Asymmetric synthesis of novel pseudo-D-vinylcyclopropyl nucleosides bearing quaternary carbon as potential anti-herpesvirus agent

Article abstract of DOI:10.1080/15257770701508232

Pseudo-d-vinylcyclopropyl nucleosides 10-12 bearing a quaternary carbon were designed and synthesized starting from (R)-epichlorohydrin using a tandem reaction of double alkylation and lactonization via oxirane-ring opening reaction, a Wittig reaction, an

Full text of DOI:10.1080/15257770701508232

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Asymmetric Synthesis of Novel Pseudo-
d-Vinylcyclopropyl Nucleosides Bearing
Quaternary Carbon as Potential Anti-
Herpesvirus Agent
Ah-Young Park a , Hyung Ryong Moon a , Kyung Ran Kim a , Moon Woo
Chun b & Lak Shin Jeong c
a College of Pharmacy and Research Institute for Drug Development,
Pusan National University, Busan, Korea
b College of Pharmacy, Seoul National University, Seoul, Korea
c College of Pharmacy, Ewha Womans University, Seoul, Korea
Published online: 10 Dec 2007.
To cite this article: Ah-Young Park , Hyung Ryong Moon , Kyung Ran Kim , Moon Woo Chun & Lak
Shin Jeong (2007) Asymmetric Synthesis of Novel Pseudo-d-Vinylcyclopropyl Nucleosides Bearing
Quaternary Carbon as Potential Anti-Herpesvirus Agent, Nucleosides, Nucleotides and Nucleic Acids,
26:8-9, 1001-1004, DOI: 10.1080/15257770701508232
To link to this article: http://dx.doi.org/10.1080/15257770701508232
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Nucleosides, Nucleotides, and Nucleic Acids, 26:1001–1004, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701508232
ASYMMETRIC SYNTHESIS OF NOVEL
PSEUDO-D-VINYLCYCLOPROPYL NUCLEOSIDES BEARING
QUATERNARY CARBON AS POTENTIAL ANTI-HERPESVIRUS AGENT
Ah-Young Park, Hyung Ryong Moon and Kyung Ran Kim
College of
2
Pharmacy and Research Institute for Drug Development, Pusan National University,
Busan, Korea
Moon Woo Chun
Lak Shin Jeong
College of Pharmacy, Seoul National University, Seoul, Korea
College of Pharmacy, Ewha Womans University, Seoul, Korea
2
2
Pseudo-D-vinylcyclopropyl nucleosides 10–12 bearing a quaternary carbon were designed and
2
synthesized starting from (R)-epichlorohydrin using a tandem reaction of double alkylation and
lactonization via oxirane-ring opening reaction, a Wittig reaction, and chemoselective reduction as
potential anti-herpesvirus agent.
Keywords Pseudo-D-vinylcyclopropyl nucleosides; anti-herpesvirus agent; oxirane-ring
reaction; double alkylation
INTRODUCTION
Acyclovir (1, Figure 1)[1] has become the drug of choice for the treat-
ment of HSV-1 and 2 (herpes simplex virus type-1 and 2) and VZV (varicella-
zoster virus) infections as a potent and selective inhibitor. Since acyclovir
(1), which belongs to acyclic nucleoside class has been found to show a po-
tent antiviral activity, a number of acyclic nucleosides and cyclic nucleosides
having a small ring size of their sugar such as three- and four-membered
rings were synthesized, and evaluated against a variety of viruses. Among
them, acyclic nucleosides such as ganciclovir (2)[2] and penciclovir (3)[3]
were launched as new antiviral agents, and cyclobut-G (4),[4] carbocylic
counterpart of oxetanocin G showed a highly potent and broad spectrum
against herpesviruses including HSV-1 and -2, varicella-zoster virus (VZV),
This work was supported by the Korea Research Foundation Grant funded by the Korean Govern-
ment (KRF-2005-202-E00211), and Pusan National University Grant (H. R. Moon).
Address correspondence to Hyung Ryong Moon, College of Pharmacy and Research Institute for
Drug Development, Pusan National University, San 30 Jangjeon-dong, Geumjeong-gu, Busan 609-735,
Korea. E-mail: mhr108@pusan.ac.kr
1001

1002
A.-Y. Park et al.
FIGURE 1 The rationale for the design of the desired nucleosides, 10–12.
and human cytomegalovirus (HCMV). Specially, penciclovir (3) in which
the ethereal oxygen of ganciclovir (2) is replaced by a carbon atom showed
anti-HBV (hepatitis B virus) activity as well as a similar activity spectrum
to acyclovir, i.e., anti-HSV-1 and 2 and anti-VZV activities and currently has
been approved for the treatment of VZV infection by the FDA. In general,
carbanucleosides such as penciclovir (3), and cyclobut-G (4) are more resis-
tant to enzymatic hydrolysis and chemical degradation than normal nucle-
osides. These properties confer on carbanucleosides an additional benefit
in developing a clinically useful drug. Several structural modifications on
cyclopropane ring have been made in the search for antiviral agents with
better efficacy and selectivity. 9-[[cis-1ꢁ,2ꢁ-Bis(hydroxymethyl)cycloprop-1ꢁ-
yl]methyl]guanine (5),[5] which retains a cyclopropane ring and a guanine
base has been reported to show extremely potent antiviral activity against
HSV-1 and VZV with good selectivity.
On the other hand, nucleosides bearing unsaturated functional groups
such as vinyl and acetylenyl at 3ꢁ or 4ꢁ position have been reported to show
potent antiviral and antitumor activities. Among them, 1-(3-C-ethynyl-β-D-
ribo-pentofuranosyl)cytosine (ECyd, 6)[6] and its uracil congener (EUrd,
7)[7] have exhibited potent antitumor activity. ECyd (6) also have shown po-
tent anti-HIV (human immunodeficiency virus) activity with its adenine con-
gener, EAdo (8). In addition, 4ꢁα-C-ethenyl- and ethynylthymidines (9a and
9b)[8] also have been found to show very potent antiviral activities against
HSV-1 and HIV-1.
On the basis of these findings, as a part of our efforts to search for novel
antiviral agents with better potency and selectivity, it was interesting to de-
sign and asymmetrically synthesize novel pseudo-D-vinylcyclopropyl pyrimi-
dine nucleosides 10–12, combining properties of nucleosides bearing cyclo-
propane ring and vinyl substituent, respectively. Herein, we wish to report
the synthesis of pseudo-D-vinylcyclopropyl nucleosides having natural bases
(Ura, Thy, and Cyt) starting from (R)-(-)-epichlorohydrin.
CHEMISTRY
Synthesis of the vinyl-substituted glycosyl donor 17 is shown in Scheme 1.
Reaction of (R)-(-)-epichlorohydrin with diethyl malonate in the presence
of sodium metal in EtOH gave bicyclolactone 13 via a tandem reaction of

Pseudo-d-Vinylcyclopropyl Nucleosides
1003
SCHEME 1 Reagents and conditions: (a) (EtO2C)2CH2, Na, EtOH, 80◦C, 20 hours; (b) i) 1 eq. NaOH,
EtOH, rt, 16 hours; ii) NaBH4, reflux, 3 hours, then 2 M HCl, rt, 18 hours; (c) TBDPSCl, imidazole,
CH2Cl2, rt, overnight; (d) Dibat-H, CH2Cl2, −78◦C, 30 minutes; (e) CH3PPh3Br, t-BuOK, THF, rt, 3
hours; (f) Ac2O, pyridine, rt, overnight; (g) n-Bu4NF, THF, rt, overnight.
double alkylations and lactonization in 70% yield.[5] Chemoselective reduc-
tion of ester group of 13 in the presence of lactone functional group was
accomplished by successive hydrolysis, reduction and cyclization reaction.
Treatment of 13 with 1 eq. of NaOH cleaved only the lactone ring over ester
group to give sodium carboxylate 13a, probably due to high ring strain of
the lactone group. Treatment of 13a with NaBH4 produced the correspond-
ing alcohol formed by reduction of ester. Finally, acidic conditions by 2 M
HCl induced a cyclization, resulting in the formation of lactone 14. Protec-
tion of hydroxyl group of 14 as the silyl ether followed by reduction with
Dibal-H affored the corresponding lactol 15. Compound 15 was converted
to vinyl-substituted cyclopropyl analog 16 by a Wittig reaction. Acetyation
of primary hydroxyl group of 16 and then removal of TBDPS group with
TBAF gave compound 17, which was glycosyl donor for the condensation
with various nucleobases.
Synthesis of pyrimidine nucleoside derivatives 10–12 is shown in
Scheme 2. Condensation of glycosyl donor 17 with N 4-benzoyluracil and
N 4-benzoylthymine under Mitsunobu conditions smoothly gave protected
N 4-benzoyluracil nucleoside 18 and protected N 4-benzoylthymine nucleo-
side 19 in 94% and 95% yield, respectively. Removal of acetyl and benzoyl
groups of 18 and 19 was accomplished by 1 M NaOMe to afford the final nu-
cleosides, 10 and 11, respectively. In order to synthesize cytosine nucleoside,
the methodology converting uracil nucleoside 10 into cytosine nucleoside
12 was tried. Uracil compound 10 was converted into cytosine nucleoside
12 via acetylation of the hydroxyl group followed by successive three con-
ventional steps (1,2,4-triazole, POCl3, pyridine; 1,4-dioxane, NH4OH; NH3,
MeOH)[9] in overall 57% yield.
SCHEME 2 Reagents and conditions: (a) PPh3, DEAD, N -benzoyluracil or N -benzoylthymine, THF, rt, 5
hours, 94% for 18, 95% for 19; (b) 1 N NaOMe, MeOH, rt, 4 hours, 94% for 10, 87% for 11; (c) (i) Ac2O,
pyridine, rt, overnight; (ii) 1,2,4-triazole, POCl3, pyridine, rt, overnight; (iii) NH4OH, 1,4-dioxane, rt,
overnight; (iv) NH3/MeOH, rt, overnight, 57% from 10.

1004
A.-Y. Park et al.
Now, biological evaluation of the synthesized final compounds 10–12 is
in progress against various viruses including herpesviruses such as HSV-1
and 2, and VSV and the antiviral activities will be compared with that of
L-counterparts of the final compounds in due course.
CONCLUSION
Based on facts that carbanucleosides bearing a small ring size of
their sugar showed extremely potent anti-herpesvirus activities and nucle-
osides having unsaturated functional groups such as vinyl and acetylenyl at
their sugar moiety also exhibited potent anti-herpesvirus inhibition, vinyl-
substituted cyclopropyl nucleoside derivatives 10–12 were designed and
enantiopurely synthesized starting from (R)-(-)-epichlorohydrin employing
the key steps such as a tandem reaction of double alkylations and lactoniza-
tion via oxirane-ring opening reaction, a Wittig reaction and chemoselective
reduction.
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