2
2
(1H, d, J 13.4, OCH2), 4.49–4.39 (1H, m, H3¢), 4.26–4.18 (1H,
(1H, d, J 13.6, OCH2), 4.48–4.39 (1H, m, H3¢), 4.22–4.14 (1H,
m, H4¢), 3.54 (1H, dd, 2J 10.7, 3J 3.0, H5¢), 3.38 (1H, dd, 2J 10.7,
m, H4¢), 3.79–3.40 (2H, m, H5¢), 2.68 (1H, s, OH), 2.54–2.33 (2H,
m, H2¢), 1.95 (3H, s, CH3); C NMR: d 168.3 (C N iso), 167.0
(C N iso), 162.7 (C2), 150.6 (C4), 135.4 (2 ¥ CO CH iso), 133.8
(C6), [131.0, 130.4, 130.2, 128.6, 128.4, 127.8, 127.2, 127.0, 126.7,
126.4, 126.2, 125.7, 125.5, 125.2, 125.1] (ArC), 110.4 (C5), 104.8
3J 2.7, H5¢), 2.67–2.56 (1H, m, H2¢), 2.38–2.26 (1H, m, H2¢), 1.56
13
=
13
=
=
=
=
(3H, s, CH3); C NMR: d 168.3 (C N iso), 167.1 (C N iso), 162.7
(C2), 162.6 (2 ¥ CO CH iso), 150.5 (C4), 143.3 (ArC), 134.1 (C6),
[133.8, 131.0, 113.4, 130.2, 128.8, 128.6, 128.5, 128.4, 128.1, 127.9,
=
=
=
127.5, 127.2, 127.0, 126.8, 126.5, 126.4, 126.2, 125.8, 125.6, 125.2,
(CH CO iso), 104.7 (CH CO iso), 87.8 (C1¢), 85.0 (C4¢), 79.9
(C3¢), 67.9 (C5¢), 62.5 (OCH2), 37.3 (C2¢), 36.3 (NCH2), 13.2 (CH3);
HRMS (ESI): m/z C38H33N4O7 requires 658.2375 [M+H]+, found
658.2388 (1.84 ppm).
=
125.1] (ArC), 110.6 (C5), 104.7 (2 ¥ CH CO iso), 87.6 (CPh3), 85.6
(C1¢), 83.9 (C4¢), 80.1 (C3¢), 63.7 (C5¢), 62.3 (OCH2), 38.0 (C2¢), 36.4
(NCH2), 12.6 (CH3); HRMS (ESI): m/z C57H46N4NaO7 requires
921.3259 [M+Na]+, found 921.3282 (2.52 ppm).
3¢-Thymidylic acid, 2-cyanoethyl 4-(2-propynyl-1-yloxy)butyl
ester 20
3-(2-Propynyl)-3¢-O-(2-propynyl)thymidine 12
The crude product was purified by flash column chromatography
over silica gel, eluting with dichloromethane and methanol (0 to
5%), to give the title compound as a off-white foam (94%).
To a round bottom flask containing a solution of alkynyl alcohol
1719 (72 mg, 0.562 mmol) in dry acetonitrile (10 mL) was added,
under argon, BMT (BMT = 5-benzylmercaptotetrazole, 215 mg,
1.119 mmol) followed by dT-CE phosphoramidite 18 (500 mg,
0.671 mmol). The mixture was stirred for 0.5 h at RT after
which analysis by TLC (hexane–EtOAc, 1 : 1) indicated complete
reaction. The mixture was cooled to 0 ◦C in order to add drop
by drop the solution of iodine (0.1 M in THF/pyridine/H2O
78 : 20 : 2/mL). The resulting mixture was stirred for 0.5 h at
1
Rf 0.39 (DCM, MeOH, 95 : 5); H NMR: d 7.43 (1H, s, H6),
3
4
6.14 (1H, t, J 7.5, H1¢), 4.72 (2H, d, J 2.4, NCH2), 4.47–4.40
(1H, m, H3¢), 4.28–4.05 (4H, m, H4, OCH2, OH), 3.97 (1H,
dd, 2J 12.5, 3J 2.7, H5¢), 3.85 (1H, dd, 2J 12.5, 3J 3.0, H5¢),
4
≡
2.49 (1H, t, J 2.4, OCH2C CH), 2.47–2.36 (2H, m, H2¢), 2.17
4
13
≡
(1H, t, J 2.4, NCH2C CH), 1.96 (3H, s, CH3); C NMR: d
162.6 (C2), 150.2 (C4), 135.5 (C6), 110.5 (C5), 88.0 (C1¢), 84.9
0
◦C, and after addition of ethyl acetate (20 mL), washed with
≡
≡
(C4¢), 79.1 (OCH2C CH), 78.4 (C3¢), 78.0 (NCH2C CH), 75.2
a saturated solution of sodium thiosulfate. The organic layer
was dried over anhydrous sodium sulfate and the solvent was
removed under reduced pressure. The crude product (551 mg)
was dissolved in a solution of DCA 3.5% in DCM (10 mL), and
was stirred for 0.5 h at RT. The reaction mixture was washed
with a saturated solution of sodium hydrogen carbonate until
the aqueous layer became neutral. The organic layer was dried
over anhydrous sodium sulfate and the solvent was removed
under reduced pressure. The crude product was purified by flash
column chromatography over silica gel using dichloromethane and
methanol (0 to 10%) as eluant to give the title compound as a
yellow oil (53%).
≡
≡
(OCH2C CH), 70.8 (NCH2C CH), 62.6 (C5¢), 56.9 (OCH2), 38.0
(C2¢), 30.5 (NCH2),13.2 (CH3); HRMS (ESI): m/z C16H18KN2O5
requires 357.0847 [M+K]+, found 357.0853 (1.46 ppm).
3-[(3-Phenylisoxazol-5-yl)methyl]-3¢-O-[(3-phenylisoxazol-5-
yl)methyl]thymidine 15
The crude product was purified by flash column chromatography
over silica gel, eluting with dichloromethane and methanol (98 : 2),
to give the title compound as an off-white solid (80%).
1
Rf 0.35 (DCM, MeOH, 98 : 2); H NMR: d 7.78–7.64 (4H, m,
=
ArH), 7.44–7.28 (7H, m, H6, ArH), 6.52 (1H, s, CH CO iso),
Rf 0.50 (DCM, MeOH, 95 : 5);1H NMR: d 9.71 (1H, br s, NH),
7.55 (1H, s, H6), 6.24 (1H, t, 3J 7.2, H1¢), 5.17 (1H, br s, H3¢), 4.35–
4.10 (7H, m, H4¢, OCH2 iso, 2 ¥ POCH2), 3.88 (1H, br s, H5¢),
3.76 (1H, br s, OH), 3.56 (2H, t, 3J 5.6, OCH2CH2), 2.82 (2H, t, 3J
3
=
6.49 (1H, s, CH CO iso), 6.11 (1H, t, J 7.7, H1¢), 5.22 (2H, s,
NCH2), 4.63 (1H, d, 2J 13.4, OCH2), 4.58 (1H, d, 2J 13.4, OCH2),
4.36–4.28 (1H, m, H3¢), 4.12–4.06 (1H, m, H4¢), 3.88 (1H, dd,
2J 11.6, J 2.4, H5¢), 3.74 (1H, br d, J 11.5, H5¢), 2.52–2.25
3
2
¯
¯
≡
5.6, CH2CN), 2.60–2.35 (3H, m, H2¢, C CH), 1.90 (3H, s, CH3),
13
=
(3H, m, H2¢, OH), 1.88 (3H, s, CH3); C NMR: d 168.0 (C N
1.86–1.63 (4H, m, OCH2CH2CH2CH2O);13C NMR: d 164.1(C2),
=
=
iso), 166.6 (C N iso), 161.6 (C2), 161.5 (2 ¥ CO CH iso), 149.5
(C4), 134.3 (C6), [129.2, 129.0, 128.1, 128.0, 127.9, 127.8, 127.7,
127.6, 127.3, 127.2, 126.5, 126.1, 125.8] (ArC), 109.4 (C5), 100.6
¯
¯
¯
¯
≡
150.6 (C4), 136.5 (C6), 116.7 (C N), 111.3 (C5), 85.8 (C1¢), 85.7
≡
≡
(C4¢), 79.8 (C CH), 78.4 (C3¢), 74.5 (C CH), 69.2 (OCH2CH2),
68.7 (POCH2), 62.3 (POCH2), 61.8 (C5¢), 58.1 (OCH2 iso), 38.5
(C2¢), 27.2 (OCH2CH2CH2CH2O), 25.4 (OCH2CH2CH2CH2O),
=
=
(CH CO iso), 100.4 (CH CO iso), 86.8 (C1¢), 84.0 (C4¢), 78.7
(C3¢), 61.7 (C5¢), 61.4 (OCH2), 36.2 (C2¢), 35.2 (NCH2), 12.2 (CH3);
HRMS (ESI): m/z C30H29N4O7 requires 557.2031 [M+H]+, found
557.2051 (3.71 ppm).
19.7 (CH2C N), 12.5 (CH3); 31P NMR: d -2.6; HRMS (ESI):
≡
m/z C20H28KN3O9P requires 524.1195 [M+K]+, found 524.1196
(0.27 ppm).
3-[3-[(Naphthyl)isoxazol-5-yl]methyl]-3¢-O-[3-[(naphthyl)isoxazol-
5-yl]methyl]thymidine 16
3¢-Thymidylic acid, 2-cyanoethyl 4-[[(3-phenylisoxazole-5-
yl)methyl]oxy]butyl ester 21
The crude product was purified by flash column chromatography
over silica gel, eluting with dichloromethane and acetone (9 : 1),
to give the title compound as an off-white solid (78%).
Rf 0.44 (DCM, MeOH, 95 : 5); H NMR: d 8.40–8.31 (2H, m,
ArH), 7.99–7.83 (4H, m, ArH), 7.73–7.44 (9H, m, H6, ArH), 6.60
The crude product was purified by flash column chromatography
over silica gel, eluting with dichloromethane and methanol (0 to
5%), to give the title compound as a yellow oil (77%).
Rf 0.54 (DCM, MeOH, 95 : 5); 1H NMR: d 9.45 (1H, br s, NH),
1
=
=
(1H, s, CH CO iso), 6.58 (1H, s, CH CO iso), 6.26–6.19 (1H,
m, H1¢), 5.37 (2H, s, NCH2), 4.76 (1H, d, J 13.6, OCH2), 4.70
7.82-7.75 (2H, m, ArH), 7.51 (1H, s, H6), 7.48–7.41 (3H, m, ArH),
2
3
=
6.58 (1H, s, CH CO iso), 6.22 (1H, t, J 7.5, H1¢), 5.19–5.12 (1H,
396 | Org. Biomol. Chem., 2010, 8, 391–397
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The Royal Society of Chemistry 2010
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