C−F‚‚‚H−C H-Bonds in Ribonucleic Acids
A R T I C L E S
1
reaction described above as the slower-migrating isomer. The product
was obtained as a white foam in 36% yield (410 mg, 0.61 mmol). TLC
(CH2Cl2/iPrOH, 98:2): Rf ) 0.32; 1H NMR (250 MHz d6-DMSO, ppm)
8.40 (1H, s, H2), 7.69 (2H, m, arom H), 7.40-6.82 (15H, m, arom H),
5.90 (1H, d, J ) 6.1 Hz, H1′), 5.50 (1H, d, J ) 6.5 Hz, OH-2′), 4.52
(1H, q, J ) 5.8 Hz, H2′), 4.35 (1H, m, H3′), 4.07 (1H, m, H4′), 3.72
(6H, s, OCH3), 3.24 (2H, m, H5′), 0.82 (9H, s, SiC(CH3)3), 0.07, 0.02
(SiCH3); 13C NMR (100.6 MHz d6-DMSO, ppm) 158.11, 144.58
(DMTr), 143.99 (C2), 142.52 (arom C), 135.26, 135.17 (DMTr), 132.64
(arom C), 129.69, 127.81, 127.63, 126.74 (DMTr), 122.47, 122.11,
119.64 (arom C), 113.16 (DMTr), 111.85 (arom C), 88.87 (C1′), 85.87
(DMTr), 83.82 (C4′), 72.47 (C2′), 71.92 (C3′), 63.14 (C5′), 55.03
(OCH3), 25.73 (SiC(CH3)3), 17.99 (SiC(CH3)3), -4.50, -5.14 (SiCH3);
ESI-MS: 667.5 ([M + H]+).
mmol). TLC (CH2Cl2/MeOH, 9:1): Rf ) 0.24; H NMR (250 MHz
d6-DMSO, ppm) 7.41-7.22 (5H, m, arom H), 4.93 (1H, d, J ) 6.8
Hz, H1′), 4.86 (1H, d, J ) 4.7 Hz, OH-3′), 4.77 (1H, t, J ) 5.5 Hz,
OH-5′), 4.54 (1H, d, J ) 7.1 Hz, OH-2′), 3.88 (1H, m, H4′), 3.80 (1H,
m, H3′), 3.68 (1H, q, J ) 5.6 Hz, H2′), 3.53 (2H, m, H5′); 13C NMR
(62.9 MHz d6-DMSO, ppm) 141.42, 127.96, 127.23, 126.24 (arom C),
85.06 (C1′), 82.99 (C4′), 77.63 (C2′), 71.44 (C3′), 62.06 (C5′); ESI-
MS: 209.0 ([M + H]-).
5′-O-(4,4′-Dimethoxytrityl)-1′-deoxy-1′-phenyl-â-D-ribofuranose
(20). To a solution of 18 (1.0 g, 4.75 mmol) in anhydrous pyridine (25
mL) and Et3N (1.0 mL, 7.2 mmol) was added DMTrCl (1.93 g, 5.7
mmol), and the mixture was stirred for 4 h under argon at room
temperature. The reaction was quenched by addition of MeOH (3 mL).
The mixture was evaporated, the residue was dissolved in CH2Cl2, and
the solution was extracted with 5% NaHCO3 solution, dried (MgSO4),
evaporated, and coevaporated twice with toluene. The crude product
was purified by FC (CH2Cl2/MeOH, 98:2). The product was obtained
as a yellow foam in 75% yield (1.83 g, 3.57 mmol). TLC (CH2Cl2/
MeOH, 98:2): Rf ) 0.23; 1H NMR (250 MHz d6-DMSO, ppm) 7.47-
6.86 (18H, m, arom H), 5.07 (1H, d, J ) 6.5 Hz, H1′), 4.93 (1H, d, J
) 5.2 Hz, OH-3′), 4.66 (1H, d, J ) 6.3 Hz, OH-2′), 3.99 (1H, m, H4′),
3.88 (1H, q, J ) 4.9 Hz, H3′), 3.74 (1H, m, H2′), 3.73 (6H, s, OCH3),
3.18 (2H, m, H5′); 13C NMR (62.9 MHz d6-DMSO, ppm) 158.08
(DMTr), 149.62 (arom C), 144.98 (DMTr), 141.29, 136.11 (arom C),
135.69, 129.77, 128.06, 127.79 (DMTr), 127.29, 126.66, 125.96, 123.89
(arom C), 113.17, 85.40 (DMTr), 83.56 (C1′), 82.99 (C4′), 77.60 (C2′),
71.41 (C3′), 64.18 (C5′), 55.03 (OCH3); ESI-MS: 511.4 ([M + H]-).
5′-O-(4,4′-Dimethoxytrityl)-2′-O-tert-butyldimethylsilyl-1′-deoxy-
1′-phenyl-â-D-ribofuranose (24). To a solution of 20 (1.09 g, 2.1
mmol) in anhydrous THF/pyridine, 1:1 (20 mL) were added AgNO3
(430 mg, 2.5 mmol) and 1 M tBuMe2SiCl in THF (2.5 mL, 2.5 mmol)
and stirred for 20 h under argon at room temperature. The reaction
was quenched by addition of saturated aqueous NaHCO3 solution. The
suspension was filtered, the filtrate was extracted with CH2Cl2, and
the organic phase was dried (MgSO4) and evaporated. The residue was
coevaporated twice with toluene and purified by FC (CH2Cl2 f CH2Cl2/
iPrOH, 95:5). The product was obtained as a white foam in 29% yield
(390 mg, 0.62 mmol). TLC (CH2Cl2): Rf ) 0.24; 1H NMR (250 MHz
d6-DMSO, ppm) 7.46-6.82 (18H, m, arom H), 4.74 (1H, d, J ) 5.2
Hz, OH-3′), 4.67 (1H, d, J ) 6.4 Hz, H1′), 3.95 (3H, m, H2′, H3′,
H4′), 3.73 (6H, s, OCH3), 3.23 (2H, m, H5′), 0.78 (9H, s, SiC(CH3)3),
-0.12, -0.17 (3H, s, SiCH3); 13C NMR (62.9 MHz d6-DMSO, ppm)
158.06, 145.02 (DMTr), 140.54, 140.21 (arom C), 135.54, 135.47,
129.75 (DMTr), 128.88, 128.17 (arom C), 128.03, 127.76 (DMTr),
127.37, 126.65 (arom C), 126.22, 113.13, 85.43 (DMTr), 83.66 (C1′),
83.13 (C4′), 79.66 (C2′), 71.55 (C3′), 63.88 (C5′), 55.01 (OCH3), 25.63
(SiC(CH3)3), 17.89 (SiC(CH3)3), -4.98, -5.28 (SiCH3); ESI-MS: 625.6
([M + H]-).
1′-Deoxy-5′-O-(4,4′-dimethoxytrityl)-2′-O-(tert-butyldimethylsilyl)-
1′-(benzimidazol-1-yl)-â-D-ribofuranose Cyanoethyl N,N-Diisopro-
pylphosphoramidite (7). To a solution of 23 (150 mg, 0.22 mmol)
in anhydrous MeCN (8 mL) were added collidine ()2,4,6-trimethyl-
pyridine, 285 µL, 2.2 mmol), 1-methyl-1H-imidazole (9 µL, 0.11 mmol)
and 2-cyanoethyl diisopropylphosphoramidochloridite (72 µL, 0.32
mmol), and the mixture was stirred for 15 min at 0 °C and for 45 min
at room temperature under argon. The reaction was quenched by
addition of saturated aqueous NaHCO3 solution, the mixture was
extracted with CH2Cl2, and the organic phase was dried (MgSO4) and
evaporated. The crude product was purified by FC (CH2Cl2/MeOH,
99:1). The product (diastereoisomer mixture) was obtained as a white
foam in 54% yield (105 mg, 0.12 mmol). TLC (hexane/AcOEt, 4:1):
1
Rf ) 0.09; H NMR (400 MHz d6-DMSO, ppm) 8.12, 8.08 (2H, s,
H2), 7.79 (2H, d, J ) 8.0 Hz, arom H), 7.63 (2H, d, J ) 8.1 Hz, arom
H), 7.48-6.80 (30H, m, arom H), 5.92, 5.86 (2H, d, J ) 7.5 Hz, J )
7.0 Hz, H1′), 4.76 (2H, m, H2′), 4.31 (2H, m, H3′), 3.95 (2H, m, H4′),
3.79, 3.78 (12H, s, OCH3), 3.56 (8H, m, H5′, CH2CN), 2.68 (4H, m,
OCH2), 1.20 (12H, m, CH(CH3)2), 0.81, 0.74 (18H, s, SiC(CH3)3),
-0.14, -0.37, -0.40, -0.49 (12H, s, SiCH3); 31P NMR (162 MHz,
CDCl3, ppm) 150.58, 149.99; ESI-MS: 867.7 ([M + H]+).
2′,3′,5′-Tri-O-benzyl-1′-deoxy-1′-phenyl-â-D-ribofuranose (17). A
solution of bromobenzene (0.76 mL, 7.1 mmol) 15 in anhydrous THF
(20 mL) was treated under argon at -78 °C within 10 min with 1.6 M
BuLi in hexane (4.5 mL, 7.2 mmol). After 20 min at -78 °C a solution
of 2,3,5-tri-O-benzyl-D-ribono-1,4-lactone (2.0 g, 4.8 mmol) 14 in THF
(20 mL) was added over 30 min, and the mixture was stirred for an
additional hour and then warmed within 2 h to -30 °C (TLC
control).The reaction was quenched by addition of water, the mixture
was extracted with Et2O, and the organic phase was dried (MgSO4)
and evaporated to afford an oil. The residue was dissolved in CH2Cl2
(20 mL) and treated at -78 °C with BF3‚Et2O (1.2 mL, 9.5 mmol) and
Et3SiH (1.5 mL, 9.5 mmol). The mixture was stirred for 1 h at -78 °C
and then warmed overnight to 10 °C. The reaction was quenched by
addition of saturated aqueous NaHCO3 solution, the mixture was
extracted with CH2Cl2, and the organic phase was dried (MgSO4) and
evaporated. The residue was purified by FC (hexane/AcOEt, 4:1). The
product was obtained as an orange solid in 75% yield (1.71 g, 3.6
5′-O-(4,4′-Dimethoxytrityl)-3′-O-tert-butyldimethylsilyl-1′-deoxy-
1′-phenyl-â-D-ribofuranose (22) was obtained from the reaction
described above as the faster-migrating isomer. The product was
obtained as a white foam in 42% yield (560 mg, 0.89 mmol). TLC
(CH2Cl2): Rf ) 0.27; 1H NMR (250 MHz d6-DMSO, ppm) 7.42-6.82
(18H, m, arom H), 4.89 (1H, d, J ) 7.2 Hz, OH-2′), 4.67 (1H, d, J )
6.4 Hz, H1′), 4.01 (1H, m, H3′), 3.94 (1H, m, H2′), 3.74 (1H, m, H4′),
3.72 (6H, s, OCH3), 3.22 (2H, m, H5′), 0.78 (9H, s, SiC(CH3)3), -0.01,
-0.06 (3H, s, SiCH3); 13C NMR (62.9 MHz d6-DMSO, ppm) 157.78,
145.01 (DMTr), 140.54, 140.22 (arom C), 135.44, 135.48, 129.75
(DMTr), 128.89, 128.04 (arom C), 127.75, 127.64 (DMTr), 127.37,
126.39 (arom C), 126.22, 112.73, 85.43 (DMTr), 83.72 (C1′),
83.38 (C4′), 79.88 (C2′), 71.63 (C3′), 63.84 (C5′), 54.98 (OCH3),
25.73 (SiC(CH3)3), 17.88 (SiC(CH3)3), -5.01, -5.25 (SiCH3); ESI-
MS: 625.5 ([M + H]-).
1
mmol). TLC (hexane/AcOEt, 4:1): Rf ) 0.45; H NMR (250 MHz
d6-DMSO, ppm) 7.40-7.19 (20H, m, arom H), 4.88 (1H, d, J ) 6.5
Hz, H1′), 4.61-4.43 (6H, m, PhCH2), 4.24 (1H, q, J ) 4.0 Hz, H4′),
4.06 (1H, t, J ) 4.4 Hz, H3′), 3.90 (1H, m, H2′), 3.64 (2H, m, H5′);
13C NMR (62.9 MHz d6-DMSO, ppm) 140.60, 138.30, 138.20, 138.07,
128.26, 128.21, 128.15, 127.84, 127.56, 127.50, 127.40, 126.25 (arom
C), 83.42 (C1′), 81.90 (C4′), 81.07 (C2′), 77.28 (C3′), 72.42, 71.07,
70.98 (PhCH2), 70.32 (C5′); ESI-MS: 498.4 ([M + NH3]+).
1′-Deoxy-1′-â-D-phenylribofuranose (18).
A solution of 17
(0.2 g, 0.42 mmol) in anhydrous CH2Cl2 was treated with 1 M BBr3
in CH2Cl2 (1 mL, 1 mmol) at -78 °C and stirred for 1.5 h under argon.
The reaction was quenched by addition of CH2Cl2/MeOH, 1:1 (5 mL)
and evaporated. The residue was purified by FC (CH2Cl2/MeOH, 9:1).
The product was obtained as a white solid in 69% yield (60 mg, 0.29
1′-Deoxy-5′-O-(4,4′-dimethoxytrityl)-2′-O-(tert-butyldimethylsilyl)-
1′-phenyl-â-D-ribofuranose Cyanoethyl N,N-Diisopropylphosphora-
midite (2). To a solution of 24 (200 mg, 0.32 mmol) in anhydrous
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J. AM. CHEM. SOC. VOL. 124, NO. 20, 2002 5671