Syntheses of pyridine C-nucleosides as analogues of the natural nucleosides dC and dU

Article abstract of DOI:10.1021/jo060066y

The syntheses of four pyrimidine C-nucleosides are described. These derivatives are designed as mimics of dC and dU, and in that respect, each can form two hydrogen bonds with complementary dG or dA residues. The minor groove O2 carbonyl in each derivativ

Full text of DOI:10.1021/jo060066y

The hydrogen-bonding faces of these analogues are designed
to function as bidentate acceptors/donors to form base pairs with
dA or dG (Figure 2) but use isosteric fluorine and methyl group
to replace the substituents bound to the C2 carbons (the minor
groove functional groups).
To maintain the correct tautomeric forms for base pairing,
or other recognition processes using the Watson-Crick func-
tional groups, it was necessary to prepare the derivatives as
pyridine C-nucleosides. Derivatives such as 2 and 4 can form
essentially normal base pairs with dA such that the exocyclic
fluorine or methyl group is placed into the minor groove.
Derivatives such as 1 and 3 can form two hydrogen bonds with
dG. The third hydrogen bond is lost due to the substitution of
the -F or -CH3 for the O2 carbonyl.
Syntheses of Pyridine C-Nucleosides as Analogues
of the Natural Nucleosides dC and dU
Zhenhua Sun, Shahadat Ahmed, and Larry W. McLaughlin*
Department of Chemistry, Merkert Chemistry Center,
Boston College, Chestnut Hill, Massachusetts 02467
mclaughl@bc.edu
ReceiVed January 11, 2006
The desired pyridine heterocycles necessary for the syntheses
of 1-4 were obtained from the readily available 2,6-substituted
pyridines 5, 12, or 14 (Scheme 1a-c). The iodo heterocycles
were prepared in each case to generate the carbon-carbon bond
of the C-nucleosides by a palladium-mediated Heck-type
coupling. The heterocycle for 3 was obtained by simple
iodination of readily available 2-amino-6-methylpyridine (f
13).7 Compound 9, which is necessary to prepare nucleoside 1,
was obtained by iodination of 2,6-diaminopyridine. Subsequent
monoacetylation generated solely the 6-acetamido derivative 7,
which could be converted to the 2-fluoro compound 8 in the
presence of HBF4/NaNO2; deacetylation resulted in the desired
9. Pyridine 11 was easily obtained from 9 by diazotization (f
10), followed by the protection of the carbonyl as the pNPE
derivative 11. The fourth heterocycle could be obtained from
14 by simple pNPE protection (f 15) and subsequent iodination
(f 16). To convert the pyridine heterocycles to the correspond-
ing C-nucleosides we employed a palladium-mediated Heck-
type coupling8,9 involving the glycal 17, which we obtained in
three steps from thymidine.10 Each coupling reaction yielded
only the â anomer in part because the bulky silyl protecting
group at the 3′-hydroxyl precludes addition of the heterocycle
from the “lower” face of the sugar. We had difficulty in
separating the initial coupling products from the starting glycal,
so the simplest procedure was to remove the silyl group from
the initial coupling products so that compounds 18-21 could
be purified. Stereospecific reduction of the carbohydrate11 and
removal of the pNPE protecting group, where necessary (e.g.,
for 22 and 23), resulted in the target compounds 1-4 (Scheme
2). Nuclear Overhauser enhancement studies confirmed the
presence of solely the â anomers for all four compounds.
Crystallographic analysis (data not shown) of 9 also confirmed
the presence of the â nucleoside.
The syntheses of four pyrimidine C-nucleosides are de-
scribed. These derivatives are designed as mimics of dC and
dU, and in that respect, each can form two hydrogen bonds
with complementary dG or dA residues. The minor groove
O2 carbonyl in each derivative is replaced by a fluorine or
a methyl group. The key carbon-carbon bond connecting
the heterocycle to the carbohydrate is formed using a Heck-
type palladium-mediated coupling reaction.
Introduction
Nucleoside analogues can be used to probe a variety of
enzyme substrate interactions, including those involving poly-
merase dNTP recognition or protein-DNA targeting. They can
also be incorporated into nucleic acid sequences using conven-
tional synthesis protocols to probe the structural and functional
aspects of DNA or RNA. Two classes of DNA analogues that
have been described recently include those in which specific
functional groups have been deleted from the pyrimidine
residues1-3 and those in which hydrophobic isosteres have the
desired molecular shape. In the latter cases, -F replaces the
carbonyls and -CH3 replaces the exocyclic amino groups in
the nucleobase heterocycles.4-6
Results and Discussion
Here we describe four pyrimidine nucleoside analogues (1-
4) in which the heterocycles are substituted in a pattern similar
to the native residues dC and dU (Figure 1).
These syntheses generate a series of four related pyrimidine-
like compounds that can be used directly for studies that probe
biological processes involving pyrimidine nucleosides. In
principle, they can also be converted to the corresponding
triphosphates or phosphoramidites for enzyme-mediated or
(1) Hsieh, H. P.; McLaughlin, L. W. J. Org. Chem. 1995, 60, 5356-
5359.
(2) Lan, T.; McLaughlin, L. W. J. Am. Chem. Soc. 2001, 123, 2064-
2065.
(7) Abe, H.; Arai, Y.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 2003,
44, 2971-2973.
(8) Farr, R. N.; Daves, G. D. J. J. Carbohydr. Chem. 1990, 9, 653-660.
(9) Daves, G. D. Acc. Chem. Res. 1990, 23, 201-206.
(10) Lan, T.; McLaughlin, L. W. J. Am. Chem. Soc. 2000, 122, 6512-
6513.
(3) Fraley, A.; Chen, D.; Johnson, K.; McLaughlin, L. W. J. Am. Chem.
Soc. 2003, 125, 616-617.
(4) Dzantiev, L.; Alekseyev, Y. O.; Morales, J. C.; Kool, E. T.; Romano,
L. J. Biochemistry 2001, 40, 3215-3221.
(5) Moran, S.; Ren, R. X. F.; Rumney, S.; Kool, E. T. J. Am. Chem.
Soc. 1997, 119, 2056-2057.
(11) Farr, R. N.; Kwok, D.-I.; Cheng, J. C.-Y.; Daves, G. D. J. Org.
Chem. 1992, 57, 2093-2100.
(6) Matray, T. J.; Kool, E. T. J. Am. Chem. Soc. 1998, 120, 6191-6192.
10.1021/jo060066y CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/09/2006
2922
J. Org. Chem. 2006, 71, 2922-2925

FIGURE 1. Structures of two dU analogues (1 and 2) and two dC analogues (3 and 4).
SCHEME 1
FIGURE 2. Structures of 1-dG and 2-dA Watson-Crick-like base
pairs.
chemical syntheses of modified DNA sequences used in
structure and function studies.
Experimental Section
Preparation of 6-Amino-3-(â-D-2-deoxy-erythro-furanosyl)-
2-fluoropyridine (1): To a solution of compound 18 (200 mg, 0.88
mmol, 1.0 equiv) in AcOH (10 mL) and acetonitrile (10 mL) at 0
°C was added sodium triacetoxyborohydride (275 mg, 1.3 mmol,
1.5 equiv). The reaction was complete within 40 min, as revealed
by TLC analysis. The reaction was quenched with a 50% aqueous
ethanol solution (5 mL). Volatiles were removed under high
vacuum, and the product was purified by flash column chroma-
tography with EtOAc/MeOH (9:1) to afford 1 (142 mg, 0.68 mmol,
78%) as a white solid. Mp 152 °C; TLC in DCM/MeOH (20:1), Rf
1
) 0.24. H NMR (500 MHz, DMSO-d6): δ 7.57 (dd, J ) 8.3,
10.1 Hz, 1H), 6.29 (d, J ) 8.2 Hz, 1H), 6.25 (br s, 2H), 5.02-4.99
(m, 2H), 4.71 (t, J ) 5.7 Hz, 1H), 4.16 (m, 1H), 3.70 (m, 1H),
3.41 (m, 2H), 1.94 (m, 1H), 1.80 (m, 1H). 13C NMR (125 MHz,
DMSO-d6): δ 159.4 (d, J ) 232.7 Hz), 158.2 (d, J ) 18.3 Hz),
139.7 (d, J ) 5.7 Hz), 107.3 (d, J ) 27.7 Hz), 104.6 (d, J ) 3.6
Hz), 87.2, 72.5, 72.2, 62.3, 41.5. ꢀ (M-1cm-1) ) 15 665 (237.5
nm), 738 (260.0 nm). Exact mass calculated for [C10H13N2O3FNa+]
requires m/z 251.0808; found, 251.0806 (ESI+).
Preparation of 5-(â-D-2-Deoxy-erythro-furanosyl)-6-fluoro-
pyridone (2): Compound 22 (23 mg, 0.061 mmol) was dissolved
in 1 M DBU in dry acetonitrile solution (0.5 mL) and stirred at
ambient temperature. The reaction was completed in 2 h, as revealed
by TLC analysis. Solvent was removed completely under high
vacuum, and the residue was dissolved in DCM (1 mL). The product
was purified by flash column chromatography, eluting with 10%
MeOH in DCM to give 2 (12 mg, 0.052 mmol, 86%) as a white
Preparation of 6-Amino-3-(â-D-2-deoxy-erythro-furanosyl)-
2-methylpyridine (3): To a solution of compound 20 (360 mg,
1.62 mmol, 1.0 equiv) in AcOH (20 mL) and acetonitrile (20 mL)
at 0 °C was added sodium triacetoxyborohydride (0.51 g, 2.43
mmol, 1.5 equiv). The reaction was complete within 50 min, as
revealed by TLC analysis. The reaction was quenched with a 50%
aqueous ethanol solution (10 mL). Volatiles were removed under
vacuum, and the residue was purified by flash column chromato-
graphy with EtOAc/MeOH (9:1), affording 3 (300 mg, 1.34 mmol,
83%) as a white color solid. Mp 169 °C; TLC in EtOAc/MeOH
1
solid. Mp 207 °C; TLC in 10% MeOH in DCM, Rf ) 0.15. H
NMR (500 MHz, DMSO-d6): δ 7.84 (t, J ) 8.4 Hz, 1H), 6.52 (d,
J ) 8.1 Hz, 1H), 5.08 (dd, J ) 5.5, 10.3 Hz, 1H), 4.18 (m, 1H),
3.75 (m, 1H), 3.43 (m, 2H), 2.02 (m, 1H), 1.81 (m, 1H). 13C NMR
(125 MHz, DMSO-d6): δ 162.8 (d, J ) 15.7 Hz), 158.9 (d, J )
236.9 Hz), 142.2 (d, J ) 5.4 Hz), 113.3 (d, J ) 27.0 Hz), 107.1
(d, J ) 4.6 Hz), 88.2, 73.2, 73.0, 63.0, 42.4. ꢀ (M-1cm-1) )
6847 (216.0 nm), 2027 (260.0 nm). Exact mass calculated for
[C10H13FNO4+] requires m/z 230.0829; found, 230.0833 (ESI+).
1
(9:1), Rf ) 0.2. H NMR (400 MHz, D2O): δ 8.0 (d, J ) 9.2 Hz,
1H), 6.83 (d, J ) 9.1 Hz, 1H), 5.27 (dd, J ) 5.4, 10.5 Hz, 1H),
4.40 (m, 1H), 4.00 (m, 1H), 3.71 (m, 2H), 2.45 (s, 3H), 2.24-2.20
(m, 1H), 2.04-1.97 (m, 1H). 13C NMR (100 MHz, D2O): δ 153.7,
144.8, 142.4, 123.2, 111.0, 87.3, 75.1, 73.0, 41.0, 16.6, ꢀ (M-1cm-1
)
J. Org. Chem, Vol. 71, No. 7, 2006 2923

SCHEME 2 a
a R ) pyridine heterocycles corresponding to structures 9, 11, 13, and 16.
) 11 872 (230.0 nm), 628 (260.0 nm), 4175 (307.0 nm). Exact
mass calculated for [C11H17N2O3+] requires m/z 225.1239; found,
225.1235 (ESI+).
Preparation of 6-[2-(4-Nitrophenylethoxy)]-3-(â-D-glycero-
pentofuran-3′-ulos-1′yl)-2-fluoropyridine (19): A mixture of tris-
(dibenzylideneacetone)palladium (300 mg, 0.33 mmol) and trispen-
tafluoro phenylphosphine (240 mg, 0.45 mmol) in dry acetonitrile
(100 mL) was stirred under argon at ambient temperature for 5 h.
Formation of the complex was evidenced by a change of reaction
color to deep yellow. N,N-Diisopropylethylamine (0.22 mL, 5.6
mmol, 2.0 equiv), compound 17 (1.0 g, 2.8 mmol, 1.0 equiv) and
compound 11 (1.6 g, 4.2 mmol, 1.5 equiv) were added, and the
reaction mixture was stirred under argon at 90 °C for 48 h. Volatiles
were removed under vacuum, and the residue was then passed
through a Celite column, eluting with MeOH to remove the
palladium catalyst. The filtrate was then treated with 0.5 mL of 1
M n-butylammonium fluoride and 0.05 mL AcOH in 5 mL of THF
at 0 °C for 30 min. Volatiles were removed, and the product was
purified by flash column chromatography, eluting with DCM/MeOH
(20:1) to afford the desired product 19 (686 mg, 1.82 mmol, 65%).
Preparation of 5-(â-D-2-Deoxy-erythro-furanosyl)-6-meth-
ylpyridone (4): Compound 23 (70 mg, 0.19 mmol) was dissolved
in 1 M DBU in dry acetonitrile solution (2 mL) and stirred at
ambient temperature. The reaction was completed in 2 h, as revealed
by TLC analysis. Solvent was removed completely under high
vacuum, and the residue was dissolved in DCM (3 mL). The product
was purified by flash column chromatography, eluting with 10%
MeOH in DCM to give 4 (40 mg, 0.18 mmol, 96%) as a white
solid. Mp 255 °C; TLC in 10% MeOH in DCM, Rf ) 0.1. 1H NMR
(400 MHz, DMSO-d6): δ 7.48 (d, J ) 9.4 Hz, 1H), 6.15 (d, J )
9.4 Hz, 1H), 5.03 (br s, 1H), 4.95 (dd, J ) 5.3, 10.6 Hz, 1H), 4.75
(br s, 1H), 4.15 (m, 1H), 3.69 (m, 1H), 3.45 (m, 2H), 2.18 (s, 3H),
1.91-1.87 (m, 1H), 1.76-1.69 (m, 1H). 13C NMR (125 MHz,
DMSO-d6): δ 162.3, 139.8, 141.9, 116.6, 115.1, 87.2, 73.9, 72.2,
62.1, 41.3, 15.5. ꢀ (M-1cm-1) ) 14 877 (231.0 nm), 4403 (260.0
nm). Exact mass calculated for [C11H16NO4+] requires m/z 226.1079;
found, 226.1077 (ESI+).
1
Mp 125 °C; TLC in CH2Cl2/MeOH (20:1), Rf ) 0.63. H NMR
(400 MHz, CDCl3): δ 8.17 (d, J ) 8.7 Hz, 2H), 7.89 (t, J ) 9.6
Hz, 1H), 7.44 (d, J ) 8.7 Hz, 2H), 6.65 (d, J ) 8.84 Hz, 1H), 5.33
(dd, J ) 5.9, 10.9 Hz, 1H), 4.54 (t, J ) 6.5 Hz, 2H), 4.04 (m, 1H),
3.96 (m, 1H), 3.19 (t, J ) 6.5 Hz, 2H), 2.90 (dd, J ) 6.3, 18.2 Hz,
1H), 2.50 (dd, J ) 10.9, 18.1 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 212.7, 162.1 (d, J ) 13.6 Hz), 158.9 (d, J ) 241.1
Hz), 146.0, 140.7, 140.4, 129.8, 123.6, 112.3 (d, J ) 26.2 Hz),
107.8 (d, J ) 5.0 Hz), 82.0, 71.5, 66.3, 61.5, 43.9, 35.1. Exact
mass calculated for [C18H17N2O6FNa+] requires m/z 399.0968;
found, 399.0963 (ESI+).
Preparation of 6-Amino-3-(â-D-glycero-pentofuran-3′-ulos-
1′yl)-2-fluoropyridine (18): A mixture of tris(dibenzylidene-
acetone)palladium (300 mg, 0.33 mmol) and trispentafluoro phe-
nylphosphine (240 mg, 0.45 mmol) in dry acetonitrile (100 mL)
was stirred under argon at ambient temperature for 5 h. Formation
of the complex was evidenced by a change of reaction color to
deep yellow. N,N-Diisopropylethylamine (0.22 mL, 5.6 mmol, 2.0
equiv), 1,4-anhydro-deoxy-3-O-[(1,1-dimethylethyl)diphenylsilyl]-
D-erythro-1-enitol compound 17 (1.0 g, 2.8 mmol, 1.0 equiv) and
compound 9 (1.0 g, 4.2 mmol, 1.5 equiv) were added, and the
reaction mixture was stirred under argon at 55 °C for 48 h. Volatiles
were removed under vacuum, and the residue was then passed
through a Celite column, eluting with MeOH to remove the
palladium catalyst. The filtrate was then treated with 0.5 mL of 1
M n-butylammonium fluoride and 0.05 mL AcOH in 5 mL of THF
at 0 °C for 30 min. Volatiles were removed, and the product was
purified by flash column chromatography, eluting with DCM/MeOH
(20:1) to afford the desired product 18 (449 mg, 1.9 mmol 71%).
Preparation of 6-Amino-3-(â-D-glycero-pentofuran-3′-ulos-
1′yl)-2-methylpyridine (20): A mixture of tris(dibenzylideneac-
etone)palladium (300 mg, 0.33 mmol) and trispentafluoro phe-
nylphosphine (240 mg, 0.45 mmol) in dry acetonitrile (100 mL)
was stirred under argon at ambient temperature for 5 h. Formation
of the complex was evidenced by a change of reaction color to
deep yellow. N,N-Diisopropylethylamine (0.22 mL, 5.6 mmol, 2.0
equiv), compound 17 (1.0 g, 2.8 mmol, 1.0 equiv), and compound
137 (see also Supporting Information; 1.0 g, 4.3 mmol, 1.5 equiv)
were added, and the reaction mixture was stirred under argon at
55 °C for 48 h. Volatiles were removed under high vacuum, and
the residue was then passed through a Celite column, eluting with
MeOH to remove the palladium catalyst. The filtrate was then
treated with 0.5 mL of 1 M n-butylammonium fluoride and 0.05
mL AcOH in 5 mL of THF at 0 °C for 30 min. Volatiles were
removed, and the product was purified by flash column chroma-
tography, eluting with DCM/MeOH (98:2) to afford the desired
product 20 (416 mg, 1.9 mmol, 67%). Mp 136 °C; TLC in CH2Cl2/
1
Mp 120 °C; TLC in CH2Cl2/MeOH (20:1), Rf ) 0.25. H NMR
(400 MHz, CDCl3): δ 7.75 (dd, J ) 8.2, 9.6 Hz, 1H), 6.46 (dd, J
) 1.2, 8.0 Hz, 1H), 5.30 (dd, J ) 5.5, 11.1 Hz, 1H), 4.83 (br s,
2H), 4.02 (t, J ) 3.0 Hz, 1H), 3.94 (d, J ) 3.0 Hz, 2H), 2.83 (dd,
J ) 6.0, 18.0 Hz, 1H), 2.55 (dd, J ) 10.8, 19.2 Hz, 1H). 13C NMR
(125 MHz, CDCl3): δ 213.9, 160.3 (d, J ) 238.0 Hz), 157.9 (d, J
) 18.3 Hz), 140.5 (d, J ) 32.0 Hz), 108.2 (d, J ) 26.6 Hz), 105.6
(d, J ) 30.0 Hz), 82.3, 72.2, 59.4, 44.0. Exact mass calculated for
[C10H11N2O3FNa +] requires m/z 249.0651; found, 249.0643 (ESI+).
MeOH (9:1), Rf ) 0.1. 1H NMR (400 MHz, acetone-d6):
δ
2924 J. Org. Chem., Vol. 71, No. 7, 2006

7.68 (d, J ) 8.4 Hz, 1H), 6.41 (d, J ) 8.4 Hz, 1H), 5.42 (br s, 2H),
5.33 (dd, J ) 5.5, 11.1 Hz, 1H), 3.97 (t, J ) 3.0 Hz, 1H), 3.83 (d,
J ) 3.0 Hz, 2H), 2.80 (dd, J ) 5.5, 17.4 Hz, 1H), 2.34 (s, 3H),
2.30 (dd, J ) 11.1, 17.9 Hz, 1H) ppm. 13C NMR (100 MHz,
acetone-d6): δ 213.9, 158.7, 153.8, 135.8, 122.8, 105.9, 83.2, 74.0,
61.3, 44.5, 21.3. Exact mass calculated for [C11H15N2O3+] requires
m/z 223.1083; found, 223.1080 (ESI+).
by column chromatography with EtOAc/MeOH (9:1) to afford 22
(320 mg, 0.85 mmol, 80%) as a white solid. Mp 100 °C; TLC in
DCM/MeOH (20:1), Rf ) 0.2. H NMR (400 MHz, CDCl3): δ
1
8.15 (d, J ) 8.6 Hz, 2H), 7.73 (dd, J ) 8.3, 9.7 Hz, 1H), 7.41 (d,
J ) 8.5 Hz, 2H), 6.56 (d, J ) 8.1 Hz, 1H), 5.24 (dd, J ) 5.6, 10.2
Hz, 1H), 4.51 (t, J ) 6.5 Hz, 2H), 4.45 (m, 1H), 3.98 (m, 1H),
3.75 (m, 2H), 3.16 (t, J ) 6.5 Hz, 2H), 2.27 (dd, J ) 5.7, 13.2 Hz,
1H), 2.01 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 161.7 (d, J )
13.6 Hz), 158.6 (d, J ) 239.0 Hz), 147.1, 147.0, 141.5, 130.4, 123.5,
115.3 (d, J ) 26.7 Hz), 107.5 (d, J ) 5.0 Hz), 88.3, 73.3, 73.2,
66.4, 63.1, 42.9, 35.0. Exact mass calculated for [C18H19N2O6FNa+]
requires m/z 401.1125; found, 401.1120 (ESI+).
Preparation of 6-[2-(4-Nitrophenylethoxy)]-3-(â-D-2-deoxy-
erythro-furanosyl)-2-methylpyridine (23): To a solution of
compound 21 (400 mg, 1.06 mmol, 1.0 equiv) in AcOH (20 mL)
and acetonitrile (20 mL) at 0 °C was added sodium triacetoxy-
borohydride (0.32 g, 1.5 mmol, 1.5 equiv). The reaction was
complete within 40 min, as revealed by TLC analysis. The reaction
was quenched with a 50% aqueous EtOH solution (10 mL).
Volatiles were then removed under high vacuum, and the residue
was purified by flash column chromatography, eluting with 5%
MeOH in DCM to afford 23 (345 mg, 0.92 mmol, 87%) as a white
solid. Mp 102 °C; TLC in DCM/MeOH (20:1), Rf ) 0.2. 1H NMR
(500 MHz, CDCl3): δ 8.17 (d, J ) 8.7 Hz, 2H), 7.74 (d, J ) 8.5
Hz, 1H), 7.59 (d, J ) 8.7 Hz, 2H), 6.58 (d, J ) 8.5 Hz, 1H), 5.13
(dd, J ) 5.4, 10.3 Hz, 1H), 5.06 (d, J ) 4.1 Hz, 1H), 4.50 (t, J )
4.5 Hz, 2H), 4.19 (m, 1H), 3.76 (m, 1H), 3.46 (m, 2H), 3.17 (t, J
) 6.6 Hz, 2H), 2.37 (s, 3H), 2.10-2.06 (m, 1H), 1.68-1.63 (m,
1H). 13C NMR (125 MHz, DMSO-d6): δ 161.8, 152.5, 147.9, 146.8,
137.6, 130.8, 129.3, 124.0, 108.3, 88.2, 75.9, 73.0, 65.7, 62.9, 42.7,
35.2, 22.1. Exact mass calculated for [C19H23N2O6+] requires m/z
375.1556; found, 375.1554 (ESI+).
Preparation of 6-[2-(4-Nitrophenylethoxy)]-3-(â-D-glycero-
pentofuran-3′-ulos-1′yl)-2-methylpyridine (21): A mixture of tris-
(dibenzylideneacetone)palladium (300 mg, 0.33 mmol) and trispen-
tafluoro phenylphosphine (240 mg, 0.45 mmol) in dry acetonitrile
(100 mL) was stirred under argon at ambient temperature for 5 h.
Formation of the complex was evidenced by a change of reaction
color to deep yellow. N,N-Diisopropylethylamine (0.22 mL, 5.6
mmol, 2.0 equiv), compound 17 (1.0 g, 2.8 mmol, 1.0 equiv), and
compound 16 (1.6 g, 4.2 mmol, 1.5 equiv) were added, and the
reaction mixture was stirred under argon at 90 °C for 48 h. Volatiles
were removed under vacuum, and the residue was then passed
through a Celite column, eluting with MeOH to remove the
palladium catalyst. The filtrate was then treated with 0.5 mL of 1
M n-butylammonium fluoride and 0.05 mL AcOH in 5 mL of THF
at 0 °C for 30 min. Volatiles were removed under high vacuum,
and the residue was purified by flash column chromatography,
eluting with DCM/MeOH (20:1) to afford the desired product 21
(595 mg, 1.6 mmol, 57%). Mp 88 °C; TLC in CH2Cl2/MeOH (98:
2), Rf ) 0.7. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J ) 8.8 Hz,
2H), 7.74 (d, J ) 8.4 Hz, 1H), 7.45 (d, J ) 8.8 Hz, 2H), 6.60 (d,
J ) 8.4 Hz, 1H), 5.33 (dd, J ) 5.6, 11.2 Hz, 1H), 4.56 (t, J ) 7.2
Hz, 2H), 4.04 (m, 1H), 3.96 (m, 1H), 3.19 (t, J ) 6.8 Hz, 2H),
2.85 (dd, J ) 5.7, 18.0 Hz, 1H), 2.47 (s, 3H), 2.40 (dd, J ) 11.0,
18.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 212.0, 162.4, 153.5,
146.8, 136.5, 130.0, 126.1, 123.8, 108.7, 82.5, 74.2, 65.7, 61.9,
44.6, 35.8, 22.2. Exact mass calculated for [C19H21N2O6+] requires
m/z 373.1400; found, 373.1395 (ESI+).
Acknowledgment. This work was supported by a grant from
Preparation of 6-[2-(4-Nitrophenylethoxy)]-3-(â-D-2-deoxy-
erythro-furanosyl)-2-fluoropyridine (22): To a solution of com-
pound 19 (400 mg, 1.06 mmol, 1.0 equiv) in AcOH (20 mL) and
acetonitrile (20 mL) at 0 °C was added sodium triacetoxyborohy-
dride (0.32 g, 1.5 mmol, 1.5 equiv). The reaction was complete
within 40 min, as revealed by TLC analysis. The reaction was
quenched with a 50% aqueous ethanol solution (10 mL). Volatiles
were then removed under vacuum, and the residue was separated
the NIH (GM 71309).
Supporting Information Available: 1H and 13C NMR spectra
for all procedures and compounds, CIF file for 1, and synthetic
procedures for compounds in Scheme 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO060066Y
J. Org. Chem, Vol. 71, No. 7, 2006 2925