8208 J . Org. Chem., Vol. 66, No. 24, 2001
Robins et al.
(s, 1H), 8.16 (s, 1H). 13C NMR:30 δ 53.0, 65.3, 79.80, 79.84,
88.4, 118.7, 138.1, 149.1, 152.6, 155.9. MS m/z: 510.0614
(M[79Br] - t-Bu ) 510.0597). Anal. Calcd for C26H30BrN5O3-
Si: C, 54.93; H, 5.32; N, 12.32. Found: C, 54.73; H, 5.12; N,
12.45.
1H NMR: δ 3.35 (m, 1H), 3.54 (m, 1H), 3.70 (m, 1H), 3.72 and
3.78 (dd × 2, J ) 6.0, 15.0 Hz, 2H), 3.92 (dt, J ) 3.2, 6.2 Hz,
1H), 4.57 (dd, J ) 4.1, 5.3 Hz, 1H), 5.27 (“t”, J ≈ 6 Hz, 1H),
5.87 (br s, 1H), 5.96 (d, J ) 3.9 Hz, 1H), 7.32 (m, 8H), 8.12 (s,
1H), 8.35 (s, 1H). 13C NMR:30 δ 51.8, 58.9, 62.3, 73.2, 84.7, 90.5,
9-[2-O-(N-Ben zylca r b a m oyl)-3-b r om o-5-O-(ter t-b u t yl-
d ip h en ylsilyl)-3-d eoxy-â-D-xylofu r a n osyl]a d en in e (4a ).
Benzylisocyanate (220 µL, 234 mg, 1.76 mmol) and Et3N (180
µL, 133 mg, 1.32 mmol) were added to 3a (500 mg, 0.88 mmol)
in THF/MeCN (1:1, 50 mL), and the solution was stirred for
48 h at ambient temperature (further reagent was added if
necessary). EtOH (1 mL) was added, and stirring was contin-
ued for 30 min. Volatiles were evaporated, and the residue
was chromatographed [silica gel; EtOH/CHCl3 (1:19)]. The
product was recrystallized (hexanes/CHCl3) to give 4a (0.55
g, 89%) with mp 178-179 °C. UV max 259 nm (ꢀ 14 700), min
119.7, 140.9, 149.4, 153.4, 156.5. MS m/z: 356.1603 (M+
)
356.1597). Anal. Calcd for: C17H20N6O3: C, 57.29; H, 5.66; N,
23.59. Found: C, 57.01; H, 5.69; N, 23.70.
The 3′-benzylamino compound (90 mg, 0.25 mmol), NH4-
HCO2 (107 mg, 1.7 mmol), and Pd(OH)2-C (17 mg) were
heated at reflux in H2O/MeOH (1:10) for 90 min. The mixture
was filtered, volatiles were evaporated, and the residue was
chromatographed [Dowex 1 × 2 (OH-); H2O and MeOH/H2O
(1:1)]. The product was diffusion crystallized (MeOH/Et2O) to
give 6a (62 mg, 92%) with mp 259-261 °C (lit.10d mp 260-
261 °C dec). UV (H2O) max 259 nm (ꢀ 14 500), min 226 nm (ꢀ
1
1
233 nm (ꢀ 3100). H NMR: δ 1.00 (s, 9H), 3.98 (dd × 2, J )
2100). H NMR: δ 1.66 (br s, 2H), 3.47 (m, 1H), 3.57 (m, 1H),
5.2, 10.8 Hz, 2H), 4.12 and 4.16 (dd × 2, J ) 6.4, 16.0 Hz,
2H), 4.50 (“q”, J ) 4.8 Hz, 1H), 4.88 (dd, J ) 4.2, 5.5 Hz, 1H),
5.86 (“t”, J ) 3.8 Hz, 1H), 6.14 (d, J ) 4.0 Hz, 1H), 7.10-7.30
(m, 18H), 8.10 (s, 1H), 8.16 (s, 1H). 13C NMR:30 δ 44.0, 49.5,
65.5, 80.3, 81.1, 86.1, 118.3, 138.4, 149.5, 153.3, 155.0, 156.1.
MS (FAB) m/z: 704 (M[81Br] + 1), 702 (M[79Br] + 1). Anal.
3.73 (m, 2H), 4.28 (dd, J ) 3.0, 5.3 Hz, 1H), 5.17 (“t”, J ) 4.8
Hz, 1H), 5.77 (br s, 1H), 5.94 (d, J ) 2.7 Hz, 1H), 7.30 (s, 2H),
8.15 (s, 1H), 8.39 (s, 1H). 13C NMR: δ 52.5, 61.2, 75.0, 85.7,
89.4, 119.2, 139.7, 149.0, 152.6, 156.1. MS m/z: 266.1130 (M+
[C10H14N6O3] ) 266.1127).
4-Am in o-7-(3-am in o-3-deoxy-â-D-r ibofu r an osyl)pyr r olo-
[2,3-d]pyr im idin e (3′-Am in o-3′-deoxytu ber cidin ) (6b). R-Ac-
etoxyisobutyryl bromide (2.26 mL, 1.55 g, 7.42 mmol) and H2O/
Me3CN (1:99, 7 mL) were added to a suspension of 1b (1.0 g,
3.76 mmol) in dry Me3CN (70 mL), and the mixture was stirred
for 45 min at ambient temperature and neutralized (NaHCO3/
H2O, 70 mL). The solution was extracted (2 × EtOAc), and
the combined organic phase was washed (brine) and dried (Na2-
SO4). Volatiles were evaporated, and the white solid foam was
dissolved (MeOH) and stirred with Dowex 1 × 2 (OH-) (washed
with MeOH) for 2 h at ambient temperature. The resin was
filtered and washed (MeOH). Volatiles were evaporated to give
4-amino-7-(2,3-anhydro-â-D-ribofuranosyl)pyrrolo[2,3-d]pyrim-
idine (2b; quant, used in the next step) with UV max 269 nm.
1H NMR: δ 3.44 (dd, J ) 5.6, 11.0 Hz, 1H), 3.54 (dd, J ) 6.2,
11.0 Hz, 1H), 4.10 (dd, J ) 5.6, 6.2 Hz, 1H), 4.19 (d, J ) 2.6
Hz, 1H), 4.27 (d, J ) 2.6 Hz, 1H), 5.05 (br s, 1H), 6.29 (s, 1H),
6.60 (d, J ) 3.7 Hz, 1H), 7.07 (s, 2H), 7.35 (d, J ) 3.7 Hz, 1H),
8.08 (s, 1H). 13C NMR: δ 58.2, 59.1, 61.4, 80.7, 82.1, 100.4,
103.0, 122.9, 150.2, 152.3, 157.8. MS m/z: 248 (M+).
Calcd for
C34H37BrN6O4Si: C, 58.20; H, 5.32; N, 11.98.
Found: C, 58.01; H, 5.25; N, 12.08.
9-[3-(Ben zyla m in o)-3-N,2-O-ca r bon yl-3-d eoxy-â-D-r ibo-
fu r a n osyl)a d en in e (5a ). NaH (50% in mineral oil; 20 mg,
0.42 mmol) under N2 in a dried three-neck round-bottom flask
was rinsed with hexane, freshly distilled THF (40 mL) was
added, and the suspension was cooled to -20 °C. A solution of
4a (250 mg, 0.36 mmol) in THF (5 mL) was added, stirring
was continued for 12 h, and the mixture was filtered (with a
layer of Celite). Volatiles were evaporated, and the residue was
used directly in the next step. A sample of this 9-[3-(benzyl-
amino)-5-O-(tert-butyldiphenylsilyl)-3-N,2-O-carbonyl-3-deoxy-
â-D-ribofuranosyl]adenine was purified by preparative TLC
(EtOH/CHCl3, 1:19) to give material with UV max 259, min
1
233 nm. IR (CHCl3 film): 1763 cm-1 (CdO). H NMR: δ 0.84
(s, 9H), 3.51 (dd, J ) 6.1, 11.1 Hz, 1H), 3.60 (dd, J ) 4.8, 10.5
Hz, 1H), 4.35 (“q”, J ) 4.5 Hz, 1H), 4.39 (d, J ) 15.6 Hz, 1H),
4.55 (dd, J ) 3.6, 8.8 Hz, 1H), 4.60 (d, J ) 15.3 Hz, 1H), 5.91
(dd, J ) 3.3, 8.1 Hz, 1H), 6.38 (d, J ) 2.9 Hz, 1H), 7.36 (m,
17H), 8.00 (s, 1H), 8.27 (s, 1H). 13C NMR:30 δ 46.8, 60.6, 63.9,
79.6, 85.4, 89.6, 119.3, 140.9, 149.1, 153.1, 156.2, 156.7. MS
(FAB) m/z: 621 (M + 1).
Treatment of 2b with TBDPSCl (1.04 mL, 1.10 g, 4.00 mmol)
in dry pyridine (20 mL) (as described for 2a ) gave a dark-green
oil that was chromatographed [EtOH/CHCl3 (1:19)] to give
4-amino-7-[2,3-anhydro-5-O-(tert-butyldiphenylsilyl)-â-D-ribo-
furanosyl)pyrrolo[2,3-d]pyrimidine as a white foam (1.64 g,
The crude TBDPS product (∼0.36 mmol) was dissolved in
freshly distilled THF (40 mL), TBAF/THF (1 M, 360 µL, 0.36
mmol) was added, and the solution was stirred for 1 h at
ambient temperature. Volatiles were evaporated, the residue
was partitioned (H2O/CHCl3), and the aqueous layer was
extracted (2 × CHCl3). The combined organic phase was
washed (NaHCO3/H2O; brine) and dried (Na2SO4). Volatiles
were evaporated, and the residue was chromatographed
(MeOH/CHCl3, 1:9) and diffusion-crystallized (MeOH/Et2O) to
give 5a (112 mg, 82% from 4a ) with mp 229-230 °C. UV max
258 nm (ꢀ 14 500), min 225 nm (ꢀ 3300). IR (CHCl3 film): 1752
cm-1 (CdO). 1H NMR (360 MHz): δ 3.40 (“t”, J ) 3.5 Hz, 2H),
4.26 (dd, J ) 3.8, 7.7 Hz, 1H), 4.32 (d, J ) 15.3 Hz, 1H), 4.36
(“d”, J ) 2.8 Hz, 1H), 4.62 (d, J ) 15.5 Hz, 1H), 5.26 (br s,
1H), 5.70 (dd, J ) 3.5, 8.5 Hz, 1H), 6.32 (d, J ) 3.5 Hz, 1H),
7.35 (m, 7H), 8.12 (s, 1H), 8.34 (s, 1H). 13C NMR:30 δ 46.5, 61.1,
61.6, 79.7, 85.6, 89.8, 119.2, 140.4, 149.2, 152.3, 156.3, 156.7.
MS (FAB) m/z: 383 (M + 1). Anal. Calcd for C18H18N6O4: C,
56.54; H, 4.75; N, 21.98. Found: C, 56.20; H, 4.54; N, 21.74.
9-(3-Am in o-3-deoxy-â-D-r ibofu r a n osyl)a den in e (3′-Am i-
n o-3′-d eoxya d en osin e) (6a ). NaOH/H2O (1 M, 5 mL) was
added to 5a (112 mg, 0.31 mmol) in THF (5 mL), and the
solution was stirred for 48 h at ambient temperature. Dowex
50 (H+) resin was added, and the mixture was stirred for 1 h
and filtered. Volatiles were evaporated, and the residue was
dissolved in H2O and chromatographed [Dowex 1 × 2 (OH-);
H2O and MeOH/H2O (1:1)]. The product was recrystallized
(CHCl3/MeOH) to give 9-[3-(benzylamino)-3-deoxy-â-D-ribo-
furanosyl]adenine (96 mg, 92%) with mp 175-176 °C (lit.23
mp 171 °C). UV max 259 nm (ꢀ 15 700), min 229 nm (ꢀ 3900).
1
90%, used in the next step) with UV max 267 nm. H NMR:
δ 0.97 (s, 9H), 3.64 (dd, J ) 6.2, 10.6 Hz, 1H), 3.83 (dd, J )
6.2, 10.6 Hz, 1H), 4.25 (m, 2H), 4.35 (d, J ) 2.4 Hz, 1H), 6.28
(s, 1H), 6.51 (d, J ) 3.6 Hz, 1H), 7.06 (br s, 2H), 7.14 (d, J )
3.6 Hz, 1H), 7.27-7.62 (m, 10H), 8.03 (s, 1H). 13C NMR:30
δ
57.8, 58.6, 63.9, 80.0, 82.5, 100.6, 115.7, 122.1, 150.1, 152.2,
157.8. MS m/z: 486 (M+).
Et3N (0.084 mL, 0.061 g, 0.6 mmol) and Me2BBr (0.49 mL,
0.6 g, 5 mmol) were added to a cold (-78 °C) solution of the
protected epoxide (1.22 g, 2.5 mmol) in dry CH2Cl2 (150 mL).
The solution was stirred for 3 h at -78 °C, overnight at -15
°C, and was then poured into stirred NaHCO3/H2O. The
organic layer was separated, and the aqueous layer was
extracted (CH2Cl2). The combined organic phase was washed
(brine) and dried (Na2SO4). Volatiles were evaporated, and the
pale-green solid was chromatographed [EtOH/CHCl3 (1:9)] and
recrystallized (Me2CO/CH2Cl2) to give 4-amino-7-[3-bromo-5-
O-(tert-butyldiphenylsilyl)-3-deoxy-â-D-xylofuranosyl]pyrrolo-
[2,3-d]pyrimidine (3b) (1.2 g, 84%) with mp ≈ 129 °C. UV max
1
266 nm. H NMR: δ 1.05 (s, 9H), 3.95 (“d”, J ≈ 5.0 Hz, 2H),
4.42 (“q”, J ≈ 5 Hz, 1H), 4.60 (dd, J ≈ 4, 5 Hz, 1H), 4.71 (“q”,
J ≈ 4 Hz, 1H), 6.12 (d, J ≈ 4 Hz, 1H), 6.38 (d, J ≈ 5 Hz, 1H),
7.01 (br s, 2H), 6.60 (d, J ) 3.7 Hz, 1H), 7.24 (d, J ) 3.7 Hz,
1H), 7.35-7.75 (m, 10H), 8.10 (s, 1H). 13C NMR:30 δ 55.0, 65.5,
78.8, 81.5, 88.2, 100.6, 102.8, 121.3, 150.7, 152.3, 157.8. MS
m/z: 510 (M[81Br] - t-Bu + 1).
Treatment of 3b (500 mg, 0.88 mmol) in THF/MeCN (1:1,
100 mL) with Et3N (184 µL, 134 mg, 1.32 mmol) and benzyl-