Notes
J . Org. Chem., Vol. 63, No. 20, 1998 7093
Sch em e 2a
Exp er im en ta l Section
Gen er a l. Melting points were recorded on a Meltemp II
melting point apparatus and are uncorrected. Combustion
analyses were performed by M-H-W Laboratories, Phoenix, AZ.
1H and 13C NMR spectra were recorded on a Bruker AC 250
spectrometer (operated at 250 and 62.5 MHz, respectively) and
are referenced to internal tetramethylsilane (TMS) at 0.0 ppm.
The spin multiplicities are indicated by the symbols s (singlet),
d (doublet), t (triplet), p (pentet), m (multiplet), and br (broad).
IR spectra were recorded on
a Nicolet 5PC spectrometer.
Reactions were monitored by thin-layer chromatography (TLC)
using 0.25-mm Whatman Diamond silica gel 60-F254 precoated
plates with visualization by irradiation with a Mineralight
UVGL-25 lamp. Column chromatography was performed on
Whatman silica, 230-400 mesh, 60 Å, and elution was with the
indicated solvent system. Yields refer to chromatographically
and spectroscopically (1H and 13C NMR) homogeneous materials.
(1R,4S)-4-Acet oxy-1-(6-a m in o-9H-p u r in -9-yl)cyclop en t -
2-en e (6). To a solution of 55 (2.5 g, 7.77 mmol) in anhydrous
CH2Cl2 (150 mL) and anhydrous DMF (30 mL) stirring at 0 °C
were added anhydrous pyridine (0.73 g, 9.2 mmol), (dimethy-
lamino)pyridine (0.02 g, 1.6 mmol), and acetic anhydride (0.92
g, 9.2 mmol). The reaction mixture was stirred at 0 °C for 30
min, followed by stirring at room temperature for 3 h. The
reaction mixture was cooled to 0 °C and quenched with a
saturated NaHCO3 solution (150 mL), and the organic layer was
separated and washed with ice-cold 1 N HCl (2 × 150 mL). The
organic layer was then dried (MgSO4) and evaporated under
reduced pressure. The residue was purified via column chro-
matography, eluting with CH2Cl2/MeOH (98:2) to afford 2.6 g
(92%) of 6 as an off-white foam: 1H NMR (CDCl3) δ 1.95 (dt,
1H), 2.09 (s, 3H), 3.11 (p, 1H), 5.78 (m, 2H), 6.22 (d, 1H), 6.37
(d, 1H), 7.44-7.55 (m, 3H), 8.02 (m, 2H), 8.08 (s, 1H), 8.79 (s,
1H), 9.40 (br, 1H); 13C NMR (CDCl3) δ 20.9, 38.6, 57.0, 76.8,
122.2, 127.9 (2), 128.8 (2), 132.4, 133.6, 133.8, 135.9, 141.3, 149.6,
151.5, 152.6, 164.8, 170.5. Anal. Calcd for C19H17N5O3‚H2O: C,
60.01; H, 5.00; N, 18.29. Found: C, 60.03; H, 5.22; N, 18.52.
(1R,4S)-N-[9-(4-Am in o-2-cyclop en ten yl)-9H-p u r in -6-yl]-
ben za m id e (7). A solution of 6 (1.40 g, 4.0 mmol) in THF (50
mL) was treated with Pd(PPh3)4 (0.23 g, 0.2 mmol), followed by
the addition of a solution of NaN3 (0.26 g, 4.0 mmol) in 5 mL of
H2O, and stirred overnight at room temperature. The reaction
mixture was then treated with Ph3P (1.15 g, 4.4 mmol) and
stirred at 50 °C for 2 h. The mixture was then extracted with
2 N HCl (3 × 20 mL), and the combined aqueous layers were
made strongly basic with NaOH and extracted further with
benzene (3 × 20 mL). The combined organic layers were washed
with brine (3 × 20 mL), dried (Na2SO4), and evaporated under
reduced pressure. The residue was then purified via column
chromatography eluting with EtOAc/MeOH (9:1) to give 0.14 g
(11.4%) of 7 as a yellow solid; mp 152-154 °C; 1H NMR (CDCl3)
δ 2.22 (dt, 1H), 3.17 (dt, 1H), 5.38 (m, 1H), 5.54 (m, 1H), 5.85
(dd, 1H), 5.93 (br, 2H), 6.23 (dd, 1H), 7.46 (m, 3H), 7.88 (m, 2H),
7.99 (s, 1H), 8.27 (s, 1H), 9.50 (br, 1H); 13C NMR (CDCl3) δ 36.8,
53.8, 61.3, 121.3, 127.3, 128.3, 128.7, 130.1, 130.7, 131.6, 135.2,
137.9, 141.1, 149.2, 152.5, 155.9, 166.8. Anal. Calcd for
C17H16N6O‚1.5 MeOH: C, 60.32; H, 5.97; N, 22.83. Found: C,
60.27; H, 5.61; N, 23.06.
a
Reaction conditions: a, NaN3, Pd2(dba)3 (CHCl3), 1,3-bis-
(diphenyl)phosphinopropane, 50 °C; b, NH4OH/MeOH, 110 °C, 3
h; c, OsO4, 60% aq 4-methylmorpholine N-oxide in THF/H2O; d,
Pd/C, MeOH, H2, 15 psi, 2 days.
constants were determined.9 These new latter coupling
constants closely matched the observed constants. Using
these latter constants, new dihedral angles were deter-
mined9 and utilized for a revised computer model of 4.8
This gave a heat of formation of -29.5 kcal/mol, which
is acceptably close to the -32.0 kcal/mol of the theoretical
model.
Computer modeling of the epimer of 4 provided theo-
retical coupling constants that were different from those
observed for 4. In addition, the calculated heat of
formation for the epimer, -11.0 kcal/mol, was less
favorable than that of 4. Thus, from this analysis, it is
concluded that the 4′-amino compound is correctly de-
picted as 4.
To ensure that the 2′,3′-diol function of 4 was in the
desired configuration (rather than the “up” orientation),
the 13C NMR spectrum of 4 was found to be in agreement
with that of 12.10
Resu lts
Compounds 4 and 11 were evaluated for their ef-
fectiveness toward HBV, influenza A, influenza B, ad-
enovirus, respiratory syncytial virus, measles, varicella
zoster virus, cytomegalovirus, vesicular stomatitis, sind-
bis virus, punta toro virus, coxsackie B4 virus, reovirus,
HSV, HIV, and vaccinia virus. Neither of these agents
proved as effective as the control drugs.
The azide derivative 11 is also foreseen as a potential
photoaffinity label for determining the mechanism by
which 2 is active toward cytomegalovirus.2a It is also
worth noting that the moderate activity of 4 toward
vesicular stomatitis virus (0.13 µg/mL) and vaccinia virus
(0.64 µg/mL) suggests11 that it may be acting via inhibi-
tion of S-adenosylhomocysteine hydrolase. More detailed
biological studies will be forthcoming.
(1R,4S)-N-[9-(4-Azid o-2-cyclop en t en yl)-9H -p u r in -6-yl]-
ben za m id e (9). A solution of 6 (2.18 g, 6.0 mmol) in THF (15
mL) was treated with Pd2(dba)3(CHCl3)4 (0.16 g, 2.5 mol %) and
1,3-bis(diphenyl)phosphinopropane (0.25 g, 10 mol %) dissolved
in THF (5 mL). To that solution was added NaN3 (0.72 g, 7.2
mmol) in 15 mL of water, and the reaction mixture was stirred
at 50 °C under N2 for 10 h. The THF was evaporated under
reduced pressure, and the aqueous layer was extracted with CH2-
Cl2 (4 × 20 mL). The organic layers were then combined, washed
with brine (50 mL), dried (Na2SO4), and evaporated to dryness.
The residue was further purified by column chromatography,
eluting with EtOAc/MeOH (9:1) to afford 1.5 g of 9 (75%) as a
1
(9) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C. Tetrahedron
1980, 36, 2783.
(10) Ghosh, A.; Ritter, A. R.; Miller, M. J . J . Org. Chem. 1995, 60,
5808.
(11) Siddiqi, S. M.; Chen, X.; Schneller, S. W.; Ikeda, S.; Snoeck,
R.; Andrei, G.; Balzarini, J .; De Clercq, E. J . Med. Chem. 1994, 37,
1382.
yellow foam: mp >50 °C dec; H NMR (CDCl3) δ 1.95 (dt, 1H),
3.13 (dt, 1H), 4.64 (m, 1H), 5.80 (m, 1H), 6.20 (dd, 1H), 6.35 (dd,
1H), 7.55 (m, 3H), 8.02 (m, 2H), 8.05 (s, 1H), 8.08 (s, 1H), 8.80
(br, 1H); 13C NMR (CDCl3) δ 38.7, 57.6, 65.2, 123.2, 128.1, 128.4,
128.9, 132.8, 133.0, 133.9, 135.1, 135.8, 141.2, 149.8, 151.8, 152.6,
165.0; IR (Nujol) 2093 cm-1 (azide). Anal. Calcd for C17H14N8O‚