37.5 (C-2’). MS (EI), m/z: 398 [M] + .
Anal. Calcd for C23H26O6 (398.45): C, 69.33; H, 6.58. Found: C, 69.18; H, 6.70.
2-Cyano-4-(methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy- -D-altropyranosid-
2-yl)crotononitrile (4). To a solution of 3 (0.398 g, 1 mmol) in dried toluene (30
mL), were added malononitrile (0.165 g, 2.5 mmol) and Al2O3 (0.1 g), and the mixture
was stirred under reflux for 1 h. After filtration the solvent was evaporated, the residue
was purified by column chromatography (toluene/ethyl acetate 3:1) and recrystallized
from ethanol to give 4 as white crystals: yield 0.388 g (87%); mp 148–150°C; [a]D21
–
1
56.7 (c 1.0, CHCl3); Rf 0.45 (toluene/ethyl acetate 3:1). IR (KBr): 2242 cm–1 (CN). H
3
NMR (250.1 MHz, CDCl3), d 7.52–7.33 (m, 10H, ArH); 6.86 (t, 1H, J3,4 = 7.8 Hz,
H-3); 5.57 (s, 1H, CH-Ph); 4.89, 4.67 (2d, 2H, JA,B = 12.5 Hz, CH2-Ph); 4.46–4.29
2
3
(m, 3H, H-1’, H-5’, H-6’a); 3.78–3.69 (m, 2H, H-4’, H-6’b); 3.58 (dd, 1H, J3’,4’ = 3.0
3
3
3
Hz, J2’,3’ = 2.0 Hz, H-3’); 3.41 (s, 3H, OMe); 2.63 (‘‘t’’, 2H, J3,4 = J2’,4 = 7.8 Hz,
H-4); 2.31 (dt, 1H, J2’,4 = 7.8 Hz, J2’,3’ = 2.0 Hz, H-2’). 13C NMR (62.9 MHz,
CDCl3), d 165.7 (C-3); 138.0, 137.4 (2 Â i-Ph); 129.1 (p-Ph), 128.4, 128.3, 128.2,
126.2 (o-,m-Ph); 128.0 (p-Ph); 111.3, 110.1 (2 Â CN); 102.3 (CH-Ph); 100.8 (C-1’);
91.7 (C-2); 76.9 (C-4’); 73.1 (CH2-Ph); 72.6 (C-3’); 69.3 (C-6’); 58.3 (C-5’); 55.7
(OMe); 43.6 (C-2’); 33.6 (C-4). MS (CI), m/z: 447 [M + 1] + .
3
3
Anal. Calcd for C26H26N2O5 (446.50): C, 69.94; H, 5.87; N, 6.27. Found: C, 69.81;
H, 5.64; N, 6.39.
2-Amino-5-(methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy- -D-altropyranosid-
2-yl)thiophene-3-carbonitrile (5). Compound 4 (0.446 g, 1 mmol) was dissolved
in dry DMF (5 mL). To this solution sulphur (0.048 g, 1.5 mmol) and triethylamine
(0.21 mL) were added, and the entire mixture was stirred at room temperature for 2 h.
Water (30 mL) was added, the mixture was extracted with CH2Cl2 (3 Â 50 mL), and
the organic phase was washed with water (2 Â 50 mL), dried (Na2SO4) and
concentrated under reduced pressure. The residue was purified by column chromato-

176
Herrera et al.
graphy (toluene/ethyl acetate 3:1) to give 5 as a light yellow solid: yield 0.392 g (82%);
mp 158–160°C; [a]D21 –65.3 (c 1.0, CHCl3); Rf 0.40 (toluene/ethyl acetate 3:1). IR
1
(KBr): 2204 cm–1 (CN). H NMR (250.1 MHz, CDCl3), d 7.50–7.20 (m, 10H, ArH);
6.51 (d, 1H, J2’,4 = 0.9 Hz, H-4); 5.52 (s, 1H, CH-Ph); 4.89 (d, 1H, JA,B = 12.5 Hz,
4
2
3
2
1 Â CH2-Ph); 4.82 (br s, 1H, J1’,2’ = 0.6 Hz, H-1’); 4.74 (d, 1H, JA,B = 12.5 Hz,
2
1 Â CH2-Ph); 4.71 (br, 2H, NH2); 4.48 (m, 1H, H-5’); 4.36 (dd, 1H, J6’a,6’b = 10.1
3
3
3
Hz, J5’,6’a = 5.5 Hz, H-6’a); 3.92 (dd, 1H, J4’,5’ = 9.7 Hz, J3’,4’ = 3.0 Hz, H-4’);
3
3
3.84 (br ‘‘t’’, 1H, J3’,4’ = 3.0 Hz, J2’,3’ = 2.5 Hz, H-3’); 3.77 (‘‘t’’, 1H,
2J6’a,6’b = J5’,6’b = 10.3 Hz, H-6’b); 3.43 (s, 3H, OMe); 3.39 (m, 1H, H-2’). 13C
3
NMR (62.9 MHz, CDCl3), d 161.3 (C-2); 138.4, 137.5 (2 Â i-Ph); 129.0 (p-Ph);
128.3, 128.2, 127.8, 126.2, (o-, m-Ph); 127.6 (p-Ph), 126.0 (C-5); 123.5 (C-4); 115.2
(CN); 102.3 (CH-Ph); 100.8 (C-1’); 87.3 (C-3); 76.4 (C-4’); 75.9 (C-3’); 72.8 (CH2-Ph);
69.4 (C-6’); 58.5 (C-5’); 55.7 (OMe); 45.5 (C-2’). MS (CI), m/z: 479 [M +1] + .
Anal. Calcd for C26H26N2O5S (478.56): C, 65.26; H, 5.48; N, 5.85; S, 6.70. Found:
C, 65.56; H, 5.69; N, 5.76; S, 6.56.
5-(Methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy- -D-altropyranosid-2-yl)-2-
[aminomethylenamino]thiophene-3-carbonitrile (7). Compound 5 (0.478 g, 1 mmol)
was dissolved in triethyl orthoformate (10 mL) and the reaction mixture was refluxed
for 1 h. The solvent was then evaporated under reduced pressure and the residue dis-
solved in a saturated solution (10 mL) of NH3 in ethanol. The mixture was then stirred
for 1 h, and the solvent was evaporated. The residue was purified by column chroma-
tography (toluene/ethyl acetate 1:1) to give 7 as a white solid: yield 0.207 g (41%); mp
113–115°C; [a]D21 –75.8 (c 0.23, CHCl3); Rf 0.41 (toluene/ethyl acetate 1:1). IR (KBr):
1
2215 cm–1 (CN). H NMR (250.1 MHz, CDCl3), d 7.83 (br, 1H, CH = N); 7.50–7.15
4
(m, 10H, ArH); 6.71 (d, 1H, J2’,4 = 0.9 Hz, H-4); 5.53 (s, 1H, CH-Ph); 5.46 (br, NH2);
2
4.89 (d, 1H, JA,B = 12.8 Hz, 1 Â CH2-Ph); 4.86 (s, 1H, H-1’); 4.76 (d, 1H,
2
2JA,B = 12.8 Hz, 1 Â CH2-Ph); 4.50 (m, 1H, H-5’); 4.37 (dd, 1H, J6’a,6’b = 10.2 Hz,
3
3
3J5’,6’a = 5.5 Hz, H-6’a), 3.93 (dd, 1H, J4’,5’ = 9.5 Hz, J3’,4’ = 3.0 Hz, H-4’); 3.88 (br
3
3
2
3
‘‘t’’, 1H, J3’,4’ = 3.0 Hz, J2’,3’ = 2.5 Hz H-3’); 3.79 (‘‘t’’, 1H, J6’a,6’b = J5’,
= 10.2 Hz, H-6’b); 3.48 (m, 1H, H-2’); 3.44 (s, 3H, OMe). 13C NMR (62.9 MHz,
6’b
CDCl3), d 164.8 (C-2); 153.8 (CH N); 138.4, 137.5 (2 Â i-Ph); 131.1 (C-5); 129.0 (p-
Ph); 128.3, 128.2, 127.7, 126.2, (o-,m-Ph); 127.6 (p-Ph); 124.4 (C-4); 116.1 (CN); 102.3
(CH-Ph); 100.8 (C-1’); 96.9 (C-3); 76.3 (C-4’); 76.0 (C-3’); 72.8 (CH2-Ph); 69.4 (C-6’);
58.5 (C-5’); 55.7 (OMe); 46.1 (C-2’). MS (CI), m/z: 506 [M + 1] + .
Anal. Calcd for C27H27N3O5S (505.58): C, 64.14; H, 5.38; N, 8.31; S, 6.34. Found:
C, 64.28; H, 5.45; N, 8.38; S, 6.30.
4-Amino-6-(methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy- -D-altropyranosid-
2-yl)thieno[2.3-d]pyrimidine (8). Compound 5 (0.478 g, 1 mmol) was dissolved in
triethyl orthoformate (10 mL) and the reaction mixture was refluxed for 1 h. The
solvent was evaporated under reduced pressure, and the residue was dissolved in a
saturated solution (10 mL) of NH3 in ethanol. The mixture was stirred for 1 h and then
heated until the product 7 disappeared (TLC control). The solvent was removed and
the residue purified by column chromatography (ethyl acetate) to give 8 as a white
solid: yield 0.323 g (64%); mp 100–102°C; [a]D21 –85.3 (c 1.0, CHCl3); Rf 0.33 (ethyl
1
acetate). IR (KBr): 3230, 3196 cm–1 (NH2). H NMR (250.1 MHz, CDCl3), d 8.42

Synthesis of Thiophene Derivatives
177
(s, 1H, H-2); 7.48–7.27 (m, 10H, ArH); 6.97 (s, 1H, H-5); 5.67 (br d, 2H, NH2); 5.49
2
(s, 1H, CH-Ph); 5.01 (s, 1H, H-1’); 4.93, 4.79 (q (AB), 2H, JA,B = 12.8 Hz, CH2-Ph);
2
3
4.55 (m, 1H, H-5’); 4.38 (dd, 1H, J6’a,6’b = 10.3 Hz, J5’,6’a = 5.5 Hz, H-6’a), 4.02 (br
3
3
‘‘t’’, 1H, H-3’); 3.95 (dd, 1H, J4’,5’ = 9.5 Hz, J3’,4’ = 3.1 Hz, H-4’); 3.78 (t, 1H,
3
3
2J6’a,6’b = J5’,6’b = 10.3 Hz, H-6b’); 3.69 (br d, 1H, J2’,3’ = 2.5 Hz, H-2’); 3.47
(s, 3H, OMe). 13C NMR (62.9 MHz, CDCl3), d 166.9, 157.2 (C-4, C-7a); 153.7 (C-2);
139.8, 116.9 (C-4a, C-6); 138.2, 137.4 (2 Â i-Ph); 129.0 (p-Ph); 128.3, 128.2, 127.9,
126.1 (o-,m-Ph); 127.6 (p-Ph); 115.7 (C-5); 102.2 (CH-Ph); 100.7 (C-1’); 76.3 (C-4’);
76.0 (C-3’); 72.9 (CH2-Ph); 69.4 (C-6’); 58.6 (C-5’); 55.8 (OMe); 46.4 (C-2’). MS (CI),
m/z: 506 [M + 1] + .
Anal. Calcd for C27H27N3O5S (505.58): C, 64.14; H, 5.38; N, 8.31; S, 6.34. Found:
C, 63.92; H, 5.54; N, 8.15; S, 6.63.
ACKNOWLEDGMENTS
We are grateful to the Deutsche Forschungsgemeinschaft and the Fonds der Che-
mischen Industrie for financial support. J. Q. is grateful to the Fundac¸a˜o de Amparo a`
Pesquisa do Estado de Sa˜o Paulo (FAPESP, Brasil) and the Deutscher Akademischer
Austauschdienst for financial support. L. H. would like to thank the Deutscher Aka-
demischer Austauschdienst for a scholarship.
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Received September 27, 2002
Accepted February 5, 2003