Synthesis of some 2′-fluoro-2′-deoxy-3′-C-ethynyl and 3′-C-vinyl-β-D-lyxofuranosyl nucleosides

Article abstract of DOI:10.1081/NCN-200060300

1-(2-Fluoro-2-deoxy-β-D-arabinofuranosyl)uracil (5) and 1-(2-fluoro-2-deoxy-β-D-arabinofuranosyl)cytosine (6) were synthesized as reported earlier. Both of these compounds were converted into 2′-fluoro-2′-deoxy-3′-C-ethynyl and 3′-C-vinyl-β-D- lyxofuranosyl nucleosides (16-19) by a multistep sequence. All these new nucleosides were evaluated against seven human tumor cell lines in vitro. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/NCN-200060300

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SYNTHESIS OF SOME 2′-FLUORO-2′-DEOXY-3′-C-
ETHYNYL AND 3′-C-VINYL-β-D-LYXOFURANOSYL
NUCLEOSIDES
O. Moukha-chafiq a , K. N. Tiwari a & J. A. Secrist a
a Southern Research Institute , Birmingham, Alabama, USA
Published online: 15 Nov 2011.
To cite this article: O. Moukha-chafiq , K. N. Tiwari & J. A. Secrist (2005) SYNTHESIS OF SOME 2′-FLUORO-2′-DEOXY-3′-C-
ETHYNYL AND 3′-C-VINYL-β-D-LYXOFURANOSYL NUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 713-715,
DOI: 10.1081/NCN-200060300
To link to this article: http://dx.doi.org/10.1081/NCN-200060300
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):713–715, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060300
SYNTHESIS OF SOME 2’-FLUORO-2’-DEOXY-3’-C-ETHYNYL AND
3’-C-VINYL-b-D-LYXOFURANOSYL NUCLEOSIDES
5
O. Moukha-chafiq, K. N. Tiwari, and J. A. Secrist III
Southern Research Institute,
Birmingham, Alabama, USA
5
1-(2-Fluoro-2-deoxy-b-D-arabinofuranosyl)uracil ( 5) and 1-(2-fluoro-2-deoxy-b-D-arabinofura-
nosyl)cytosine ( 6) were synthesized as reported earlier. Both of these compounds were converted into 2’-
fluoro-2’-deoxy-3’-C-ethynyl and 3’-C-vinyl-b-D-lyxofuranosyl nucleosides ( 16---19) by a multistep
sequence. All these new nucleosides were evaluated against seven human tumor cell lines in vitro.
INTRODUCTION
The search for nucleoside analogues which function as selective inhibitors of
polymerases, and other enzymes for the control of viral diseases and cancer has
been the subject of intense research.[1] However, as some of these nucleosides also
undergo enzymatic degradations, a number of modifications has been carried out
on both the sugar portion and the heterocycle to circumvent these deactivating
processes. Nucleoside analogues that are good substrates for cellular kinases, but
are resistant to other host enzymes such as phosphorylases and deaminases are
potentially important for the development of therapeutic agents.
One important discovery in this area is that the replacement of the hydroxyl in
the sugar portion of the nucleosides with a fluorine results in nucleoside analogues
which have been found to have interesting biological activities. Clofarabine (2-
chloro-2’-fluoro-ara-A) (1) (Figure 1), for example, which has been synthesized in
our laboratory,[2] was found to have potent anti-leukemic activity and currently is in
human clinical trials.
In addition, the 3’-alkyl or alkynyl branched nucleoside analogues have been
reported to exhibit a potent antiviral and anti-cancer activity. Several years ago,
This investigation was supported by the National Cancer Institute, National Institute of Health (P01-
CA34200). The authors are indebted to Drs. Bill Parker and Bill Waud for cytotoxicity data; Dr. James M. Riordan,
Mr. Mark Richardson, and Ms. Joan Bearden for spectral data, and Ms. Stephanie Brannon for help in preparation
of this poster.
Address correspondence to J. A. Secrist III, Southern Research Institute, Birmingham, AL, USA; E-mail:
secrist@sri.org
713
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714
O. Moukha-Chafiq, K. N. Tiwari, and J. A. Secrist III
FIGURE 1
1-(3-C-ethynyl-b-D-ribo-pentofuranosyl)cytosine (2) (Figure 1) was synthesized by
Matsuda et al.[3] and showed good activity against various human solid tumors.
This compound is undergoing human clinical trials. On the basis of these con-
siderations, we have prepared some 2’-fluoro-2’-deoxy-3’-C-ethynyl and 3’-C-vinyl-b-
D-lyxofuranosyl nucleosides. The synthesis and biological data on these compounds
are presented.
RESULTS AND DISCUSSION
Our route (Scheme 1) to this series was accomplished by preparing the 2’-
fluoro-2’-deoxy-b-D-arabinofuranosyl nucleosides ( 5) and ( 6) following the
synthetic pathway previously described.[4] Protection of the primary alcohol of
these nucleosides was carried out using tert-butyldimethylsilyl chloride in pyridine
at room temperature for 3 h to lead to compounds (7) and (8) in 94 and 92% yields,
SCHEME 1 Conditions: (a) HBr/HOAc; (b) bis-silylated uracil or cytosine/CCl4/reflux; (c) NH3/MeOH, r. t.;
(d) TBDMSCl/pyridine, r.t; (e) BzCl/DMF, r.t; (f) Dess-Martin periodinane/CH2Cl2; (g) HCCMgBr or H2CCHMgBr,
THF, À 78°C; (h) TBAF/THF, r.t.; (i) NH3/MeOH, r.t.

O. Moukha-Chafiq, K. N. Tiwari, and J. A. Secrist III
715
respectively. Benzoylation of amino group in cytosine nucleoside (8) with benzoic
anhydride in DMF provided compound (9) in 91% yield.
We next investigated the oxidation of the secondary alcohol at C-2’ position of
(8) and (9) using CrO3-pyridine-Ac2O or Ac2O-DMSO mixtures. Attempts to
prepare the desired ketonucleosides (10) and (11), however, failed because of
their instability under these conditions. Only the a,b-unsaturated ketone resulting
from the elimination of the base was observed.
As an alternative, we decided to use Dess-Martin periodinane. Thus, treatment
of (10) and (11) with Dess-Martin periodinane (4.5 eq) in methylene chloride at
0°C during 10 h followed by addition, in situ, of ethynyl magnesium bromide or
vinyl magnesium bromide in tetrahydrofuran at À78°C gave lyxo-adducts (12–
15), respectively, with high stereoselectivity.
For the deblocking of these nucleosides, compounds (12) and (13) were
treated with tertrabutylammonium fluoride in tetrahydrofuran to obtain compounds
(16) and (17), respectively. On the other hand, compounds (14) and (15) were
deblocked as in the case of nucleosides (12) and (13) and further treated with
NH3/MeOH to furnish quantitatively the desired nucleosides (18) and (19).
1
The structures of these compounds were confirmed by H and 13C-NMR and
mass spectrometry along with elemental analysis. Nucleosides (16---19) were
examined in vitro against a panel of human tumor cell lines. No marked
cytotoxicity was noted. The antiviral tests of these nucleosides are still in progress.
REFERENCES
1. Nair, V.; Jahnke, T.S. Antiviral activities of isometric dideoxynucleosides of D- and L-related stereochemistry.
Antimicrob. Agents Chemother. 1995, 39, 1017–1029.
2. Montgomery, J.A.; Shortancy-Fowler, A.T.; Clayton, S.D.; Riordan, J.M.; Secrist, J.A., III. J. Med. Chem.
1992, 35, 397–401.
3. Hattori, H.; Tanaka, M.; Fukushima, M.; Sasaki, T.; Matsuda, A. Nucleosides and nucleotides. 158. 1-(3-C-
ethynyl-b-D-ribo-pentofuranosyl)cytosine, 1-(3-C-ethynyl-b-D-ribo-pentofuranosyl)uracil, and their nucleobase
analogues as new potential multifunctional anti-tumor nucleosides with a broad spectrum of activity. J.
Med. Chem. 1996, 39, 5005–5011.
4. Wilds, C.J.; Damha, M.J. 2’-deoxy-2’-fluoro-b-D-arabinonucleosides and oligonucleotides (2’F-ANA): synthesis
and physicochemical studies. Nucleic Acids Res. 2000, 28, 3625–3635.