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P. Perlíková et al. / Bioorg. Med. Chem. 19 (2011) 229–242
(m, 2H, H-40); 4.26–4.40 (m, 6H, H-30,50); 4.50, 4.51 (2 ꢀ t, 2 ꢀ 1H,
(dq, 1H, JH,P = 10.0, Jvic = 7.2, CH-Ala); 4.22 (m, 2H, H-40); 4.26–
J2 ,3 = J2 ,1 = 5.3, H-20); 5.03, 5.06, 5.08, 5.09 (4 ꢀ d, 4 ꢀ 1H,
4.40 (m, 6H, H-30,50); 4.50, 4.51 (2 ꢀ t, 2 ꢀ 1H, J2 ,1 = J2 ,3 = 5.3, H-
0
0
0
0
0
0
0
0
Jgem = 12.2, CH2Ph); 6.35, 6.36 (2 ꢀ d, 2 ꢀ 1H, J1 ,2 = 5.3, H-10);
6.71, 6.72 (2 ꢀ dd, 2 ꢀ 1H, J4,3 = 3.4, J4,5 = 1.7, H-4-furyl); 7.06,
7.09 (2 ꢀ d, 2 ꢀ 1H, J5,6 = 3.8, H-5); 7.14–7.23 (m, 6H, H-o,p-Ph);
7.24–7.34 (m, 14H, H-m-Ph, H-o,m,p-Bn); 7.44, 7.45 (2 ꢀ dd,
2 ꢀ 1H, J3,4 = 3.4, J3,5 = 0.8, H-3-furyl); 7.60, 7.64 (2 ꢀ d, 2 ꢀ 1H,
J6,5 = 3.8, H-6); 7.87 (dd, 2H, J5,4 = 1.7, J5,3 = 0.8, H-5-furyl); 8.698
and 8.703 (2 ꢀ s, 2 ꢀ 1H, H-2). 13C NMR (125.7 MHz, CD3OD):
20.23 (d, JC,P = 7.5, CH3-Ala); 20.36 (d, JC,P = 6.6, CH3-Ala); 51.55,
51.64 (d, JC,P = 1.2, CH-Ala); 67.28, 67.75 (d, JC,P = 5.4, CH2-50);
67.86, 67.92 (CH2Ph); 71.65, 71.75 (CH-30); 75.58, 75.62 (CH-20);
83.86, 83.90 (d, JC,P = 8.3, CH-40); 89.09, 89.18 (CH-10); 103.52,
103.54 (CH-5); 113.56, 113.58 (CH-4-furyl); 114.69 (CH-3-furyl);
114.83 (C-4a); 121.36, 121.38 (d, JC,P = 4.8, CH-o-Ph); 126.18,
126.20 (d, JC,P = 1.1, CH-p-Ph); 128.72, 128.76 (CH-6); 129.21,
129.23 (CH-o-Bn); 129.26, 129.29 (CH-p-Bn); 129.52, 129.55 (CH-
m-Bn); 130.80 (CH-m-Ph); 137.14, 137.22 (C-i-Bn); 147.21 (CH-5-
furyl); 148.15, 148.18 (C-4); 151.86, 151.90 (CH-2); 152.12 (d,
JC,P = 6.9, C-i-Ph); 153.68, 153.71, 153.73, 153.75 (C-7a, C-2-furyl);
174.62 (d, JC,P = 5.0, CO-Ala); 174.82 (d, JC,P = 4.0, CO-Ala). 31P NMR
20); 5.03, 5.06, 5.07, 5.09 (4 ꢀ d, 4 ꢀ 1H, Jgem = 12.3, CH2Ph); 6.36,
0
0
6.37 (2 ꢀ d, 2 ꢀ 1H, J1 ,2 = 5.3, H-10); 6.98, 7.00 (2 ꢀ d, 2 ꢀ 1H,
J5,6 = 3.8, H-5); 7.14–7.22 (m, 6H, H-o,p-Ph); 7.24–7.33 (m, 16H,
H-4-thienyl, H-m-Ph, H-o,m,p-Bn); 7.62, 7.66 (2 ꢀ d, 2 ꢀ 1H,
J6,5 = 3.8, H-6); 7.717, 7.722 (2 ꢀ dd, 2 ꢀ 1H, J5,4 = 5.0, J5,3 = 1.1, H-
5-thienyl); 8.026, 8.033 (2 ꢀ dd, 2 ꢀ 1H, J3,4 = 3.9, J3,5 = 1.1, H-3-
thienyl); 8.686 and 8.690 (2 ꢀ s, 2 ꢀ 1H, H-2). 13C NMR
(150.9 MHz, CD3OD): 20.22 (d, JC,P = 7.5, CH3-Ala); 20.35 (d,
JC,P = 6.7, CH3-Ala); 51.53, 51.63 (d, JC,P = 1.2, CH-Ala); 67.24, 67.73
(d, JC,P = 5.3, CH2-50); 67.87, 67.93 (CH2Ph); 71.62, 71.72 (CH-30);
75.60, 75.63 (CH-20); 83.83 (d, JC,P = 8.3, CH-40); 83.87 (d, JC,P = 8.6,
CH-40); 89.14, 89.23 (CH-10); 102.64, 102.65 (CH-5); 115.33 (C-4a);
121.36, 121.38 (d, JC,P = 4.8, CH-o-Ph); 126.19, 126.21 (CH-p-Ph);
128.71, 128.75 (CH-6); 129.21, 129.24 (CH-o-Bn); 129.27, 129.30
(CH-p-Bn); 129.52, 129.56 (CH-m-Bn); 129.65, 129.66 (CH-4-thie-
nyl); 130.68 (CH-3-thienyl); 130.81 (CH-m-Ph); 131.22, 131.24
(CH-5-thienyl); 137.12, 137.20 (C-i-Bn); 143.08, 143.12 (C-2-thie-
nyl); 151.89, 151.92 (CH-2); 152.10 (d, JC,P = 6.9, C-i-Ph); 152.34,
152.35 (C-4); 153.58, 153.61 (C-7a); 174.65 (d, JC,P = 5.0, CO-Ala);
174.85 (d, JC,P = 4.1, CO-Ala). 31P NMR (162.0 MHz, CD3OD): 4.82,
0
0
(162.0 MHz, CD3OD): 4.84, 5.02. IR (ATR):
m = 3233, 2922, 1740,
1600, 1566, 1488, 1455, 1209, 1146, 1009 cmꢁ1; ESI MS m/z
(rel.%): 673 (10) [M+K], 657 (100) [M+Na], 635 (17) [M+H]. HR
MS (ESI) for C31H32O9N4P [M+H]: calcd 635.1901; found 635.1900.
5.01. IR (ATR): m = 3257, 2937, 1739, 1563, 1490, 1453, 1212, 1146,
1023 cmꢁ1; ESI MS m/z (rel.%): 689 (11) [M+K], 673 (100) [M+Na],
651 (18) [M+H]. HR MS (ESI) for C31H32O8N4PS [M+H]: calcd
651.1673; found 651.1671.
4.4.14. b-
D
-Ribofuranosyl-4-(3-furyl)-7H-pyrrolo[2,3-d]pyrim-
-alaninyl)]phosphate (17b)
idine-50-O-[phenyl(benzyloxy-
L
4.4.16. b-D-Ribofuranosyl-4-(3-thienyl)-7H-pyrrolo[2,3-d]
Protected ProTide 14b (85 mg, 0.13 mmol) was used. Column
chromatography (SiO2, 2% of methanol in chloroform). Yield:
55 mg, 69% (mixture of diastereomers 1:1.15). mp: 51–57 °C; 1H
NMR (600.1 MHz, CD3OD): 1.24, 1.29 (2 ꢀ d, 2 ꢀ 3H, Jvic = 7.2,
CH3-Ala); 3.92 (dq, 1H, JH,P = 9.8, Jvic = 7.2, CH-Ala); 3.97 (dq, 1H,
JH,P = 9.1, Jvic = 7.2, CH-Ala); 4.22 (m, 2H, H-40); 4.26–4.40 (m, 6H,
pyrimidine-50-O-[phenyl(benzyloxy-
L-alaninyl)]phosphate
(17d)
Protected ProTide 14d (234 mg, 0.34 mmol) was used. Column
chromatography (SiO2, 2% of methanol in chloroform). Yield:
136 mg, 62% (mixture of diastereomers 1:1). mp: 55–62 °C; 1H
NMR (500.0 MHz, CD3OD): 1.24, 1.29 (2 ꢀ dd, 2 ꢀ 3H, Jvic = 7.2,
JH,P = 1.2, CH3-Ala); 3.92 (dq, 1H, JH,P = 9.3, Jvic = 7.2, CH-Ala); 3.97
(dq, 1H, JH,P = 10.0, Jvic = 7.2, CH-Ala); 4.22 (m, 2H, H-40); 4.26–
H-30,50); 4.50, 4.51 (2 ꢀ dd, 2 ꢀ 1H, J2 ,3 = 5.6, J2 ,1 = 5.1, H-20);
5.03, 5.08 (2 ꢀ d, 2 ꢀ 1H, Jgem = 12.4, CH2Ph); 5.09 (s, 2H, CH2Ph);
0
0
0
0
6.36, 6.37 (2 ꢀ d, 2 ꢀ 1H, J1 ,2 = 5.1, H-10); 6.88, 6.90 (2 ꢀ d,
2 ꢀ 1H, J5,6 = 3.9, H-5); 7.14–7.22 (m, 8H, H-4-furyl, H-o,p-Ph);
7.25–7.34 (m, 14H, H-m-Ph, H-o,m,p-Bn); 7.61, 7.65 (2 ꢀ d,
2 ꢀ 1H, J6,5 = 3.9, H-6); 7.72 (br s, 2H, H-5-furyl); 8.42 (br s, 2H,
H-2-furyl); 8.728 and 8.732 (2 ꢀ s, 2 ꢀ 1H, H-2). 13C NMR
(150.9 MHz, CD3OD): 20.22 (d, JC,P = 7.5, CH3-Ala); 20.35 (d,
JC,P = 6.8, CH3-Ala); 51.54, 51.65 (d, JC,P = 1.3, CH-Ala); 67.29,
67.73 (d, JC,P = 5.3, CH2-50); 67.88, 67.93 (CH2Ph); 71.65, 71.73
(CH-30); 75.58, 75.62 (CH-20); 83.87, 83.92 (d, JC,P = 8.1, CH-40);
89.09, 89.17 (CH-10); 102.54 (CH-5); 110.30, 110.31 (CH-4-furyl);
116.73 (C-4a); 121.37, 121.38 (d, JC,P = 4.8, CH-o-Ph); 125.90,
125.93 (C-3-furyl); 126.20, 126.22 (CH-p-Ph); 128.53, 128.55
(CH-6); 129.23 (CH-o-Bn); 129.28, 129.31 (CH-p-Bn); 129.53,
129.56 (CH-m-Bn); 130.82 (CH-m-Ph); 137.13, 137.20 (C-i-Bn);
145.64, 145.66 (CH-5-furyl); 145.99 (CH-2-furyl); 151.85, 151.88
(CH-2); 152.06, 152.07 (C-4); 152.09 (d, JC,P = 6.7, C-i-Ph); 153.17,
153.19 (C-7a); 174.65 (d, JC,P = 5.0, CO-Ala); 174.84 (d, JC,P = 3.9,
CO-Ala). 31P NMR (162.0 MHz, CD3OD): 4.82, 5.02. IR (ATR):
4.40 (m, 6H, H-30,50); 4.51, 4.52 (2 ꢀ t, 2 ꢀ 1H, J2 ,1 = J2 ,3 = 5.2, H-
0
0
0
0
0
0
20); 5.03, 5.06, 5.07, 5.09 (4 ꢀ d, 4 ꢀ 1H, Jgem = 12.3, CH2Ph); 6.38,
6.39 (2 ꢀ d, 2 ꢀ 1H, J1 ,2 = 5.2, H-10); 6.95, 6.96 (2 ꢀ d, 2 ꢀ 1H,
J5,6 = 3.8, H-5); 7.13–7.22 (m, 6H, H-o,p-Ph); 7.24–7.33 (m, 14H,
H-m-Ph, H-o,m,p-Bn); 7.626, 7.631 (2 ꢀ dd, 2 ꢀ 1H, J5,4 = 5.2,
J5,2 = 2.9, H-5-thienyl); 7.64, 7.68 (2 ꢀ d, 2 ꢀ 1H, J6,5 = 3.8, H-6);
7.84, 7.86 (2 ꢀ dd, 2 ꢀ 1H, J4,5 = 5.2, J4,2 = 1.3, H-4-thienyl); 8.28,
8.29 (2 ꢀ dd, 2 ꢀ 1H, J2,5 = 2.9, J2,4 = 1.3, H-2-thienyl); 8.764 and
8.767 (2 ꢀ s, 2 ꢀ 1H, H-2). 13C NMR (125.7 MHz, CD3OD): 20.22
(d, JC,P = 7.6, CH3-Ala); 20.35 (d, JC,P = 6.8, CH3-Ala); 51.55, 51.66
(d, JC,P = 1.2, CH-Ala); 67.29 (d, JC,P = 5.1, CH2-50); 67.75 (d,
JC,P = 5.5, CH2-50); 67.87, 67.92 (CH2Ph); 71.66, 71.74 (CH-30);
75.61, 75.66 (CH-20); 83.89, 83.94 (d, JC,P = 8.3, CH-40); 89.19,
89.26 (CH-10); 102.92, 102.93 (CH-5); 116.91 (C-4a); 121.37,
121.38 (d, JC,P = 4.8, CH-o-Ph); 126.19 (CH-p-Ph); 127.86, 127.88
(CH-5-thienyl); 128.41, 128.42 (CH-4-thienyl); 128.82 (CH-6);
129.22 (CH-o-Bn); 129.27, 129.30 (CH-p-Bn); 129.47 (CH-2-thie-
nyl); 129.53, 129.56 (CH-m-Bn); 130.81 (CH-m-Ph); 137.14,
137.22 (C-i-Bn); 140.44, 140.47 (C-3-thienyl); 151.71, 151.75
(CH-2); 152.11 (d, JC,P = 6.8, C-i-Ph); 152.55, 152.56, 153.57 (C-
4,7a); 174.63 (d, JC,P = 4.7, CO-Ala); 174.83 (d, JC,P = 3.7, CO-Ala).
0
0
m
= 3297, 2923, 1738, 1590, 1568, 1490, 1456, 1210, 1146,
1023 cmꢁ1; ESI MS m/z (rel.%): 657 (100) [M+Na], 635 (22)
[M+H]. HR MS (ESI) for C31H32O9N4P [M+H]: calcd 635.1901; found
635.1900.
31P NMR (162.0 MHz, CD3OD): 4.82, 5.00. IR (ATR):
m = 3252,
2941, 1740, 1566, 1490, 1455, 1205, 1144, 1023 cmꢁ1; ESI MS m/
z (rel.%): 673 (100) [M+Na], 651 (31) [M+H]. HR MS (ESI) for
4.4.15. b-
D
-Ribofuranosyl-4-(2-thienyl)-7H-pyrrolo[2,3-d]
-alaninyl)]phosphate (17c)
pyrimidine-50-O-[phenyl(benzyloxy-
L
C31H32O8N4PS [M+H]: calcd 651.1673; found 651.1672.
Protected ProTide 14c (203 mg, 0.29 mmol) was used. Column
chromatography (SiO2, 2% of methanol in chloroform). Yield:
113 mg, 59% (mixture of diastereomers 1:1.11). mp: 51–54 °C; 1H
NMR (600.1 MHz, CD3OD): 1.24, 1.29 (2 ꢀ dd, 2 ꢀ 3H, Jvic = 7.2,
JH,P = 1.2, CH3-Ala); 3.91 (dq, 1H, JH,P = 9.3, Jvic = 7.2, CH-Ala); 3.97
4.4.17. b-
D
-Ribofuranosyl-4-phenyl-7H-pyrrolo[2,3-d]pyrim-
idine-50-O-[phenyl(benzyloxy-
L-alaninyl)]phosphate (17e)
Protected ProTide 14e (180 mg, 0.26 mmol) was used. Column
chromatography (SiO2, 2% of methanol in chloroform). Yield: