Synthesis of reversed C-nucleosides

Article abstract of DOI:10.1080/00397910903064849

A number of C-nucleoside analogs of the D-furanose series were synthesized by using push-pull activated monosaccharide-dimethylaminomethyleneulose (1) as a precursor. Enaminoketone 1 was reacted with o-phenylenediamine, cyanamide, and dialkyl-3-oxoglutarates to obtain benzodiazepine nucleoside analog 2, reversed C-nucleoside analog with pyrimidine ring 3, and isophthalic acid derivative 4, respectively.

Full text of DOI:10.1080/00397910903064849

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Synthesis of Reversed C-Nucleosides
Imran Ali Hashmi a b , Firdous Imran Ali a , Holger Fiest b & Klaus
Peseke b
a Department of Chemistry , University of Karachi , Karachi,
Pakistan
b University of Rostock, Institute for Chemistry , Rostock, Germany
Published online: 12 Mar 2010.
To cite this article: Imran Ali Hashmi , Firdous Imran Ali , Holger Fiest & Klaus Peseke (2010)
Synthesis of Reversed C-Nucleosides, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:8, 1243-1247, DOI: 10.1080/00397910903064849
To link to this article: http://dx.doi.org/10.1080/00397910903064849
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Synthetic Communications1, 40: 1243–1247, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903064849
SYNTHESIS OF REVERSED C-NUCLEOSIDES
Imran Ali Hashmi,1,2 Firdous Imran Ali,1 Holger Fiest,2 and
Klaus Peseke2
1Department of Chemistry, University of Karachi, Karachi, Pakistan
2University of Rostock, Institute for Chemistry, Rostock, Germany
A number of C-nucleoside analogs of the D-furanose series were synthesized by using
push–pull activated monosaccharide a-dimethylaminomethyleneulose (1) as a precursor.
Enaminoketone 1 was reacted with o-phenylenediamine, cyanamide, and dialkyl-3-
oxoglutarates to obtain benzodiazepine nucleoside analog 2, reversed C-nucleoside analog
with pyrimidine ring 3, and isophthalic acid derivative 4, respectively.
Keywords: Benzodiazepine; dialkyl-3-oxoglutarates; enaminoketone; D-furanose; isophthalic acid;
reversed C-nucleosides
INTRODUCTION
C-Nucleosides exhibit pharmacological activities such as antibiotic, antiviral,
and antitumor properties and are an important subclass of nucleosides. Further-
more, C-nucleosides are stable against enzymatic and chemical hydrolysis and so
are potential glycosidase inhibitors.[1–7] However, despite the large amount of data
collected, C-nucleosides and especially C-nucleosides belonging to the 2-deoxy-D-
ribose series have not been explored to an adequate extent,[8] but the development
of strategies for the formation of C-nucleoside analogs is a topic of current interest
in organic synthesis.
In recent years, we have reported the preparation of C-branched monosacchar-
ides[9,10] with push–pull functionality, which are used as precursors for the synthesis
of reversed C-nucleoside analogs.
Earlier studies showed that Knoevenagel compounds derived from carbonyl
compounds with neighboring active methylene groups react with carbon disulfide
and alkyl halide in the presence of bases to afford butadienes.[11] Such compounds,
the aryl substituted 2-cyano-5,5-bis(methylthio)-2,4-pentadienenitriles, were converted
into substituted nicotinonitriles.[12,13]
Received April 22, 2009.
Address correspondence to Imran Ali Hashmi, Department of Chemistry, University of Karachi,
University Road, Karachi 75270, Pakistan. E-mail: imran_ali_hashmi@yahoo.com
1243

1244
I. A. HASHMI ET AL.
Scheme 1. Synthesis of benzodiazepine nucleoside analog 2.
Reaction of a-Dimethylaminomethyleneulose 1
with N,N-Dinucleophiles
Both 1,4- and 1,5-benzodiazapines are therapeutic agents with widespread biologi-
cal activities. It was reported by our group that the reaction of 1,4-dinucleophiles with
pentopyranosid-4-ulose failed to get the benzodiazepine nucleoside analogs.[14] There-
fore, we decided to utilize enaminoketone 1 and o-phenylenediamine to get the desired
benzodiazepine nucleoside analog 2 (Scheme 1). The reaction was carried out in ethanol
at reflux. After 2 h, the reaction was completed to give compound 2 in good yield.
1
The disappearance of carbonyl and dimethylamine functionalities in the H
and 13C NMR spectra confirmed that the cyclization was taken place. In addition,
the infrared (IR) spectrum showed absorption of CN at 2232 cmꢀ1. The mass
spectrum was also in accordance with the proposed structure.
Reaction of a-Dimethylaminomethyleneulose 1 with Cyanamide
To prepare the reversed C-nucleoside analog with pyrimidine ring, we
developed a facile route in which cyanamide was reacted with compound 1 under
basic conditions.[15,16] Following the same previous strategy, we reacted compound
1 with cyanamide under basic conditions (Scheme 2). In the first step of the reaction,
the amino group of cyanamide replaced the dimethylamino group of compound 1 in
the presence of NaH in tetrahydrofuran (THF). The reaction was completed after
30 min at reflux, and product 3 was isolated in 70% yield (Scheme 2), which did
not contain a pyrimidine ring as indicated by spectroscopic studies.
The intense carbonyl resonance was found at 189.8 ppm, and two CN signals
appeared at 121.4 ppm and 118.7 ppm, respectively, in the 13C NMR spectrum. In
addition, the IR spectrum showed absorption typical for the NH group.
Synthesis of Isophthalic Acid Derivatives
The dialkyl 3-oxo-glutarate was reacted in the presence of NaOEt in EtOH
under reflux with compound 1 to furnish compound 4 in 50% yield (Scheme 3).
Scheme 2. Reaction of compound 1 with cyanamide.

SYNTHESIS OF REVERSED C-NUCLEOSIDES
1245
Scheme 3. Synthesis of 2-hydroxy isophthalic acid derivative.
The one aromatic proton H-5 appeared as a singlet at 8.1 ppm in the 1H NMR
spectrum. The signal for the OH proton was observed at about 11.5 ppm. In the 13
C
NMR spectrum, two carbonyl of ester groups appeared at 169.5 ppm and 169.0 ppm,
respectively. The mass spectrum was also in accordance with the proposed structure.
EXPERIMENTAL
General Procedures
Optical rotations were measured with a Gyromat-HP (Dr. Kernchen Ltd.)
polarimeter. IR spectra were recorded with a Nicolet 205 Fourier transform (FT)–
IR spectrometer. 1H and 13C NMR spectra were recorded with Bruker spectrometers
AC 250 (250.1 MHz and 62.9 MHz, respectively) and ARX 300 (300.1 MHz and
75.5 MHz, respectively). Mass spectra were obtained with an AMD 402=3 spec-
trometer (AMD Intectra GmbH). Elemental analyses were performed with a Leco
CHNS-932. Column chromatography was carried out on silica gel 60 (63–200 mm,
Merck). Thin-layer chromatography (TLC) was performed on silica-gel 60 GF254
foils (Merck) with detection by ultraviolet (UV) light and by charring with 10%
sulfuric acid in methanol. Solvents and liquid reagents were purified and dried
according to recommended procedures.[17]
Synthesis of 4-(3-O-Benzyl-1,2-O-isopropylidene-a-D-xylo-
tetrafuranos-4-yl)-1H-benzo[b][1,4]diazepine-3-carbonitrile (2)
1,2-Phenylenediamine (57 mg, 0.52 mmol) was added to a solution of 1
(100 mg, 0.26 mmol) in EtOH (5 ml). The reaction mixture was heated under reflux
for 2 h. After completion of the reaction (monitored by TLC), the solvent was
evaporated in vacuum, and the residue was purified by column chromatography
(toluene=EtOAc, 9:1) to obtain 2 as a brown syrup.
Data for 4-(3-O-Benzyl-1,2-O-isopropylidene-a-D-xylo-tetrofuranos-
4-yl)-1H-benzo[b][1,4]diazepine-3-carbonitrile (2)
25
Yield: 50 mg (44%, brown syrup); Rf: 0.35 (toluene=ethyl acetate, 9:1); ½aꢁD :
1
ꢀ165 (c ¼ 1.0, CHCl3); H NMR (250.133 MHz, CDCl3), d (ppm): 1.30, 1.49 [2s,
6H, C(CH3)2], 3.22 (br.s, 1H, NH), 4.53 (d, 1H, JCH(a),CH(b) ¼ 11.0 Hz, CHHPh),
4.55 (d, 1H, J3,4 ¼ 3.6 Hz, H-30), 4.65 (d, 1H, JCH(a),CH(b) ¼ 9.4 Hz, CHHPh), 4.68
(d, 1H, J1,2 ¼ 3.6 Hz, H-20), 5.36 (d, 1H, J3,4 ¼ 3.3 Hz, H-40), 6.03 (d, 1H,
J1,2 ¼ 3.6 Hz, H-10), 6.62–6.48 (m, 3H, Ph, H-9), 6.85 (m, 1H, H-7), 7.0 (m, 1H,

1246
I. A. HASHMI ET AL.
H-8), 7.25–7.30 (m, 4H, H-6, Ph), 7.30 (s, 1H, H-2); 13C NMR (62.89 MHz, CDCl3),
d (ppm): 26.3, 26.9 [C(CH3)2]; 59.9 (C-3), 78.9 (C-40), 81.9 (C-30), 83.0 (C-20), 105.1
(C-10), 113.0 [C(CH3)2], 115.0 (C-6), 118.2 (C-9), 119.8 (CN), 121.8 (C-9a), 125.1
(C-8), 127.8 (C-7), 128.9 (C-5a), 127.9, 128.2, 128.4 (Ph), 136.3 (i-Ph), 142.6 (C-2),
156.7 (C-4). MS (EI), m=z (%): 417 [M]þ C24H23N3O4 (417.462) calcd.: C, 69.05;
H, 5.55; N, 10.07. Found: C, 69.22; H, 5.78; N, 10.23.
Synthesis of 3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-a-D-xylo-
hept-5-ulofuranurononitrile-6-cyanoaminomethylene (3)
NaH (24 mg, 0.5 mmol) was added to a vigorously stirred solution of 1 (100 mg,
0.26 mmol) and cyanamide (22 mg, 0.5 mmol) in anhyd. THF (5 ml) at 0 ꢂC. After
30 min, the reaction mixture was allowed to warm up to room temperature and
heated under reflux for 30 min. After completion of the reaction (monitored by
TLC), the resulting solution was diluted with water (25 ml) and extracted with
chloroform (3 ꢃ 25 ml). Then the combined organic layers were dried over Na2SO4,
filtered, and evaporated under reduced pressure. The residue obtained was purified
by column chromatography (100% ethyl acetate) to give compound 3.
Data for 3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-a-D-xylo-hept-
5-ulofuranurononitrile-6-cyanoaminomethylene (3)
22
Yield: 70 mg (70%, colorless syrup); Rf: 0.51 (ethyl acetate); ½aꢁD : ꢀ46.8
1
(c ¼ 1.0, CHCl3); H NMR (250.133 MHz, acetone), d (ppm): 1.13, 1.29 [2s, 6H,
C(CH3)2], 4.40–4.56 (m, 4H, H-2, H-3, CH2Ph), 5.05 (d, 1H, J3,4 ¼ 3.6 Hz, H-4),
6.04 (d, 1H, J1,2 ¼ 3.3 Hz, H-1), 7.16–7.19 (m, 5H, Ph), 8.72 (s, 1H, H-10); 13C
NMR (62.89 MHz, acetone), d (ppm): 26.4, 27.1 [C(CH3)2], 73.1 (CH2Ph), 77.5
(C-6), 83.0 (C-2), 83.5 (C-3), 84.6 (C-4), 105.5 (C-1), 112.9 [C(CH3)2], 118.7 (CN),
121.4 (CN), 128.6, 128.7, 129.1 (Ph), 138.2 (i-Ph), 174.4 (C-10), 189.8 (CO); IR (capil-
þ
lary), n (cmꢀ1): 1689 (C O), 2192 (CN), 2242 (CN). MS(EI), m=z(%): 369 [M]
C19H19N3O5 (369.374) calcd.: C, 61.78; H, 5.18; N, 11.38. Found: C, 61.51; H,
=
5.38; N, 11.05.
Synthesis of Diethyl-6-(3-O-benzyl-1,2-O-isopropylidene-a-D-xylo-
tetrofuranose-4-yl)-5-cyano-2-hydroxyisopthalate (4)
A mixture of compound 1 (100 mg, 0.26 mmol), 3-oxo-pentanedioic acid
diethyl ester (0.14 ml, 0.78 mmol), sodium ethanolate (53 mg, 0.78 mmol), and dry
ethanol (5 ml) was refluxed for 6 h. After completion of the reaction (monitored
by TLC), the solvent was evaporated in vacuo, and the residue was purified by
column chromatography (toluene=EtOAc 8:2) to obtain product 4.
Diethyl-6-(3-O-benzyl-1,2-O-isopropylidene-a-D-xylo-tetrofuranose-
4-yl)-5-cyano-2-hydroxyisopthalate (4)
22
Yield: 68.5 mg (50%, colorless syrup); Rf: 0.51 (ethyl acetate); ½aꢁD : ꢀ46.8
1
(c ¼ 1.0, CHCl3); H NMR (250.133 MHz, acetone), d (ppm): 1.12–1.43 [m, 12H,

SYNTHESIS OF REVERSED C-NUCLEOSIDES
1247
C(CH3)2, 2 CH3-COOEt], 3.99–4.43 (m, 7H, H-30, CH2Ph, 2 CH2-COOEt), 4.61 (d,
1H, J2,1 ¼ 3.0 Hz, H-20), 5.38 (d, 1H, J3,4 ¼ 3.0 Hz, H-40), 6.10 (d, 1H, J1,2 ¼ 3.0 Hz,
H-10), 6.97–7.19 (m, 5H, Ph), 8.10 (s, 1H, H-4), 11.5 (br.s, OH); 13C NMR
(62.89 MHz, acetone), d (ppm): 13.9, 14.1 (2 CH3-COOEt), 26.4, 27.1 [C(CH3)2],
60.8, 61.1 (2 CH2-COOEt), 72.5 (CH2Ph), 80.6 (C-40), 83.4 (C-20), 83.8 (C-30), 97.5
(C-5), 105.8 (C-10), 111.6 (C-1), 112.5 (C-3), 112.6 [C(CH3)2], 119.7 (CN), 128.6,
128.7, 129.1 (Ph), 136.9 (i-Ph), 140.7 (C-6), 144.1 (C-4), 164.7, 165.6 (2 CO-COOEt),
168.1 (C-2). MS (EI), m=z (%): 511 [M]þ C27H29NO9 (511.524) calcd.: C, 63.40; H,
5.71; N, 2.74. Found: C, 63.51; H, 6.08; N, 2.05.
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