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J. R. Rao et al. / Bioorg. Med. Chem. 15 (2007) 839–846
25
½aꢂ ꢀ 99:9 (c 0.25, MeOH); UV (H2O) kmax, nm: 273
removed under reduced pressure. The residue was puri-
fied by silica gel column chromatography (hexane–
EtOAc = 4:1) to give 13 (0.986 g, 18% from 7) as a white
D
(14,946, pH 2), 272 (12,040, pH 7), 270 (11,003, pH
1
11); H NMR (DMSO-d6, 500 MHz) d 11.16 (s, 1H,
25
solid. Mp 86 ꢁC; ½aꢂ ꢀ 16:94 (c 0.50, CHCl3); 1H
NH), 6.90 (s, 1H, H-8), 6.24 (s, 2H, NH2), 5.76 (d,
1H, J = 1.5 Hz, H-60), 4.78 (br s, 1H, –NH), 4.34 (d,
1H, J = 5.5 Hz, H-30), 4.05 (t, 2H, J = 16 Hz, H-50a,b),
3.94 (t, 1H, J = 6.0 Hz, H-20), 3.75 (d, 1H, J = 2.5 Hz,
H-10), 3.42 (br s, 3H, 3· OH); 13C NMR (DMSO-d6,
125 MHz) d 155.6, 151.8, 145.4, 144.8, 128.2, 123.8,
115.3, 113.2, 78.5, 73.2, 59.0, 46.0; HRMS-ESI (m/z):
(M+Na)+ calcd for C12H14N4O4, 301.0912; found,
301.0921; Anal. Calcd for C12H14N4O4Æ0.2H2O: C,
51.13; H, 5.15; N, 19.88; found: C, 51.12; H, 5.15; N,
19.84.
D
NMR (CDCl3, 500 MHz) d 7.49–7.46 (m, 6H, Tr-H),
7.32–7.22 (m, 9H, Tr-H), 6.45 (br s, 1H, H-5), 6.0
(s, 1H, H-60), 5.10 (d, 1H, J = 5.5 Hz, H-30), 4.53 (d,
1H, J = 6.5 Hz, H-20), 4.31 (q, 2H, –CH2), 3.90 (d, 1H,
J = 14 Hz, H-50a), 3.81 (s, 1H, H-10), 3.73 (d,
1H, J = 14 Hz, H-50b), 1.41 (s, 3H, –CH3), 1.35 (t, 3H,
J = 7 Hz, –CH3), 1.31 (s, 3H, –CH3); 13C NMR (CDCl3,
125 MHz) d 162.1, 144.0, 142.7, 128.6, 127.8, 127.5,
127.0, 120.2, 113.2, 111.0, 87.05, 85.2, 84.8, 61.4, 47.0,
27.6, 26.0, 14.7; HRMS-ESI (m/z): (M+Na)+ calcd for
C35H36N2O5, 587.2521; found, 587.2438.
3.1.9. (10S,20S,30R)-2-[20,30-(isopropylidenedioxy)-40-(tri-
tyloxymethyl)-40-cyclopenten-10-yl]-2-diethyl-malonate (15).
To a solution of NaH (1.98 g, 82.9 mmol) in THF
(200 mL), diethyl malonate (20.9 mL, 138.17 mmol) in
THF (100 mL) was added under nitrogen atmosphere
at rt. After 1 h, compound 6 (14 g, 27.6 mmol) in THF
(0.8 L) was added to the reaction mixture. The mixture
was stirred at 38 ꢁC for 48 h and then cooled to room
temperature, H2O (100 mL) was added and extracted
with ethyl acetate (2· 300 mL). The combined organic
layers were dried over MgSO4, concentrated, and then
purified on silica gel column chromatography (hexane–
EtOAc = 9:1) to give compound 15 (11.35 g, 72%) as a
3.1.7. (10S,20S,30R)-9-(20,30-(Isopropylidenedioxy)-40-(tri-
tyloxymethyl)-40-cyclopenten-10-yl)-9-deazaguanosine (14).
N-Benzoylisothiocyanate
(0.214 mL,
1.59 mmol)
was added to a solution of 13 (0.6 g, 1.06 mmol) in
CH2Cl2 (20 mL) at 0 ꢁC. The reaction mixture was stir-
red for 1 h at rt and concentrated under vacuum. The
residue was purified by silica gel column chromatogra-
phy (hexane–EtOAc = 4:1) to give a residue (1.55 g).
After being dried under high vacuum, the residue
(1.55 g, 2.12 mmol) was dissolved in CH2Cl2 (15 mL)
and treated consecutively with DBN (1.39 mL,
11.68 mmol) and MeI (0.30 mL, 4.67 mmol). The result-
ing reaction mixture was stirred for 2 h at rt, diluted
with CH2Cl2 (30 mL), washed with water (2· 20 mL),
dried over MgSO4, and concentrated. The residue was
purified by silica gel column chromatography (hexane–
EtOAc = 4:1) to give a residue. The residue was dis-
solved in MeOH (10 mL), saturated with NH3 (g) at
ꢀ78 ꢁC in a steel bomb under anhydrous conditions.
The mixture was then heated for 16 h at 95 ꢁC under
tight sealing. After being cooled to rt, the mixture was
concentrated under vacuum and the residue was purified
by silica gel chromatography (hexane–EtOAc = 1:4) to
25
1
colorless liquid. ½aꢂ ꢀ 11:68 (c 1, CHCl3); H NMR
D
(CDCl3, 500 MHz) d 7.45–7.42 (m, 6H, Tr-H), 7.30–
7.20 (m, 9H, Tr-H), 5.86 (d, J = 1 Hz, 1H, H-60), 5.01
(d, 1H, J = 7.5 Hz, H-30), 4.70 (d, 1H, J = 7 Hz, H-20),
4.20 (m, 4H, –OCH2–), 3.80 (d, 1H, J = 18.5 Hz, H-
50a), 3.62 (d, 1H, J = 18.5 Hz, H-50b), 3.46 (m, 2H, H-
10, –CH–), 1.35 (s, 3H, –CH3), 1.31 (s, 3H, –CH3),
1.29–1.24 (m, 6H, 2· CH3); 13C NMR (CDCl3,
125 MHz) d 168.2, 168.1, 144.4, 143.9, 128.5, 127.9,
127.8, 127.0, 125.8, 110.6, 86.8, 84.5, 82.0, 61.6, 61.5,
61.3, 54.2, 50.9, 27.5, 26.0, 14.1, 14.0; HRMS-ESI (m/
z): (M+Na)+ calcd for C35H38O7, 593.2515; found,
593.2519.
give 14 (380 mg, 64%) as a white solid. Mp 168ꢁC;
25
½aꢂ ꢀ 6:51 (c 0.50, MeOH); 1H NMR (CD3OD,
D
500 MHz) d 7.48–7.44 (m, 6H, Tr-H), 7.31–7.20 (m,
9H, Tr-H), 6.89 (s, 1H, H-8), 5.93 (s, 1H, H-60), 5.20
(d, 1H, J = 7 Hz, H-30), 4.60 (d, 1H, J = 6.5 Hz, H-20),
4.11 (s, 1H, H-10), 3.80 (d, 1H, J = 14 Hz, H-50a), 3.74
(d, 1H, J = 14 Hz, H-50b), 1.34 (s, 3H, –CH3), 1.28 (s,
3H, –CH3); HRMS-ESI (m/z): (M+H)+ calcd for
C34H32N4O4, 561.2503; found, 561.2501; Anal. Calcd
for C34H32N4O4: C, 72.84; H, 5.75; N, 9.99; found: C,
72.77; H, 5.69; N, 9.98.
3.1.10.
(10R,20S,30R)-Ethyl-2-[20,30-(isopropylidenedi-
oxy)-40-(trityloxymethyl)-40-cyclopenten-10-yl]-acetate (16).
To a solution of 15 (7.5 g, 13.4 mmol) in DMSO
(50 mL), LiCl (1.67 g, 39.4 mmol) and H2O (2 drops)
were added. The mixture was heated up to 175 ꢁC for
3 h. After cooling the mixture, H2O (50 mL) was added
and extracted with ethyl acetate (2· 200 mL), washed
with brine, dried over MgSO4, and concentrated under
reduced pressure. The product was purified using silica
gel column chromatography (hexane–EtOAc = 9:1) to
3.1.8. (10S,20S,30R)-9-(20,30-Dihydroxy-40-hydroxymeth-
yl-40-cyclopenten-10-yl)-deazaguanosine (2). A solution
of 14 (220 mg, 0.39 mmol) in 12% methanolic HCl
(10 mL) was stirred at rt for 2 h. The solvent was evap-
orated under reduced pressure and the residue was co-
evaporated with MeOH (3· 30 mL). The product was
dissolved in MeOH (15 mL), neutralized with solid
NaHCO3, stirred for 2 h, filtered, and concentrated to
dryness under reduced pressure. The residue was puri-
fied by combiflash column chromatography (amine
functionalized silica gel) (CH2Cl2–MeOH = 5:1) to give
give 16 (5.69 g, 86%) as a white solid. Mp 119 ꢁC;
25
½aꢂ ꢀ 6:58 (c 1, CHCl3); 1H NMR (CDCl3,
D
500 MHz) d 7.46 (m, 6H, Tr-H), 7.30–7.20 (m, 9H, Tr-
H), 5.86 (s, 1H, H-60), 5.01 (d, 1H, J = 5.5 Hz, H-30),
4.48 (d, 1H, J = 5.5 Hz, H-20), 4.15 (q, 2H, –OCH2–),
3.83 (d, 1H, J = 14.5 Hz, H-50a), 3.65 (d, 1H,
J = 14.5 Hz, H-50b), 3.19 (t, 1H, J = 6 Hz, H-10), 2.40
(dd, 2H, J = 2, 7.5 Hz, –CH2–), 1.36 (s, 3H, –CH3),
1.31 (s, 3H, –CH3), 1.26 (t, 3H, J = 7 Hz, –CH3); 13C
NMR (CDCl3, 125 MHz) d 171.9, 144.0, 142.7, 128.6,
128.2, 127.8, 127.0, 110.6, 86.9, 84.5, 83.7, 61.4, 60.6,
2
(76 mg, 70%) as
a
white solid. Mp 198 ꢁC;