Novel nucleosides with vinyl fluoride or vinyl bromide moiety as open-chain analogs of neplanocin A

Article abstract of DOI:10.1081/NCN-100002350

Novel nucleosides with vinyl fluoride and vinyl bromide were designed, synthesized and evaluated their antiviral activities against poliovirus, HSV, HIV, and HBV.

Full text of DOI:10.1081/NCN-100002350

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NOVEL NUCLEOSIDES WITH VINYL FLUORIDE OR
VINYL BROMIDE MOIETY AS OPEN-CHAIN ANALOGS OF
NEPLANOCIN A
Myung-Hee Choi a , Chong-Kyo Lee b , Lak Shin Jeong c , Moon Woo Chun d & Hee-Doo
Kim e
a College of Pharmacy, Sookmyung Women's University , Seoul, 140-742, Korea
b Research Institute of Chemical Technology , Taejeon, 305-606, Korea
c College of Pharmacy, Ewha Womans University , Seoul, 120-750, Korea
d College of Pharmacy, Seoul National University , Seoul, 151-742, Korea
e College of Pharmacy, Sookmyung Women's University , Seoul, 140-742, Korea
Published online: 07 Feb 2007.
To cite this article: Myung-Hee Choi , Chong-Kyo Lee , Lak Shin Jeong , Moon Woo Chun & Hee-Doo Kim (2001) NOVEL
NUCLEOSIDES WITH VINYL FLUORIDE OR VINYL BROMIDE MOIETY AS OPEN-CHAIN ANALOGS OF NEPLANOCIN A, Nucleosides,
Nucleotides and Nucleic Acids, 20:4-7, 681-684, DOI: 10.1081/NCN-100002350
To link to this article: http://dx.doi.org/10.1081/NCN-100002350
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 681–684 (2001)
NOVEL NUCLEOSIDES WITH VINYL FLUORIDE
OR VINYL BROMIDE MOIETY AS OPEN-CHAIN
ANALOGS OF NEPLANOCIN A
Myung-Hee Choi,1 Chong-Kyo Lee,2 Lak Shin Jeong,3
Moon Woo Chun,4 and Hee-Doo Kim1,∗
1College of Pharmacy, Sookmyung Women’s University,
Seoul 140-742, Korea
2Research Institute of Chemical Technology, Taejeon 305-606, Korea
3College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea
4College of Pharmacy, Seoul National University, Seoul 151-742, Korea
ABSTRACT
Novel nucleosides with vinyl fluoride and vinyl bromide were designed, syn-
thesized and evaluated their antiviral activities against poliovirus, HSV, HIV,
and HBV.
Neplanocin A and penciclovir are the most well known carbonucleosides to
date. Because of the unusual presence of the double bond in neplanocin A and
acyclic nature of penciclovir (1,2), these two compounds have stimulated extensive
research in the synthesis of new cyclic and acyclic carbonucleoside analogues mim-
icking the sugar portion of naturally occurring nucleosides (3). In an effort to obtain
more chemically and enzymatically stable carbonucleosides, while causing mini-
mal structural disturbance, we designed the 2-halo-4-hydroxy-3-hydroxymethyl-2-
butenyl nucelosides, which mimic both features of neplanocin A and penciclovir.
The incorporation of halogen atoms into organic molecules has often been associ-
ated with profound changes in the biological profiles of the halogenated analogues
compared to their hydrocarbon counterparts (4). It has also been suggested that
∗ Corresponding author.
681
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Copyright 2001 by Marcel Dekker, Inc.
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CHOI ET AL.
Figure 1.
a fluoromethylene group is a better isostere of oxygen than the methylene group
(5) and therefore carboacyclic derivatives substituted by halogen at the lꢁa position
were also attractive targets.
At first, our attention had been directed to the design and synthesis of nucle-
oside 6 in an attempt to mimic the natural nucleoside most closely by installing a
fluorine at the lꢁa position.
As shown in Scheme I, the key synthetic intermediate 3 for nucleoside 6
with vinyl fluoride was synthesized by Horner-Wadsworth-Emmons reaction using
triethyl 2-fluoro-2-phosphonoacetate and 1, followed by Dibal-H reduction. The
fluorinated allyl alcohol 3 was, then, converted to the corresponding mesylates 4,
Scheme I.

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OPEN-CHAIN ANALOGS OF NEPLANOCIN A
683
Scheme II.
which was used for the coupling with adenine (NaH, DMF) or pyrimidine bases
(Cs2CO3, DMF) under basic conditions, followed by deprotection of silyl group
with TBAF to afford the desired nucleosides 6a-e. In a similar way, as shown in
Scheme II, we were able to synthesize the corresponding bromonucleosides 15a-e.
Horner-Wadsworth-Emmons reaction of ketone 8 with triethyl phosphonoac-
etate gave the α, β-unsaturated ester 9 in 89% yield. The bromination of ester 9
under basic conditions was unsuccessful, but did give dibromoester 10 with Br2 and
LiBr in acetic acid. Treatment of 10 with TEA followed by reduction with DIBAL-H
afforded the allylic alcohol 12 via 11 in good yield. Conversion of 12 to 13 was
accomplished by addition of NBS to a solution of the alcohol and triphenylphos-
phine in CH2Cl2 in 97% yield. The coupling of 13 with adenine or pyrimidine
bases in basic conditions, followed by the removal of benzyl group with BCl3
gave 15a(58%), 15b(88%), 15c(83%), 15d(62%), and 15e(67%), respectively. The
synthesized nucleosides (15a-e) were evaluated for their antiviral activity against
poliovirus, HSV-1, HSV-2 and HIV. However, all compounds were found to be
inactive in the assay.
ACKNOWLEDGMENT
This research was supported by the grant from STEPI (99-N6-02-01-A-05),
Korea.

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CHOI ET AL.
REFERENCES
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R. T.; Drach, J. C.; Kitaoka, S.; Konno, T. Antimicrob. Agents Chemother., 1989, 33,
1291–1297.
2. Harnden, M. R.; Jarvest, R. L.; Bacon, T. H., Boyd; M. R. J. Med. Chem., 1987, 30,
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3. Marquez, V. E. Carbocyclic nucleosides. In advances in antiviral drug design, JAI
Press, 1996, Vol. 2, pp 89–146, and references therein.
4. Pankiewicz, K. W. Carbohydr. Res., 2000, 327, 87–105.
5. Blackburn, G. M.; Kent, D. E. J. Chem. Soc. (Perkin I), 1986, 913–917.

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