Synthesis of L-2′-deoxypentofuranonucleoside derivatives of thymine from D-glucose

Article abstract of DOI:10.1080/15257770701528198

Convergent synthesis of L-2′-deoxypentofuranonucleoside derivatives of thymine was carried out from D-glucose via 6-O-toluoyl-3-deoxy-1,2-O- isopropylidene-β-L-lyxo-hexofuranose as a key intermediate. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701528198

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Synthesis of L-2′-
Deoxypentofuranonucleoside Derivatives
of Thymine From D-Glucose
Grigorii G. Sivets a
a Institute of Bioorganic Chemistry , National Academy of Sciences ,
Minsk, Belarus
Published online: 05 Dec 2007.
To cite this article: Grigorii G. Sivets (2007) Synthesis of L-2′-Deoxypentofuranonucleoside
Derivatives of Thymine From D-Glucose, Nucleosides, Nucleotides and Nucleic Acids, 26:10-12,
1241-1244, DOI: 10.1080/15257770701528198
To link to this article: http://dx.doi.org/10.1080/15257770701528198
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Nucleosides, Nucleotides, and Nucleic Acids, 26:1241–1244, 2007
Copyright ꢀ Taylor & Francis Group, LLC
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ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701528198
SYNTHESIS OF L-2ꢀ-DEOXYPENTOFURANONUCLEOSIDE
DERIVATIVES OF THYMINE FROM D-GLUCOSE
Grigorii G. Sivets
Institute of Bioorganic Chemistry, National Academy of Sciences,
2
Minsk, Belarus
Convergent synthesis of L-2 ꢁ-deoxypentofuranonucleoside derivatives of thymine was carried
2
out from D-glucose via 6-O-toluoyl-3-deoxy-1,2-O-isopropylidene-β-L-lyxo-hexofuranose as a key in-
termediate.
Keywords L-Deoxynucleosides; thymine; convergent synthesis; L-sugars; D-glucose
INTRODUCTION
L-Nucleoside analogues, the mirror images of the natural D-nucleosides,
are extensively investigated and their use in antiviral chemotherapy has grea-
tly increased.[1]Among these, L-2ꢁ-fluoro-arabinofuranosyl-5-methyluracil
(L-FMAU), L-2ꢁ,3ꢁ-dideoxy-2ꢁ,3ꢁ-didehydro-5-fluorocytidine (L-Fd4C), L-thy-
midine (L-dT), and L-2ꢁ-deoxycytidine (L-dC) have shown potent, selective
activity against HBV replication, whereas L-3ꢁ-thiacytidine (L-3TC), L-2ꢁ,3ꢁ-
dideoxy-5-fluorocytidine (L-FddC) have been found to be active against
HIV.[1−2] The main advantage of the L-nucleosides is their lower toxic-
ity profiles in comparison with their D-counterparts. A number of syn-
thetic approaches to different L-nucleosides have been explored from D-
carbohydrates such as D-galactose, D-xylose, D-ribitol and D-ribose.[3−6] This
report describes the synthesis of L-2ꢁ-deoxypentofuranonucleoside deriva-
tives of thymine 12–18 from cheap D-glucose, using a new sequence for
preparing intermediate L-2-deoxysugars.
This work was supported by Belarus State Program of FOI “Physiological Active Compounds” (Grant
2.04).
Address correspondence to G. G. Sivets, Laboratory of Nucleotides and Polynucleotides, Institute
of Bioorganic Chemistry, Minsk, Acad. Kuprevicha 5/2, Belarus. E-mail: gsivets@yahoo.com
1241

1242
G. G. Sivets
RESULTS AND DISCUSSION
The synthetic route to L-ribose has been reported from D-glucose.[7]
From retrosynthetic analysis it was inferred that the synthesis of deriva-
tives of L-2-deoxy-threo-pentofuranose is possible from D-glucose via read-
ily available diacetone-D-glucose (1). 3-Deoxy-1,2;5,6-di-O-isopropylidene-α-
D-ribo-hexofuranose (2) was synthesized by Barton deoxygenation process
of thiocarbonylimidazolide derivative of 1 (Scheme 1).[8] Nucleophilic dis-
placement of the primary and secondary sulphonyloxy groups of ditosyl
derivative 4, prepared in two steps from 2, by treatment with potassium
p-toluate in aqueous N,N-dimethylformamide under reflux afforded 6-O-
toluoyl- and 5,6-di-O-toluoyl derivatives of 3-deoxy-1,2-O-isopropylidene-β-
L-lyxo-hexofuranose 5 and 6 which were separated and purified by column
chromatography in 57% and 30% yield, respectively. Thus, key crystalline
derivative 5 was prepared by inversion configuration at C-5 of 5,6-di-O-
tosyl-3-deoxy-1,2-O-isopropylidene-α-D-ribo-hexofuranose (4). Intermediate
SCHEME 1 Reagents and conditions: (a) [i] (lm)2C = S/(CH2Cl)2; [ii] Bu3SnH. toluene, ꢀ69%; (b)
0.01 N HCl, rt, 82%; (c) TsCl/Py, rt, 70%; (d) TolOK, DMF/H2O, 150–155◦C, (5, 57%, 6, 30%); (e)
[i] 90% CF3COOH, rt. [ii] NalO4, dioxane/H2O, rt. [iii] 0.2% HCl/MeOH, rt ꢀ68%; (f) [i] 90%
CF3COOH, rt [ii] KlO4, H2O/EtOH, rt. [iii] Ac2O, Py, rt, ꢀ40%, (g) MsCl, Py, O◦C, +4◦C, 69% (h)
NaN3, DMF, 80–84◦C, 60%; (i) TolOK, DMF/H2O, 100◦C, 85%.

L-2ꢁ-Deoxynucleoside Derivatives of Thymine
1243
SCHEME 2 Reagents and conditions: (j) 2, 4-bis(trimethyl)silylthymine, Me3SiOTf, CH3CN, −30◦C to
rt for 8 (21%, 12; 9%, 13,); 60–65◦C for 10; rt for 11 (ꢀ60%, 2.6/1); (k) NH3/MeOH, rt, 85%; (l)
Ph3P/Py, rt; NH4OH, rt, 55%; (m) (CF3CO)2O/Py/CH2Cl2, O◦C to rt, MeOH, 57%.
derivative of L-hexofuranose 5 was converted in three steps into methyl 5-
O-toluoyl-2-deoxy-L-threo-pentofuranoside 7 or peracylated derivative of L-2-
deoxy-threo-pentofuranose 8 as mixtures of anomers in 68% and 40% over-
all yields, respectively, after column chromatography on silica gel. Start-
ing from 9, the synthesis of L-sugars 10 and 11 was carried out by nu-
cleophilic substitution of mesyloxy group by sodium azide and potassium
p-toluate, respectively, in DMF (Scheme 1). The condensation of 8 and
11 with silylated thymine in Vorbru¨ggen conditions yielded L-nucleosides
12-14 (Scheme 2). It should be noted that the formation of mixture nu-
cleosides 12 and 13 (α/β–2.3/1), which was difficult to separate by col-
umn chromatography on silica gel, as well as of unseparable mixture of
1
β- and α-nucleosides 14 (2.6/1 according to H NMR data, overall 60%)
was observed as a result of the coupling reactions of 8 and 11 with sily-
lated thymine in the presence TMSOTf of in acetonitrile. The standard
deacylation of 14 yielded the mixture of L-dT (15) and its α-anomer af-
ter chromatography. The condensation of L-azidosugar (10) with thymine
(Scheme 2) followed by treatment of anomeric mixture of intermediate
protected nucleosides with methanolic ammonia afforded β-L-nucleoside
16a (27%) and α-L-nucleoside 16b (16%) which were separated by col-
umn chromatography on silica gel. The reduction of azido group of β-
L-AZT (16a) by consecutive treatment with Ph3P/Py and aqueous ammo-
nia generated 3ꢁ-amino-2ꢁ,3ꢁ-dideoxy-β-L-thymidine (17). Trifluoroacetyla-
tion of the latter with trifluoroacetic anhydride in pyridine/methylene

1244
G. G. Sivets
chloride afforded nucleoside 18 (57%). Biological evaluation of 3ꢁ-N-
trifluoroacetamido-2ꢁ,3ꢁ-dideoxy-β-L-analogue of thymidine 18 is under
investigation.
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