Asym m etr ic Syn th esis of Novel Th ioiso
Did eoxyn u cleosid es w ith Exocyclic
Meth ylen e a s P oten tia l An tivir a l Agen ts
Prashantha Gunaga,† Masanori Baba,‡ and
Lak Shin J eong*,†
Laboratory of Medicinal Chemistry, College of Pharmacy,
Ewha Womans University, Seoul 120-750, Korea, and
Center for Chronic Viral Diseases, Division of Human
Retrovirology, Faculty of Medicine, Kagoshima University,
8-35-1 Sakuragaoka, Kagoshima 890-8520, J apan
lakjeong@ewha.ac.kr
F IGURE 1. The rationale for the design of the target
nucleosides.
Received November 25, 2003
Abstr a ct: Novel thioiso pyrimidine and purine nucleosides
substituted with exocyclic methylene have been synthesized,
starting from D-xylose. The glycosyl donor 14 was synthe-
sized from D-xylose, using cyclization of dimesylate 10 with
sodium sulfide as a key step. Cyclization proceeded in pure
SN2 reaction without going through SN1 reaction in the
presence of an allylic functional group at low reaction
temperature (0 °C) in polar solvent (DMF), affording com-
pound 12 as a major product. At higher temperatures, SN2′
product 11 was almost exclusively obtained as a major
product. On the other hand, glycosylation of 14 with 6-chlo-
ropurine under Mitsunobu conditions afforded the desired
SN2 product 26, while palladium-catalyzed glycosylation
resulted in the sole formation of SN2′ product 34.
that unusual sugar structures can provide very active
compounds. Since then the nucleoside analogues with
unusual ribose mimics have been considered as main
stream in developing new antiviral agents.
BMS-200475 (1, entecavir),5 showing potent anti-HBV
activity, belongs to one of these aforementioned classes
in that it possesses exocyclic methylene in place of oxygen
of the furanose ring. It was 100 times more potent than
lamivudine and is currently undergoing phase III clinical
trials.
On the basis of these findings, we have designed and
synthesized iso dideoxynucleosides with exocyclic meth-
ylene since C3′-OH of compound 1 might act as a
bioisostere of oxygen, among which adenine analogue 2
exhibited potent anti-HBV activity.6 Iso dideoxynucleo-
sides also belong to unique nucleosides in that furanose
oxygen moves to the C3 position. Among these, adenine
analogue (iso-ddA) and guanine analogue (iso-ddG) showed
not only potent anti-HIV activity comparable to 2′,3′-
dideoxyadenosine (ddA) and 2′,3′-dideoxyguanosine (ddG),
respectively, but also chemical and metabolic stability.7
On the basis of the potent anti-HBV activity of 2, it
was interesting to design and synthesize compound 3
because sulfur is well-known as a bioisostere of oxygen
and to compare its anti-HBV activity with that of
compound 2. Here, we wish to report the asymmetric
synthesis of novel thioiso dideoxynucleosides 3 with
exocyclic methylene as potential antiviral agents and
their related chemistry, in which the hitherto unknown
SN2′ reaction is involved.
1,3-Dioxolanyl and 1,3-oxathiolanyl nucleosides, show-
ing potent antiviral activity against human immuno-
deficiency virus (HIV) and hepatitis B virus (HBV),
opened a new era in developing the area of antiviral
nucleosides. Among them, (-)-L-â-1,3-oxathiolanyl cy-
tosine (3TC, lamivudine)1 is clinically used worldwide for
HBV- and/or HIV-infected patients and (-)-L-â-1,3-oxa-
thiolanyl 5-fluorocytosine (FTC, emtricitabine)2 is also
currently in phase III clinical trials for the treatment of
HBV. (-)-L-â-1,3-Dioxolanyl cytosine (L-OddC, troxacit-
abine)3 is undergoing phase II clinical trials as an
anticancer drug and (+)-D-â-1,3-dioxolanyl 2,6-diami-
nopurine (DAPD, amdoxivir)4 is also in phase II clinical
trials for the treatment of HIV. The discovery of promis-
ing 1,3-dioxolanyl and 1,3-oxathiolanyl nucleosides proved
As illustrated in Scheme 1, retrosynthetic analysis
shows that the target nucleosides could be synthesized
from the Mitsunobu condensation with the glycosyl donor
I. The introduction of the exocyclic methylene group to
get the key intermediate I can be visualized in two ways.
† Ewha Womans University.
‡ Kagoshima University.
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10.1021/jo035735b CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/31/2004
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J . Org. Chem. 2004, 69, 3208-3211