Stereoselective synthesis of novel thioiso dideoxy nucleosides with exocyclic methylene as potential antiviral agents

Article abstract of DOI:10.1081/NCN-200060072

Novel thioiso pyrimidine and purine nucleosides substituted with exocyclic methylene have been synthesized, starting from D-xylose. Cyclization of the dimesylate to the 4-thiosugar 6a proceeded in pure S_N2 reaction in the presence of allylic fu

Full text of DOI:10.1081/NCN-200060072

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STEREOSELECTIVE SYNTHESIS OF NOVEL THIOISO
DIDEOXY NUCLEOSIDES WITH EXOCYCLIC METHYLENE
AS POTENTIAL ANTIVIRAL AGENTS
Prashantha Gunaga a , Hea Ok Kim a , Hyun Ji Kim a , Moon Woo Chun b & Lak Shin Jeong a
a Laboratory of Medicinal Chemistry, College of Pharmacy , Ewha Womans University , Seoul,
Korea
b College of Pharmacy, Seoul National University , Seoul, Korea
Published online: 15 Nov 2011.
To cite this article: Prashantha Gunaga , Hea Ok Kim , Hyun Ji Kim , Moon Woo Chun & Lak Shin Jeong (2005)
STEREOSELECTIVE SYNTHESIS OF NOVEL THIOISO DIDEOXY NUCLEOSIDES WITH EXOCYCLIC METHYLENE AS POTENTIAL
ANTIVIRAL AGENTS, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 1115-1117, DOI: 10.1081/NCN-200060072
To link to this article: http://dx.doi.org/10.1081/NCN-200060072
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):1115–1117, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060072
STEREOSELECTIVE SYNTHESIS OF NOVEL THIOISO DIDEOXY
NUCLEOSIDES WITH EXOCYCLIC METHYLENE AS
POTENTIAL ANTIVIRAL AGENTS
5
Prashantha Gunaga, Hea Ok Kim, and Hyun Ji Kim
Laboratory of Medicinal
Chemistry, College of Pharmacy, Ewha Womans University, Seoul, Korea
5
Moon Woo Chun
College of Pharmacy, Seoul National University, Seoul, Korea
5
Lak Shin Jeong
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha
Womans University, Seoul, Korea
5
Novel thioiso pyrimidine and purine nucleosides substituted with exocyclic methylene have been
synthesized, starting from D-xylose. Cyclization of the dimesylate to the 4-thiosugar 6a proceeded in pure
SN2 reaction in the presence of allylic functional group.
INTRODUCTION
BMS-200475 (1, entecavir),[1] has shown potent anti-HBV activity and was
found to be 100 times more potent than lamivudine and is in phase III clinical trials.
On the basis of the chemical structure of 1, we have designed and synthesized iso
dideoxynucleosides among which adenine analogue 2 exhibited potent anti-HBV
activity[2] (Figure 1).
Based on the potent anti-HBV activity of 2, and the principle of bioisosterism,
we designed the target nucleoside 3 to compare its anti-HBV activity with that of
compound 2. Here, we wish to report the stereoselective synthesis of novel thioiso
dideoxynucleosides 3 with exocyclic methylene as potential antiviral agents and
their related chemistry.
RESULTS AND DISCUSSION
Synthesis of the glycosyl donors, 10 and 11, starting from D-xylose is shown in
Scheme 1. D-Xylose was converted to methylene derivative 4 according to the
Address correspondence to Lak Shin Jeong, Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha
Womans University, Seoul 120-750, Korea.
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1116
P. Gunaga et al.
FIGURE 1 The rationale for the design of the target nucleosides.
known procedures.[2–5] Hydrolysis of 4 under acidic conditions followed by
reduction of the lactol with lithium borohydride gave diol 5. Treatment of 5 with
mesyl chloride followed by treating with sodium sulfide in DMF afforded the
desired thiosugar 6a along with SN2’ product 6b as a mixture of (E)- and (Z)-
isomers. The optimum yield of 6a was obtained on stirring in DMF at 0°C for 4 h.
It is interesting to note that cyclization proceeded in pure SN2 reaction, not SN1
reaction in the presence of allylic fuctional group. Thiosugar 6 was debenzylated
and slectively protected with TBDPS group to give the glycosyl donor 8. For the
synthesis of cis-nucleosides, another glycosyl donor 9 was obtained by the inversion
of the stereochemistry of C3-hydroxyl group using Mitsunobu reaction.[6]
For the synthesis of trans-purine nucleosides, glycosyl donor 8 was condensed
with 6-chloropurine under the Mitsunobu conditions[6] to give the protected
nucleoside which in turn was desilylated and converted to adenine derivative, N6-
methyladenine derivative, and hypoxanthine derivative. Condensation of 8 with
N3-benzoylthymine and N3-benzoyluracil under the standard Mitsunobu conditions
followed by removal of the protecting groups also yielded cis-pyrimidine
nucleosides, thymine, and uracil derivatives. Unlike cyclization to get 4-thiosugar
SCHEME 1 Reagents: (a) HCl/Dioxane; (b) LiBH4, THF; (c) MsCl, Pyridine, CH2Cl2; (d) Na2S, DMF, 0°C;
(e) BCl3, CH2Cl2; (f) TBDPSCI, Imidazole, DMF; (g) BzOH, PPh3, DEAD, THF then MeOH/NH3; (h) Base,
PPh3, DEAD, 0°C.

P. Gunaga et al.
1117
6a, Mitsunobu condensation reaction proceeded in pure SN2 fashion without the
formation of SN2’ product. Cis-uracil derivative was converted to the cis-cytosine
derivative according to the conventional method. Similarly, another glycosyl donor
9 was converted to the trans-purine and pyrimidine nucleosides.
All synthesized final nucleosides were tested against several viruses such as
HIV-1, HBV, HCV, and HCMV. The 6-chloropurine derivatives only exhibited
very weak anti-HCV activity.
In summary, we have accomplished the asymmetric synthesis of novel thioiso
nucleosides with exocyclic methylene, starting from D-xylose. The pure SN2
cyclization reaction in the presence of allylic mesylate was obtained by stirring a
solution of dimesylate in DMF at low temperature.
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