Efficient and selective synthesis of glycofuranosyl azides and nucleosides from cyclic 1,2-thiocarbonate sugars

Article abstract of DOI:10.1021/ol034975a

(Matrix presented) Cyclic 1,2-thiocarbonate sugars are convenient starting materials for the selective and efficient preparation of glycofuranosyl azides and nucleosides by regio- and stereoselective thiocarbonate ring-opening.

Full text of DOI:10.1021/ol034975a

ORGANIC
LETTERS
2
003
Vol. 5, No. 15
743-2745
Efficient and Selective Synthesis of
Glycofuranosyl Azides and Nucleosides
from Cyclic 1,2-Thiocarbonate Sugars
2
Luis AÄ lvarez de Cienfuegos, Concepci o´ n Rodr ´ı guez, Antonio J. Mota, and
Rafael Robles*
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias, UniVersidad de Granada,
Campus de FuentenueVa s/n, 18071 Granada, Spain
rrobles@ugr.es
Received June 2, 2003
ABSTRACT
Cyclic 1,2-thiocarbonate sugars are convenient starting materials for the selective and efficient preparation of glycofuranosyl azides and
nucleosides by regio- and stereoselective thiocarbonate ring-opening.
1
6
The biological role of nucleoside-related compounds keeps
synthesis using persilylated pyrimidinic bases with good
the development of more efficient synthetic methods as a
permanent current topic due to the importance of this type
of compounds in the development of new lines of anti-
yields and, in some cases, stereoselectivities. Nevertheless,
in these reactions, the opening of the 1,2-cyclic sulfite ring
usually requires long reaction times and high temperatures.
2
neoplastic therapeutic agents. The greatest challenge is the
Glycosyl azides are important intermediates for the
synthesis of a wide variety of sugar derivatives. For their
synthesis, three general methods are normally used: (a)
reaction of glycosyl halides with metal azides or tetrameth-
achievement of a good stereoselectivity to avoid the forma-
tion of R/â diastereomeric mixtures, which are difficult to
separate. In other cases, the employment of strong glycosy-
lating promoters or conditions limits the use of many
7
8
ylguanidium azide under homogeneous conditions or by
3
protecting groups.
9
using phase transfer catalysts, (b) reaction of glycosyl esters
4
Cyclic 1,2-thiocarbonate sugars are stable compounds that
with trimethylsilyl azide in the presence of a Lewis acid
are easily prepared and handled. They have previously been
employed as glycosyl donors in glycosidation reactions by
sulfur methylation that promotes the attack of the glycosyl
acceptor. Other related glycosyl donors are cyclic 1,2-
sulfite sugars that have also been employed for nucleoside
(
5) Patroni, J. J.; Stick, R. V.; Tilbrook, D. M. G.; Skelton, B. W.; White,
A. H. Aust. J. Chem. 1989, 42, 2127-2141.
(6) (a) Gagnieu, C. H.; Guiller, A.; Pacheco, H. Carbohydr. Res. 1988,
4
,5
1
80, 233-242. (b) See also: Moon, H. R.; Kim, H. O.; Chun, M. W.;
Jeong, L. S. J. Org. Chem. 1999, 64, 4733-4741.
7) Li, C.; Arasappan, A.; Fuchs, P. L. Tetrahedron Lett. 1993, 34, 3535-
3538.
(
(
1) Mizuno, Y. The Organic Chemistry of Nucleic Acids; Elsevier:
Amsterdam, 1986.
2) Montgomery, J. A.; Johnston, T. P.; Shealy, Y. F. Burger’s Medicinal
Chemistry; Wiley: New York, 1980, part 2.
3) (a) Kennedy J. F. Carbohydrate Chemistry; Oxford University
(8) (a) Micheel, F.; Klemer, A. AdV. Carbohydr. Chem. Biochem. 1961,
(
16, 85-103. (b) Nakabayashi, S.; Warren, C. D.; Jeanloz, R. W. Carbohydr.
Res. 1988, 174, 279-289. (c) Peto C., Batta G., Gy o¨ rgyde a´ k, Z.; Sztaricskai,
F. Liebigs Ann. Chem. 1991, 505-507.
(
Press: Oxford, 1988. (b) Collins, P. M.; Ferrier, R. J. Monosaccharides.
Their Chemistry and Their Roles in Natural Products; John Wiley & Sons,
Ltd.: Chichester, England, 1995.
(9) (a) Kunz, H.; Waldmann, H.; M a¨ rz, J. Liebigs Ann. Chem. 1989,
45-49. (b) Thiem, J.; Wiemann, T. Angew. Chem., Int. Ed. Engl. 1990,
29, 80-82. (c) Tropper, F. D.; Andersson, F. O.; Braun, S.; Roy, R.
Synthesis 1992, 618-620.
(4) Murakami, M.; Mukaiyama, T. Chem. Lett. 1983, 1733-1736.
1
0.1021/ol034975a CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/26/2003

catalyst,8c,10 and (c) reaction of cyclic 1,2-sulfite sugar
derivatives with sodium azide.6b,11
Scheme 2. General Mechanism for the Nucleosidation Process
Considering the particular charge density at the anomeric
carbon of the cyclic 1,2-thiocarbonate sugars as a conse-
quence of the concurrence of the sugar and thiocarbonate
rings, we thought that these bicyclic compounds should be
easily opened by attack with nucleophiles such as sodium
azide allowing the synthesis of the corresponding glycosyl
azides. This hypothesis was corroborated when compounds
1
and 2 were treated with sodium azide,12 leading to the
corresponding 3,5-di-O-benzyl-â-D-xylo (3) and the already
1
1
described 3,5-di-O-benzyl-â-D-ribofuranosyl azide (4) in
95 and 90% yields, respectively (Scheme 1).
disposable silylating agent [N,O-bis(trimethylsilyl) aceta-
mide] (Table 1). The better results correspond to the use of
Scheme 1. Thiocarbonate Ring-Opening with NaN
3
Table 1. Optimization of the Nucleosidation Process: Yields
of 5-7
basea
silylating agentb
4 equiv 6 equiv
86 90
compd
1 equiv
2 equiv
5
6
7
29
25
26
73
39
43
70
57
76
71
On the basis of these satisfactory results, we thought that
a
In all cases, 2 equiv of silylating agent was employed. b In all cases, 2
equiv of nucleobase was employed.
the pyrimidinic bases could also be used as nucleophiles for
the opening of cyclic 1,2-thiocarbonate sugars, allowing an
easy access to nucleosides. Preliminary experiments were
carried out using thymine as a nucleophile, but treatment of
this base with compound 1 using NaH or DBU led to
complex mixtures.
2
equiv of base and a large excess of silylating agent (see
General Method).
To demonstrate unequivocally the â-configuration at the
anomeric position of nucleosides 5-7, the substituent at C-2′
4
was first removed by basic (KOH, DABCO) or acid (KHSO )
treatment leading to the corresponding nucleosides 8-10 in
almost quantitative yield. Compound 8 was then mesylated
and treated with DBU to obtain the tricycle 11, which showed
physical and spectroscopic data identical to those previously
1
4
1
3
Sugimura has previously reported the use of NBS to
promote nucleosidation of thioglycosides achieving good
yields with moderate stereoselectivity in a variety of
examples. Taking this antecedent into consideration, we
chose NIS as the promoter for the nucleosidation of cyclic
1
,2-thiocarbonates sugars. The use of NIS proves to be
particularly efficient when persilylated pyrimidinic bases
thymine, uracil, and 5-fluoruracil) were used as nucleophilic
1
5
described (Scheme 3).
(
agents and acetonitrile as a solvent. The thiocarbonate ring-
opening of compound 1 was thus effectively achieved at
room temperature, and â-nucleosides 5-7 were exclusively
obtained in high yields having the hydroxyl group at C-2′
protected as indicated in Scheme 2.
Scheme 3. Chemical Correlation Demonstrating the Obtained
â-1′ Configuration
Yields were drastically affected by the number of equiva-
lents of the pyrimidine base used and the proportion of the
(
10) (a) Paulsen, H.; Gy o¨ rgyde a´ k, Z.; Friedmann, M. Chem. Ber. 1974,
1
1
07, 1568-1578. (b) Szil a´ gyi, L.; Gy o¨ rgyde a´ k, Z. Carbohydr. Res. 1985,
43, 21-41. (c) Viaud, M. C.; Rollin, P. Synthesis 1990, 130-132.
(11) (a) Guiller, A.; Gagnieu, C. H.; Pacheco, H. J. Carbohydr. Chem.
1
986, 5, 161-168.
(
12) General Procedure for Azide Glycosidation. To a stirred solution
of 1 (1.12 g, 3.0 mmol) in DMF (10 mL) was added NaN3 (585 mg, 9.0
mmol), and the mixture was heated at 60 °C until TLC indicated the
disappearance of the starting material (15 min). Water (100 mL) was then
added and the solution extracted with toluene (3 × 50 mL). The combined
organic extracts were dried over MgSO4 and evaporated, giving a residue
that was purified by column chromatography (ether-hexane 2:1) to achieve
In summary, we report a new methodology for the
synthesis of glycofuranosyl azides and nucleosides using
cyclic 1,2-thiocarbonate sugars as readily available and useful
starting materials. The reactions were shown to be mild, fast,
and selective, allowing the isolation of only one of the
3
(1.02 g, 95%).
13) Sugimura, H.; Muramoto, I.; Nakamura, T.; Osumi, K. Chem. Lett.
993, 169-172.
(
1
2744
Org. Lett., Vol. 5, No. 15, 2003

anomers. It could be anticipated that this approach should
constitute an adequate method for the synthesis of a wide
variety of nucleoside derivatives. Studies with other cyclic
Acknowledgment. This work was supported by a re-
search grant from the Ministerio de Ciencia y Tecnolog ´ı a
PB-98-1321). We are also thankful for the grant to L.
AÄ lvarez from the same institution.
(
1,2-thiocarbonate sugars are currently under investigation.
Supporting Information Available: Complete IR, mass
spectra, [R] , and NMR data of products 3-10. This material
is available free of charge via the Internet at http://pubs.acs.org.
D
(
14) General Procedure for Nucleosidation. To a stirred suspension
of thymine (252 mg, 2 mmol) in CH3CN (15 mL) was added N,O-bis-
trimethylsilyl)acetamide (1.5 mL, 6 mmol). Once the thymine was dissolved
15 min), compound 1 (372 mg, 1 mmol) and NIS (450 mg, 2 mmol) were
(
(
OL034975A
added, and the solution stirred at room temperature until TLC indicated
the disappearance of the starting material (10 min). After evaporation, the
crude was dissolved in CH2Cl2 (25 mL) and the solution washed succes-
sively with NaHCO3 saturated aqueous solution, water, 10% Na2S2O3
solution, and water. The organic layer was dried over MgSO4 and
evaporated, giving a residue that was purified by column chromatography
(15) (a) Gurjar, M. K.; Lalitha, S. V. S.; Sharma, P. A.; Rama Rao, A.
V. Tetrahedron Lett. 1992, 33, 7945-7948. (b) Gurjar, M. K.; Kunwar, A.
C.; Reddy, D. V.; Islam, A.; Lalitha, S. V. S.; Jagannadh B.; Rama Rao,
A. V. Tetrahedron 1993, 49, 4373-4382. (c) Robles, R.; Rodr ´ı guez, C.;
Izquierdo, I.; Plaza, M. T.; Mota, A.; AÄ lvarez de Cienfuegos, L. Tetrahe-
dron: Asymmetry 2000, 11, 3069-3077.
(CH2Cl2-MeOH 25:1) to achieve 5 (500 mg, 90%).
Org. Lett., Vol. 5, No. 15, 2003
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