A Chemo-Enzymatic Synthesis
of β-d-Arabinofuranosyl Purine
Nucleosides

Irina D. Konstantinova; Konstantin V. Antonov; Ilja V. Fateev; Anatoly I. Miroshnikov; Vladimir A. Stepchenko; Alexander V. Baranovsky; Igor A. Mikhailopulo

doi:10.1055/s-0030-1260010

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Synthesis 2011(10): 1555-1560
DOI: 10.1055/s-0030-1260010

PAPER

A Chemo-Enzymatic Synthesis of β-d-Arabinofuranosyl Purine Nucleosides

Irina D. Konstantinova^a, Konstantin V. Antonov^a, Ilja V. Fateev^a, Anatoly I. Miroshnikov^a, Vladimir A. Stepchenko^b, Alexander V. Baranovsky^b, Igor A. Mikhailopulo*^b
^a Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow B-437, 117997 GSP, Russian Federation
^b Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Acad. Kuprevicha 5/2, 220141 Minsk, Belarus
Fax: +375(17)2678761; e-Mail: igor_mikhailo@yahoo.de;

Further Information

Publication History

Received 18 November 2010
Publication Date:
19 April 2011 (online)

Abstract
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Abstract

A chemo-enzymatic synthesis of 9-(β-d-arabinofuranosyl)-2-fluoroadenine (Fludarabine) and 9-(β-d-arabinofuranosyl)-2-amino-6-methoxypurine (Nelarabine) using α-d-arabinofuranose 1-phosphate as a universal substrate and recombinant E. coli purine nucleoside phosphorylase (PNP) as a biocatalyst is described. MacDonald’s method was employed for the synthesis of α-d-arabinofuranose 1-phosphate, which was prepared as a mixture with β-d-arabinopyranose 1-phosphate, starting from peracyl derivatives of d-arabinose of different isomeric (anomeric) composition. It was found that the mixed phosphates can be successfully used in the reaction with purine base catalyzed by PNP pointing to the inertia of β-d-arabinopyranose 1-phosphate in regard to PNP. Reaction of 2-fluoroadenine and α-d-arabinofuranose 1-phosphate is shifted towards the formation of Fludarabine, whereas the reaction of 2-amino-6-methoxypurine reached equilibrium at a ca. equimolar ratio of the base and Nelarabine. Recombinant E. coli uridine phosphorylase catalyzed the synthesis of 1-(β-d-arabinofuranosyl)thymine (ara-T) from thymine and α-d-arabinofuranose 1-phosphate.

Key words

α-d-arabinofuranose 1-phosphate - recombinant E.coli nucleoside phosphorylases - purine nucleosides - ara-T

Supporting Information

References

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26

It is noteworthy that a mixture of the 1α and 1β furanosides^¹5 is unstable at r.t. giving rise to the formation of two new fractions that have been isolated by silica gel column chromatography. One of them consists of two triacetates (^¹H, ^¹³C NMR). Detailed NMR analysis (^¹H, ^¹³C NMR; COSY, HMBC, TOCSY, and NOE) along with the ab initio geometry optimization (HyperChem, 8.1; in vacuo, basis set; 6-31G*) of the relevant structures led us to conclusion that the major constituent is 2,3,5-tri-O-acetyl-α-d-arabino-furanose and the minor is 2,3,4-tri-O-acetyl-β-d-arabino-pyranose. The formation of the former as a byproduct was previously mentioned^²² in the transformation of methyl 2,3,5-tri-O-acetyl-α-d-arabinofuranoside into 1,2,3,5-tetra-O-acetyl-α-d-arabinofuranose through the intermediate
1-bromide, however, no NMR data was given. The other fraction consists of three (ca. 1:1:1 according to ^¹H NMR) supposedly acyclic closely related isomeric tetraacetates, the structures of which have not yet been established.

31

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