Communication
RSC Advances
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Scheme 5 Synthesis of clofarabine 9: (i) Tf2O, pyridine, ꢁ20 ꢀC, 5
hours, 95%; (ii) Et3N$3HF, ethyl acetate, 70 ꢀC, 24 hours, 66%; (iii) NH3,
MeOH, 60 ꢀC, 5 hours, 90%.
active compounds.16,17 Several synthetic approaches were re-
ported. As shown in Scheme 4, glycosylation of nucleoside 4a
with a little excess of 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofur-
anose gave the corresponding disaccharide nucleoside in 42%
yield. Aer deprotection of all ester groups, nucleoside 6 (10
grams) was obtained in high purity. All the characterization
spectra were identied with the reported data.
To further extend the application of this methodology, we also
attempted to develop a new approach for synthesis of antitumor
drug clofarabine 9.18,19 As presented in Scheme 5, the reaction of
nucleoside 4h with triuoromethanesulfonic anhydride (Tf2O) in
pyridine gave corresponding triuoromethanesulfonic ester of 20-
OH in almost quantitative yield. Aer uorination with Et3N$HF,
deacylation with ammonia in methanol gave clofarabine (16
grams) in 56% overall yield. HPLC analysis showed the purity is
above 99% and coincidence with reference standard from Sigma
Aldrich.
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In summary, ortho-alkynyl benzoate was proved to be an
efficient neighboring participation group in stereoselective
¨
synthesis of nucleosides by using Vorbruggen glycosylation. It
could be removed as isocoumarin 5 using gold(I)-catalysis to
afford 20-OH nucleosides in high yield and selectivity. The
powerfulness of present strategy was further demonstrated by
the synthesis of 9-(2-O-b-D-ribofuranosyl-b-ribofuranosyl)-
adenine 6 and antitumor drug clofarabine 9 in high overall
yields. This novel protocol could be used as a general alternative
approach for the synthesis of 20-modied nucleosides. Its
application in carbohydrate synthesis is under way.
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Acknowledgements
16 S. N. Mikhailov, E. V. Emtseva, A. A. Rodionov,
G. V. Bobkov, I. V. Kulikova and P. Herdewijn, Curr. Protoc.
Nucleic Acid Chem., 2007, 27, 1.14.1–1.14.19.
We thank National Science Foundation of China (No. 21462019
and No. 21676131), Bureau of Science & Technology of Jiangxi
Province (20143ACB20012) for nancial support.
17 E. V. Emtseva and S. N. Mikhailov, Russ. Chem. Rev., 2004,
73, 401–414.
18 P. L. Bonate, L. Arthaud, W. R. Cantrell, K. Stephenson,
J. A. Secrist and S. Weitman, Nat. Rev. Drug Discovery, 2006,
5, 855–863.
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