Synthesis of 1′-β-D-glucopyranosyl-1,2,3-triazole-4,5-dimethanol-4,5-bis (isopropylcarbamate) as potential antineoplastic agent

Article abstract of DOI:10.1016/S0040-4039(02)00733-5

The title compound 5 was prepared from the 1-β-D-azido-glucose 1 via four steps. Alternatively, 5 was synthesized from 1, via acetalation, cycloaddition with acetylene derivative, reduction, then carbamoylation followed by an acid hydrolysis.

Full text of DOI:10.1016/S0040-4039(02)00733-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4021–4022
Synthesis of
1%-b- -glucopyranosyl-1,2,3-triazole-4,5-dimethanol-4,5-bis-
D
(isopropylcarbamate) as potential antineoplastic agent
Najim A. Al-Masoudia,* and Yaseen A. Al-Soudb
aFakulta¨t fu¨r Chemie, Universita¨t Konstanz, Postfach 5560, D-78457 Konstanz, Germany
bDepartment of Chemistry, College of Science, University of Al al-Bayt, Al-Mafraq, Jordan
Received 13 February 2002; accepted 11 April 2002
Abstract—The title compound 5 was prepared from the 1-b-D-azido-glucose 1 via four steps. Alternatively, 5 was synthesized from
1, via acetalation, cycloaddition with acetylene derivative, reduction, then carbamoylation followed by an acid hydrolysis. © 2002
Elsevier Science Ltd. All rights reserved.
Recent studies showed that some carbamates, such as
5-aryl-2,3-dihydropyrrolo[2,1-b]thiazole-6,7-dimethanol-
6,7-bis(isopropylcarbamates)1 and the bis(carbamate)
derivatives of 4,5-bis(hydroxymethyl)imidazoles2 exhib-
ited in vitro potential activity against HL-60 human
leukemia and HT-29 human colon carcinoma cells as
well as antineoplastic activities. These findings and in
vitro antileukemic activity of 1-aryl-1,2,3-triazole-4,5-
dimethanol-4,5-bis(isopropylcarbamates)3 encouraged
us to synthesize the nucleoside analogue as a potential
antineoplastic agent.
The title compound 4,5-bis(carbamate) 5 was synthe-
sized from the glucose azide 1 via two routes with
Scheme 1. Reagents and conditions: (a) AC2O–pyr., rt, 24 h; (b) HOH2C-CꢀC-CH2OH–toluene–pyr. 9:1, reflux, 18 h; (c)
Me2CHNCO, Sn(Bu)2(OAc)2, rt, 4 h; (d) K2CO3–MeOH, rt, 18 h; (e) Me2CO–DMP–pTSA, rt, 30 min; (f) DHP-H+, rt, 16 h; (g)
MEO2C-CꢀC-CO2Me, 80°C, 24 h; (h) LAH, dry ether, rt, 18 h; (i) pTSA, rt, 18 h.
* Corresponding author. E-mail: najim.al-masoudi@uni-konstanz.de
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00733-5

4022
N. A. Al-Masoudi, Y. A. Al-Soud / Tetrahedron Letters 43 (2002) 4021–4022
diverse yields. Cycloaddition of 2,4 prepared from 1, with
2-butyn-1,4-diol in a mixture of toluene/pyridine (9:1)
under reflux for 18 h afforded, after chromatography, the
crystalline triazole 35 in 38% yield. The carbamoylation3
of 3 with isopropyl isocyanate was carried out in the
presence of Sn(Bu)2(OAc)2 as a catalyst2 in CH2Cl2 at rt
for 4 h to give, after purification, 46 (72%) as crystals,
mp 157–160°C. Deblocking of 4 with K2CO3 in MeOH
at rt for 18 h afforded, after purification, the crystalline
57 in 73% yield. Alternatively, 5 was prepared from 1 via
six steps. Thus, acetalation of 1 with a mixture of
acetone/dimethoxypropane (3:1) in the presence of p-
toluenesulphonic acid at rt furnished 6 in 76% yield. The
hydroxyl groups of 6 were protected with tetrahy-
dropyran8 in the presence of p-toluenesulphonic acid and
gave 7 as a crystalline material in 81% yield. The gluco
azide 7 and dimethyl acetylenedicarboxylate were heated
in toluene at 80°C for 24 h to give 8 (61%), which was
reduced3 to the alcohol 9 on treatment with LAH in dry
ether (48%). Carbamoylation of 9 afforded the crys-
talline 10 in 67% yield. Acid hydrolysis of 10 furnished
5 in 76% yield (Scheme 1).9 The anticancer activity of 5
is under evaluation.
2. Anderson, W. K.; Bhattacharjee, D.; Houston, D. M. J.
Med. Chem. 1989, 32, 119–127.
3. Lalezari, I.; Gomez, L. A.; Khorshidi, M. J. Heterocyclic
Chem. 1990, 27, 687–689.
4. Bertho, A. Ber. Dtsch. Chem. Ges. 1930, 63, 841–843.
5. de las Heras, F.; Alonso, R.; Alonso, G. J. Med. Chem.
1979, 22, 496–501.
6. Selected spectroscopic data of 4: 1H NMR (CDCl3): l 7.35
(br, 1H, NH); 6.13 (d, 1H, J1%,2%=9.3 Hz, H-1%); 5.95 (t,
1H, J2%,3%=9.3 Hz, H-2%); 5.41 (t, 1H, J3%,4%=9.4 Hz, H-3%);
5.34 (s, 4H, 2CH2); 5.25 (t, 1H, J4%,5%=9.5 Hz, H-4%); 4.31
(dd, 1H, J5%,6%=4.8 Hz, H-6%); 4.12 (dd, 1H, J6%,6%%=12.6 Hz,
H-6%%); 4.03 (dt, 1H, J5%,6%%=2.8 Hz, H-5%); 3.54 (m, 2H,
CH); 2.07, 2.05, 2.03, 1.90 (4s, 12H, 4×OAc); 1.05 (d, 6H,
2CH3); 0.92 (d, 6H, 2CH3). 13C NMR (CDCl3): 170.3,
170.1, 169.1, 168.5 (4OAc); 159.7, 158.3 (CꢁO); 140.1
(C-4); 130.7 (C-5); 85.5 (C-1%); 75.1 (C-5%); 73.1 (C-3%); 69.5
(C-2%); 67.3 (C-4%); 61.3 (C-6%); 58.1, 54.1 (2CH2); 50.1, 49.2
[CH(Me)2]; 20.7, 20.6, 20.5, 20.3 (4OAc); 10.8, 10.6, 9.2,
8.5 [CH(Me)2].
7. Selected spectroscopic data of 5: 1H NMR (DMSO-d6/
D2O): l 5.97 (d, 1H, J1%,2%=9.5 Hz, H-1%); 5.19 (s, 4H,
2CH2); 4.01 (t, 1H, J2%,3%=9.5 Hz, H-2%); 3.69 (dd, 1H,
J5%,6%=4.6 Hz, H-6%); 3.65 (m, 2H, 2CH); 3.44 (dd, 1H,
J6%,6%%=12.0 Hz, H-6%%); 3.34 (dt, 1H, J5%,6%%=3.0 Hz, H-5%);
3.33 (t, 1H, J3%,4%=9.4 Hz, H-3%); 3.23 (t, 1H, J4%,5%=9.5 Hz,
H-4%); 1.37 (d, 6H, 2CH3); 0.89 (d, 6H, 2CH3). 13C NMR
(DMSO-d6/D2O): l 163.2, 158.4 (CꢁO); 139.3 (C-4); 132.6
(C-5); 86.3 (C-1%); 80.2 (C-5%); 77.1 (C-3%); 71.8 (C-2%); 69.6
(C-4%); 60.6 (C-6%); 57.0, 54.5 (2CH2); 48.8, 47.9 [CH(Me)2];
10.5, 10.2, 9.7, 9.0 [CH(Me)2].
Acknowledgements
We thank Miss A. Friemel and Mr. K. Ha¨gele, Fakulta¨t
fu¨r Chemie and der Universita¨t Konstanz, Germany, for
the NMR experiments and the mass spectra measure-
ments, respectively.
8. Uesugi, S.; Kaneyasu, T.; Matsugi, J.; Ikehara, M.
Nucleosides Nucleotides 1983, 2, 373–385.
9. All new compounds were purified by column chromatog-
raphy characterized by 1H NMR (600 MHz, HMQC,
COSY, ROESY), 13C NMR and mass spectroscopy and
gave correct elemental analysis.
References
1. Lalezari, I.; Schwartz, E. D. Med. Chem. 1988, 31, 1427–
1429.