C-Furyl glycosides, II: Synthesis and antimicrobial evaluation of C-furyl glycosides bearing pyrazolines, isoxazolines, and 5,6-dihydropyrimidine-2(1H)- thiones

Article abstract of DOI:10.1007/s00706-008-0033-2

New C-furyl glycosides bearing pyrazolines, isoxazolines, and dihydropyrimidine-2(1H)-thiones were synthesized in order to increase the number of tested compounds screened for antimicrobial activity. The antimicrobial activity screening showed that the py

Full text of DOI:10.1007/s00706-008-0033-2

Monatsh Chem (2009) 140:365–370
DOI 10.1007/s00706-008-0033-2
ORIGINAL PAPER
C-Furyl glycosides, II: synthesis and antimicrobial
evaluation of C-furyl glycosides bearing pyrazolines,
isoxazolines, and 5,6-dihydropyrimidine-2(1H)-thiones
Wael A. El-Sayed Æ Ibrahim F. Nassar Æ
Adel A.-H. Abdel-Rahman
Received: 23 May 2008 / Accepted: 23 June 2008 / Published online: 24 September 2008
Ó Springer-Verlag 2008
Abstract New C-furyl glycosides bearing pyrazolines,
isoxazolines, and dihydropyrimidine-2(1H)-thiones were
synthesized in order to increase the number of tested
compounds screened for antimicrobial activity. The anti-
microbial activity screening showed that the pyrazoline
derivatives were the most active compounds.
and synthetic utility [10–16]. C-Glycosyl derivatives hab-
itually exist in a variety of biologically important natural
products as papulacandins, pluramycins, vineomycin, gil-
vocarcin V, and urdamycin A, which are recognized for
their various biological activities, including antibiotic,
antitumoral, and antiplatelet aggregation activities [17–21].
Furthermore, they have become increasingly useful as
building blocks for the synthesis of various types of natural
products and as potential enzyme inhibitors [22–24]. It has
been found that the tetrahydrofuran moiety is a basic
structural constituent of a large number of C-glycosides
[25–30] of considerable biological and chemical interest.
C-Furyl glycosides are useful precursors for the synthesis
of many C-glycosyl antibiotics [31]. The synthesis of
arylpyrazolines is of major interest [32, 33]. Functional-
ized isoxazoline and isoxazole derivatives are active
pharmacophores in several pharmacologically important
molecules [34–36], and are also useful intermediates for
the synthesis of a wide variety of bioactive natural products
[37–39]. Thioxopyrimidine is an essential structural unit of
several heterocycles that display a wide range of interesting
biological and pharmacological properties, such as anti-
cancer and antimicrobial activities [40, 41]. Our interest in
the synthesis of such compounds was focused on biological
studies of them as antimicrobial agents as a part of our
program aimed at the development of a new heterocyclic
compounds with potential biological activities [42–44].
Keywords C-Furyl glycosides ꢀ Pyrazolines ꢀ
Isoxazolines ꢀ Antimicrobial activity
Introduction
Carbohydrates exist on cell surfaces as glycoproteins or
glycolipid conjugates and are engaged in important struc-
tural functions in various biological recognition processes,
such as cancer metastasis, inflammatory response, innate
and adaptive immunity, viral and bacterial infections, and
many other receptor-mediated signaling processes [1–6].
Moreover, a large number of natural products require
glycosylation in order to show proper biological perfor-
mance [7–9]. Interest continues to rise in new applications
of natural and synthetic C-glycoside to basic research and
medicine owing to their potential therapeutic applications
W. A. El-Sayed (&)
Department of Photochemistry, National Research Centre,
Cairo, Egypt
e-mail: wshendy@yahoo.com
I. F. Nassar
Faculty of Specific Education, Ain Shams University,
Abbassia, Cairo, Egypt
Results and discussion
Synthesis
A. A.-H. Abdel-Rahman (&)
Department of Chemistry, Faculty of Science,
Menoufia University, Shebin El-Koam, Egypt
e-mail: adelnassar63@hotmail.com
It has been reported that a,b-unsaturated ketones can react
with hydrazine hydrate or phenyl hydrazine to give the
123

366
W.A. El-Sayed et al.
Ar
corresponding pyrazolines [45, 46]. So, 1a–1f [49] were
treated with hydrazine hydrate or phenyl hydrazine in
ethanol to afford the D2-pyrazolines 2a–2f in 70–74%
yields, and N-phenyl-D2-pyrazolines 3a–3f in 75–80%
yields. The 1H NMR spectra of 2a–2f showed two doublets
at d 3.00–3.04 and 3.45–3.53 for the pyrazoline-H-4, while
pyrazoline-H-5 appeared as a triplet at d 4.90–5.03 ppm.
N
N
H
N
N
N
O
NH2NH2
O
O
O
HO
OH
Ar
2a-2f
1
The H NMR spectra of 3a–3f showed two doublets at d
Ph
3.00–3.02 and 3.44–3.50 for the pyrazoline-H-4 and a
triplet at d 4.92–5.04 ppm for the pyrazoline-H-5. Con-
densation of 1a–1f with hydroxylamine hydrochloride or
thiourea in ethanolic sodium hydroxide solution gave 4,5-
dihydroisoxazoles 4a–4f in 78–82% yields, and 5,6-dihy-
dropyrimidine-2-(1H)-thiones 5a–5f in 72–75% yields. The
1H NMR spectra of 4a–4f showed a multiplet at d 3.53–
3.80 for the isoxazoline-H-4, H-30, and H-40a, and a triplet
PhNHNH2
O
O
Ar
4
3
HO
Ar
OH
2
3a-3f
5
1'
O
4'
3'
O
O
1
2'
O
NH2OH
HO
1a-1f
OH
NaOEt
1
at d 5.90–5.98 ppm for the isoxazoline-H-5. The H NMR
HO
OH
S
spectra of 5a–5f showed a multiplet at d 5.07–5.29 for the
dihydro-2-thioxopyrimidine-H-5 and 2xOH, and a triplet at
d 5.39–5.55 for the dihydro-2-thioxopyrimidine-H-6, and a
broad singlet at d 12.69–12.74 ppm for the NH group
(Scheme 1).
4a-4f
N
NH
Ar
NH2CSNH2
O
O
NaOEt
HO
5a-5f
OH
Ar-CHO
benzaldehyde
1-5
a
Antimicrobial activity
b
c
2-bromobenzaldehyde
4-bromobenzaldehyde
2,4-dibromobenzaldehyde
2-fluorobenzaldehyde
3-nitrobenzaldehyde
The newly synthesized compounds were tested for their
antimicrobial action [47, 48] against four different bac-
terial species, namely Pseudomonas sp. (Gram-negative
bacterium), Bacillus subtilis (Gram-positive bacterium),
Bacillus cereus (Gram-positive bacterium), and Strepto-
myces sp. (one of the important actinomycetes). All of the
tested compounds exhibited different degrees of antibac-
terial activity or inhibitory action. The most susceptible
organisms were the two Gram-positive bacteria (Bacillus
subtilis and Bacillus cereus), followed by Streptomyces
sp., while the lowest inhibitory effect was encountered in
the case of Pseudomonas sp. The highest degrees of
inhibition were recorded for compounds 2a–2f and 3a–3c
followed by 3d–3f, 4a–4f, and 5a–5f (Table 1). The
results were compared to amoxicillin (penicillin) as a
reference drug.
d
e
f
Scheme 1
The microanalyses were performed at the microanalytical
unit, Cairo University, Egypt, and were found to agree
favorably with the calculated values. The antimicrobial
activities of the synthesized compounds were evaluated at
the Botany Department, Faculty of Science, Menoufia
University, Shebin El-Koam, Egypt.
General procedure for the preparation of pyrazolines
2a–2f and N-phenylpyrazolines 3a–3f
A mixture of 1a–1f [49] (5 mmol), 0.13 cm3 N2H4ꢀH2O
(5 mmol) and/or 0.27 cm3 phenylhydrazine (5 mmol) in
25 cm3 ethanol was refluxed for 8 h (TLC). The reaction
mixture was cooled; the precipitate was filtered off and
recrystallized from ethanol to give 2a–2f in 70–74% yields,
and 3a–3f in 75–80% yields.
Experimental
Melting points were determined using a Kofler block
1
instrument. H NMR spectra were recorded with Bruker
(Rheinstetten, Germany) AC 250 FT NMR spectrometer at
250 MHz with TMS as an internal standard. MALDI-MS
were measured with a Kratos Analytical (Manchester, UK)
Compact, using 2,5-dihydroxybenzoic acid (DHB) as
matrix. The (M ? Na)? ions were peak-matched using
ions derived from the 2,5-dihydroxybenzoic acid matrix.
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-phenyl-4,5-dihydro-1H-pyrazole
(2a; C18H20N2O4)
White powder (74%); Rf = 0.30 (petroleum ether/EtOAc,
2:1). M.p.: 120–122 °C; 1H NMR (DMSO-d6, d,
123

Synthesis and antimicrobial evaluation of C-furyl glycosides
367
H-40b), 4.15 (m, H-20), 4.87 (br, s, 29OH), 4.92 (t,
J = 3.6 Hz, pyrazoline-H-5), 5.30 (d, J = 6.4 Hz, H-10),
6.44 (s, H-4), 7.06 (br, s, NH), 7.06–7.13 (m, Ar-H), 7.34–
7.38 (m, Ar-H) ppm; (MALDI, positive mode, matrix:
DHB): m/z (%) = 429 [(M ? Na)?, 17].
Table 1 Antimicrobial activity of the newly synthesized compounds
2–5
Compound no.
Pseudomonas Bacillus Bacillus Streptomyces
sp.
subtilis cereus
Amoxicillin
(penicillin)
–
?? ???
?
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(4-bromophenyl)-4,5-dihydro-1H-pyrazole
(2c; C18H19BrN2O4)
2a
2b
2c
2d
2e
2f
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
???? ???? ??
???? ???? ??
???? ???? ??
Pale yellow powder (74%); Rf = 0.37 (petroleum ether/
1
EtOAc, 2:1). M.p.: 163–165 °C; H NMR (DMSO-d6, d,
???? ????
???? ???
???? ????
?
?
250 MHz): 2.26 (s, CH3), 3.02, 3.52 (2dd, J = 8.0, 3.6 Hz,
pyrazoline-H-4), 3.67 (m, H-30), 3.71 (m, H-40a), 4.07 (m,
H-40b), 4.18 (m, H-20), 4.89 (br, s, 29OH), 4.99 (t,
J = 3.6 Hz, pyrazoline-H-5), 5.37 (d, J = 6.4 Hz, H-10),
6.44 (s, H-4), 7.03 (br, s, NH), 7.11–7.18 (m, Ar-H), 7.30–
7.32 (m, Ar-H) ppm; (MALDI, positive mode, matrix:
DHB): m/z (%) = 429 [(M ? Na)?, 39].
?
3a
3b
3c
3d
3e
3f
???
???
???
??
??
??
??
??
??
??
??
??
??
??
??
??
??
??
???
???
???
??
??
??
??
??
??
??
??
??
??
??
??
??
??
??
?
??
?
?
?
?
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(2,4-dibromophenyl)-4,5-dihydro-1H-
pyrazole (2d; C18H18Br2N2O4)
4a
4b
4c
4d
4e
4f
??
?
?
Yellow powder (71%); Rf = 0.39 (petroleum ether/EtOAc,
2:1). M.p.: 196–198 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.24 (s, CH3), 3.02, 3.53 (2dd, J = 8.0,
3.6 Hz, pyrazoline-H-4), 3.65 (m, H-30), 3.70 (m, H-40a),
4.09 (m, H-40b), 4.22 (m, H-20), 4.88 (br, s, 29OH), 4.90 (t,
J = 3.6 Hz, pyrazoline-H-5), 5.33 (d, J = 6.4 Hz, H-10),
6.49 (s, H-4), 7.02 (br, s, NH), 7.37–7.52 (m, Ar-H) ppm;
(MALDI, positive mode, matrix: DHB): m/z (%) = 509
[(M ? Na)?, 13].
?
?
?
5a
5b
5c
5d
5e
5f
?
?
?
??
?
?
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(2-fluorophenyl)-4,5-dihydro-1H-pyrazole
(2e; C18H19FN2O4)
– No antimicrobial effect
? Low antimicrobial effect (4 mm)
?? Moderate antimicrobial effect (8–10 mm)
??? High antimicrobial effect (15–18 mm)
???? Complete antimicrobial effect (20–22 mm)
White powder (70%); Rf = 0.36 (petroleum ether/EtOAc,
2:1). M.p.: 138–140 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.22 (s, CH3), 3.00, 3.47 (2dd, J = 8.0,
3.6 Hz, pyrazoline-H-4), 3.65 (m, H-30), 3.71 (m, H-40a),
4.00 (m, H-40b), 4.13 (m, H-20), 4.81 (br, s, 29OH), 4.95 (t,
J = 3.6 Hz, pyrazoline-H-5), 5.32 (d, J = 6.4 Hz, H-10),
6.47 (s, H-4), 7.01 (br, s, NH), 7.07–7.15 (m, Ar-H), 7.40–
7.50 (m, Ar-H) ppm; (MALDI, positive mode, matrix:
DHB): m/z (%) = 369 [(M ? Na)?, 44].
250 MHz): 2.22 (s, CH3), 3.03, 3.49 (2dd, J = 8.0, 3.6 Hz,
pyrazoline-H-4), 3.60 (m, H-30), 3.70 (m, H-40a), 4.00 (m,
H-40b), 4.12 (m, H-20), 4.80 (br, s, 29OH), 4.90 (t,
J = 3.6 Hz, pyrazoline-H-5), 5.33 (d, J = 6.4 Hz, H-10),
6.40 (s, H-4), 7.00 (br, s, NH), 7.12–7.23 (m, Ar-H), 7.25–
7.34 (m, Ar-H) ppm; (MALDI, positive mode, matrix:
DHB): m/z (%) = 351 [(M ? Na)?, 22].
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazole
(2f; C18H19N3O6)
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(2-bromophenyl)-4,5-dihydro-1H-pyrazole
(2b; C18H19BrN2O4)
Yellow powder (7o%); Rf = 0.40 (petroleum ether/EtOAc,
2:1). M.p.: 158–160 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.23 (s, CH3), 3.02, 3.49 (2dd, J = 8.0,
3.6 Hz, pyrazoline-H–4), 3.62 (m, H-30), 3.77 (m, H-40a),
4.05 (m, H-40b), 4.14 (m, H-20), 4.88 (br, s, 29OH), 5.03 (t,
J = 3.6 Hz, pyrazoline-H-5), 5.35 (d, J = 6.4 Hz, H-10),
6.48 (s, H-4), 7.00 (br, s, NH), 7.39–7.52 (m, Ar-H),
Pale yellow powder (73%); Rf = 0.37 (petroleum ether/
1
EtOAc, 2:1). M.p.: 178–180 °C; H NMR (DMSO-d6, d,
250 MHz): 2.20 (s, CH3), 3.04, 3.45 (2dd, J = 8.0, 3.6 Hz,
pyrazoline-H-4), 3.62 (m, H-30), 3.69 (m, H-40a), 4.04 (m,
123

368
W.A. El-Sayed et al.
8.05–8.15 (m, Ar-H) ppm; (MALDI, positive mode,
matrix: DHB): m/z (%) = 396 [(M ? Na)?, 53].
ppm; (MALDI, positive mode, matrix: DHB): m/z (%) =
585 [(M ? Na)?, 14].
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(2-fluorophenyl)-1-phenyl-4,5-dihydro-1H-
pyrazole (3e; C24H23FN2O4)
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-1,5-diphenyl-4,5-dihydro-1H-pyrazole
(3a; C24H24N2O4)
White powder (76%); Rf = 0.48 (petroleum ether/EtOAc,
2:1). M.p.: 211–213 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.26 (s, CH3), 3.00, 3.48 (2dd, J = 8.0,
3.6 Hz, pyrazoline-H-4), 3.66 (m, H-30), 3.71 (m, H-40a),
4.05 (m, H-40b), 4.18 (m, H-20), 4.89 (br, s, 29OH), 4.97 (t,
J = 3.6 Hz, pyrazoline-H-5), 5.30 (d, J = 6.4 Hz, H-10),
6.39 (s, H-4), 7.08–7.24 (m, Ar-H), 7.40–7.55 (m, Ar-H)
ppm; (MALDI, positive mode, matrix: DHB): m/z
(%) = 445 [(M ? Na)?, 27].
White powder (79%); Rf = 0.40 (petroleum ether/EtOAc,
2:1). M.p.: 180–182 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.21 (s, CH3), 3.02, 3.44 (2dd, J = 8.0,
3.6 Hz, pyrazoline-H-4), 3.62 (m, H-30), 3.74 (m, H-40a),
4.02 (m, H-40b), 4.13 (m, H-20), 4.84 (br, s, 29OH), 4.92 (t,
J = 3.6 Hz, pyrazoline-H-5), 5.39 (d, J = 6.4 Hz, H-10),
6.48 (s, H-4), 7.07–7.23 (m, Ar-H), 7.30–7.44 (m, Ar-H)
ppm; (MALDI, positive mode, matrix: DHB): m/z
(%) = 427 [(M ? Na)?, 28].
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(3-nitrophenyl)-1-phenyl-4,5-dihydro-1H-
pyrazole (3f; C24H23N3O6)
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(2-bromophenyl)-1-phenyl-4,5-dihydro-
1H-pyrazole (3b; C24H23BrN2O4)
Pale yellow powder (75%); Rf = 0.49 (petroleum ether/
1
EtOAc, 2:1). M.p.: 225–227 °C; H NMR (DMSO-d6, d,
Pale yellow powder (80%); Rf = 0.44 (petroleum ether/
1
EtOAc, 2:1). M.p.: 190–192 °C; H NMR (DMSO-d6, d,
250 MHz): 2.22 (s, CH3), 3.02, 3.50 (2dd, J = 8.0,
3.6 Hz, pyrazoline-H-4), 3.62 (m, H-30), 3.71 (m, H-40a),
4.00 (m, H-40b), 4.12 (m, H-20), 4.94 (br, s, 29OH), 5.04
(t, J = 3.6 Hz, pyrazoline-H-5), 5.33 (d, J = 6.4 Hz,
H-10), 6.40 (s, H-4), 7.17–7.28 (m, Ar-H), 7.30–7.32
(m, Ar-H), 8.03–8.15 (m, Ar-H) ppm; (MALDI,
positive mode, matrix: DHB): m/z (%) = 472 [(M ?
Na)?, 26].
250 MHz): 2.21 (s, CH3), 3.00, 3.48 (2dd, J = 8.0, 3.6 Hz,
pyrazoline-H-4), 3.63 (m, H-30), 3.70 (m, H-40a), 4.00 (m,
H-40b), 4.12 (m, H-20), 4.91 (br, s, 29OH), 5.03 (t,
J= 3.6 Hz, pyrazoline-H-5), 5.39 (d, J = 6.4 Hz, H-10),
6.40 (s, H-4), 7.19–7.30 (m, Ar-H), 7.33–7.39 (m, Ar-H)
ppm; (MALDI, positive mode, matrix: DHB): m/z
(%) = 505 [(M ? Na)?, 22].
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(4-bromophenyl)-1-phenyl-4,5-dihydro-
1H-pyrazole (3c; C24H23BrN2O4)
General procedure for the preparation of isoxazolines
4a–4f
Pale yellow powder (78%); Rf = 0.47 (petroleum ether/
1
EtOAc, 2:1). M.p.: 212–214 °C; H NMR (DMSO-d6, d,
A mixture of 1a–1f [49] (5 mmol), 0.16 g HONH2ꢀHCl
(5 mmol), and 0.5 g NaOH (12 mmol) in 60 cm3 ethanol
was refluxed for 8 h (TLC). The reaction mixture was
cooled and poured onto crushed ice. The precipitate was
filtered, washed with H2O, and purified on silica gel col-
umn chromatography using CH2Cl2 in petroleum ether (3:7
v/v) to give 4a–4f in 78–82% yields.
250 MHz): 2.25 (s, CH3), 3.02, 3.44 (2dd, J = 8.0, 3.6 Hz,
pyrazoline-H-4), 3.63 (m, H-30), 3.68 (m, H-40a), 4.01 (m,
H-40b), 4.13 (m, H-20), 4.86 (br, s, 29OH), 4.96 (t,
J = 3.6 Hz, pyrazoline-H-5), 5.33 (d, J = 6.4 Hz, H-10),
6.39 (s, H-4), 7.03–7.15 (m, Ar-H), 7.26–7.37 (m, Ar-H)
ppm; (MALDI, positive mode, matrix: DHB): m/z
(%) = 505 [(M ? Na)?, 31].
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-phenyl-4,5-dihydroisoxazole
(4a; C18H19NO5)
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(2,4-dibromophenyl)-1-phenyl-4,5-
dihydro-1H-pyrazole (3d; C24H22Br2N2O4)
White powder (81%); Rf = 0.41 (petroleum ether/EtOAc,
2:1). M.p.: 139–141 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.20 (s, CH3), 3.58–3.80 (m, isoxazoline-H-4,
H-30, H-40a), 4.09 (m, H-40b), 4.21 (m, H-20), 5.09 (br, s,
29OH), 5.39 (d, J = 6.4 Hz, H-10), 5.95 (t, J = 3.5 Hz,
isoxazoline-H-5), 6.47 (s, H-4), 7.19–7.40 (m, Ar-H) ppm;
(MALDI, positive mode, matrix: DHB): m/z (%) = 352
[(M ? Na)?, 33].
Yellow powder (75%); Rf = 0.48 (petroleum ether/EtOAc,
2:1). M.p.: 236–238 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.24 (s, CH3), 3.00, 3.45 (2dd, J = 8.0,
3.6 Hz, pyrazoline-H-4), 3.62 (m, H-30), 3.67 (m, H-40a),
4.02 (m, H-40b), 4.19 (m, H-20), 4.88 (br, s, 29OH), 4.99 (t,
J = 3.6 Hz, pyrazoline-H-5), 5.35 (d, J = 6.4 Hz, H-10),
6.43 (s, H-4), 7.11–7.23 (m, Ar-H), 7.39–7.50 (m, Ar-H)
123

Synthesis and antimicrobial evaluation of C-furyl glycosides
369
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(2-bromophenyl)-4,5-dihydroisoxazole
(4b; C18H18BrNO5)
H-30, H-40a), 4.02 (m, H-40b), 4.20 (m, H-20), 5.03 (br, s,
29OH), 5.30 (d, J = 6.4 Hz, H-10), 5.90 (t, J = 3.5 Hz,
isoxazoline-H-5), 6.40 (s, H-4), 7.49–7.64 (m, Ar-H), 8.20–
8.33 (m, Ar-H) ppm; (MALDI, positive mode, matrix:
DHB): m/z (%) = 397 [(M ? Na)?, 18].
Yellow powder (82%); Rf = 0.46 (petroleum ether/EtOAc,
2:1). M.p.: 166–168 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.23 (s, CH3), 3.55-3.77 (m, isoxazoline-H-4,
H-30, H-40a), 4.08 (m, H-40b), 4.24 (m, H-20), 5.11 (br, s,
29OH), 5.36 (d, J = 6.4 Hz, H-10), 5.94 (t, J = 3.5 Hz,
isoxazoline-H-5), 6.45 (s, H-4), 7.11–7.23 (m, Ar-H), 7.29–
7.36 (m, Ar-H) ppm; (MALDI, positive mode, matrix:
DHB): m/z (%) = 430 [(M ? Na)?, 17].
General procedure for the preparation
of 5,6-dihydropyrimidine-2-(1H)-thiones 5a–5f
A mixture of 1a–1f [49] (10 mmol), 0.1 g thiourea
(14 mmol), and 1.0 g NaOH (25 mmol) in 30 cm3 ethanol
was refluxed for 6 h. The reaction mixture was con-
centrated, cooled, and filtered. The precipitate was
recrystallized from ethanol to give 5a–5f in 72–75% yields.
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(4-bromophenyl)-4,5-dihydroisoxazole
(4c; C18H18BrNO5)
Yellow powder (80%); Rf = 0.48 (petroleum ether/EtOAc,
2:1). M.p.: 149–151 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.22 (s, CH3), 3.58–3.78 (m, isoxazoline-H-4,
H-30, H-40a), 4.03 (m, H-40b), 4.27 (m, H-20), 5.06 (br, s,
29OH), 5.43 (d, J = 6.4 Hz, H-10), 5.90 (t, J = 3.5 Hz,
isoxazoline-H-5), 6.49 (s, H-4), 7.09–7.23 (m, Ar-H), 7.28–
7.33 (m, Ar-H) ppm; (MALDI, positive mode, matrix:
DHB): m/z (%) = 430 [(M ? Na)?, 23].
4-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-6-phenyl-5,6-dihydropyrimidine-2(1H)-
thione (5a; C19H20N2O4S)
Yellow powder (74%); Rf = 0.51 (petroleum ether/EtOAc,
2:1). M.p.: 205–207 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.27 (s, CH3), 3.44–3.70 (m, H-30, H-40a),
4.06 (m, H-40b), 4.20 (m, H-20), 5.10–5.25 (m, 29OH,
dihydro-2-thioxopyrimidine-H-5), 5.43–5.55 (m, dihydro-
2-thioxopyrimidine-H-6, H-10), 6.44 (s, H-4), 7.10–7.20
(m, Ar-H), 7.30–7.39 (m, Ar-H), 12.70 (br, s, NH) ppm;
(MALDI, positive mode, matrix: DHB): m/z (%) = 395
[(M ? Na)?, 23].
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(2,4-dibromophenyl)-4,5-dihydroisoxazole
(4d; C18H17Br2NO5)
Yellow powder (79%); Rf = 0.48 (petroleum ether/EtOAc,
2:1). M.p.: 177–179 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.24 (s, CH3), 3.55–3.74 (m, isoxazoline-H-4,
H-30, H-40a), 4.03 (m, H-40b), 4.24 (m, H-20), 5.12 (br, s,
29OH), 5.43 (d, J = 6.4 Hz, H-10), 5.92 (t, J = 3.5 Hz,
isoxazoline-H-5), 6.43 (s, H-4), 7.10–7.24 (m, Ar-H), 7.44–
7.50 (m, Ar-H ppm; (MALDI, positive mode, matrix:
DHB): m/z (%) = 510 [(M ? Na)?, 12].
4-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-meth-
ylfuran]-6-(2-bromophenyl)-5,6-dihydropyrimidine-2(1H)-
thione (5b; C19H19BrN2O4S)
Yellow powder (75%); Rf = 0.53 (petroleum ether/EtOAc,
2:1). M.p.: 237–239 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.25 (s, CH3), 3.40–3.70 (m, H-30, H-40a),
4.00 (m, H-40b), 4.27 (m, H-20), 5.10–5.29 (m, 29OH,
dihydro-2-thioxopyrimidine-H-5), 5.40–5.52 (m, dihydro-
2-thioxopyrimidine-H-6, H-10), 6.40 (s, H-4), 7.00–7.17
(m, Ar-H), 7.29–7.38 (m, Ar-H), 12.71 (br, s, NH) ppm;
(MALDI, positive mode, matrix: DHB): m/z (%) = 475
[(M ? Na)?, 16].
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)–2-
methylfuran]–5-(2-fluorophenyl)-4,5-dihydroisoxazole
(4e; C18H18FNO5)
White powder (78%); Rf = 0.41 (petroleum ether/EtOAc,
2:1). M.p.: 160–162 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.27 (s, CH3), 3.53–3.77 (m, isoxazoline-H-4,
H-30, H-40a), 4.06 (m, H-40b), 4.20 (m, H-20), 5.07 (br, s,
29OH), 5.33 (d, J = 6.4 Hz, H-10), 5.98 (t, J = 3.5 Hz,
isoxazoline-H-5), 6.44 (s, H-4), 7.09–7.20 (m, Ar-H), 7.66–
7.73 (m, Ar-H) ppm; (MALDI, positive mode, matrix:
DHB): m/z (%) = 370 [(M ? Na)?, 41].
4-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-6-(4-bromophenyl)-5,6-dihydropyrimidine-
2(1H)-thione (5c; C19H19BrN2O4S)
Yellow powder (73%); Rf = 0.54 (petroleum ether/EtOAc,
2:1). M.p.: 271–273 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.23 (s, CH3), 3.40–3.66 (m, H-30, H-40a),
4.07 (m, H-40b), 4.22 (m, H-20), 5.07–5.27 (m, 29OH,
dihydro-2-thioxopyrimidine-H-5), 5.40–5.55 (m, dihydro-
2-thioxopyrimidine-H-6, H-10), 6.46 (s, H-4), 7.05–7.20
(m, Ar-H), 7.30–7.37 (m, Ar-H), 12.74 (br, s, NH) ppm;
(MALDI, positive mode, matrix: DHB): m/z (%) = 475
[(M ? Na)?, 20].
3-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-5-(3-nitrophenyl)-4,5-dihydroisoxazole
(4f; C18H18N2O7)
Yellow powder (78%); Rf = 0.41 (petroleum ether/EtOAc,
2:1). M.p.: 169–171 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.25 (s, CH3), 3.58–3.74 (m, isoxazoline-H-4,
123

370
W.A. El-Sayed et al.
10. Du Y, Linhardt RJ (1998) Tetrahedron 54:9913
4-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-6-(2,4-dibromophenyl)-5,6-dihydropyrimi-
dine-2(1H)-thione (5d; C19H18Br2N2O4S)
11. Beau JM, Gallagher T (1997) Top Curr Chem 187:1
12. Xie J (1999) Recent Res Dev Org Chem 3:505
13. Hacksell U, Daves GD Jr (1985) Progr Med Chem 22:1
14. Rohr J, Thiericke R (1992) Nat Prod Rep 9:103
15. Nicotra F (1997) Top Curr Chem 187:55
16. Weymouth-Wilson AC (1997) Nat Prod Rep 14:99
17. Jay M, Viricel MR, Gonnet JF (2006) In: Andersen OM,
Markham KR (eds) Flavonoids: chemistry, biochemistry and
applications. CRC Press, Boca Raton, FL, pp 857–915
18. Hansen MR, Hurley LH (1996) Acc Chem Res 29:249
19. Qian-Cutrone J, Kolb JM, McBrien K, Huang S, Gustavson D,
Lowe SE, Manly SP (1998) J Nat Prod 61:1379
20. Ford PW, Gadepalli M, Davidson BS (1998) J Nat Prod 61:1232
21. Bililign T, Griffth BR, Thorson JS (2005) Nat Prod Pep 22:742
22. Hanessian S (1983) Total synthesis of natural products: the
Chiron approach. Pergamon, Oxford
Yellow powder (74%); Rf = 0.57 (petroleum ether/EtOAc,
2:1). M.p.: 266–268 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.23 (s, CH3), 3.39–3.69 (m, H-30, H-40a),
4.09 (m, H-40b), 4.27 (m, H-20), 5.10–5.29 (m, 29OH,
dihydro-2-thioxopyrimidine-H-5), 5.43–5.53 (m, dihydro-
2-thioxopyrimidine-H-6, H-10), 6.41 (s, H-4), 7.16–7.29
(m, Ar-H), 7.39–7.55 (m, Ar-H), 12.72 (br, s, NH) ppm;
(MALDI, positive mode, matrix: DHB): m/z (%) = 553
[(M ? Na)?, 13].
4-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-6-(2-fluorophenyl)-5,6-dihydropyrimidine-
2(1H)-thione (5e; C19H19FN2O4S)
23. BeMiller JN, Yadav MP, Kalabokis VN, Myers RW (1990)
Carbohydr Res 200:111
24. Schmidt RR, Dietrich H (1991) Angew Chem Int Ed 30:1328
25. Postema MHD (1992) Tetrahedron 48:8545
26. Schmidt RR, Effenberger G (1998) Liebigs Ann Chem 825
27. Maeba I, Iwata K, Usami F, Furukawa H (1983) J Org Chem
48:2998
28. Grynkiewcz G, BeMiller JN (1984) Carbohydr Res 131:273
29. Maeba I, Usami F, Ishikawa T, Furukawa H (1985) Carbohydr
Res 141:1
Yellow powder (72%); Rf = 0.56 (petroleum ether/EtOAc,
2:1). M.p.: 259–261 °C; 1H NMR (DMSO-d6, d,
250 MHz): 2.20 (s, CH3), 3.40–3.63 (m, H-30, H-40a),
4.09 (m, H-40b), 4.28 (m, H-20), 5.12–5.27 (m, 29OH,
dihydro-2-thioxopyrimidine-H-5), 5.41–5.52 (m, dihydro-
2-thioxopyrimidine-H-6, H-10), 6.38 (s, H-4), 7.00–7.16
(m, Ar-H), 7.40–7.60 (m, Ar-H), 12.69 (br, s, NH) ppm;
(MALDI, positive mode, matrix: DHB): m/z (%) = 413
[(M ? Na)?, 22].
30. Lipshutz BH (1986) Chem Rev 86:795
31. Chakraborty TK, Ghosh S, Jayaprakash S, Sharma JARP, Rav-
ikanth V, Diwan PV, Nagaraj R, Kunwar AC (2000) J Org Chem
65:6441
32. Elguero J (1984) In: Katrizky A (ed) Comprehensive heterocyclic
chemistry. Pergamon, Oxford, 5:277
33. Elguero J (1996) In: Shinkai I (ed) Comprehensive heterocyclic
chemistry II. Elsevier, Oxford, 3:3
4-[5-C-(1,4-Anhydro-b-D-erythro-tetrofuranosyl)-2-
methylfuran]-6-(3-nitrophenyl)-5,6-dihydropyrimidine-
2(1H)-thione (5f; C19H19N3O6S)
34. Wagner E, Becan L, Nowakowska E (2004) Bioorg Med Chem
12:265
Yellow powder (742%); Rf = 0.59 (petroleum ether/EtOAc,
2:1). M.p.: 247–249 °C; 1H NMR (DMSO-d6, d, 250 MHz):
2.24 (s, CH3), 3.38–3.68 (m, H-30, H-40a), 4.08 (m, H-40b),
4.18 (m, H-20), 5.12-5.28 (m, 29OH, dihydro-2-thioxopyr-
imidine-H-5), 5.39–5.49 (m, dihydro-2-thioxopyrimidine-
H-6, H-10), 6.41 (s, H-4), 7.40–7.50 (m, Ar-H), 8.05–8.15 (m,
Ar-H), 12.73 (br, s, NH) ppm; (MALDI, positive mode,
matrix: DHB): m/z (%) = 440 [(M ? Na)?, 28].
35. Pastor J, Alca0zar J, Alvarez RM, Andre’s JI, Cid JM, De Lucas
AI, Di0az A (2004) Bioorg Med Chem Lett 14:2917
36. Sadashiva BPS, Nanjunda SS, Mahendra M, Shashidhara PJ,
Viswanath BS, Rangappa KS (2004) Bioorg Med Chem Lett
14:3679
37. Bashiardes G, Safir I, Barbot F, Laduranty J (2003) Tetrahedron
Lett 44:8417
38. Sadashiva BPS, Mantelingu K, Nanjunda SS, Rangappa KS
(2003) Bioorg Med Chem 11:4539
39. Ulgheri F, Bacsa J, Nassimbeni L, Spanu P (2003) Tetrahedron
Lett 44:671
40. Cocco MT, Congiu C, Onnis V, Piras R (2001) Farmaco 56:741
41. Cocco MT, Congiu C, Onnis V (1995) Farmaco 50:73
42. El-Essawy FA, Khattab AF, Abdel-Rahman AA-H (2007) Mon-
atsh Chem 138:777
References
1. Sturgeon RJ (2003) Advances in macromolecular carbohydrate
research, vol 2. JAI, Stamford, CT
43. Abdel-Rahman AA-H, Abdel-Megied AE-S, Hawata MAM,
Kasem ER, Shabaan (2007) Monatsh Chem 138:889
44. El-Sayed WA, Hegab MI, Tolan HEM, Abdel-Rahman AA-H
(2008) Monatsh Chem (in press)
2. Osborn HMI, Harwood LM (2003) In: Best synthetic methods:
carbohydrates. Academic, San Diego, CA
3. Stick RV (2003) In: Carbohydrates: the sweet molecules of life.
Academic, San Diego, CA
45. Kamel MM, Gadalla KZ, El-Hamouly WS, El-Wassimi MT
(1985) Z Naturforsch 40B:661
4. Ferrier RJ (2003) Carbohydrate chemistry, vol 34. Royal Society
of Chemistry, Cambridge, UK
46. Kamel MM, Nabih I, Gadalla KZ, Ashour MM (1986) Pharmazie
1:56
47. Janssen AM, Scheffer JJ, Svendsen AB (1986) Planta Medica 395
48. Shaaban MT, El-Sharif ME (2001) Afr J Mycol Biotechnol
9(2):15
5. Hricovini M (2004) Curr Med Chem 11:2565
6. Ali A, Gowda DC, Vishwakarma RA (2005) Chem Commun
1224
7. Gabius HJ, Gabius S (1997) Glycosciences: status and perspec-
tives. Chapman & Hall, Weinheim
49. El-Sayed WA, Ramiz MMM, Abdel-Rahman AA-H (2008)
Monatsh Chem (in press)
8. Paulson JC (1989) Trends Biochem Sci 14:272
9. Dwek RA (1996) Chem Rev 96:683
123