New synthesis of L-FMAU from L-arabinose

Article abstract of DOI:10.1081/NCN-120003179

A new synthesis of 2′-deoxy-2′-fluoro-5-methyl-β-L-arabinofuranosyl uracil (13, L-FMAU) was achieved in 10 steps from L-arabinose.

Full text of DOI:10.1081/NCN-120003179

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NEW SYNTHESIS OF L-FMAU FROM L-ARABINOSE
Marcos L. Sznaidman a , Merrick R. Almond a & Amir Pesyan a
a Division of Organic Chemistry , Triangle Pharmaceuticals Inc., RTP , North Carolina, 27717,
U.S.A.
Published online: 17 Aug 2006.
To cite this article: Marcos L. Sznaidman , Merrick R. Almond & Amir Pesyan (2002) NEW SYNTHESIS OF L-FMAU FROM L-
ARABINOSE, Nucleosides, Nucleotides and Nucleic Acids, 21:2, 155-163, DOI: 10.1081/NCN-120003179
To link to this article: http://dx.doi.org/10.1081/NCN-120003179
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 21(2), 155–163 (2002)
NEW SYNTHESIS OF L-FMAU FROM
L-ARABINOSE
Marcos L. Sznaidman,* Merrick R. Almond, and Amir Pesyan
Division of Organic Chemistry, Triangle Pharmaceuticals Inc.,
RTP, North Carolina 27717
ABSTRACT
Anew synthesis of 2 0-deoxy-20-fluoro-5-methyl-b-L-arabinofuranosyl
uracil (13, L-FMAU) was achieved in 10 steps from L-arabinose.
INTRODUCTION
Hepatitis B virus (HBV) is estimated to chronically infect approximately
300 million people worldwide1. These individuals are at risk for the devel-
opment of liver failure, cirrhosis, and hepatocellular carcinoma. In addition,
it is estimated that of those chronically infected, approximately 1 million die
annually from HBV-induced liver disease. At present, interferon (IFN)2 and
lamivudine (3TC)3a are the only available treatments for chronic hepatitis B
in the United States. IFN efficacy is partial and of limited duration, with less
than 30% of the chronic carriers being treated with IFN responding to the
treatment2. In clinical trials, lamivudine, has proven to be effective in
decreasing the levels of HBV DNAin the serum of chronically infected
patients3b. However, many patients relapsed shortly after cessation
of therapy3b. In addition, there are now reports of the isolation of 3TC-
resistant variants of HBV from the serum of patients undergoing 3TC
therapy3b. Several other nucleoside analogs are currently undergoing inves-
tigation as potential anti-HBV agents; emtricitabine, entecavir, famciclovir4,
DAPD5 and L-FMAU6a.
*Corresponding author.
155
Copyright # 2002 by Marcel Dekker, Inc.
www.dekker.com

156
SZNAIDMAN, ALMOND, AND PESYAN
L-FMAU, originally reported by Chu and coworkers6a based on a
previous synthesis of D-FMAU6b, is one of the most promising agents against
HBV. L-FMAU showed low toxicity in rats and woodchucks7, potent in vivo
antiviral activity against chronically infected woodchuck (WHV), respectable
bioavailability in rats8 and woodchucks9, and showed no significant virus
rebound up to 36 weeks after cessation of the drug treatment10. For these
reasons an extensive effort was recently devoted to identifying an efficient and
inexpensive synthesis of L-FMAU6a,11–12
.
Originally, L-FMAU (13, Scheme 1) was synthesized from L-ribose by
Chu and coworkers6a adapting a synthetic method already published by Tann
and coworkers6b for D-FMAU. Since L-ribose is an expensive and not readily
available material, Chu and his coworkers developed a procedure for the
synthesis of L-FMAU from L-xylose11. Finally the same group developed a
synthesis from L-arabinose12. These processes either start from an expensive
sugar (L-ribose or L-xylose) and=or involve very long synthetic routes (14
steps from L-arabinose and 14 steps from L-xylose). In addition they involve
the use of a nucleophilic form of fluoride, like KHF2 or Et3N-3HF, which is
difficult to handle and requires the activation of the hydroxyl group to be
displaced. The instability of DAST prevents the use of this reagent on large
Scheme 1.

SYNTHESIS OF L-FMAU
157
scale. The conversion of 1-O-acetyl-2,3,5-tri-O-benzoyl-b-L-ribofuranose
(TBAR) to 1,3,5-tri-O-benzoyl-b-L-ribofuranose also generates 2,3,5-tri-O-
benzoyl-b-L-ribofuranose that has to be separated and reconverted to
TBAR.
In pursuit of a better route we envisioned a synthetic procedure that
involved two key steps (Scheme 1):
1 electophilic addition of a fluorine to the double bond of L-arabinal
(easily accessible from commercially available L-arabinose) to afford com-
pound 5. There are several precedents in the literature for the addition of
these electrophilic reagents to D-arabinal:
a
Trifluoromethyl hypofluorite (CF3OF)13. The inconvenience of this
reagent is that the reaction must be run at À78ꢀC and gives a
mixture of compounds that require separation by column chroma-
tography.
b
c
Acetyl Hypoflurite (CH3COOF)14. This reagent is hard to handle.
At À78ꢀC gives good stereoselectivity, but at room temperature the
selectivity is poor.
SelectfluorTM (F-TEDA-BF4)15. SelectfluorTM is an easy to handle
and inexpensive reagent that gives relatively good yield (68%) and
selectivity (7:1) at room temperature.
Other reagents known to add to glycals are:
d
e
Xenon difluoride (XeF2)16a-c, and
Elemental fluorine (F2)17.
The last two reagents give poor yields and 1,2-difluoro products are difficult
to hydrolyze.
2 Another key step of this synthesis is the conversion of the pyranose 6
to the methyl-furanoside 7 for which there is no precedent in the literature for
either enantiomer.
RESULTS AND DISCUSSION
Peracetylated bromosugar 3 (Steps 1 and 2) was obtained as a solid,
following a literature procedure18, in 57% yield after crystallization from
ether. The material was very unstable at room temperature and was used
immediately or stored in a freezer. L-Arabinal (4, Step 3) was obtained as a
syrup, according to a literature procedure19, in 60% yield after column
chromatography. Initial attempts to run the reaction under aprotic20
conditions or in one-pot from L-arabinose21 gave poor yields. Addition of
SelectfluorTM to L-arabinal (4, Step 4) was done by a modification of a
literature procedure15 to afford compound 5 as a syrup in 70% yield. Traces
of what could possibly be the L-ribo isomer were detected by 19F-NMR
(ratio L-arabino:L-ribo 30:1). The D-isomer of 5 was made by a similar

158
SZNAIDMAN, ALMOND, AND PESYAN
procedure15. Deacetylation (Step 5) was achieved with NaOMe in methanol
in one hour at room temperature. The desired unprotected sugar 6 was
obtained as an oil in 100% yield. 1H-NMR and 13C-NMR were in agreement
with the ones described in the literature for the D-isomer22a. The D-isomer
of 6 was previously made by three different groups, but in less efficient
ways13,22a,b. Treatment of 6 (Step 6) with one equivalent of either sulfuric or
hydrochloric acid at room temperature failed to give the desired furanoside.
Only unreacted starting material was detected. Using nine equivalents of
hydrochloric acid gave the desired product 7, which was contaminated with
starting material. The best result, so far, was achieved by refluxing 6 with 1
equivalent of sulfuric acid in dry methanol. After 6 hours, all of the starting
1
material had disappeared affording 7 as an oil in 80% yield. H-, 13C- and
19F-NMR indicated a 3:1 a:b mixture of anomers, with some minor im-
purities. The a-D22b and b-D23 isomers of 7 were previously made by two
different groups, but in less efficient ways. Benzoylation of crude 7 (Step 7)
gave a mixture that was resolved by flash column chromatography to afford
the a furanoside form of 8 as an oil in 44% yield. Other fractions were
isolated and are being characterized. The same reaction was described24 for
the D-isomer. Wright et al.24 partially describe the D-isomer of 8: optical
rotation and CHF, but no spectroscopic data was provided. The absolute
value for the optical rotation was similar to the one described for the D-
isomer: [a]D ¼ À 98 (c 1.0 EtOH) (lit.24 [a]D ¼ þ108 (c 1.8 EtOH for the
20
20
D-isomer).
Coupling of the methyl glycoside 8 with thymine (10) (Steps 8 and 9)
under standard conditions12 afforded the known di-O-benzoyl-L-FMAU (12)
in 42% yield after crystallization from EtOH. The 1H-NMR was identical to
spectra described in the literature for the L11,12- and D-isomers6b, and to a
reference sample. The melting point (160ꢀC) was identical to the reference
sample but differed with the values published in the literature: 120–122ꢀC for
the D-isomer6b and 118–120ꢀC for the L-isomer11. Debenzoylation of 12
(Step 10) was achieved with n-butylamine in refluxing methanol, reducing the
reaction time to 3 hs in comparison to the 24 or 48 hs required when
ammonia was used at room temperature11,12. Yield of L-FMAU (13) was
82%. Melting point: 188ꢀC (lit.12 mp 185–187ꢀC, lit11 184–185ꢀC, lit.6b 187–
20
20
188ꢀC) for the D-isomer; [a]D ¼ À 93 (c 0.25 MeOH) (lit.11 [a]D ¼ À111 (c
20
0.23 MeOH), lit.12 [a]D ¼ À112 (c 0.23 MeOH)); 1H-NMR was identical to
the ones described in the literature6b,11,12 and to a reference sample.
Conclusions
In summary, we have achieved the first ‘‘true’’ synthesis of L-FMAU
from L-arabinose in 10 steps. All the reagents and starting materials are
inexpensive and no special equipment was required.

SYNTHESIS OF L-FMAU
159
EXPERIMENTAL SECTION
GeneralMethods
Melting points were determined in open glass capillaries by use of a
1
Thomas-Hoover apparatus and were uncorrected. H-NMR spectra were
recorded at 400 MHz with a Varian XL-400 spectrometer. Hexa-
fluorobenzene (d: À163 ppm) was used as an internal standard for 19F-NMR.
Evaporations were performed under diminished pressure using a Buchi
rotatory evaporator at 40ꢀC unless otherwise indicated. Solutions were dried
over anhydrous Na2SO4. TLC was performed on precoated glass plates
(0.25 mm) with Silica Gel 60F254 (E. Merck, Darmstad). Flash column
chromatography was performed with Silica Gel 60 (230–400 mesh, E. Merck,
Darmstad). Elemental analyses were performed by Atlantic Microlab
(Atlanta, GA).
1,2,3,4-Tetra-O-acetyl-L-arabinopyranose18 (2). Acetic anhydride
(360 mL, 388 g, 2.8 mol) was added slowly over a period of 30 min to a well
stirred suspension of L-arabinose (1) (100 g, 0.67 mol) in dry pyridine
(270 mL) at 0ꢀC. The suspension was then stirred at room temperature for
4 hs after which it became a light brown colored solution. Excess pyridine
and acetic anydride were removed by azeotropic evaporation with toluene.
Crude 2 was obtained as a clear oil and was used in the next step without any
further purification.
1-a-Bromo-2,3,4-tri-O-acetyl-L-arabinopyranose18 (3). Crude tetra-
O-acetyl-L-arabinopyranose (2) was dissolved in a mixture of 30% wt HBr in
AcOH (400 mL, 2.0 mol) and acetic anhydride (8.0 mL). The solution was
stirred at room temperature for 36 h. The reaction mixture was diluted with
methylene chloride (400 mL) and successively washed with: water
(36600 mL), sat. NaHCO3 (26500 mL) and water (36600 mL), dried,
filtered and evaporated to a syrup that was crystallized from ethyl ether to
afford 3 (129 g, 0.380 mol, 57% from 1) as a white solid; 1H-NMR (CDCl3) d:
6.67 (1H, d, J ¼ 3.8, H-1), 5.37 (2H, m) and 5.06 (1H, m) (H-2, H-3 and H-4),
4.18 (1H, d, J ¼ 13.3, H-5), 3.91 (1H, dd, J ¼ 13.3 and J ¼ 1.7, H-50), 2.13 (3H,
s, CH3COO), 2.09 (3H, s, CH3COO), 2.01 (3H, s, CH3COO).
3,4-di-O-Acetyl-L-arabinal18,19 (4). To a well stirred solution of
NaOAc (35 g, 0.43 mol) and AcOH (115 mL) in water (200 mL) at À5ꢀC, was
slowly added a solution of CuSO4ꢁ5H2O (7 g, 28 mmol) in water (23 mL), and
then Zn dust (70 g, 0.11 mol) in portions, maintaining the temperature at or
below À5ꢀC. Bromosugar 3 (34 g, 0.10 mol), was added to this suspension in
portions and the mixture stirred vigorously for 3 hs at À5ꢀC and then
overnight at room temperature. The mixture was filtered and washed with
water (250 mL) and methylene chloride (250 mL). The phases were separated,

160
SZNAIDMAN, ALMOND, AND PESYAN
and the aqueous layer washed with methylene chloride (26125 mL). The
combined organic layers were successively washed with: water (26250 mL),
sat. NaHCO3 (261250 mL) and water (26250 mL), dried, filtered, and
evaporated to a colorless syrup ( ꢂ 20 g). The syrup was purified by flash
column chromatography (300 g silica gel, hexane:EtOAc 4:1) to afford 4
(12.0 g, 60 mmol, 60%) as a colorless syrup; 1H-NMR (CDCL3) d: 6.48 (1H,
d, J ¼ 6.0, H-1), 5.44 (1H, m, H-3), 5.19 (1H, dt, J ¼ 4.0, J ¼ 4.0, J ¼ 9, H-4),
4.83 (1H, dd, J ¼ 5.0, J ¼ 6.0, H-4), 4.00 (2H, m, H-5 and H-50), 2.08 (3H, s,
CH3COO), 2.07 (3H, s, CH3COO).
3,4-di-O-Acetyl-2-deoxy-2-£uro-L-arabinopyranose (5). To a well
stirred solution of glycal 4 (12.0 g, 60 mmol) in nitromethane:water (4:2,
120 mL) was added SelectfluorTM (26 g, 73 mmol). The solution was stirred
overnight at room temperature. The solution was then heated at reflux for
1 h to complete the reaction. After cooling to room temperature, the nitro-
methane was removed in vacuo. Water (150 mL) was added and extracted
with EtOAc (36150 mL). The combined organic fractions were successively
washed with: 1N HCl (26200 mL), and water (26200 mL), dried, filtered,
and evaporated to afford crude 5 (9.9 g, 42 mmol, 70%) as a syrup; 13C-
NMR (CDCl3) d: 170.35 (CH3COO), 170.27 (CH3COO), 95.01 (C-1a, d,
JC-1,F ¼ 24.5), 90.81 (C-1b, d, JC-1,F ¼ 21.5), 89.10 (C-2a, d, JC-2,F ¼ 184.3),
85.85 (C-2b, d, JC-2,F ¼ 188.0), 70.61 (C-3a, d, JC-3,F ¼ 19.5), 69.57 (C-4b, d,
JC-4,F ¼ 7.7), 68.66 (C-4a, d, JC-4,F ¼ 8.3), 67.53 (C-3b, d, JC-3,F ¼ 17.8), 63.90
(C-5a), 60.26 (C-5b), 20.73 (CH3COO), 20.67 (CH3COO), 20.62 (CH3COO),
20.56 (CH3COO). 19F-NMR (CDCl3) d -205.61 (dd, J ¼ 11.0 and J ¼ 51.8,
F-2a-anomer), -207.02 (dd, J ¼ 9.0 and J ¼ 49.0, F-2b-anomer).
Anal.Calcd. For C9H13O6F: C, 45.77; H, 5.55. Found: C, 45.64; H, 5.51.
2-Deoxy-2-£uoro-L-arabinopyranose (6). Asolution of
5 (5.7 g,
24.1 mmol) in dry methanol (220 mL) was treated with 0.1 N NaOMe in
methanol (114 mL, 11.4 mmol) and stirred for 1 h at room temperature. The
solution was then neutralized with DOWEX 50W X8-100, filtered and eva-
porated to afford crude 6 (3.7 g, 24 mmol, 100%) as a yellow syrup; 13C-
NMR (D2O) d: 94.19 (C-1a, d, JC-1,F ¼ 23.0), 92.24(C-2a, d, JC-2,F ¼ 179.6),
90.10 (C-1b, d, JC-1,F ¼ 20.3), 88.60 (C-2b, d, JC-2,F ¼ 182.3), 70.77 (C-3a, d,
JC-3,F ¼ 18.2), 69.03 (C-4b, d, JC-4,F ¼ 8.0), 68.90 (C-4a, d, JC-4,F ¼ 10.2),
66.85 (C-3b, d, JC-3,F ¼ 18.2), 66.32 (C-5a), 62.21 (C-5b). 19F-NMR
(CD3OD) d -204.11 (dd, J ¼ 12.6 and J ¼ 51.7, F-2a-anomer), -206.45 (d,
J ¼ 47.3, F-2b-anomer).
1-O-Methyl-2-deoxy-2-£uoro-L-arabinofuranoside (7). Asolution of 6
(790 mg, 5.2 mmol) and H2SO4 (60.1 mL, 1.1 mmol) in dry methanol
(12.2 mL) was heated at reflux for 6 hs. The reaction was cooled to room
temperature, neutralized with DOWEX SBR, filtered and evaporated to

SYNTHESIS OF L-FMAU
161
afford crude 7 (700 mg, 4.21 mmol, 80%) as a syrup; 13C-NMR (CD3OD) d:
107.48 (C-1a, d, JC-1,F ¼ 35.6), 103.20 (C-2a, d, JC-2,F ¼ 178.8), 101.98 (C-1b,
d, JC-1,F ¼ 16.8), 96.80 (C-2b, d, JC-2, F ¼ 199.3), 85.15 (C-4a, d, JC-3,F ¼ 5.0),
83.69 (C-4b, d, JC-4,F ¼ 10.7), 76.70 (C-3a, d, JC-4,F ¼ 27.0), 74.54 (C-3b, d,
JC-3,F ¼ 21.5), 65.00 (C-5b), 62.52 (C-5a). 55.58 (OCH3 b), 54.94 (OCH3 a).
19F-NMR (CD3OD) d -189.97 (ddd, J ¼ 12.0, J ¼ 26.0 and J ¼ 51.0, F-2a-
anomer), -207.83 (dd, J ¼ 19.0 and J ¼ 50.0, F-2b-anomer).
1-O-Methyl-2-deoxy-2-£uro-3,5-di-O-benzoyl-L-arabinofuranoside (8).
To a well stirred solution of 7 (664 mg, 4 mmol) in dry pyridine (10 mL) at
0ꢀC, benzoyl chloride (2.5 mL, 3.0 g, 21.5 mmol) was added slowly. After
stirring for 30 min at 0ꢀC, it was left at room temperature for 3 hs. The
reaction was quenched with water (10 mL) and sat. NaHCO3 (30 mL) and
stirred for 30 min. It was then diluted with methylene chloride (50 mL) and
more sat. NaHCO3 (30 mL). The organic layer was separated and succes-
sively washed with: sat. NaHCO3 (50 mL), water (2650 mL), 1N HCl
(2650 mL), water (50 mL), sat. NaHCO3 (50 mL) and water (2650 mL),
dried, filtered and evaporated to a brown syrup (1.9 g), that was purified by
flash column chromatography (50 g silica gel, hexane:EtOAc 95:5).
Amajor fraction was isolated as a syrup and characterized as 8 (a anomer,
20
20
670 mg, 1.79 mmol, 44%); [a]D ¼ À 98 (c 1.0 EtOH) (lit.24 [a]D ¼ þ108 (c
1.8 EtOH for the D-isomer); 1H-NMR (CDCl3) d:8.20–7.40 (15 H, m, ArH),
5.48 (1H, dd, J ¼ 5.0, J ¼ 23.1, H-3), 5.21 (1H, d, J ¼ 10.6, H-1), 5.11 (1H, d,
J ¼ 49.2, H-2), 4.76 (1H, dd, J ¼ 3.6 and J ¼ 12.0, H-5), 4.63 (1H, dd, J ¼ 4.4
and J ¼ 12.0, H-50), 3.45 (3H, s, OCH3); 13C-NMR (CDCl3) d 166.20 (C¼O),
165.67 (C¼O), 133.57 (Ar), 133.07 (Ar), 129.87 (Ar), 129.76 (Ar), 128.49 (Ar),
128.31 (Ar) 106.22 (C-1, d, JC-1,F ¼ 35.1), 98.20 (C-2, d, JC-2,F ¼ 182.7), 80.85
(C-4), 77.58 (C-3, D, JC-3,F ¼ 30.4), 63.62 (C-5), 54.86 (OCH3); 19F-NMR
(CDCl3) d -191.70 (ddd, J ¼ 10.0, J ¼ 23.0 and J ¼ 50.0, F-2a-anomer).
Anal. Calcd. For C20H19O6F: C, 64.17; H, 5.12. Found: C, 64.14;
H, 5.08.
1-(30,50 -di-O-Benzoyl-20-deoxy-20-£uoro-b-L-
arabinofuranosyl)thymine11 (12). To a well stirred solution of 8 (1.31 g,
3.5 mmol) in dry methylene chloride (2.6 mL) at 0ꢀC, was slowly added 30% wt
HBr in AcOH (3.7 mL, 5.1 g, 1.5 g of HBr, 18.6 mmol). The solution was then
stirred at room temperature overnight. The brown-red solution was evaporated
under vacuum at or below 40ꢀC. It was then coevaporated with dry benzene
(363 mL) and then once with dry chloroform (3 mL). Bromosugar 9 was obtained
as a syrup, which was redissolved in dry chloroform (4 mL): solution A.
At the same time a mixture of thymine (10, 971 mg, 7.7 mmol),
ammonium sulfate (89 mg), and 1,1,1,3,3,3-hexamethyldisilazane (3.7 g,
4.9 mL, 23.0 mmol) in dry chloroform (33.0 mL) was heated at reflux over-
night. The resulting clear solution, (an indication that all the thymine

162
SZNAIDMAN, ALMOND, AND PESYAN
was silylated to form compound 11) was cooled to room temperature:
solution B.
Solution Awas added to solution B and heated at reflux for 4 hs. The
reaction was quenched with MeOH (2 mL). Aprecipitate appeared and the
suspension was further stirred for 1 h at room temperature. The solids were
filtered through celite and washed with chloroform. The organic phase
( ꢂ100 mL) was washed with water (100 mL), NaHCO3 (100 mL) and water
(26100 mL), dried, filtered and evaporated to a solid. It was crystallized
from EtOH to afford pure 12 (700 mg, 1.5 mmol, 42%) as a white solid; mp
160ꢀC was identical to an original sample of 12 (lit6b 120–122 C for the D-
1
isomer and 118–120ꢀC for the L-isomer11); H-NMR (CDCl3) d: 8.52 (1H,
bs, N-H), 8.13–7.43 (10H, m, ArH), 7.36 (1H, q, J ¼ 1, C-H thymine), 6.35
(1H, dd, J ¼ 3.0 and J ¼ 22.2, H-1), 5.64 (1H, dd, J ¼ 3.0 and J ¼ 18.0, H-3),
5.32 (1H, dd, J ¼ 3.0 and J ¼ 50.0, H-2), 4.86–4.77 (2H, m, H-5 and H-s0),
4.49 (1H, q, H-4), 1.76 (3H, d, J ¼ 1.0, Thymine CH3).
1-(20-Deoxy-20-£uoro-b-L-arabinofuranosyl)thymine11,12 (13). Asolu-
tion of 12 (700 mg, 1.5 mmol) and n-butylamine (55 g, 7.5 mL, 75 mmol) in
methanol (15 mL) was heated at reflux for 3 hs. The solution was evaporated
to dryness, coevaporated three times with EtOAc and finally suspended in
EtOAc, filtered and dried to afford 13 (320 mg, 1.23 mmol, 82%) as a white
solid; mp: 188ꢀC (lit.12 mp 185–187ꢀC, lit11 184–185ꢀC, lit.6b 187–188ꢀC for
20
20
the D-isomer); [a]D ¼ À93 (c 0.25 MeOH) (lit.11 [a]D ¼ À111 (C 0.23
20
1
MeOH), lit.12 [a]D ¼ À112 (c 0.23 MeOH)); H-NMR (DMSO-d6) d 11.0
(1H, bs, N-H), 7.58 (1H, s, C-H thymine), 6.09 (1H, dd, J ¼ 4.2 and J ¼ 15.6,
H-1), 5.85 (1H, bs, OH), 5.10 (1H, bs, OH), 5.02 (1H, dt, J ¼ 4.0, J ¼ 3.8 and
J ¼ 52.8, H-2), 4.22 (1H, dt, J ¼ 3.8, J ¼ 4.0 and J ¼ 20.3, H-3), 3.76 (1H, q,
J ¼ 4.0 and J ¼ 9.5, H-4), 3.69–3.57 (2H, m, H-5 and H-50), 1.77 (3H, s,
Thymine CH3).
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Received August 1, 2001
Accepted December 7, 2001