The Effect of Systematic Structural Modifications
Medicinal Chemistry, 2011, Vol. 7, No. 1 51
reduced pressure, the residue was purified by flash chroma-
tography.
94.1, 107.3, 114.1, 119.2, 119.2, 124.7, 132.6, 132.7, 136.4,
136.5, 145.0, 146.8, 153.6, 153.9, 154.6, 156.5, 165.9.
(R)-3-(3-fluoro-4-morpholinophenyl)-5-((4-(13-hydroxy-
2,5,8,11-tetraoxatridecyl)-1H-1,2,3-triazol-1-yl)methyl)oxa-
zolidin-2-one (12a)
(R)-1-(1-(1-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazoli-
din-5-yl)methyl)-1H-1,2,3-triazol-4-yl)-2,5,8,11-tetraoxatri-
decan-13-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (12c)
Purification by flash chromatography (CH2Cl2 / acetone,
1:1) and then C-18 reverse phase chromatography (MeOH /
H2O, 1:1) gave 12a (110 mg, 54% yield) as white amorphous
substance. MALDI-TOF MS 576.20 m/z [M+Na]+. 1H NMR
(CDCl3, 360 MHz) δ: 3.03 (t, 4 H), 3.57-3.71 (m, 16 H), 3.85
(t, 4 H), 3.91 (q, 1 H), 4.13 (t, 1 H), 4.66 (s, 2 H), 4.75 (t, 2
H), 5.03-5.10 (m, 1 H), 6.89 (t, 1 H), 6.99-7.02 (dd, 1 H),
7.32-7.37 (dd, 1 H), 7.87 (s, 1 H). 13C NMR (CDCl3, 90.55
MHz) δ: 47.5, 50.8, 51.9, 61.5, 64.4, 66.8, 69.7, 70.1, 70.3,
70.4, 72.5, 107.5, 107.8, 114.1, 118.7, 124.3, 132.2, 136.7,
136.7, 145.7, 153.4, 153.9, 156.7.
Purification by flash chromatography (CH2Cl2 / acetone,
1:1 → 4:6 → 3:7 → 1:9) and then C-18 reverse phase chro-
matography (MeOH / H2O, 1:1) gave 12c (100 mg, 41%
yield) as white amorphous solid substance. MALDI-TOF
1
MS 684.23 m/z [M+Na]+. H NMR (CDCl3, 360 MHz) δ:
1.87 (s, 3 H), 3.03 (t, 3 H), 3.61-3.71 (m, 16 H), 3.86 (t, 4
H), 3.89-3.93 (q, 1 H), 4.15 (t, 1 H), 4.66 (s, 2 H), 4.72-4.82
(m, 2 H), 5.04-5.11 (m, 1 H), 6.88 (t, 1 H), 6.99-7.02 (dd, 1
H), 7.20 (s, 1 H) 7.32-7.36 (dd, 1 H), 7.86 (s, 1 H), 9.94 (s, 1
H). 13C NMR (CDCl3, 90.55 MHz) δ: 12.2, 47.4, 48.0, 50.9,
52.1, 64.4, 66.8, 68.9, 69.8, 70.3, 70.4, 70.5, 107.5, 107.8,
109.5, 114.1, 118.7, 118.8, 124.2, 132.2, 132.3, 136.7, 136.8,
141.9, 145.7, 150.9, 153.4, 153.9, 156.7, 164.4.
(R)-tert-butyl 4-(2-fluoro-4-(5-((4-(13-hydroxy-2,5,8,11-tetra-
oxatridecyl)-1H-1,2,3-triazol-1-yl)methyl)-2-oxooxazolidin-
3-yl)phenyl)piperazine-1-carboxylate (12f)
(R)-tert-butyl 4-(2-fluoro-4-(5-((4-(13-(5-methyl-2,4-dioxo-
3,4-dihydro pyrimidin-1(2H)-yl)-2,5,8,11-tetraoxatridecyl)-
1H-1,2,3-triazol-1-yl)methyl)-2-oxooxazolidin-3-
yl)phenyl)piperazine-1-carboxylate (12h)
Purification by flash chromatography (CH2Cl2 / acetone,
1:1 → 4:6 → 3:7) gave 12f (50 mg, 26% yield) as white
amorphous substance. MALDI-TOF MS 675.24 m/z
[M+Na]+. 1H NMR (CDCl3, 360 MHz) δ: 1.48 (s, 9 H), 2.98
(t, 4 H), 3.57-3.71 (m, 20 H), 3.91-3.95 (q, 1 H), 4.12 (t, 1
H), 4.68 (s, 2 H), 4.76 (t, 2 H), 5.06-5.11 (m, 1 H), 6.89 (t, 1
H), 6.99-7.02 (dd, 1 H), 7.33-7.37 (dd, 1 H), 7.89 (s, 1 H).
13C NMR (CDCl3, 90.55 MHz) δ: 28.3, 47.4, 50.4, 52.0,
61.3, 64.2, 69.6, 70.3, 70.4, 79.7, 107.3, 107.6, 114.0, 119.2,
124.3, 132.4, 132.5, 136.5, 136.6, 145.5, 153.4, 153.9, 154.5,
156.6.
Purification by flash chromatography (CH2Cl2 / acetone,
1:1) and then C-18 reverse phase chromatography (MeOH /
H2O, 7:3) gave 12h (115 mg, 41% yield) as white crystals,
m.p. 108-111 °C. MALDI-TOF MS 783.28 m/z [M+Na]+. 1H
NMR (CDCl3, 360 MHz) δ: 1.48 (s, 9 H), 1.87 (s, 3 H), 2.96-
2.99 (t, 4 H), 3.57-3.71 (m, 16 H), 3.86-3.94 (m, 3 H), 4.14
(t, 1 H), 4.66 (s, 2 H), 4.72-4.82 (m, 2 H), 5.04-5.10 (m, 1
H), 6.88 (t, 1 H), 6.98-7.00 (dd, 1 H), 7.19 (d, 1 H), 7.31-
7.36 (dd, 1 H), 7.84 (s, 1 H), 9.76 (s, 1 H). 13C NMR (CDCl3,
90.55 MHz) δ: 12.2, 28.3, 47.4, 48.0, 50.5, 52.0, 64.3, 68.9,
69.7, 70.4, 70.5, 79.8, 107.4, 107.7, 109.5, 114.0, 114.1,
119.2, 124.2, 132.4, 132.5, 136.6, 136.7, 141.9, 145.7, 150.9,
153.3, 153.9, 154.6, 156.7, 164.4.
(R)-5-((4-(13-(4-amino-2-oxopyrimidin-1(2H)-yl)-2,5,8,11-
tetraoxatridecyl)-1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-
4-morpholinophenyl)oxazolidin-2-one (12b)
Purification by flash chromatography (CH2Cl2 / hexane /
MeOH, 7:2:1 → CH2Cl2 / MeOH, 9:1) gave 12b (150 mg,
46% yield) as pale yellow crystals, m.p. 51-54 °C. MALDI-
TOF MS 669.39 m/z [M+Na]+. 1H NMR (CDCl3, 360 MHz)
δ: 3.02 (t, 4 H), 3.57-3.69 (m, 16 H), 3.85 (t, 4 H), 3.90-3.94
(m, 3 H), 4.16 (1 H), 4.63 (s, 2 H), 4.73-4.86 (m, 2 H), 5.07-
5.11 (m, 1 H), 5.79 (d, 1 H), 6.88 (t, 1 H), 6.98 (d, 1 H), 7.33
(d, 1 H), 7.40 (d, 1 H), 7.91 (s, 1 H). 13C NMR (CDCl3,
90.55 MHz) δ: 47.4, 49.3, 50.8, 52.1, 64.1, 66.8, 68.9, 69.6,
70.2, 70.3, 70.4, 70.5, 93.7, 107.4, 107.7, 114.1, 118.6,
124.5, 132.2, 132.3, 136.5, 136.6, 145.2, 146.9, 153.5, 153.8,
156.5, 156.6, 166.1.
(R)-1-(1-(1-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazo-
lidin-5-yl)methyl)-1H-1,2,3-triazol-4-yl)-2,5,8,11-tetraoxatri-
decan-13-yl)-2,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-metha-
noisoindole (12d)
Purification by flash chromatography (hexane / acetone,
95:5 → 9:1 → acetone 100 %) gave 12d (449 mg, 75%
yield) as white amorphous substance. MALDI-TOF MS
1
721.33 m/z [M+Na]+. H NMR (CDCl3, 360 MHz) δ: 1.54
(d, 1 H), 1.70-1.73 (dt, 1 H), 3.04 (t, 4 H), 3.24-3.25 (m, 2
H), 3.35-3.37 (m, 2 H), 3.49-3.69 (m, 16 H), 3.86 (t, 4 H),
3.91-3.95 (q, 1 H), 4.14 (t, 1 H), 4.69 (s, 2 H), 4.72-4.82 (m,
2 H), 5.03-5.10 (m, 1 H), 6.08 (t, 2 H), 6.90 (t, 1 H), 6.99-
7.02 (dd, 1 H), 7.32-7.37 (dd, 1 H), 7.85 (s, 1 H). 13C NMR
(CDCl3, 90.55 MHz) δ: 37.1, 44.6, 45.4, 47.2, 50.6, 51.8,
51.9, 64.1, 66.6, 66.8, 69.4, 69.6, 70.2, 70.2, 107.2, 107.5,
113.8, 118.4, 118.53, 124.1, 132.1, 132.2, 134.1, 136.3,
136.4, 145.4, 153.2, 153.7, 156.4.
(R)-tert-butyl 4-(4-(5-((4-(13-(4-amino-2-oxopyrimidin-1(2H)-
yl)-2,5,8,11-tetraoxatridecyl)-1H-1,2,3-triazol-1-yl)methyl)-
2-oxooxazolidin-3-yl)-2-fluoro phenyl)piperazine-1-carboxy-
late (12g)
Purification by flash chromatography (CH2Cl2 / MeOH,
95:5) gave 12g (176 mg, 52% yield) as pale yellow crystals.
m.p. 127-131 °C. MALDI-TOF MS 768.31 m/z [M+Na]+. 1H
NMR (CDCl3, 360 MHz) δ: 1.48 (s, 9 H), 2.97 (t, 4 H), 3.57-
3.71 (m, 20 H), 3.91-3.95 (m, 3 H), 4.17 (t, 1 H), 4.64 (s, 2
H), 4.74-4.87 (m, 2 H), 5.07-5.13 (m, 1 H), 5.79 (d, 1 H),
6.88 (t, 1 H), 6.97-7.00 (dd, 1 H), 7.31-7.36 (dd, 1 H), 7.44
(d, 1 H), 7.91 (s, 1 H). 13C NMR (CDCl3, 90.55 MHz) δ:
28.3, 47.5, 49.3, 50.5, 52.2, 64.0, 68.8, 69.6, 70.3, 70.7, 79.8,
(R)-tert-butyl 4-(2-fluoro-4-(5-((4-(13-(2,3,3a,4,7,7a-hexa-
hydro-1,3-dioxo-4,7-methano-isoindol -2-yl)-2,5,8,11-tetra-
oxatridecyl)-1H-1,2,3-triazol-1-yl)methyl)-2-oxooxazolidin-
3-yl)phenyl)piperazine-1-carboxylate (12i)
Purification by flash chromatography (hexane / acetone,
1:1 → acetone 100 %) gave 12i (430 mg, 70% yield) as whi-