Total Synthesis of L-2′,3′-Dideoxyisonucleosides
J . Org. Chem., Vol. 63, No. 9, 1998 2979
1H), 2.68 (dd, J ) 11.2, 4.1 Hz, 1H), 3.53-3.68 (m, 3H), 4.14
(m, 1H); 13C NMR (100 MHz, C6D6) δ -5.3, -5.2, 18.5, 26.0,
39.9, 41.2, 47.7, 67.8, 74.8; IR (neat) 3346, 2954, 2857, 1472,
1256, 1111, 1076, 837, 777 cm-1; HRMS (EI) calcd for C11H25O2-
SSi 249.1345, found 249.1354 (M + H); [R]20D ) -62.0° (c 0.40,
CHCl3). Data for compound 14: 1H NMR (400 MHz, CDCl3)
δ 1.79 (m, 2H), 2.48 (dd, J ) 13.1, 7.3 Hz, 2H), 2.70 (dd, J )
13.1, 2.1 Hz, 2H), 4.17 (m, 2H) (OH protons appear at 2.56
ppm together with those of 9b); 13C NMR (100 MHz, CDCl3) δ
35.1, 41.5, 65.5. Under less dilute conditions, up to 10% of
the minor biproduct, (2S,4S)-1,5-diethoxypentane-2,4-diol, was
formed and could be isolated from the major products by
column chromatography (SiO2, 20:1 CHCl3/MeOH) as a color-
less oil.
stirred for 30 min. Addition of 1 mL of silica gel, evaporation
to dryness, and column chromatography (SiO2, 10:1 CHCl3/
MeOH) yielded 13 mg (57 µmol, 99%) of the dideoxyuridine
isonucleoside 4a as a colorless hygroscopic gum: Rf 0.10
(CHCl3/MeOH ) 10/1); 13C NMR (100 MHz, DMSO-d6) δ 31.7,
35.1, 45.7, 57.8, 65.7, 101.4, 142.0, 150.9, 163.1; [R]20D ) -4.4°
(c 0.20, DMSO-d6) [lit.7 [R]23 ) -8.7° (c 0.23, DMSO)].
D
6-Am in o-9-[(3R,5R)-5-[[[(1,1-d im eth yleth yl)d im eth ylsi-
lyl]oxy]m eth yl]tetr a h yd r oth iop h en -3-yl]p u r in e, 17b. To
a solution of the mesylate 16 (70 mg, 214 mmol) in 6 mL of
DMF was added 118 mg (857 µmol) of K2CO3, 113 mg (429
µmol) of 18-crown-6, and 87 mg (643 µmol) of adenine. The
mixture was then warmed to 95 °C and stirred at that
temperature for 18 h. After removal of the solvent under
reduced pressure, the residue was taken up in 5 mL of MeOH,
and 2 mL silica gel were added. Evaporation to dryness and
column chromatography (SiO2, 10:1 CHCl3/MeOH) gave 35 mg
(96 µmol, 45%) of the protected isonucleoside 17b as a colorless
solid: Rf 0.44 (CHCl3/MeOH ) 9/1); 1H NMR (400 MHz, CDCl3)
δ 0.06 (s, 6H), 0.87 (s, 9H), 2.27-2.60 (m, 1H), 2.70 (m, 1H),
3.31 (m, 2H), 3.60-3.73 (m, 3H), 5.14 (m, 1H), 6.03 (s, br, 2H),
7.94 (s, 1H), 8.34 (s, 1H); 13C NMR (100 MHz, CDCl3) δ -5.4,
-5.3, 18.2, 25.8, 34.9, 37.7, 46.4, 57.9, 67.2, 119.8, 138.3, 150.0,
152.9, 155.6; IR (KBr) 3294, 3180, 2953, 2855, 1667, 1607,
1122, 1109, 841, 779 cm-1; HRMS (FAB+ on NBA) calcd for
(3S ,5R )-5-(H yd r oxym e t h yl)t e t r a h yd r ot h iop h e n e -3-
ol, 9a . To a stirred solution of 16 mg (60 µmol) 15 in 5 mL of
THF was added dropwise 120 µL of a solution of TBAF in THF
(1.0 molar) and the resulting solution stirred for 2 h. After
addition of 1 mL of silica gel and evaporation to dryness, the
residue was subjected to column chromatography (SiO2, ethyl
acetate) to yield 7.6 mg of 9a (57 µmol, 95%) as a colorless oil:
Rf 0.23 (ethyl acetate); 1H NMR (400 MHz, C6D6) δ 1.19 (d, J
) 6.0 Hz, 1H), 1.43 (ddd, J ) 13.0, 8.5, 3.9 Hz, 1H), 1.51 (t, J
) 6.0 Hz, 1H), 1.73 (dddd, J ) 13.0, 6.7, 3.2, 1.5 Hz, 1H), 2.42
(ddd, J ) 11.2, 2.6, 1.5 Hz, 1H), 2.56 (dd, J ) 11.2, 4.0 Hz,
1H), 3.23-3.48 (m, 3H), 4.10 (s, 1H); 13C NMR (100 MHz, C6D6)
δ 40.2, 40.6, 48.6, 65.0, 75.1; IR (neat) 3357, 2932, 1643, 1428,
1325, 1196, 1018 cm-1; HRMS (EI) calcd for C5H10O2S 134.0402,
C
16H28N5OSSi 366.1801, found 366.1784 (M + H); [R]20
)
D
-17.1° (c 0.13, CHCl3).
6-Am in o-9-[(3R ,5R )-5-(h yd r oxym e t h yl)t e t r a h yd r o-
th iop h en -3-yl]p u r in e, 4b. A stirred solution of 16 mg (44
µmol) of the protected isonucleoside 17b in THF was treated
with 132 µL (132 µmol) of a 1.0 molar solution of TBAF in
THF at room temperature and stirred for 30 min. Addition
of 1 mL of silica gel, evaporation to dryness, and column
chromatography (SiO2, 9:1 CHCl3/MeOH) yielded 11 mg (44
µmol, quant) of the dideoxyadenosine isonucleoside 4b as a
colorless solid: Rf 0.17 (CHCl3/MeOH ) 9/1); 13C NMR (100
MHz, DMSO-d6) δ 33.2, 36.7, 46.4, 57.5, 65.9, 119.0, 139.4,
149.4, 152.3, 156.0; [R]20 ) -3.9° (c 0.16, MeOH) [lit.7 [R]23
found 134.0399; [R]20 ) -61.5° (c 0.16, CHCl3).
D
(3S ,5R )-5-[[[(1,1-Dim e t h yle t h yl)d im e t h ylsilyl]oxy]-
m eth yl]-3-[(m eth ylsu lfon yl)oxy]tetr ah ydr oth ioph en e, 16.
The alcohol 15 (560 mg, 2.26 mmol) and DMAP (70 mg, 0.57
mmol) were dissolved in 9 mL of CH2Cl2 and cooled to 0 °C.
After addition of 1 mL of triethylamine and 350 µL (4.52 mmol)
of mesyl chloride, the mixture was allowed to warm to room
temperature and stirred for 12 h. Addition of SiO2, removal
of volatile compounds in vacuo, and chromatography on silica
gel (1:4 ethyl acetate/hexanes) afforded 654 mg (2.00 mmol,
89%) of 16 as a colorless oil: Rf 0.19 (ethyl acetate/hexanes )
D
D
) -1.3° (c 1.13, MeOH)].
1
1/4); H NMR (400 MHz, CDCl3) δ 0.06 (s, 6H), 0.89 (s, 9H),
(3S,5R)-5-(Hyd r oxym eth yl)tetr a h yd r ofu r a n -3-ol, 9b. A
vigorously stirred suspension of 100 mg (1.00 mmol) of the S,S-
bis-epoxide 5 in 20 mL of water was treated dropwise with 1
mL of 1 M NaOH at 0 °C. After being warmed to ambient
temperature, the mixture was stirred for additional 36 h,
neutralized with 1 mL of 1 M hydrochloric acid, and after
addition of 2 mL of silica gel, evaporated to dryness. The
residue was subjected to column chromatography (SiO2, 6:1
ethyl acetate/MeOH) to afford 92 mg (0.779 mmol, 78%) of the
diol 9b as a colorless oil along with some unreacted starting
1.95 (ddd, J ) 13.6, 7.8, 4.2 Hz, 1H), 2.44 (ddd, J ) 13.6, 9.2,
5.1 Hz, 1H), 3.05 (s, 3H), 3.10-3.30 (m, br, 2H), 3.68 (m, 3H),
5.43 (m, 1H); 13C NMR (100 MHz, CDCl3) δ -5.4 (2), 18.3, 25.8,
37.0, 38.8, 39.3, 47.0, 66.8, 82.8; IR (neat) 2955, 2857, 1472,
1360, 1258, 1169, 837, 777 cm-1; HRMS (EI) calcd for
C
12H27O4S2Si 327.1120, found 327.1126 (M + H); [R]20
)
D
-60.3° (c 0.87, CHCl3).
1-[(3R,5R)-5-[[[(1,1-d im eth yleth yl)d im eth ylsilyl]oxy]-
m et h yl]t et r a h yd r ot h iop h en -3-yl]p yr im id in e-2,4-d ion e,
17a . To a solution of the mesylate 16 (154 mg, 0.472 mmol)
in 13 mL of DMF were added 260 mg (1.881 mmol) of K2CO3,
250 mg (0.946 mmol) of 18-crown-6, and 159 mg (0.472 mmol)
of uracil. The mixture was then warmed to 105 °C and stirred
at that temperature for 18 h. After removal of the solvent
under reduced pressure, the residue was taken up in 5 mL of
MeOH, and 2 mL of silica gel was added. Evaporation to
dryness and column chromatography (SiO2, 1:2 ethyl acetate/
hexanes) gave after recrystallization from ethanol 59 mg (0.172
mmol, 36%) of the protected isonucleoside 17a as colorless
prisms: mp 149-151 °C (ethanol); Rf 0.20 (ethyl acetate/
hexanes ) 1/1); 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 6H),
0.90 (s, 9H), 1.88 (ddd, J ) 12.4, 10.8, 9.3 Hz, 1H), 2.48 (dt, J
) 12.4, 6.4 Hz, 1H), 2.88 (dd, J ) 10.8, 9.9 Hz, 1H), 3.12 (dd,
J ) 10.8, 6.8 Hz, 1H), 3.58 (ddd, J ) 12.6, 9.1, 6.2 Hz, 1H),
3.71 (m, 2H), 5.18 (m, 1H), 5.76 (dd, J ) 8.1, 2.3 Hz, 1H), 7.38
(d, J ) 8.1 Hz, 1H), 8.49 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ -5.3 (2), 18.3, 25.8, 33.8, 36.5, 46.1, 58.0, 66.9, 102.8, 140.2,
150.5, 162.4; IR (KBr) 3193, 2928, 2859, 1705, 1686, 1464,
1371, 1289, 1102, 841, 777 cm-1; HRMS (FAB+ on NBA) calcd
1
material: Rf 0.37 (ethyl acetate/MeOH ) 3/1); H NMR (400
MHz, CDCl3) δ 1.89 (ddd, J ) 13.4, 9.1, 4.9 Hz, 1H), 1.93 (dddd,
J ) 13.4, 6.6, 2.0, 1.0 Hz, 1H), 2.30 (s, br, 2H), 3.51 (dd, J )
11.9, 5.4 Hz, 1H), 3.75 (dd, J ) 11.9, 3.0 Hz, 1H), 3.78 (dd, J
) 9.8, 2.0 Hz, 1H), 3.94 (dd, J ) 9.8, 4.0 Hz, 1H), 4.30 (m,
1H), 4.52 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 36.7, 64.2,
72.6, 75.6, 78.4; IR (neat) 3359, 2934, 2876, 1658, 1439, 1331,
1233, 1063, 976, 820 cm-1; HRMS (EI) calcd for C5H11O3
119.0708, found 119.0706 (M + H); [R]20 ) -14.7° (c 0.40,
D
CHCl3).
(3S ,5R )-5-[[[(1,1-Dim e t h yle t h yl)d im e t h ylsilyl]oxy]-
m eth yl]tetr a h yd r ofu r a n -3-ol, 18. The diol 9b (85 mg, 0.720
mmol) was dissolved in 10 mL of CH2Cl2 and 1 mL of Et3N,
treated with 163 mg (1.08 mmol) of TBSCl and 22 mg (0.180
mmol) of DMAP, and stirred for 12 h. After the mixture was
diluted with 10 mL of CH2Cl2 and 10 mL of water, the mixture
was extracted twice with 15 mL of CH2Cl2, and the combined
organic phases were washed with brine and dried over MgSO4.
Removal of the solvents and column chromatography on silica
gel (1:3 ethyl acetate/hexanes) yielded 100 mg (0.430 mmol,
60%) of the alcohol 18 as a colorless oil: Rf 0.20 (ethyl acetate/
hexanes ) 1/2); 1H NMR (400 MHz, CDCl3) δ 0.03 (s, 6H), 0.87
(s, 9H), 1.90 (m, 2H), 2.64 (s, br, 1H), 3.58 (dd, J ) 10.9, 4.5
Hz, 1H), 3.65 (dd, J ) 10.9, 4.0 Hz, 1H), 3.75 (d, br, J ) 9.6
Hz, 1H), 3.88 (dd, J ) 9.6, 4.0 Hz, 1H), 4.20 (m, 1H), 4.45 (m,
1H); 13C NMR (100 MHz, CDCl3) δ -5.5, -5.4, 18.3, 25.8, 37.1,
for C15H27N2O3SSi 343.1514, found 343.1512 (M + H); [R]20
) -5.4° (c 0.15, CHCl3).
D
1-[(3R,5R)-5-(H yd r oxym et h yl)t et r a h yd r ot h iop h en -3-
yl]p yr im id in e-2,4-d ion e, 4a . A stirred solution of 20 mg (58
mmol) of 17a in THF was treated with 120 µL (120 µmol) of a
1.0 M solution of TBAF in THF at room temperature and