Synthesis and Studies of 3′-C-Trifluoromethyl-β -D-ribonucleosides Bearing the Five Naturally Occurring Nucleic Acid Bases

Article abstract of DOI:10.1081/NCN-120026874

3′-C-Trifluoromethyl-β-D-ribonucleoside derivatives bearing the five naturally occurring nucleic acid bases have been synthesized. All these derivatives were prepared by glycosylation reactions of purine and pyrimidine bases with a suitable peracylated 3-

Full text of DOI:10.1081/NCN-120026874

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Synthesis and Studies of 3′-C-Trifluoromethyl-β-D-
ribonucleosides Bearing the Five Naturally Occurring
Nucleic Acid Bases
Frédéric Jeannot a , Gilles Gosselin a b & Christophe Mathé a c
a Laboratoire de Chimie Organique Biomoléculaire de Synthèse , UMR 5625 CNRS-Université
Montpellier II, Montpellier, France
b Laboratoire Coopératif Idenix-CNRS-Université Montpellier II , Montpellier, France
c Laboratoire de Chimie Organique Biomoléculaire de Synthèse , UMR 5625 CNRS-Université
Montpellier II, Montpellier cedex 5, France
Published online: 19 Dec 2011.
To cite this article: Frédéric Jeannot , Gilles Gosselin & Christophe Mathé (2003) Synthesis and Studies of 3′-C-
Trifluoromethyl-β-D-ribonucleosides Bearing the Five Naturally Occurring Nucleic Acid Bases, Nucleosides, Nucleotides and
Nucleic Acids, 22:12, 2195-2202, DOI: 10.1081/NCN-120026874
To link to this article: http://dx.doi.org/10.1081/NCN-120026874
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, No. 12, pp. 2195–2202, 2003
Synthesis and Studies of 30-C-Trifluoromethyl-
b-D-ribonucleosides Bearing the Five Naturally
Occurring Nucleic Acid Bases#
1
1,2
1,
*
´
´ ´
Frederic Jeannot, Gilles Gosselin, and Christophe Mathe
1
´
`
Laboratoire de Chimie Organique Biomoleculaire de Synthese, UMR 5625
´
CNRS-Universite Montpellier II, Montpellier, France
´
Laboratoire Cooperatif Idenix-CNRS-Universite Montpellier II,
2
´
Montpellier, France
ABSTRACT
30-C-Trifluoromethyl-b-D-ribonucleoside derivatives bearing the five naturally
occurring nucleic acid bases have been synthesized. All these derivatives were pre-
pared by glycosylation reactions of purine and pyrimidine bases with a suitable
peracylated 3-C-trifluoromethyl ribofuranose precursor. After deprotection, the
resulting title nucleoside analogues were tested for their inhibitory properties
against the replication of HIV, HBV and several RNA viruses. However, none
of these compounds showed significant antiviral activity.
Key Words: 30-C-Trifluoromethyl-b-D-ribonucleosides; Antiviral agents.
#In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.
´
*Correspondence: Christophe Mathe, Laboratoire de Chimie Organique Biomoleculaire
de Synthese, UMR 5625 CNRS-Universite Montpellier II, Montpellier cedex 5, France; Fax:
´
`
´
+33-4-67-04-20-29; E-mail: cmathe@univ-montp2.fr.
2195
DOI: 10.1081/NCN-120026874
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

´
Jeannot, Gosselin, and Mathe
2196
INTRODUCTION
Nucleoside analogues represent one of the main classes of therapeutic agents for
the treatment of viral affections. To date, numerous nucleoside derivatives have been
approved by the FDA for the treatment of various viral diseases including Herpes
viruses, Human Immunodeficiency Virus (HIV) and Hepatitis B virus (HBV) infec-
tions.[1] The mechanism of action of those compounds is based upon the intracellular
phosphorylation to their 50-triphosphate form which can interact with virus-specific
polymerases, acting as inhibitors or chain terminator of viral nucleic acid synthesis.
In order to discover new nucleoside derivatives endowed with potent antiviral activ-
ity, modifications of the base and=or the sugar moiety of natural nucleosides can be
attempted. As a part of our ongoing research program on trifluoromethyl nucleoside
analogues,[2–5] we have synthesized 30-C-trifluoromethyl-b-D-ribonucleoside deriva-
tives bearing the five naturally occurring nucleic acid bases (1–5) (Chart 1).
Compounds 1, 3 and 4 have been previously reported.[6] Nevertheless, we decided
to undertake the synthesis of these 30-C-CF3-ribonucleosides of adenine (1), uracil
(3) and thymine (4) as well as the synthesis of the hitherto unknown derivatives of
guanine (2) and cytosine (5) in order to perform the antiviral evaluation of the whole
series against HIV, HBV and several RNA viruses.
RESULTS AND DISCUSSION
The synthesis began with the preparation of an appropriate trifluoromethyl
sugar precursor, namely, 1,2,3-tri-O-acetyl-5-O-benzoyl-3-C-trifluoromethyl-b-D-
ribofuranose (6) that was obtained from commercially available D-xylose following
a procedure previously described in the literature.[6] The syntheses of the purine
derivatives (1, 2) are depicted in Sch. 1. A glycosylation reaction with adenine and
6 in acetonitrile using stannic [tin(IV)] chloride as a catalyst afforded 9-(2,3-di-O-
acetyl-5-O-benzoyl-3-C-trifluoromethyl-b-D-ribofuranosyl)adenine in 45%. Total
deprotection of the latter with methanolic ammonia provided crystalline nucleoside 1.
For the preparation of the guanosine analogue 2, a condensation reaction of
Chart 1.

30-C-Trifluoromethyl-b-D-ribonucleosides
2197
Scheme 1. Reagents and conditions: a) 1) Adenine, SnCl4, CH3CN, r.t.; 2) MeOH=NH3, r.t.;
b) 1) silylated 2-amino-6-chloropurine, TMSOTf, toluene, reflux; 2) HS(CH2)2OH, MeONa,
MeOH, reflux.
silylated 2-amino-6-chloropurine with 6 was carried out under Vorbruggen
¨
conditions using trimethylsilyl trifluoromethane sulfonate (TMSOTf) as a catalyst
in refluxing toluene to afford the protected intermediate 2-amino-6-chloro purine
30-C-trifluoromethyl 9-b-D-riboside. After purification, the latter was directly treated
with 2-mercaptoethanol and sodium methanolate in refluxing methanol[7] to provide
the target nucleoside 2 in 30% overall yield.
The syntheses of the 30-C-trifluoromethyl b-D-ribonucleoside pyrimidine
derivatives are depicted in Sch. 2. Briefly, glycosylation reactions with uracil or
thymine and sugar 6, under Vorbruggen conditions, using TMSOTf as a catalyst
¨
in anhydrous acetonitrile at 50ꢀC afforded 1-(2,3-di-O-acetyl-5-O-benzoyl-3-C-
trifluoromethyl-b-D-ribofuranosyl) nucleosides of uracil and thymine which were
directly deprotected using methanolic ammonia to give compounds 3 and 4.
The cytosine derivative 5 was obtained from the protected 30-C-CF3 ribo-
nucleoside of uracil by using the nitrophenylation-ammonolysis procedure.[8]
Scheme 2. Reagents and conditions: a) 1) silylated uracil, TMSOTf, CH3CN, r.t.;
2) MeOH=NH3; b) 1) silylated thymine, TMSOTf, CH3CN, r.t.; 2) MeOH=NH3, r.t.;
c) 1) silylated uracil, TMSOTf, CH3CN, r.t.; 2) 1-methylpyrrolidine, CH3CN, (CF3CO)2O,
0ꢀC; 3) 4-nitrophenol, 0ꢀC; 4) concd aq NH3=dioxane, 55ꢀC; 5) MeOH=NH3, r.t.

´
Jeannot, Gosselin, and Mathe
2198
BIOLOGICAL RESULTS
The title nucleosides 1–5 were tested for their effects on the replication of HIV,
HBV and several RNA viruses (including yellow fever virus and bovine viral
diarrhea virus) in cell culture experiments. However, none of these compounds
showed marked antiviral effects or detectable alteration of host-cell morphology at
the highest concentration tested (generally 100 mM), with the exception of 30-C-
CF3 adenosine (1) [MT-4 cells (CC50 ¼ 66 mM)].
CONCLUSION
The syntheses of 30-C-trifluoromethyl-b-D-ribonucleosides bearing the five natu-
rally occurring acid bases were undertaken with the hope to discover new nucleoside
derivatives endowed with antiviral effects. However, none of the target compounds
exhibited significant antiviral activity. Several factors could be responsible for the
inactivity of these nucleoside derivatives. Their inability to enter cells or to serve
as substrates for intracellular enzymes catalysing phosphorylation, as well as a lack
of inhibition of viral polymerases by their triphosphate forms, would all account for
their antiviral inactivity. Further research would be needed to support these hypoth-
eses, but since no significant antiviral activity emerged both from previously reported
work[6] and from the present data, it does not seem worthwhile to pursue additional
studies on 30-C-trifluoromethyl-b-D-ribonucleoside analogues.
EXPERIMENTAL SECTION
Evaporation of solvents was carried out on a rotary evaporator under reduced
pressure. Melting points were determined in open capillary tubes on a Gallenkamp
MFB-595-010 M apparatus and are uncorrected. UV spectra were recorded on an
Uvikon 931 (Kontron) spectrophotometer. 1H NMR spectra were recorded at
400 MHz, 13C NMR spectra at 100 MHz and 19F NMR at 235 MHz in (CD3)2SO
at ambient temperature with a Bruker DRX 400. Chemical shifts (d) are quoted in
¨
parts per million (ppm) referenced to the residual solvent peak, (CD3)CD2HSO
being set at d-H 2.49 and d-C 39.5 relative to tetramethylsilane (TMS). 19F chemical
shifts are reported using trichlorofluoromethane as external reference. Deuterium
exchange and COSY experiments were performed in order to confirm proton assign-
ments. Coupling constants, J, are reported in Hertz. 2D 1H-13C heteronuclear COSY
were recorded for the attribution of 13C signals. FAB mass spectra were recorded in
the positive-ion or negative-ion mode on a JEOL SX 102. The matrix was a mixture
(50:50, v=v) of glycerol and thioglycerol (G-T), or 3-nitrobenzyl alcohol (NBA). Spe-
cific rotations were measured on a Perkin-Elmer Model 241 spectropolarimeter (path
length 1 cm), and are given in units of 10ꢁ1 deg cm2 gꢁ1. Elemental analyses were
carried out by the Service de Microanalyses du CNRS, Division de Vernaison
(France). Thin layer chromatography was performed on precoated aluminium sheets
of Silica Gel 60 F254 (Merck, Art. 5554), visualization of products being accom-
plished by UV absorbency followed by charring with 5% ethanolic sulfuric acid

30-C-Trifluoromethyl-b-D-ribonucleosides
2199
and heating. Column chromatography was carried out on Silica Gel 60 (Merck, Art.
9385). All moisture-sensitive reactions were carried out under rigorous anhydrous
conditions and under an argon atmosphere using oven-dried glassware. Solvents
were dried and distilled prior to use and solids were dried over P2O5 under reduced
pressure.
9-(3-C-Trifluoromethyl-b-D-ribofuranosyl)adenine (1). Stannic chloride (0.4 mL,
3.41 mmol) was added cautiously to a stirred suspension of adenine (0.25 g, 1.85 mmol)
and 1,2,3-tri-O-acetyl-5-O-benzoyl-3-C-trifluoromethyl-b-D-ribofuranose 6 (0.7 g,
1.56 mmol) in dry acetonitrile (14 mL) at room temperature. After 72 h, pyridine
(6 mL) was added to the resultant solution. The white precipitate was filtered and
washed with chloroform (3ꢂ50 mL). The combined filtrates were washed with a solu-
tion of saturated sodium hydrogen carbonate (3ꢂ100 mL), water (3ꢂ100 mL), dried
over sodium sulfate and evaporated. Silica gel column chromatography of the residue
using a stepwise gradient of methanol (1–2%) in dichloromethane afforded 9-(2,3-di-
O-acetyl-5-O-benzoyl-3-C-trifluoromethyl-b-D-ribofuranosyl)adenine (367 mg, 45%)
as a white foam. A solution of 9-(2,3-di-O-acetyl-5-O-benzoyl-3-C-trifluoromethyl-b-
D-ribofuranosyl)adenine (0.367 mg, 0.7 mmol) in methanolic ammonia (previously
saturated at ꢁ10ꢀC and tightly stoppered) (20 mL) was stirred for 14 h at room tem-
perature, then evaporate to dryness. Crystallisation in MeOH gave compound 1
20
(160 mg, 64%). Melting point ¼ 247ꢀC (mp > 250ꢀC lit.[6]). ½aꢃD -15 (c ¼ 1.02, DMSO).
UV (Ethanol 95) lmax 258 nm, (e 14800). NMR 1H (DMSO-d6, 400 MHz) d 8.41 (1H,
s, H-8), 8.15 (1H, s, H-2), 7.35 (2H, br s, NH2), 6.58 (1H, br s, OH), 6.16 (01H, br s, OH),
0
0
0
5.89 (1H, d, J1 -2 ¼ 7.8 Hz, H-1 ), 5.34 (1H, br s, OH), 5.14 (1H, d, H-2 ), 4.06 (1H, t,
J4 -5 ,5 ¼ 4.2 Hz, H-4 ), 3.68 (2H, m, H-5 and H-5 ). NMR 13C (DMSO-d6, 100 MHz)
0
0
00
0
0
00
d 157 (C-6), 153.5 (C-2), 150.4 (C-4), 141.1 (C-8), 127 (q, 1JC-F ¼ 279 Hz, CF3), 120.1
2
(C-5), 86.9 (C-10), 86.5 (C-40), 78.7 (q, JC-F ¼ 28.8 Hz, C-30), 72.5 (C-20), 61 (C-50).
NMR 19F (DMSO-d6, 235 MHz) d ꢁ 73.8 (s, CF3). SM FABþ (GT) m=z 336
(M þ H)þ, 136 (BH2)þ. FABꢁ (GT) m=z 334 (M ꢁ H)ꢁ, 134 (B)ꢁ. Anal. Calcd. for
C11H12F3N5O4.0.6 H2O : C, 38.18, H, 3.84, N, 20.24, F, 16.47. Found : C, 38.28, H,
3.71, N, 20.05, F, 16.41.
9-(3-C-Trifluoromethyl-b-D-ribofuranosyl)guanine (2). To a suspension of 2-
amino-6-chloropurine (0.42 g, 2.48 mmol) in anhydrous toluene (10 mL) was added
N,O-bis(trimethylsilyl) acetamide (2.2 mL, 9 mmol). The suspension was refluxed
for 2 hours, then 1,2,3-tri-O-acetyl-5-O-benzoyl-3-C-trifluoromethyl-D-ribofuranose
(6) (1 g, 2.23 mmol), previously dissolved in anhydrous toluene (10 mL), and
TMSOTf (0.52 mL, 2.7 mmol) were added. The reaction was refluxed for 4 hours
then diluted with ethyl acetate (30 mL) and washed with a saturated sodium
hydrogen carbonate solution (2 ꢂ 30 mL). The organic layer was dried over sodium
sulfate and evaporated under reduced pressure. The residue was purified using a
silica gel column chromatography [eluent:ethyl acetate=petroleum ether (1=1)] to
afford 2-amino-6-chloro-9-(2,3-di-O-acetyl-5-O-benzoyl-3-C-trifluoromethyl-b-D-
ribofuranosyl)purine (0.50 g, 40%) as a white foam. To a solution of 2-amino-6-
chloro-9-(2,3-di-O-acetyl-5-O-benzoyl-3-C-trifluoromethyl-b-D-ribofuranosyl)purine
(0.85 g, 1.53 mmol) in methanol (128 mL) were added 2-mercaptoethanol (0.43 mL,
6.13 mmol) and sodium methylate (0.33 g, 6.12 mmol). The reaction was refluxed

´
Jeannot, Gosselin, and Mathe
2200
for 12 hours, then neutralised with a 1N chlorhydric acid solution. After evaporation
under reduced pressure the crude product was subjected to silica gel column chroma-
tography using a stepwise gradient of methanol (10–50%) in dichloromethane to afford
9-(3-C-trifluoromethyl-b-D-ribofuranosyl)guanine (0.4 g, 74%) which was crystallised
20
from water after filtration over Millex HV filter. Melting point > 350ꢀC. ½aꢃD þ 4
1
(c ¼ 1.01, DMSO). UV (Ethanol 95) lmax 252 nm, (e 9500). NMR H (DMSO-d6,
400 MHz) d 10.75 (1H, br s, N-H), 8.07 (1H, s, H-8), 6.56 (3H, br s, NH2 þ OH),
0
0
0
6.25 (1H, br s, OH), 5.78 (1H, d, J1 -2 ¼ 7.8 Hz, H-1 ), 5.19 (1H, t, J ¼ 4.8 Hz, OH-
50), 4.93 (1H, d, H-20), 4.04 (1H, m, H-40), 3.69 (2H, m, H-50 and H-500). NMR 13C
(DMSO-d6, 100 MHz) d 157.6 (C-6), 154.7 (C-2), 152.7 (C-4), 136.6 (C-8), 125.6 (q,
2
1JC-F ¼ 284.5 Hz, CF3), 117.5 (C-5), 86.1 (C-40), 85.4 (C-10), 78.6 (q, JC-F ¼ 28.4 Hz,
C-30), 73 (C-20), 60.8 (C-50). NMR 19F (DMSO-d6, 235 MHz) d ꢁ73.9 (s, CF3). Anal.
Calcd. for C11H12F3N5O5.0.9 H2O : C, 35.96, H, 3.79, N, 19.06, F, 15.51. Found : C,
36.09, H, 3.57, N, 18.71, F, 15.27.
1-(3-C-Trifluoromethyl-b-D-ribofuranosyl)uracil (3). The preparation of com-
pound 3 was achieved following a protocol already reported in the literature.[6]
20
Melting point ¼ 267–268ꢀC (mp > 250ꢀC lit.[6]). ½aꢃD þ 3 (c ¼ 1.05, DMSO). UV
1
(Ethanol 95) lmax 258 nm, (e 10900). NMR H (DMSO-d6, 400 MHz) d 11.57 (1H,
br s, N-H), 8.11 (1H, d, J6-5 ¼ 8.1 Hz, H-6), 6.69 (1H, br s, OH), 6.29 (1H, br s,
0
0
0
0
OH), 6.05 (1H, d, J1 -2 ¼ 7.8 Hz, H-1 ), 5.87 (1H, d, H-5), 5.34 (1H, br s, OH-5 ),
4.55 (1H, d, H-20), 4.12 (1H, m, H-40), 3.78 (2H, m, H-50 and H-500). NMR 13C
1
(DMSO-d6, 100 MHz) d 163.8 (C-4), 151.8 (C-2), 141.8 (C-6), 125.5 (q, JC-F
¼
2
280 Hz, CF3), 103.4 (C-5), 86.4 (C-10), 85.6 (C-40), 78.6 (q, JC-F ¼ 28.6 Hz, C-30),
72.6 (C-20), 60.6 (C-50). NMR 19F (DMSO-d6, 235 MHz) d ꢁ74.1 (s, CF3). SM FABþ
(GT) m=z 313 (M þ H)þ, 201 (S)þ, 113 (BH2)þ. FABꢁ (GT) m=z 311 (M ꢁ H)ꢁ, 111
(B)ꢁ. Anal. Calcd. for C10H11F3N2O6 : C, 38.47, H, 3.55, N, 8.97. Found: C, 38.82,
H, 3.65, N, 9.00.
1-(3-C-Trifluoromethyl-b-D-ribofuranosyl)thymine (4). The preparation of
compound 4 was achieved following a protocol already reported in the literature.[6]
20
1
½aꢃD þ 1 (c ¼ 1.00, DMSO). UV (Ethanol 95) lmax 263 nm, (e 10300). NMR H
(DMSO-d6, 400 MHz) d 11.00 (1H, br s, N-H), 7.84 (1H, d, J6-CH3 ¼ 0.8 Hz, H-6),
0
0
0
6.30 (1H, br s, OH), 5.94 (1H, d, J1 -2 ¼ 8 Hz, H-1 ), 5.30 (1H, br s, OH), 4.47
(1H, d, H-20), 4.00 (1H, m, H-40), 3.68 (2H, m, H-50 and H-500), 1.86 (3H, s, CH3).
NMR 13C (DMSO-d6, 100 MHz) d 164.6 (C-4), 152.0 (C-2), 137.1 (C-6), 125.6 (q,
1JC-F ¼ 285 Hz, CF3), 110.9 (C-5), 86.1 (C-10), 85.5 (C-40), 78.5 (q, JC-F ¼ 28.9 Hz,
2
C-30), 72.3 (C-20), 60.6 (C-50), 13.0 (CH3). NMR 19F (DMSO-d6, 235 MHz)
d ꢁ74.0 (s, CF3). SM FABþ (GT) m=z 327 (M þ H)þ, 127 (BH2)þ. FABꢁ (GT)
m=z 325 (M ꢁ H)ꢁ, 125 (B)ꢁ. Anal. Calcd. for C11H13F3N2O6.0.9 H2O : C, 38.58,
H, 4.36, N, 8.18,.F 16,64. Found : C, 38.69, H, 4.22, N, 8.10, F 16.60.
1-(3-C-Trifluoromethyl-b-D-ribofuranosyl)cytosine (5). A solution of 1-(2,3-di-
O-acetyl-5-O-benzoyl-3-C-trifluoromethyl-b-D-ribofuranosyl)uracil[6] (0.804 g, 1.61 mmol)
and 1-methyl-pyrrolidine (1.6 mL, 15.38 mmol) in anhydrous acetonitrile (8 mL)
was cooled to 0ꢀC. Trifluoroacetic anhydride (0.57 mL, 4.03 mmol) was then added.
After 45 minutes at 0ꢀC, 4-nitrophenol (0.67 g, 4.82 mmol) was added to the

30-C-Trifluoromethyl-b-D-ribonucleosides
2201
solution. After stirring for 18 hours at 0ꢀC, the solution was then poured into a solu-
tion of saturated sodium hydrogen carbonate (50 mL), and the resultant mixture was
extracted with dichloromethane (3ꢂ50 mL). The combined organic layers were dried
over sodium sulfate and evaporated under reduced pressure. The residue was dis-
solved in dioxane (8 mL) and concentrated aqueous ammonia (1.6 mL, d 0.89), and
stirred at 55ꢀC for 12 hours. The resulting yellow solution was concentrated under
reduced pressure and directly treated with methanolic ammonia (previously saturated
at ꢁ10ꢀC and tightly stoppered) (32 mL) for 12 hours at room temperature. After eva-
poration to dryness under reduced pressure, the residue was subjected to silica gel
column chromatography, with a stepwise gradient of methanol (10–20%) in dichlor-
omethane to afford the title compound 5 (0.13 g, 26%). An analytical sample of 5 was
20
obtained as its chlorhydrate salt. Melting point ¼ 240ꢀC. ½aꢃD þ 13 (c ¼ 1.00, DMSO).
1
UV (Ethanol 95) lmax 272 nm, (e 9000). NMR H (DMSO-d6, 400 MHz) d 9.93 and
8.82 (3H, 2 x br s, NH3þ), 8.24 (1H, d, J6-5 ¼ 7.8 Hz, H-6), 6.62 (1H, br s, OH), 6.21
0
0
0
0
(2H, m, H-5 and OH), 5.86 (1H, d, J1 -2 ¼ 7.5 Hz, H-1 ), 4.36 (1H, d, H-2 ), 3.99 (1H,
m, H-40), 3.58 (2H, m, H-50 and H-500). NMR 13C (DMSO-d6, 100 MHz) d 160.3 (C-4),
1
148.5 (C-2), 145.5 (C-6), 125.3 (q, JC-F ¼ 284 Hz, CF3), 95.9 (C-5), 87.5 (C-10), 86.1
(C-40), 78.6 (q, JC-F ¼ 29 Hz, C-30), 73.6 (C-20), 60.4 (C-50). NMR 19F (DMSO-d6,
2
235 MHz) d ꢁ74.0 (s, CF3). Anal. Calcd. for C10H13ClF3N3O5.1.3 H2O : C, 32.37,
H, 4.24, N, 11.32. Found: C, 32.28, H, 3.90, N, 11.25.
ACKNOWLEDGMENTS
`
We gratefully acknowledge Prof. P. La Colla (Universita di Cagliari, Cagliari,
Italy) for the biological results. One of us (F.J.) is particularly grateful to the
`
Ministere de l’Education Nationale, de la Recherche et de la Technologie, France,
for a doctoral fellowship.
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Jeannot, Gosselin, and Mathe
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Received July 22, 2003
Accepted September 5, 2003