(CH2Cl2–MeOH, 10 : 1). MALDI-TOF m/z [M + H]+ 578.19
(Calcd. 578.21 for C30H32N3O9). 1H NMR (600 MHz, CDCl3):
8.50 (br s, 1H, NH), 8.04–7.96 (m, 1H, H-6), 7.87–7.78 (m, 2H,
Bz), 7.64–7.49 (m, 5H, Bz and Tol), 7.30–7.22 (m, 1H, H-5),
142.7 (C-8), 141.8, 129.2, 129.1, 129.0, 127.0 (br), 125.6, 121.7,
114.4 (C–Me2), 98.4 (C-2ꢀ), 85.1 (C-3ꢀ), 84.5 (C-5ꢀ), 82.0 (C-4ꢀ),
64.9 (C-1ꢀ), 64.2 (C-6ꢀ), 26.0 (CH3, i-Pr), 25.2 (CH3, AcNH),
24.5 (CH3, i-Pr), 21.5 (CH3, Tol), 20.5 (CH3, Ac).
7.10 (d, 2H, J = 8.0 Hz, Tol), 5.51 (d, 1H, J3 –4 = 6.2 Hz, H-3ꢀ),
ꢀ
ꢀ
1-[3ꢀ,4ꢀ-O-Isopropylidene-6ꢀ-O-(4-toluoyl)-b-D-psicofuranosyl]-
uracil (15). (Method A) Nucleoside 14a (1.5 g, 3.16 mmol)
in 16% methanolic ammonia (50 ml) was stirred at ambient
temperature for 6 h (after that time TLC indicated nearly
complete conversion of the starting material). The mixture
was evaporated with silica and chromatographed on silica
(CH2Cl2 with gradient of MeOH: 0–5%) providing the partially
deprotected nucleoside 15 (656 mg, 48%) and diol 16 (437 mg,
44%). Compound 15 is a colorless amorphous solid. Rf = 0.5
(CH2Cl2–MeOH, 10 : 1). MALDI-TOF m/z [M–H]− 431.1
4.93 (dd, 1H, J4 –5 = 1.2 Hz, H-4ꢀ), 4.90–4.87 (m, 2H, H-1ꢀ and
ꢀ
ꢀ
H-5ꢀ), 4.68 (dd, 1H, Jgem = 12.6 Hz, J5 –6 = 2.5 Hz, H-6ꢀ), 4.57
ꢀ
ꢀ
(d, 1H, Jgem = 12.1 Hz, H-1ꢀ), 4.29 (dd, 1H, J5 –6 = 3.1 Hz,
H-6ꢀꢀ), 2.16 (s, 3H, CH3, Tol), 1.96 (s, 3H, CH3, Ac), 1.67, 1.44
(2 × s, 2 × 3H, 2 × CH3, i-Pr). 13C NMR (67.9 MHz, CDCl3):
ꢀ
ꢀꢀ
=
169.9, 165.7, 162.2 (3 × C O), 145.3 (br, C-6), 144.3 (Tol),
133.2 (Bz), 129.25, 129.21, 129.0 (1 × Bz and 2 × Tol), 127.5
(Bz), 126.1 (Tol), 113.8 (C–Me2), 100.4 (C-2ꢀ), 95.8 (br, C-5),
86.4 (C-3ꢀ), 84.0 (C-5ꢀ), 81.7 (C-4ꢀ), 64.7 (C-6ꢀ), 64.4 (C-1ꢀ), 25.9,
24.5 (2 × CH3, i-Pr), 21.5 (CH3, Tol), 20.7 (CH3, Ac).
1
(Calcd. 431.1 for C21H23N2O8). H NMR (600 MHz, CDCl3):
9-[1ꢀ -O-Acetyl-3ꢀ,4ꢀ -O-isopropylidene-6ꢀ -O-(4-toluoyl)-b-D-
psicofuranosyl]-N6-benzoyladenine (14c). A mixture of di-
acetate 13 [prepared from compound 5a (378 mg,
7.90 (br s, 1H, NH), 7.72 (d, 2H, J = 8.0 Hz, Tol), 7.63 (d, 1H,
J5–6 = 8.3 Hz, H-6), 7.22 (d, 2H, Tol), 5.48 (d, 1H, H-5), 5.44 (d,
1H, J3 –4 = 6.2 Hz, H-3ꢀ), 4.90 (dd, 1H, J4 –5 = 1.2 Hz, H-4ꢀ),
ꢀ
ꢀ
ꢀ
ꢀ
mmol)], N6-benzoyladenine (287 mg, 1.2 mmol) and
4.82 (ddd, 1H, J5 -6 = 2.7 Hz, J5 –6 = 3.4 Hz, H-5ꢀ), 4.59 (dd,
1H, Jgem = 12.6 Hz, H-6ꢀ), 4.38 (dd, 1H, H-6ꢀꢀ), 4.16 (m, d after
1ꢀ-OH decoupling, 1H, Jgem = 12.4 Hz, H-1ꢀ), 3.89 (m, d after
1ꢀ-OH decoupling, 1H, H-1ꢀꢀ), 2.41 (s, 3H, CH3, Tol), 2.01 (br s,
1H, OH), 1.61, 1.41 (2 × s, 2 × 3H, 2 × CH3, i-Pr). 13C NMR
1
ꢀ
ꢀ
ꢀ
ꢀꢀ
N,O-bis(trimethylsilyl)acetamide (◦0.59 ml, 2.4 mmol) in dry
CH3CN (10 ml) was stirred at 90 C for 1 h under a nitrogen
atmosphere. After cooling, TMSOTf (0.2 ml, 1.1 mmol) was
added and the mixture was stirred 30 min at 90 ◦C. After
cooling, saturated aqueous NaHCO3 (20 ml) was added and
the mixture was extracted with CH2Cl2 (20 ml, 2 × 10 ml). The
combined organic extracts were dried over MgSO4, evaporated
and chromatographed on silica (petroleum ether–EtOAc, 1 :
1) providing pure b-anomer 14c (234 mg, 39% in 2 steps
from 5a). A 1D differential NOE experiment showed a 2.2%
enhancement of H-8 signal while H-3ꢀ was irradiated. Rf = 0.70
(CH2Cl2–MeOH, 10 : 1). MALDI-TOF m/z [M + H]+ 602.2
=
(67.9 MHz, CDCl3): 165.9 (C O), 164.4 (C-4), 150.4 (C-2),
144.8 (Tol), 141.8 (C-6), 129.5, 129.3, 126.1 (3 × Tol), 113.6
(C–Me2), 101.6 (C-2ꢀ), 100.7 (C-5), 86.0 (C-3ꢀ), 83.6 (C-5ꢀ), 81.9
(C-4ꢀ), 64.5 (C-6ꢀ), 64.2 (C-1ꢀ), 25.8, 24.5 (2 × CH3, i-Pr), 21.8
(CH3, Tol).
1-[3ꢀ,4ꢀ-O-Isopropylidene-1ꢀ-O-methanesulfonyl-6ꢀ-O-(4-toluoyl)-
b-D-psicofuranosyl]uracil (17). Compound 15 (2.16 g, 5 mmol)
was twice co-evaporated with dry pyridine and dissolved in dry
pyridine (30 ml). Methanesulfonyl chloride (0.584 ml, 7.5 mmol)
was added dropwise at 0 ◦C and the mixture was stirred at 0 ◦C
for 2 h. Then saturated aqueous NaHCO3 (20 ml) was added
and the mixture was extracted with CH2Cl2 (40 ml, 2 × 20 ml).
The organic extracts were dried over MgSO4, evaporated and
co-evaporated three times with toluene. Crystallization from
MeOH–diethyl ether provided 16 as a white crystalline solid
(2.31 g, 90%). Purification of the mother liquors by passing
through a short column of silica (CH2Cl2 with gradient of
MeOH: 0–1%) provided additional 130 mg (5%) of product 17.
Total yield is 2.44 g (95%). Mp 156–158 ◦C (dec.). Rf = 0.61
(CH2Cl2–MeOH, 10 : 1). MALDI-TOF m/z [M–H]− 509.1
(Calcd. 509.1 for C22H25N2O10S). 1H NMR (600 MHz, CDCl3):
8.82 (br s, 1H, NH), 7.70 (d, 2H, J = 8.0 Hz, Tol), 7.62 (d,
1H, J5–6 = 8.3 Hz, H-6), 7.22 (d, 2H, Tol), 5.51 (d, 1H, H-5),
1
(Calcd. 602.2 for C31H32N5O8). H NMR (600 MHz, CDCl3):
8.89 (s, 1H, H-2), 8.86 (br s, 1H, NH), 8.15 (s, 1H, H-8),
ꢀ
ꢀ
7.99–6.88 (m, 9H, Tol and Bz), 6.14 (d, 1H, J3 –4 = 6.0 Hz,
H-3ꢀ), 5.05 (d, 1H, J4 –5 = 1.2 Hz, H-4ꢀ), 4.93 (ddd, 1H, J5 –6
=
ꢀ
ꢀ
ꢀ
ꢀ
2.7 Hz, J5 –6 = 3.5 Hz, H-5ꢀ), 4.67 (dd, 1H, Jgem = 12.7 Hz,
H-6ꢀ), 4.63 (ABq, 2H, Jgem = 12.1 Hz, H-1ꢀ and H-1ꢀꢀ), 4.29 (dd,
1H, H-6ꢀꢀ), 2.26 (s, 3H, CH3, Tol), 1.86 (s, 3H, CH3, Ac), 1.70,
1.51 (2 × s, 2 × 3H, 2 × CH3, i-Pr). 13C NMR (150.9 MHz,
ꢀ
ꢀꢀ
=
CDCl3): 169.7, 165.5, 164.0 (3 × C O), 152.8 (C-2), 149.3
(C-4), 144.7 (Tol), 141.7 (C-8), 133.7 (Bz), 132.8 (Bz), 128.94,
128.91, 128.7, 127.7, 125.4, 123.2, 114.4 (C–Me2), 98.9 (C-2ꢀ),
85.2 (C-3ꢀ), 84.6 (C-5ꢀ), 82.3 (C-4ꢀ), 65.5 (C-1ꢀ), 64.6 (C-6ꢀ), 26.1,
24.7 (2 × CH3, i-Pr), 21.6 (CH3, Tol), 20.5 (CH3, Ac).
N2 -Acetyl-9-[1ꢀ -O-acetyl-3ꢀ,4ꢀ -O-isopropylidene-6ꢀ -O-(4-
toluoyl)-b-D-psicofuranosyl]-O6-diphenylcarbamoylguanine (14d).
A mixture of diacetate 13 [prepared from compound 5a (378 mg,
1 mmol)], N2-acetyl-O6-diphenylcarbamoylguanine (410 mg,
1.2 mmol) and N,O-bis(trimethylsilyl)acetamide (0.59 ml,
5.39 (d, 1H, J3 –4 = 5.9 Hz, H-3ꢀ), 4.98 (d, 1H, Jgem = 11.5 Hz,
ꢀ
ꢀ
H-1ꢀ), 4.91 (dd, 1H, J4 –5 = 1.2 Hz, H-4ꢀ), 4.90 (ddd, 1H, J5 –6
=
ꢀ
ꢀ
ꢀ
ꢀ
2.6 Hz, J5 –6 = 3.9 Hz, H-5ꢀ), 4.58 (dd, 1H, Jgem = 12.7 Hz,
ꢀ
ꢀꢀ
◦
2.4 mmol) in dry CH3CN (10 ml) was stirred at 90 C for 1 h
H-6ꢀ), 4.42–4.38 (m, 2H, H-1ꢀꢀ and H-6ꢀꢀ), 2.97 (s, 3H, CH3, Ms),
under a nitrogen atmosphere. After cooling, TMSOTf (0.2 ml,
1.1 mmol) was added and the mixture was stirred for 30 min
at 90 ◦C. After cooling, saturated aqueous NaHCO3 (20 ml)
was added and the mixture was extracted with CH2Cl2 (20 ml,
2 × 10 ml). Combined organic extracts were dried over MgSO4,
evaporated and chromatographed on silica (c-hexane–EtOAc,
1 : 1) providing pure b-anomer 14d (299 mg, 40% in 2 steps
from 5a). A 1D differential NOE experiment showed a 10%
enhancement of the H-8 signal while H-3ꢀ was irradiated. Rf =
0.90 (CH2Cl2–MeOH, 10 : 1). MALDI-TOF m/z [M + H]+
2.39 (s, 3H, CH3, Tol), 1.62, 1.40 (2 × s, 2 × 3H, 2 × CH3, i-Pr).
13
=
C NMR (67.9 MHz, CDCl3): 165.8 (C O), 162.8 (C-4), 150.3
(C-2), 145.0 (Tol), 140.1 (C-6), 129.5, 129.2, 126.0 (3 × Tol),
114.0 (C–Me2), 101.7 (C-5), 98.8 (C-2ꢀ), 86.8 (C-3ꢀ), 84.3 (C-5ꢀ),
81.7 (C-4ꢀ), 69.6 (C-1ꢀ), 64.3 (C-6ꢀ), 37.7 (CH3, Ms), 25.9, 24.3
(2 × CH3, i-Pr), 21.7 (CH3, Tol).
1-[1ꢀ-O-Methanesulfonyl-6ꢀ-O-(4-toluoyl)-b-D-psicofuranosyl]-
uracil (18). The mesylate 17 (2.60 g, 5.09 mmol) was treated
with 90% (v/v) aqueous trifluoroacetic acid (15 ml) for 40 min
at RT. The volatiles were removed in vacuo and the residue
was dissolved in CH2Cl2 (70 ml) and washed with saturated
aqueous NaHCO3 (20 ml). The aqueous phase was re-extracted
with CH2Cl2 (2 × 15 ml). Combined organic phases were
dried over MgSO4 and evaporated. This material was dried
by co-evaporation with dry toluene (3 times) and used in the
next step without further purification. Colorless foam. Rf = 0.4
(CH2Cl2–MeOH, 10 : 1). MALDI-TOF m/z [M + H]+ 471.1
(Calcd. 471.1 for C19H23N2O10S). 1H NMR (600 MHz, CDCl3):
1
751.24 (Calcd. 751.27 for C39H39N6O10). H NMR (600 MHz,
CDCl3): 8.39 (br s, 1H, NH), 8.17 (s, 1H, H-8), 7.51–7.19 (m,
12H, Tol and DPC), 6.87–6.83 (m, 2H, DPC), 5.85 (d, 1H,
J3 –4 = 5.5 Hz, H-3ꢀ), 5.00 (dd, 1H, J4 –5 = 1.8 Hz, H-4ꢀ), 4.86
ꢀ
ꢀ
ꢀ
ꢀ
(m, 1H, H-5ꢀ), 4.60–4.52 (m, 3H, H-1ꢀ, H-1ꢀꢀ and H-6ꢀ), 4.38 (dd,
1H, Jgem = 12.2 Hz, J5 –6 = 3.1 Hz, H-6ꢀꢀ), 2.58 (s, 3H, CH3,
AcNH), 2.19 (s, 3H, CH3, Tol), 1.87 (s, 3H, CH3, Ac), 1.64, 1.41
(2 × s, 2 × 3H, 2 × CH3, i-Pr). 13C NMR (67.9 MHz, CDCl3):
171.4, 169.8, 165.6, 156.1 (3 × CO), 153.5, 151.9, 150.2, 144.4,
ꢀ
ꢀꢀ
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 6 2 – 4 3 7 2
4 3 6 7