Conformationally Locked Analogue of Stavudine
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15 3297
ethyl acetate, 8/1) to give 8 (0.551 g, 51%) as a colorless
syrup: [R]22 -36.8° (c 0.73, CHCl3); 1H NMR (CDCl3) δ 8.06-
7.36 (m, 15 H, Ph), 6.18 (d, J ) 5.5 Hz, 1 H, H-2), 6.12 (br d,
J ) 6.5 Hz, 1 H, H-4), 5.44 (br d, J ) 5.9 Hz, 1 H, H-3), 3.83
(AB q, J ) 5.4 Hz, 2 H, OCH2), 1.86-1.81 (m, 1 H, H-1), 1.06
(s, 9 H, t-Bu), 0.86 (distorted t, 1 H, H-6a), 0.80 (dd, J ) 8.2,
4.1 Hz, 1 H, H-6b); FABMS (relative intensity) 469 (MH+, 0.9);
Anal. Calcd for C30H32O3Si: C, 76.88; H, 6.88. Found: C, 76.91;
H, 6.97.
mg, 0.227 mmol). After the solution was stirred at room
temperature for 30 min, the reaction mixture was cooled to -
78 °C, and a solution of m-chloroperbenzoic acid (m-CPBA,
77%, 26.6 mg, ∼0.119 mmol) in CH2Cl2 (1 mL) was added
rapidly. This step was carefully monitored by TLC to avoid
overoxidation of the double bond. After oxidation, saturated
solutions of NaHCO3 (10 mL) and Na2SO3 (10 mL) were added.
After being stirred for 10 min at room temperature, the
aqueous layer was extracted with ethyl acetate (3 × 20 mL)
and the combined organic extracts were washed with saturated
NaHCO3 (10 mL), dried (Na2SO4), filtered, and evaporated in
vacuo. The residue was purified by column chromatography
on silica gel with a step gradient from hexane/EtOAc, 1/1 to
CHCl3/CH3OH, 10/1 to give 12 (18.5 mg, 97%) as an oil: 1H
NMR (CDCl3) δ 8.37 (br s, 1 H, NH), 7.19 (d, J ) 1.1 Hz, 1 H,
H-6), 6.40 (m, 1 H, H-4′), 5.53 (m, 1 H, H-2′), 5.39 (m, 1 H,
H-3′), 4.63 (dd, J ) 11.5, 5.8, Hz, 1 H, OCHH), 3.69 (dd, J )
11.5, 6.6 Hz, 1 H, OCHH), 1.96 (d, J ) 1.1 Hz, 3 H, CH3), 1.74
(dd, J ) 8.3, 4.4 Hz, 1 H, H-1′), 1.49 (s, 18 H, t-Bu), 1.23 (dd,
J ) 8.8, 4.7 Hz, 1 H, H-6′a), 0.59 (dd, J ) 4.7, 4.4 Hz, 1 H,
H-6′b). FABMS (negative-ion) 425 [M2- + H+]-.
(1′S,2′S,5′R)-5-Met h yl-1-{5-[(p h osp h or yloxy)m et h yl]-
b icyclo[3.1.0]h ex-3-en -2-yl}-1,3-d ih yd r op yr im id in e-2,4-
d ion e (13). Compound 12 (18 mg, 0.042 mmol) was dissolved
in a 5% solution of trifluoroacetic acid (TFA) in CH2Cl2 (3 mL).
The solution was stirred at room temperature for 30 min, and
the volatiles were removed in vacuo. The residue was dissolved
in CH2Cl2 (3 mL) and evaporated four times to remove traces
of TFA. The crude product 18 (13.5 mg) was used in the next
step without further purification: 1H NMR: (D2O) δ 7.35 (m,
1 H), 6.52 (m, 1 H), 4.65-4.92 (m, 2 H), 4.53 (dd, J ) 11.3,
6.0, 11.3 Hz, 1 H), 3.84 (dd, J ) 11.3, 6.6 Hz, 1 H), 1.86 (d, J
) 1.1 Hz, 3 H), 1.81-1.89 (m, 1 H), 1.29 (dd, J ) 8.5, 4.7, Hz,
1 H), 0.62 (t, J ) 4.7 Hz, 1 H). FABMS (negative-ion) 313 [M2-
+ H+]-
(1′S,2′S,5′R)-5-Meth yl-1-{5-[(tr ip h osp h or yloxy)m eth yl]-
b icyclo[3.1.0]h ex-3-en -2-yl}-1,3-d ih yd r op yr im id in e-2,4-
d ion e, Tetr a a m on iu m Sa lt (14). A solution of crude 13 (13.5
mg) was dissolved in deionized water (3 mL) and treated with
1 M triethylammonium bicarbonate (0.1 mL). The mixture was
lyophilized to give the triethylammonium salt which was
dissolved in dimethylformamide (DMF, 2 mL) and treated with
1,1-carbonyldiimidazole (17.4 mg, 0.107 mmol) at room tem-
perature. The resulting mixture was stirred for 4 h at the room
temperature, and excess 1,1-carbonyldiimidazole was quenched
by the addition of water (1 mL). After being stirred 30 min,
all volatiles were removed with the aid of a nitrogen stream.
The residue was dried under high vacuum, dissolved in
anhydrous DMF (2 mL) and treated with tri-n-butylamine (200
uL, 0.84 mmol) and tri-n-butylammonium pyrophosphate (35
mg, 0.129 mmol). The reaction mixture was stirred for 4 days
at room temperature. DMF was removed by a nitrogen stream,
and the residue was purified by an ion-exchange column
chromatography using Sephadex-DEAE A-25 resin with a
linear gradient (0.01 to 0.5 M) of ammonium bicarbonate as
the mobile phase to give 14 (14 mg, 61%): HPLC purity
(>98%); 1H NMR: (D2O) δ 7.39 (m, 1 H), 6.60 (m, 1 H), 5.34-
5.46 (m, 2 H), 4.43 (dd, J ) 11.3, 6.0 Hz, 1 H), 4.00 (dd, J )
11.3, 6.6 Hz, 1 H), 1.89 (d, J ) 1.1 Hz, 3 H), 1.85-1.94 (m, 1
H), 1.32 (dd, J ) 8.8, 4.7 Hz, 1 H), 0.60 (dd, J ) 4.7, 4.4 Hz,
1 H). 31P NMR (D2O) δ t (-21.95, -21.79, -21.63), d (-10.93,
-10.77), d (-6.02, -5.87).
(1S,2R,5R)-5-[(2,2-Dim eth yl-1,1-diph en yl-1-silapr opoxy)-
m eth yl]bicyclo[3.1.0]h ex-3-en -2-ol (9). A solution of 8 (0.123
g, 0.263 mmol) in methanol (10 mL) was treated with 0.5 M
NaOMe in methanol (0.58 mL) at 0 °C. The resulting solution
was stirred at room-temperature overnight under nitrogen gas.
After the mixture was concentrated in vacuo, the residue was
purified on silica gel (hexanes/ethyl acetate, 8/1) to give 9
(0.093 g, 97%) as a colorless syrup: [R]22 -10.2° (c 1.07, CHCl3);
1H NMR (CDCl3) δ 7.60-7.28 (m, 10 H, Ph), 5.94 (dd, J ) 5.5,
0.6 Hz, 1 H, H-4), 5.21 (dt, J ) 5.5, 1.6 Hz, 1 H, H-3), 5.14-
5.13 (dm, J ) 6.4 Hz, 1 H, H-2), 3.72 (AB q, J ) 10.9 Hz, 2 H,
OCH2), 1.52-1.47 (m, 1 H, H-1), 1.25 (br s, 1 H, OH), 0.97 (s,
9 H, t-Bu), 0.64 (dd, J ) 8.2, 4.1 Hz, 1 H, H-6a), 0.80 (t, J )
4.1 Hz, 1 H, H-6b); FABMS (relative intensity) 347.1 (MH+
-
H2O, 6.6), 363.1 (MH+ - H2, 6.2); Anal. Calcd for C23H28O2Si:
C, 75.78; H, 7.74. Found: C, 75.65; H, 7.81.
(1′S,2′S,5′R)-1-{5-[(2,2-Dim eth yl-1,1-silapr opoxy)m eth yl]-
bicyclo[3.1.0]h ex-3-en -2-yl}-5-m eth yl-3-(p h en ylca r bon yl)-
1,3-d ih yd r op yr im id in e-2,4-d ion e (10). A solution of tri-
phenylphosphine (0.893 g, 3.41 mmol) in anhydrous THF (10
mL) was treated dropwise with diethylazodicarboxylate (DEAD,
0.52 mL, 3.27 mmol) at 0 °C. After the mixture was stirred 30
min at 0 °C, a THF (30 mL) suspension of 9 (0.48 g, 1.32 mmol)
and N3-benzoylthymine (0.456 g, 1.98 mmol) was added. The
mixture was stirred at 0 °C for 1 h and at room-temperature
overnight. The next day all volatiles were removed in vacuo,
and the residue was purified by silica gel chromatography
(hexanes/ethyl acetate, 6/1) to give 10 (0.340 g, 45%) as a white
1
foam: [R]23 +47.5° (c 0.16, CHCl3); H NMR (CDCl3) δ 7.89-
7.30 (m, 15 H, Ph), 7.11 (br s, 1 H, H-6), 6.38 (d, J ) 5.5 Hz,
1 H, H-4′), 5.41 (br s, 1 H, H-2′), 5.35-5.33 (m, 1 H, H-3′),
4.19 (AB d, J ) 11.3 Hz, 1 H, OCHH), 3.46 (AB d, J ) 11.3
Hz, 1 H, OCHH), 1.63 (m, 1 H, H-1′), 1.60 (d, J ≈ 1 Hz, 3 H,
CH3), 1.04 (s, 9 H, t-Bu), 1.00 (dd, J ) 8.5, 4.5 Hz, 1 H, H-6a′),
0.35 (irregular t, J ) 4.5, 4.3 Hz, 1 H, H-6b′); FABMS (relative
intensity) 577.1 (MH+, 12.8); Anal. Calcd for C35H36N2O4Si: C,
72.89; H, 6.29; N, 4.86. Found: C, 72.90; H, 6.53; N, 4.65.
(1′S,2′S,5′R)-1-[5-(Hyd r oxym eth yl)bicyclo[3.1.0]h ex-3-
en -2-yl]-5-m eth yl-1,3-d ih yd r op yr im id in e-2,4-d ion e (2). A
solution of 10 (0.589 g, 1.02 mmol) in methanol (50 mL) was
treated with concentrated NH4OH (3.6 mL) and stirred at room
temperature for 4 h. After all volatiles were removed in vacuo,
the residue was purified by silica gel chromatography (hex-
anes/ethyl acetate, 2/1) to give 11 (0.45 g, 93%) as a white foam.
This compound was immediately dissolved in anhydrous THF
(20 mL) and treated with a solution of n-tetrabutylammonium
fluoride (TBAF) in THF (1.1 mL, 1 M). The resulting mixture
was stirred at room temperature for 1 h, and after concentrat-
ing in vacuo, the residue was purified by silica gel chroma-
tography (chloroform/methanol, 24/1) to give 2 (0.223 g, 100%)
as a white foam: mp 181-182 °C; [R] +170° (c 0.3, MeOH);
1H NMR (CD3OD) δ 7.28 (dd, J ) 2.5, 1.2 Hz, 1 H, H-6), 6.42
(m, 1 H, H-4′), 5.36 (m, 2 H, H-2′, H-3′), 4.03 (AB d, J ) 12.0
Hz, 1 H, OCHH), 3.30 (AB d, J ) 12.0 Hz, 1 H, OCHH), 1.74
(d, J ) 1.2 Hz, 3 H, CH3), 1.60 (m, 1 H, H-1′), 1.06 (dd, J )
8.5, 4.3 Hz, 1 H, H-6a′), 0.36 (distorted t, 1 H, H-6b′); FABMS
(relative intensity) 235 (MH+, 100); Anal. Calcd for C12H14N2O3‚
0.25H2O: C, 60.37; H, 6.12; N, 11.73. Found: C, 60.70; H, 6.37;
N, 11.35.
Sin gle-Cr ysta l X-r a y Diffr a ction An a lysis of 2. C12H14
-
N2O3 , FW ) 234.25, orthorhombic space group P212121, a )
5.6026(1), b ) 8.0713(1), c ) 24.8961(4) Å. V ) 1171.03(3) Å3,
Z ) 4, Fcalcd ) 1.329 mg mm-3, λ(Cu KR) ) 1.54178 Å, µ )
0.801 mm-1, F (000) ) 496, T ) 293 K. A colorless 0.60 × 0.05
× 0.02 mm crystal was used for data collection with a Bruker
SMART1 6K CCD detector on a Platform goniometer. The
Rigaku rotating Cu anode source was equipped with incident
beam Gobel mirrors. Lattice parameters were determined
using SAINT19 from 3914 reflections within 6.8< 2θ < 133.8°.
The data collection range had a {(sin θ)/λ}max ) 0.60. A set
of 5983 reflections was collected in the ω scan mode. There
(1′S,2′S,5′R)-tert-Butyl{[4-(5-Methyl-2,4-dioxo-1,3-dihydro-
pyrimidinyl)bicyclo[3.1.0]hex-3-en-2-enyl]methyl}phosphate
(12). Neat di-tert-butyl diethylphosphoramidite (33 µL, 0.119
mmol) was added by syringe to a stirred solution of 2 (10.5
mg, 0.0448 mmol) in anhydrous THF (1.5 mL) at room
temperature, followed by the addition of solid tetrazole (15.7