Design and synthesis of novel fluorocyclopropanoid nucleosides

Article abstract of DOI:10.1081/NCN-100002349

Novel fluorocyclopropanoid nucleosides were designed, synthesized and evaluated their antiviral activities against poliovirus, HSV, HIV, and HBV.

Full text of DOI:10.1081/NCN-100002349

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DESIGN AND SYNTHESIS OF NOVEL
FLUOROCYCLOPROPANOID NUCLEOSIDES
Young Rang Lee a , Ju-Hyun Park a , Raok Jeon a , Lak Shin Jeong b , Moon Woo Chun c
Hee-Doo Kim c
&
a College of Pharmacy, Sookmyung Women's University, Seoul, 140-742, Korea
b College of Pharmacy, Ewha Womans University, Seoul, 120-750, Korea
c College of Pharmacy, Seoul National University, Seoul, 151-742, Korea
Published online: 07 Feb 2007.
To cite this article: Young Rang Lee , Ju-Hyun Park , Raok Jeon , Lak Shin Jeong , Moon Woo Chun & Hee-Doo Kim (2001)
DESIGN AND SYNTHESIS OF NOVEL FLUOROCYCLOPROPANOID NUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids,
20:4-7, 677-679
To link to this article: http://dx.doi.org/10.1081/NCN-100002349
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 677–679 (2001)
DESIGN AND SYNTHESIS OF NOVEL
FLUOROCYCLOPROPANOID NUCLEOSIDES
Young Rang Lee,1 Ju-Hyun Park,1 Raok Jeon,1 Lak Shin Jeong,2
Moon Woo Chun,3 and Hee-Doo Kim3
1College of Pharmacy, Sookmyung Women’s University,
Seoul 140-742, Korea
2College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea
3College of Pharmacy, Seoul National University, Seoul 151-742, Korea
ABSTRACT
Novel fluorocyclopropanoid nucleosides were designed, synthesized and eval-
uated their antiviral activities against poliovirus, HSV, HIV, and HBV.
Despite the intensive synthetic efforts, cyclopropanoid nucleosides have not
been of interest until A-5021 was discovered recently (1). A-5021, (1ꢀS,2ꢀR)-9-
[[1ꢀ,2ꢀ-bis(hydroxymethyl)cycloprop-1ꢀ-yl]methyl]guanine, was reported more ac-
tive than acyclovir or penciclovir against HSV, HCMV and VZV (2). In an effort to
search for the chemically and enzymatically stable carbonucleoside, we designed
(E)-(1ꢀ-fluoro-2ꢀ-hydroxymethylcyclopropylmethyl)purines and pyrimidines. The
underlying concept for our design is to seek relatively conformationally-locked
compound with minimal structural disturbance from acyclic carbonucleoside such
as acyclovir or penciclovir.
To meet such a requirement, we need to introduce cyclopropane and fluorine
moiety. Due to its hybrid character of cyclic and acyclic molecules, cyclopropyl
group could render the conformational rigidity to the target molecule. It is also
envisioned that fluorine could play a role to control the conformation by gauche
effect between fluorine and nitrogen in nucleoside base moiety (3). As shown in
Scheme 1, N-alkylation of purine or pyrimidine bases with the mesylate 7 or the
iodide 8 under basic condition (NaH, DMF, 80◦C) was chosen as a simple and con-
venient approach to the synthesis of the fluorocyclopropanoid nucleoside 9. The key
677
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Copyright 2001 by Marcel Dekker, Inc.
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678
LEE ET AL.
Figure 1.
synthetic intermediate 7 or 8 were synthesized starting from allyl alcohol. Protec-
tion of allyl alcohol with TBDPSCl, followed by ozonolysis afforded the aldehyde
2 in good yield. Introduction of fluorine and double bond for the installation of
cyclopropyl group was achieved by Horner-Wadsworth-Emmons reaction of the
aldehyde 3 with triethyl 2-fluoro-2-phosphonoacetate using n-BuLi in THF. The
α-fluoro-α, β-unsaturated ester 3 with (E)-stereochemistry was formed preferen-
tially over 4 in a ratio of 95 to 5. Unusual preference of (E)-isomer is well-known
phenomenon in Horner-Wadsworth-Emmons reaction of aldehydes with triethyl
2-fluoro-2-phosphonoacetate (4). The similar stereoselectivity was also observed
when using PrꢀMgBr in THF at 0◦C. The relatively unstable ester 3 was directly
subjected to DIBAL-H reduction in CH2Cl2 at −78◦C to room temperature to fur-
nish the allylic alcohol 5 in 71% yield. Conventional cyclopropanation of the allylic
Scheme 1.

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FLUOROCYCLOPROPANOID NUCLEOSIDES
679
alcohol 5 using Simmons-Smith or Furukawa modification method proceeded too
slowly, and provided the desired product 6 in low yield. However, encouraged with
the previous reports on Lewis acid-catalyzed cyclopropanation (5), we had tried
several kinds of Lewis-acid, then, finally selected ZnI2. The tendency of alkylzinc
alkoxides (ROZnEt) to aggregate in solution (6) could be circumvented by sonifi-
cation. By the dual action of sonification and ZnI2, chemical yield and the reaction
rate were greatly improved.
Unseparable mixture of 5 and 6 by conventional chromatography could be
isolated using radial chromatography. The fluorinated cyclopropyl alcohol 6 was,
then, converted to the corresponding mesylate 7 or iodide 8. The coupling 7 or 8
with purine or pyrimidine bases under basic conditions, followed by removal of
TBDPS group to afford the desired nucleosides 10a(81% from 8), 10b(46% from
7), 10c(40% from 8), and 10d(40% from 8), respectively. Treatment of 10d with
2-mercaptoethanol and sodium methoxide in methanol, followed by hydrolysis with
glacial acetic acid gave 10e in 14% yield. The synthesized nucleosides (10a∼e)
were evaluated for their antiviral activity against poliovirus, HSV-1, HSV-2, HBV
and HIV. However, all compounds were found to be inactive in the assay.
ACKNOWLEDGMENT
This research was supported by the grant from the Good Health R & D project
(HMP-98-D-4-0057), Ministry of Health and Welfare, Korea.
REFERENCES
1. Rife, J.; Ortuno, R. M. Org. Lett., 1999, 1, 1221–1223.
2. Sekiyama, T.; Hatsuya, S.; Tanaka, Y.; Uchiyama, M.; Ono, N.; Iwayama, S.; Oikawa,
M.; Suzuki, K.; Okunishi, M.; Tsuji, T. J. Med. Chem., 1998, 41, 1284–1298.
3. Pankiewicz, K. W. Carbohydr. Res., 2000, 327, 87–105.
4. Sano, S.; Ando, T.; Yokoyama, K.; Nagao, Y. Synlett, 1998, 777–779.
5. Charette, A. B.; Brochu, C. J. Am. Chem. Soc., 1995, 117, 11367–11368.
6. Denmark, S.E.; O’Connor S. P. J. Org. Chem., 1997, 62, 584–594.

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