Synthesis of enantiopure pseudo-L-vinylcyclopropyl nucleosides bearing quaternary carbon as potential anti-herpesvirus agent

Article abstract of DOI:10.1080/15257770701508372

Pseudo-l-vinylcyclopropyl adenine and guanine nucleosides 11 and 12 were designed and enantiopurely synthesized starting from (S)-epichlorohydrin using tandem alkylation, regioselective oxirane-ring opening, and chemoselective reduction as key steps. Copy

Full text of DOI:10.1080/15257770701508372

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Synthesis of Enantiopure Pseudo-l-
Vinylcyclopropyl Nucleosides Bearing
Quaternary Carbon as Potential Anti-
Herpesvirus Agent
a
a
a
Hyung Ryong Moon , Ah-Young Park , Kyung Ran Kim , Moon Woo
b
c
Chun & Lak Shin Jeong
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: Hyung Ryong Moon , Ah-Young Park , Kyung Ran Kim , Moon Woo Chun & Lak Shin
Jeong (2007) Synthesis of Enantiopure Pseudo-l-Vinylcyclopropyl Nucleosides Bearing Quaternary
Carbon as Potential Anti-Herpesvirus Agent, Nucleosides, Nucleotides and Nucleic Acids, 26:8-9,
975-978, DOI: 10.1080/15257770701508372
To link to this article: http://dx.doi.org/10.1080/15257770701508372
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Nucleosides, Nucleotides, and Nucleic Acids, 26:975–978, 2007
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701508372
SYNTHESIS OF ENANTIOPURE PSEUDO-L-VINYLCYCLOPROPYL
NUCLEOSIDES BEARING QUATERNARY CARBON AS POTENTIAL
ANTI-HERPESVIRUS AGENT
Hyung Ryong Moon, Ah-Young Park, and Kyung Ran Kim
2
College of
Pharmacy and Research Institute for Drug Development, Pusan National University,
Busan, Korea
Moon Woo Chun
Lak Shin Jeong
2
College of Pharmacy, Seoul National University, Seoul, Korea
College of Pharmacy, Ewha Womans University, Seoul, Korea
2
2
Pseudo-L-vinylcyclopropyl adenine and guanine nucleosides 11 and 12 were designed and
enantiopurely synthesized starting from (S)-epichlorohydrin using tandem alkylation, regioselective
oxirane-ring opening, and chemoselective reduction as key steps.
Keywords Pseudo-L-vinylcyclopropyl; anti-herpesvirus agent; tandem alkylation;
chemoselective reduction
INTRODUCTION
Since the discovery of acyclovir (1, Figure 1),[1] which is an acyclic nu-
cleoside and has shown very potent and selective anti-herpes simplex virus
(HSV) and anti-varicella-zoster virus (VSV) activities, medicinal chemists
have paid their attentions to the synthesis of acyclic nucleosides and cyclic
nucleoside derivatives bearing three- and four-membered sugar ring. As a
[2]
result of their endeavors, acyclic nucleosides such as ganciclovir (2) and
[3]
its carbanucleoside, penciclovir (3) were approved as a clinically useful
antiviral drug, and cyclobut-G (4),[ carbocyclic counterpart of oxetanocin
G has been found to exhibit a highly potent and broad spectrum against
herpesviruses including HSV-1 and 2, VZV, and human cytomegalovirus
4]
(HCMV). In particular, penciclovir (3), one of carbanucleosides in which
the ethereal oxygen of normal nucleosides is replaced by a carbon atom
exhibited a broad antiviral spectrum. Carbocyclic nucleosides such as
This work was supported by the Grants from Korea Research Foundation (KRF-2003-042-E20111).
Address correspondence to Hyung Moon, College of Pharmacy and Research Institute for Drug
Development, Pusan National University, Busan 609-735, Korea. E-mail: mhr108@pusan.ac.kr
9
75

9
76
H. R. Moon et al.
FIGURE 1 The rationale for the design of the desired nucleosides, 11 and 12.
penciclovir (3) and cyclobut-G (4) obtain the benefit to be more stable
under acidic conditions or to enzymes that cleave normal nucleosides. It is
of interest to note that in cases of acyclic nucleosides or small sugar-ring
sized nucleosides, guanine nucleoside usually has been found to exhibit
the most potent and selective antiviral activity against HSV-1 and 2, VZV
and other herpes viruses (HCMV and Epstein-Barr virus). Up to now, sev-
eral structural modifications on cyclopropane ring have been made in the
ꢁ
ꢁ
search for antiviral agents with better efficacy and selectivity. 9-[[cis-1 ,2 -
ꢁ
[5]
Bis(hydroxymethyl)cycloprop-1 -yl]methyl]guanine (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. Re-
cently, cyclopropyl guanine nucleoside 6 bearing exo-methylene group
has been found to show a potent inhibition against herpesviruses including
HCMV and MCMV (murine cytomegalovirus).
[6]
On the other hand, nucleosides bearing unsaturated functional groups
ꢁ
ꢁ
such as vinyl and acetylenyl at 3 or 4 position have been reported to show
potent antiviral and antitumor activities. Among them, 1-(3-C-ethynyl-β-D-
[7]
ribo-pentofuranosyl)cytosine (ECyd, 7) and its uracil congener (EUrd, 8)
have exhibited potent antitumor activity. ECyd (7) has also shown potent
anti-HIV (human immunodeficiency virus) activity with its adenine con-
ꢁ
gener, EAdo (9). In addition, 4 α-C-ethenyl- and ethynylthymidines, (10a
[8]
and 10b) also have been found to show very potent anti-HSV-1 and anti-
HIV-1 activities.
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 synthesize novel pseudo-L-vinylcyclopropyl nucleosides 11 and 12,
combining properties of nucleosides bearing cyclopropane ring and vinyl
substituent, respectively. Herein, we wish to report the synthesis of pseudo-
L-vinylcyclopropyl adenine and guanine nucleosides 11 and 12 starting from
(
S)-(+)-epichlorohydrin.
CHEMISTRY
It was envisioned that analog of cyclopropyl alcohol 16 could be an ap-
propriate glycosyl donor for the condensation with various natural bases.
Synthesis of the vinyl-substituted glycosyl donor 16 is shown in Scheme 1.
Formation of bicyclolactone 13[ was accomplished by a tandem reaction of
9]

Enantiopure Pseudo-L-Vinylcyclopropyl Nucleosides
977
◦
SCHEME 1 Reagents and conditions: (a) (EtO2C)2CH2, Na, EtOH, 80 C, 24 hours; (b) i) 1 eq. NaOH,
EtOH, rt, 16 hours; ii) NaBH4, reflux, 3 hours then 2 N HCl, rt, 18 hours; (c) TBDPSCl, imidazole,
◦
CH2Cl2,rt, overnight; (d) Dibal-H, CH2Cl2, −78 C 50 minutes;(e) CH3PPh3Br, t-BuOK, THF, rt 2 hours;
(f) Ac2O. pyridine. rt, overnight; (g) n-Bu4NF, THF, rt, 1 hour.
double alkylations and lactonization. Reaction of (S)-(+)-epichlorohydrin
with diethyl malonate in the presence of sodium metal in EtOH first formed
alkylated compound 13a, which was deprotonated by sodium ethoxide to
give 13a anion. The enolate anion attacked more substituted oxirane car-
bon to open the epoxide ring and the resulting oxide anion formed lac-
tone compound 13 in 65% yield by attacking carbonyl group of ester func-
tional group. The regioselectivity in oxirane ring-opening reaction appears
to result from more favorable formation of three-membered ring than four-
membered ring. Chemoselective reduction of ester group of 13 in the pres-
ence of lactone functional group was accomplished by successive hydrolysis,
reduction and cyclization reaction.[ Protection of hydroxyl group of 14 as
the silyl ether followed by lactone reduction with Dibal-H afforded the cor-
responding lactol 15. A Wittig reaction of lactol 15 gave vinyl-substituted cy-
clopropyl analog. Successive acetylation and desilyation gave glycosyl donor
10]
16.
6
Coupling of 16 with N -benzoyladenine and 2-amino-6-chloropurine un-
der Mitsunobu conditions smoothly generated protected purine nucleo-
sides 17 and 18, respectively (Scheme 2). Treatment of 17 with 1 M NaOMe
afforded the final adenine nucleoside 11 in 63% yield from 16. Conversion
of 18 into the final guanine nucleoside 12 was accomplished by treating with
◦
[11]
2
-mercaptoethanol and 1 M NaOMe at 80 C
in 42% yield from 16.
Now, biological evaluation of the synthesized final compounds 11 and
2 is in progress against various herpesviruses and their antiviral activities
1
will be compared with those of D-counterparts of the final compounds.
6
SCHEME 2 Reagents and conditions: (a) PPh. DEAD, N -benzoyladenine, or 2-amino-6-chloropurine,
THF, rt, 2 hours for 17 and 18; (b) 1 N NaOMe, rt, 5 hours, 63% from 16 for 11, 2 -mercaptoethanol,
◦
1
N NaOMe, MeOH, 80 C, 7 hours 42% from 16 for 12.

9
78
H. R. Moon et al.
CONCLUSION
On the basis of facts that cyclopropyl nucleosides and nucleosides hav-
ing substituent of multiple bond such as vinyl and acetylenyl groups showed
highly potent anti-herpesvirus inhibition and in particular, guanine nucle-
osides have shown higher anti-herpesvirus potency than nucleosides with
other natural bases, vinyl-substituted cyclopropyl nucleoside derivatives 11
and 12 with adenine and guanine bases were designed and enantiopurely
synthesized starting from (S)-(+)-epichlorohydrin employing key steps such
as a tandem reaction of double alkylations and lactonization via oxirane-ring
opening reaction, a Wittig reaction and chemoselective reduction.
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