Photoactivatable Phospholipid Derivatives
J . Org. Chem., Vol. 61, No. 1, 1996 197
reduced in vacuo. The residue was dissolved in ether (50 mL).
This solution was washed with saturated NaHCO3 solution,
dried over MgSO4, and reduced. The obtained residue was
purified by chromatography on silica gel with ether/hexane
(7:3) and gave 6a (273 mg, 92.3%) as a white crystalline
compound: mp 62-64 °C; TLC (hexane/ether (4:1)) Rf 0.25;
THF (5 mL) was added dropwise at 0 °C. The reaction mixture
was stirred at 0 °C for 2 h and at rt for 12 h before the addition
of H2O (2 mL), and the mixture was stirred again at rt for an
additional 4 h. Then the organic solvent was removed, and
1% HCl (10 mL) was added to acidify the solution to pH ) 1.
After extraction of the product with CHCl3 (15 mL), the extract
was dried over MgSO4 and reduced in vacuo. The obtained
residue was purified by chromatography on Bio-Sil A with
MeOH/CH2Cl2 (1:9) to give 8b (410 mg, 50%) as a white solid:
[R] D +6.50 (c ) 0.080, CHCl3); 1H NMR (CDCl3) δ 0.88 (t, 6H,
25
J ) 6.30 Hz), 1.25 (s, 48H), 1.52-1.68 (m, 4H), 2.23-2.35 (m,
4H), 3.56 (d, 2H, J ) 5.20 Hz), 3.87 (s, 3H), 3.89 (s, 3H), 4.17
(dd, 1H, J ) 6.44, 11.86 Hz), 4.34 (dd, 1H, J ) 3.72, 11.86
Hz), 4.47 (AB system, 2H, νA ) 4.45 ppm, νB ) 4.49 ppm, J AB
) 14.1 Hz), 5.18-5.25 (m, 1H), 6.80-6.88 (m, 3H); 13C NMR
(CDCl3) δ 14.06, 22.63, 24.87, 29.05, 29.26, 29.62, 31.87, 34.04,
34.26, 55.77, 62.63, 67.86, 69.90, 73.15, 110.72, 110.86, 120.22,
130.10, 148.64, 173.05, 173.34; IR (film) 2954, 2916, 2848,
1732, 1514, 1453, 1444, 1420, 1258, 1246, 1142, 1084, 1020
cm-1. Anal. Calcd for C44H78O7: C, 73.49; H, 10.93. Found:
C, 73.44; H, 11.08.
mp 41-43 °C; TLC (MeOH/CH2Cl2 (1:9)) Rf 0.15; [R]25 +2.50
D
(c ) 0.020, CHCl3);1H NMR (CD3OD/CDCl3 (1:1)) δ 0.85 (t, 6H,
J ) 6.30 Hz), 1.24 (s, 48H), 1.41 (s, 9H), 1.52-1.64 (m, 4H),
2.26-2.32 (m, 4H), 3.16 (t, 1H, J ) 5.54 Hz), 3.56 (t, 1H, J )
5.53 Hz), 3.80-4.00 (m, 4H), 4.13 (dd, 1H, J ) 7.09, 12.0 Hz),
4.42 (dd, 1H, J ) 2.32, 12.0 Hz), 5.25-5.55 (m, 1H); 13C NMR
(CD3OD/CDCl3 (1:1)) δ 14.40, 23.25, 25.49, 28.70, 29.75, 29.97,
30.29, 32.53, 34.62, 34.76, 41.58, 43.24, 61.68, 63.30, 64.24,
65.20, 71.03, 71.21, 79.99, 157.58, 174.12, 174.49; IR (film)
3300-3400 (br), 2954, 2917, 2850, 1740, 1516, 1467, 1244,
1170, 1053 cm-1. Anal. Calcd for C42H82NPO10: C, 63.77; H,
10.32; N, 1.77. Found: C, 63.8; H, 10.39; N, 1.92.
Octa d eca n oic Acid 3-((3,4-Dim eth oxylben zyl)oxy)-2-
(octa d eca n oyloxy)p r op yl Ester (6b). Using a similar
procedure to that of 6a , 6b was obtained as a white crystalline
compound: mp 70-72 °C; TLC (hexane/ether (4:1)) Rf 0.25;
Octa d eca n oic Acid 3-[((2-((ter t-Bu toxyca r bon yl)a m i-
n o)e t h oxy)h yd r oxyp h osp h or yl)oxy]-2-(oct a d e ca n oyl-
oxy)p r op yl Ester (8b). Using a similar procedure to that of
8a , 8b was obtained as a white solid: mp 51-53 °C; TLC
[R] D +6.20 (c ) 0.080, CHCl3); 1H NMR (CDCl3) δ 0.88 (t, 6H,
25
J ) 6.14 Hz), 1.25 (s, 56H), 1.52-1.64 (m, 4H), 2.24-2.36 (m,
4H), 5.57 (d, 2H, J ) 5.12 Hz), 3.87 (s, 3H), 3.89 (s, 3H), 4.18
(dd, 1H, J ) 6.38, 11.74 Hz), 4.34 (dd, 1H, J ) 3.48, 11.84
Hz), 4.47 (AB system, 2H, νA ) 4.45 ppm, νB ) 4.49 ppm, J AB
) 14.1 Hz), 5.18-5.25 (m, 1H), 6.78-6.88 (m, 3H); 13C NMR
(CDCl3) δ 14.09, 22.67, 24.90, 28.60, 29.09, 29.32, 31.90, 34.08,
34.30, 55.81, 62.66, 67.90, 69.93, 73.18, 110.75, 110.89, 120.25,
130.14, 148.66, 149.02, 173.07, 173.37; IR (film) 2954, 2917,
(MeOH/CH2Cl2 (1:9)) Rf 0.15; [R]25 +2.80 (c ) 0.022, CHCl3);
D
1H NMR (CD3OD/CDCl3 (1:1)) δ 0.85 (t, 6H, J ) 6.29 Hz), 1.24
(s, 56H), 1.41 (s, 9H), 1.52-1.64 (m, 4H), 2.28-2.36 (m, 4H),
3.22-3.35 (m, 2H), 3.83-3.98 (m, 4H), 4.13 (dd, 1H, J ) 7.00,
12.0 Hz), 4.39 (dd, 1H, J ) 2.62, 12.0 Hz), 5.12-5.27 (m, 1H);
13C NMR (CD3OD/CDCl3 (1:1)) δ 14.42, 23.28, 25.51, 28.72,
29.79, 30.00, 30.33, 32.56, 34.64, 34.77, 41.63, 63.33, 64.22,
65.18, 71.05, 71.21, 79.98, 157.58, 174.11, 174.46; IR (film)
3350, 2917, 2850, 1740, 1708, 1698, 1652, 1558, 1540, 1467,
2850, 1738, 1592, 1516, 1466, 1264, 1159, 1098, 1028 cm-1
.
Anal. Calcd for C48H68O7: C, 74.37; H, 11.18. Found: C,
74.19; H, 11.43.
1367, 1255, 1174, 1098 cm-1. Anal. Calcd for C46H90NPO10
:
Hexa d eca n oic Acid 2-(Hexa d eca n oyloxy)-3-h yd r oxy-
p r op yl Ester (7a ). To a mixture of 6a (3.00 g, 4.17 mmol) in
CH2Cl2 (18 mL) and H2O (1 mL) was added dichlorodicy-
anobenzoquinone (1.01 g, 4.38 mmol). The colored reaction
mixture turned progressively black. After 10 min at rt, the
reaction mixture was filtered through Celite, and the filtrate
was reduced in vacuo. The residue was purified by flash
chromatography on silica gel with ether/hexane (1:3), followed
by recrystallization with ether and hexane to give 7a (2.07 g,
C, 65.21; H, 10.58; N, 1.65. Found: C, 65.06; H, 10.66; N, 1.58.
Hexa d eca n oic Acid 3-[((2-Am in oeth oxy)h yd r oxyp h os-
p h or yloxy)-2-(h exa d eca n oyloxy)p r op yl Ester (9a ).
A
solution of 8a (177 mg, 0.22 mmol) in CH2Cl2 (9 mL) and TFA
(1 mL) was stirred at rt for 45 min. After removal of the
solvent, the residue was purified by chromatography on Bio-
Sil A with MeOH/CH2Cl2 (1:9) to give 9a (167 mg, 93%) as a
white solid: mp 103-107 °C; TLC (MeOH/CH2Cl2 (1:9)) Rf
1
90%) as white crystals: mp 67-69 °C; TLC (hexane/ether (3:
0.12; [R]25 +3.48 (c ) 0.022, CHCl3 + 0.05% TFA); H NMR
D
1
1)) Rf 0.25; [R]25 -2.60 (c ) 0.080, CHCl3); H NMR (CDCl3)
(CD OD/CDCl3 (1:1)) δ 0.84 (t, 6H, J ) 6.28 Hz), 1.23 (s, 48H),
1.483-1.65 (m, 4H), 2.15-2.31 (m, 4H), 3.10 (t, 2H, J ) 4.28
Hz), 3.94-4.23 (m, 5H), 4.36 (dd, 1H, J ) 2.89, 12.0 Hz), 5.12-
5.24 (m, 1H); 13C NMR (CD3OD/CDCl3 (1:1)) δ 14.31, 23.17,
25.40, 29.64, 29.87, 30.20, 32.46, 34.55, 34.67, 39.70, 62.24,
63.10, 64.32, 71.39, 108.40, 114.18, 119.97, 124.75, 162.04,
162.75, 163.46, 164.17, 174.30, 174.60; 31P NMR (CD3OD/
CDCl3 (9:1) + 0.05% TFA) δ 0.23; IR (film) 3300-3000 (br),
D
δ 0.89 (t, 6H, J ) 6.40 Hz), 1.26 (s, 48H), 1.56-1.72 (m, 4H),
2.05 (t, 1H, J ) 6.57 Hz), 2.30-2.39 (m, 4H), 3.74 (dd, 2H, J
) 4.30, 5.59 Hz), 4.24 (dd, 2H, J ) 5.61, 11.93 Hz), 4.33 (dd,
1H, J ) 4.53, 11.89 Hz), 5.07-5.11 (m, 1H); 13C NMR (CDCl3)
δ 14.09, 22.67, 24.90, 29.10, 29.35, 29.67, 31.90, 34.08, 34.26,
61.49, 61.98, 72.05, 173.42, 173.79; IR (film) 3505, 2922, 2852,
1731, 1702, 1464, 1380, 1288, 1215, 1179, 1091, 1065 cm-1
.
Anal. Calcd for C35H68O5: C, 73.89; H, 12.05. Found: C,
74.14; H, 12.13.
2954, 2918, 2850, 1740, 1467, 1205, 1165, 1080, 1025 cm-1
;
FABMS+ (m-nitrobenzyl alcohol) m/z 692 (M + H+, 65), 551
(M+ - HOPO3CH2CH2NH2, 100).
Oct a d eca n oic Acid 2-(Oct a d eca n oyloxy)-3-h yd r oxy-
p r op yl Ester (7b). Using a similar procedure to that of 7a ,
7b was obtained as white crystals: mp 75-77 °C; TLC
Octa d eca n oic Acid 3-[((2-Am in oeth oxy)h yd r oxyp h os-
p h or yl)oxy]-2-(octa d eca n oyloxy)p r op yl Ester (9b). Using
a similar procedure to that of 9a , 9b was obtained as a white
(hexane/ether (4:1)) Rf 0.18; [R]25 -2.50 (c ) 0.060, CHCl3);
D
1H NMR (CDCl3) δ 0.89 (t, 6H, J ) 6.39 Hz), 1.26 (s, 56H),
1.56-1.70 (m, 4H), 2.05 (t, 1H, J ) 6.48 Hz), 2.29-2.39 (m,
4H), 3.74 (dd, 2H, J ) 4.53, 5,70 Hz), 4.24 (dd, 1H, J ) 5.62,
12.0 Hz), 4.33 (dd, 1H, J ) 4.63, 12.0 Hz), 5.07-5.11 (m, 1H);
13C NMR (CDCl3) δ 14.09, 22.67, 24.89, 29.10, 29.35, 29.67,
31.91, 34.08, 34.26, 61.39, 62.08, 72.06, 173.44, 173.76; IR
(film) 3503, 2955, 2916, 2849, 1732, 1709, 1465, 1380, 1287,
1255, 1177, 1091 cm-1. Anal. Calcd for C39H76O5: C, 74.94;
H, 12.26. Found: C, 74.68; H, 12.42.
solid: mp 124-127 °C; TLC (MeOH/CH2Cl2 1:9) Rf 0.12; [R]
25
D
+3.59 (c ) 0.034, CHCl3 + 0.05% TFA); 1H NMR (CD3OD/
CDCl3 (1:1)) δ 0.84 (t, 6H, J ) 6.40 Hz), 1.22 (s, 56H), 1.50-
1.95 (m, 4H), 2.24-2.31 (m, 4H), 3.08-3.16 (m, 2H), 3.91-
4.15 (m, 5H), 4.36 (dd, 1H, J ) 2.89, 12.0 Hz), 5.12-5.24 (m,
1H); 13C NMR (CD3OD/CDCl3 (1:1)) δ 14.33, 23.16, 25.39, 29.63,
29.87, 30.20, 32.45, 34.54, 34.67, 40.92, 62.24, 63.10, 64.32,
70.96, 108.20, 114.14, 119.93, 125.90, 162.66, 163.37, 174.30,
174.60; IR (film) 3300-3000 (br), 2916, 2850, 1742, 1683, 1467,
1175, 1162, 1096, 1065, 1026 cm-1; FABMS+ (m-nitrobenzyl
alcohol) m/z 748 (M + H+, 40), 607 (M+ - HOPO3CH2CH2-
NH2, 100).
Hexa d eca n oic Acid 3-[((2-((ter t-Bu toxyca r bon yl)a m i-
n o)et h oxy)h yd r oxyp h osp h or yl)oxy]-2-(h exa d eca n oyl-
oxy)p r op yl Ester (8a ). To a solution of triethylamine (0.146
mL, 1.05 mmol) and phosphorus oxychloride (0.096 mL, 1.05
mmol) in THF (5 mL) at 0 °C was added dropwise a solution
of 7a (580 mg, 1.05 mmol) in THF (5 mL) over 30 min. After
the reaction mixture was stirred at 0 °C for 1 h and at rt for
4 h, a solution of N-(tert-butoxycarbonyl)ethanolamine (190
mg, 1.47 mmol) and triethylamine (0.351 mL, 2.52 mmol) in
Hexa d eca n oic Acid 3-(({2-[3-(4-((ter t-Bu toxyca r bon yl)-
a m i n o )p h e n y l )-3 -m e t h y l u r e i d o ]e t h o x y }h y d r o x y -
p h osp h or yl)oxy)-2-(h exa d eca n oyloxy)p r op yl Ester (10a ).
A solution of 9a (100 mg, 0.115 mmol) and N-[4-((tert-
butoxycarbonyl)amino)phenyl]-N-methylcarbamic chloride (33
mg, 0.115 mmol) in dry triethylamine (1 mL) and THF (1 mL)