5166 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 23
Meier et al.
2H, H4-aryl); 6.86 (d, 1H, H7); 6.82 (d, 1H, H7); 6.15 (dd, 1H,
H1′); 6.13 (dd, 1H, H1′); 5.52-5-38 (m, 4H, H-benzyl); 4.40-
4.25 (m, 4H, H5′); 4.23-4.20 (m, 2H, H4′); 3.93-3.91 (m, 2H,
H3′); 2.20-2.11 (m, 4H, H2′); 13C NMR (101 MHz, CDCl3) δ
156.21 (C4); 156.19 (C5-aryl); 149.21 (C2); 143.20 (d, C2-aryl);
143.19 (d, C2-aryl); 137.29 (C4-aryl); 137.18 (C4-aryl); 128.31
(C7); 128.24 (C7); 121.20 (d, C1-aryl); 121.19 (d, C1-aryl);
119.20 (d, C3-aryl); 119.10 (d, C3-aryl); 111.31 (C8); 111.26
(C8); 110.33 (C5-aryl); 110.31 (C5-aryl); 109.40 (C5); 109.33
(C5); 85.30 (C1′), 85.20 (C1′); 84.75 (d, C4′); 84.52 (d, C4′); 69.72
(C3′); 69.35 (C3′), 68.74 (d, C5′); 68.64 (d, C5′); 67.37 (d,
C-benzyl); 67.03 (d, C-benzyl); 40.31 (C2′); 40.19 (C2′); 31P NMR
(202 MHz, CDCl3) δ -8.79; -8.89; MS (FAB) m/z 535.0; 537.0
(M + H+); UV (H2O/CH3CN) λmax 289.6 nm, 248.0 nm; λmin
268.8 nm, 224.7 nm; Rf value 0.23 (CH2Cl2/MeOH, 9:1);
analytical HPLC tR 13.36 min (98%, gradient II).
6H, H-benzyl, OH); 4.38-4.22 (m, 6H, H5′, H3′); 3.94-3.90
(m, 2H, H4′); 2.20-2.13 (m, 2H, H2′); 2.20 (s, 3H, CH3-C3-
aryl); 2.18 (s, 3H, CH3-C3-aryl); 13C NMR (101 MHz, DMSO-
d6) δ 161.81 (C4); 161.79 (C4); 149.39 (C2); 148.12 (d, C2-aryl);
148.07 (d, C2-aryl); 139.48 (C6); 139.41 (C6); 131.10 (C4-aryl);
131.08 (C4-aryl); 129.94 (C7); 127.07 (C3-aryl); 126.99 (C3-
aryl); 124.15 (C5-aryl); 123.74 (C6-aryl); 123.71 (C6-aryl);
121.14 (d, C1-aryl); 121.09 (d, C1-aryl); 110.37 (C5); 110.34
(C5); 107.19 (C8); 84.87 (C1′); 84.80 (C1′); 84.67; (d, C4′); 84.63
(d, C4′); 69.89 (C3′); 69.83 (C3′); 68.66 (d, C5′); 68.59 (d, C5′);
67.97 (d, C-benzyl); 67.91 (d, C-benzyl); 15.07 (CH3-C3-aryl);
15.04 (CH3-C3-aryl); 31P NMR (162 MHz, DMSO-d6) δ -8.82;
-8.90; MS (FAB) m/z 515.3 (M); UV (CH3CN) λmax 293.39 nm,
250.10 nm, 196.82 nm; λmin 270.08 nm, 226.79 nm; IR (KBr) ν
3423, 2346, 1701, 1560, 1466, 1364, 1286, 1187, 1086, 1023,
955, 869, 526, 478; Rf value 0.51 (CH2Cl2/MeOH, 9:1); analyti-
cal HPLC tR 12.69 min (>97%, gradient II).
cycloSa ligen yl-5′-O-(E)-5-(2-br om ovin yl)-2′-d eoxyu r id i-
n yl)p h osp h a te (cycloSa l-BVDUMP ) 2b: yield 88%; 1H
NMR (500 MHz, CDCl3/MeOD) δ 7.55 (s, 1H, H6); 7.52 (s, 1H,
H6); 7.39 (d, 1H, H8); 7.34 (d, 1H, H8); 7.37-7.33 (m, 2H, H4-
aryl); 7.21-7.14 (m, 4H, H3-aryl, H6-aryl); 7.10 (t, 2H, H5-
aryl); 6.66 (d, 1H, H7); 6.56 (d, 1H, H7); 6.23 (dd, 4H, H1′);
5.47 (dd, 1H, HA-benzyl); 5.46 (dd, 1H, HA-benzyl); 5.39 (dd,
2H, HB-benzyl); 4.49-4.40 (m, 6H, H5′, H4′); 4.09-4.06 (m,
2H, H3′); 2.43 (ddd, 1H, H2′); 2.40 (ddd, 1H, H2′); 2.14 (ddd,
1H, H2′′); 2.09 (ddd, 1H, H2′′); 13C NMR (101 MHz, CDCl3) δ
161.42 (C4); 149.11 (C2); 149.07 (C2); 146.24 (C2-aryl); 146.18
(C2-aryl); 137.42 (C6); 137.27 (C6); 134.19 (C5-aryl); 134.12
(C5-aryl); 132.27 (C4-aryl); 132.22 (C4-aryl); 128.26 (C7);
128.09 (C7); 127.42 (d, C3-aryl); 127.34 (d, C3-aryl); 123.52
(C6-aryl); 123.39 (C6-aryl); 120.35 (d, C2-aryl); 120.07 (d, C2-
aryl); 111.45 (C8); 111.43 (C8); 110.09 (C5); 110.05 (C5); 85.55
(C1′), 85.28 (C1′); 84.98 (d, C4′); 84.65 (d, C4′); 70.54 (C3′);
69.59 (C3′), 69.17 (d, C5′); 68.88 (d, C5′); 66.64 (d, C-benzyl);
66.65 (d, C-benzyl); 40.62 (C2′); 40.34 (C2′); 31P NMR (202
MHz, CDCl3) δ -2.95; MS (FAB) m/z 501.0; 502.9 (M + H+);
UV (H2O/CH3CN) λmax 289.6 nm, 248.0 nm; λmin 268.8 nm,
224.7 nm; IR (KBr) ν 3471, 3453, 3424, 3311, 3195, 3104, 3070,
2958, 2923, 1714, 1594, 1488, 1459, 1411, 1365, 1292, 1247,
1224, 1191, 1157, 1106, 1058, 1020, 946, 844, 759, 435; Rf value
0.28 (CH2Cl2/MeOH, 9:1); analytical HPLC tR 12.19 min (98%,
gradient II)
cyclo(3,5-Dim eth ylsa ligen yl)-5′-O-(E)-5-(2-br om ovin yl)-
2′-deoxyu r idin yl)ph osph ate (3,5-DiMe-cycloSal-BVDUMP )
2e: yield 77%; 1H NMR (500 MHz, CDCl3) δ 9.34 (s, 2H, NH-
BVU); 7.59 (s, 1H, H6); 7.57 (s, 1H, H6); 7.38 (d, 1H, H8); 7.36
(d, 1H, H8); 7.00 (d, 2H, H4-aryl); 6.77 (d, 2H, H6-aryl); 6.61
(d, 1H, H7); 6.55 (d, 1H, H7); 6.26 (dd, 1H, H1′); 6.24 (dd, 1H,
H1′); 5.45-5.26 (m, 6H, H-benzyl, H3′); 4.58-4.36 (m, 4H, H5′);
4.14 (m, 1H, H4′); 4.09 (m, 1H, H4′); 2.28 (s, 6H, CH3-C5-aryl);
2.27 (s, 6H, CH3-C3-aryl); 2.22-2.00 (m, 4H, H2′); 13C NMR
(101 MHz, CDCl3) δ 161.42 (C4); 149.11 (C2); 149.07 (C2);
146.24 (C2-aryl); 146.18 (C2-aryl); 137.42 (C6); 137.27 (C6);
134.19 (C5-aryl); 134.12 (C5-aryl); 132.27 (C4-aryl); 132.22 (C4-
aryl); 128.26 (C7); 128.09 (C7); 127.42 (d, C3-aryl); 127.34 (d,
C3-aryl); 123.52 (C6-aryl); 123.39 (C6-aryl); 120.35 (d, C2-aryl);
120.07 (d, C2-aryl); 111.45 (C8); 111.43 (C8); 110.09 (C5);
110.05 (C5); 85.55 (C1′), 85.28 (C1′); 84.98 (d, C4′); 84.65 (d,
C4′); 70.54 (C3′); 69.59 (C3′), 69.17 (d, C5′); 68.88 (d, C5′); 66.64
(d, C-benzyl); 66.65 (d, C-benzyl); 40.62 (C2′); 40.34 (C2′); 20.61
(CH3-C5-aryl); 15.19 (CH3-C3-aryl); 31P NMR (202 MHz,
CDCl3) δ -5.55; -5.98; MS (FAB) m/z 529.1; 531.5 (M + H+);
UV (H2O/CH3CN) λmax 289.6 nm, 248.0 nm; λmin 268.8 nm,
224.7 nm; IR (KBr) ν 3424, 3195, 3102, 3066, 2950, 2923, 2832,
1704, 1594, 1481, 1463, 1363, 1284, 1199, 1149, 1108, 1085,
1025, 995, 950, 856, 802, 665, 532, 430; Rf value 0.49 (CH2-
Cl2/MeOH, 9:1); analytical HPLC tR 13.65 min (98%, gradient
II)
cyclo(5-Meth oxysa ligen yl)-5′-O-(E)-5-(2-br om ovin yl)-2′-
d eoxyu r id in yl)p h osp h a t e (5-OMe-cycloSa l-BVDUMP )
2c: yield 71%; 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 2H, NH-
BVU); 7.58 (s, 1H, H6); 7.56 (s, 1H, H6); 7.40 (d, 1H, H8); 7.36
(d, 1H, H8); 7.02 (d, 1H, H4-aryl); 7.00 (d, 1H, H4-aryl); 6.85
(m, 2H, H3-aryl); 6.65 (d, 1H, H7); 6.64 (d, 1H, H6-aryl); 6.63
(d, 1H, H6-aryl); 6.54 (d, 1H, H7); 6.25 (m, 2H, H1′); 5.46-
5.24 (m, 4H, H-benzyl); 4.57-4.39 (m, 6H, H3′, H5′); 4.13-
4.09 (m, 2H, H4′); 3.79 (s, 3H, OMe); 3.78 (s, 3H, OMe); 2.53-
2.45 (m, 2H, H2′); 2.23-2.12 (m, 2H, H2′); 13C NMR (101 MHz,
CDCl3) δ 156.21 (C4); 156.19 (C5-aryl); 149.21 (C2); 143.20 (d,
C2-aryl); 143.19 (d, C2-aryl); 137.29 (C4-aryl); 137.18 (C4-aryl);
128.31 (C7); 128.24 (C7); 121.20 (d, C1-aryl); 121.19 (d, C1-
aryl); 119.20 (d, C3-aryl); 119.10 (d, C3-aryl); 111.31 (C8);
111.26 (C8); 110.33 (C5-aryl); 110.31 (C5-aryl); 109.40 (C5);
109.33 (C5); 85.30 (C1′), 85.20 (C1′); 84.75 (d, C4′); 84.52 (d,
C4′); 69.72 (C3′); 69.35 (C3′), 68.74 (d, C5′); 68.64 (d, C5′); 67.37
(d, C-benzyl); 67.03 (d, C-benzyl); 55.56 (OMe); 55.53 (OMe);
40.31 (C2′); 40.19 (C2′); 31P NMR (202 MHz, CDCl3) δ -6.40;
-6.54; MS (FAB) m/z 531.4; 533.4 (M + H+); UV (H2O/CH3-
CN) λmax 289.6 nm, 248.0 nm; λmin 268.8 nm, 224.7 nm; IR
(KBr) ν 3423, 3193, 3102, 3068, 2948, 2836, 1708, 1594, 1496,
1465, 1432, 1363, 1284, 1197, 1159, 1085, 1024, 950, 914, 865,
848, 804, 665, 530, 431; Rf value 0.30 (CH2Cl2/MeOH, 9:1);
analytical HPLC tR 12.32 min (98%, gradient II)
cyclo(3-tBu t ylsa ligen yl)-5′-O-(E)-5-(2-b r om ovin yl)-2′-
d eoxyu r id in yl)p h osp h a te (3-tBu -cycloSa l-BVDUMP ) 2f:
yield 62%; 1H NMR (500 MHz, CDCl3) δ 9.63 (s, 1H, NH-BVU);
9.59 (s, 1H, NH-BVU); 7.63 (s, 1H, H6); 7.59 (s, 1H, H6); 7.41
(d, 1H, H8); 7.36 (d, 1H, H8); 7.36 (d, 2H, H4-aryl); 7.12 (dd,
1H, H5-aryl); 7.11 (dd, 1H, H5-aryl); 7.06 (d, 1H, H6-aryl); 7.01
(d, 1H, H6-aryl); 6.60 (d, 2H, H7); 6.28 (dd, 1H, H1′); 6.25 (dd,
1H, H1′); 5.47-5.28 (m, 4H, H-benzyl); 4.59-4.52 (m, 4H, H5′);
4.48-4.38 (m, 2H, H4′); 2.54-2.45 (m, 2H, H3′); 2.24-2.09 (m,
4H, H2′); 1.43 (s, 9H, CH3-tBu); 1.40 (s, 9H, CH3-tBu); 13C NMR
(101 MHz, CDCl3) δ 161.61 (C4); 149.25 (C2); 149.16 (C2);
149.10 (C3-aryl); 149.01 (C3-aryl); 139.54 (d, C2-aryl); 139.44
(d, C2-aryl); 137.48 (C6); 137.38 (C6); 128.24 (C7); 128.13 (C7);
128.04 (C4-aryl); 127.99 (C4-aryl); 124.65 (C5-aryl); 124.51 (C5-
aryl); 124.05 (C6-aryl); 123.92 (C6-aryl); 122.24 (d, C1-aryl);
122.16 (d, C1-aryl); 111.58 (C8); 111.43 (C8); 110.14 (C5); 85.42
(C1′), 85.27 (C1′); 84.89 (d, C4′); 84.70 (d, C4′); 70.63 (C3′);
69.52 (C3′), 69.10 (d, C5′); 68.77 (d, C5′); 67.84 (d, C-benzyl);
67.05 (d, C-benzyl); 40.65 (C2′); 40.28 (C2′); 34.80 (C7-aryl);
34.78 (C7-aryl); 29.85 (C8-aryl); 29.80 (C8-aryl); 31P NMR (202
MHz, CDCl3) δ -5.68; -6.08; MS (FAB) m/z 557.4 (M + H+);
UV (H2O/CH3CN) λmax 289.6 nm, 248.0 nm; λmin 268.8 nm,
224.7 nm; IR (KBr) ν 3424, 3262, 3249, 3232, 3216, 3205, 3068,
2996, 2960, 2884, 1708, 1693, 1594, 1463, 1440, 1365, 1284,
1214, 1199, 1180, 1145, 1087, 1018, 997, 944, 802, 784, 742,
665, 530, 428; Rf value 0.49 (CH2Cl2/MeOH, 9:1); analytical
HPLC tR 14.77; 14.96 min (98%, gradient II).
cyclo(3-Meth ylsa ligen yl)-5′-O-(E)-5-(2-br om ovin yl)-2′-
d eoxyu r id in yl)p h osp h a te (3-Me-cycloSa l-BVDUMP ) 2d :
yield 99%; 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 2H, NH-
BVU); 7.76 (s, 1H, H6); 7.75 (s, 1H, H6); 7.29 (d, 1H, H8); 7.28
(d, 1H, H8); 7.23 (dd, 1H, H5-aryl); 7.22 (dd, 1H, H5-aryl);
7.07-7.05 (m, 4H, H4-aryl, H6-aryl); 6.86 (d, 1H, H7); 6.84
(d, 1H, H7); 6.15 (d, 1H, H1′); 6.14 (d, 1H, H1′); 5.48-5.36 (m,
Gen er a l P r oced u r e for th e P r ep a r a tion of th e cy-
cloSa l-BVDUMP s 3a -g a n d 7a -m . To a solution of 3′-
esterified BVDU 5 (0.28 mmol) in 10 mL of CH3CN was added
diisopropylethylamine (0.56 mmol, DIPEA), and the mixture