Communications
Bioconjugate Chem., Vol. 21, No. 9, 2010 1585
2.67-2.54 (m, 4H), 2.43(dt, J ) 14.0, 7.2 Hz, 2H), 2.35-2.27
(m, 4H), 2.25 (s, 6H), 2.03-1.90 (m, 2H), 1.89-1.66 (m, 3H),
1.68-0.82 (m, 58H), 0.67 (s, 3H).
(m, 5H), 3.16-3.08 (m, 2H), 3.01 (dd, J ) 10.0, 5.2 Hz, 2H),
2.90-2.78 (m, 4H), 0.98 (s, 18H).
3-[N,N-Bis(2-tert-butyldiphenylsilyloxyethyl)amino]-1,2-pro-
panol (14). To a solution of 13 (2.0 g, 2.23 mmol) in diethyl
ether (3 mL) was added 85% formic acid (8.2 mL) at room
temperature. The reaction mixture was stirred for 20 h and
cooled at 0 °C, and solid NaHCO3 was added in portions to
neutralize the acidic solution. It was then diluted with diethyl
ether (80 mL) and washed with water (25 mL), followed by
saturated aqueous NaCl (25 mL). The organic layer was dried
(Na2SO4), filtered, and concentrated in Vacuo. Purification by
column chromatography (silica gel, elution with 4% MeOH in
CHCl3) furnished 14 (0.97 g, 67%) as an oily liquid.1H NMR
(CDCl3): δ 7.70-7.61 (m, 8H), 7.49-7.31 (m, 12H), 3.73-3.55
(m, 6H), 4.397 (dd, J ) 11.6, 4.4 Hz, 1H), 2.78-2.54 (m, 5H),
2.57 (d, J ) 6.8 Hz, 1H) 1.02 (s, 18H).
N,N,N-Trimethyl-N-[2-(9(Z)-octadecanoyloxy),3-succinyloxy(4-
cholesteryloxy)-propyl]ammonium Iodide (4). A solution of 10
(175 mg, 0.2 mmol) and methyl iodide (0.0152 mL, 0.246
mmol) in CHCl3 (1 mL) and DMSO (1 mL) was taken in a 10
mL microwave vial covered with a plastic cap. The reaction
mixture was subjected to 150 W microwave irradiation at 70
°C for 1 h. The reaction mixture was concentrated to dryness
under high vacuum. Purification of this crude product by column
chromatography (silica gel, elution with 8% MeOH in CHCl3)
1
furnished 4 (183 mg, 90%) as a yellowish solid. H NMR
(CDCl3): δ 5.62-5.54 (m, 1H), 5.39-5.27 (m, 3H), 4.60-4.52
(m, 1H), 4.48 (dd, J ) 12.0, 4.0 Hz, 1H), 4.39 (d, J ) 13.2 Hz,
1H), 4.22 (dd, J ) 12.0, 4.4 Hz, 1H), 3.96 (dd, J ) 14.4, 9.2
Hz, 1H), 3.53 (s, 9H), 2.71-2.57 (m, 4H), 2.36 (dt, J ) 7.2,
3.6 Hz, 2H), 2.33-2.22 (m, 2H), 2.08-1.75 (m, 9H), 1.66-0.82
(m, 58H), 0.66 (s, 3H); 13C NMR (CDCl3) δ 172.89, 172.23,
172.13, 139.68, 130.28, 129.88, 123.11, 74.87, 66.17, 65.89,
62.77, 56.87, 56.34, 54.95, 50.13, 42.52, 39.90, 39.72, 38.32,
38.29, 37.12, 36.81, 36.39, 36.02, 34.38, 32.13, 32.11, 32.05,
29.99, 29.96, 29.77, 29.55, 29.42, 29.36, 29.30, 28.45, 28.23,
27.98, 27.46, 27.42, 24.80, 24.50, 24.07, 23.05, 22.91, 22.78,
21.24, 19.52, 18.93, 14.37, 12.07; MS (ESI) m/z calculated:
867.4 [M+H]+, found: 867.6 [M+H]+.
3-[N,N-Bis(2-tert-butyldiphenylsilyloxyethyl)amino]-1,2-bis(tet-
radecanoyloxy)propane (15). To a solution of 14 (0.65 g, 0.99
mmol), Et3N (0.35 mL, 2.48 mmol), and DMAP (12 mg, 0.1
mmol) in CH2Cl2 (5 mL) at 0 °C was added dropwise myristoyl
chloride (0.65 mL, 2.43 mmol). The reaction mixture was
allowed to warm up slowly to room temperature. It was stirred
for 5 h at room temperature, diluted with CH2Cl2 (50 mL), and
washed sequentially with 5% aqueous sodium bicarbonate (15
mL), water (15 mL), and saturated aqueous NaCl (15 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated in
Vacuo. Purification by column chromatography (silica gel,
elution with 2.5% EtOAc in hexane) furnished 15 (0.50 g, 47%)
N,N,N-Trimethyl-N-[2-(tetradecanoyloxy),3-succinyloxy(4-cho-
1
lesteryloxy)-propyl]ammonium Iodide (5). H NMR (CDCl3): δ
1
as an oily liquid. H NMR (CDCl3): δ 7.67-7.23 (m, 20H),
5.62-5.52 (m, 1H), 5.37-5.29 (m, 1H), 4.60-4.50 (m, 1H),
4.48 (dd, J ) 12.4, 4.4 Hz, 1H), 4.41 (d, J ) 13.6 Hz, 1H),
4.21 (dd, J ) 12.4, 4.8 Hz, 1H), 3.96 (dd, J ) 16.0, 9.2 Hz,
1H), 3.52 (s, 9H), 2.70-2.56 (m, 4H), 2.35 (dt, J ) 7.6, 3.6
Hz, 2H), 2.32-2.22 (m, 2H), 2.04-1.75 (m, 5H), 1.64-0.78
(m, 58H), 0.65 (s, 3H); 13C NMR (CDCl3) δ 172.93, 172.22,
172.07, 139.69, 123.07, 74.82, 66.12, 65.92, 62.89, 56.87, 56.34,
54.96, 50.14, 42.51, 39.90, 39.71, 38.30, 38.28, 37.12, 36.80,
36.39, 36.01, 34.40, 32.16, 32.09, 32.04, 29.96, 29.93, 29.91,
29.76, 29.61, 29.53, 29.35, 29.28, 28.45, 28.23, 27.98, 27.96,
24.81, 24.50, 24.07, 23.05, 22.93, 22.78, 21.23, 19.52, 18.92,
14.37, 12.06; MS (ESI) m/z calculated: 813.3 [M+H]+, found:
813.5 [M+H]+.
5.04-4.95 (m, 1H), 4.25 (dd, J ) 12.0, 2.8 Hz, 1H), 4.03 (dd,
J ) 11.6, 5.6 Hz, 1H), 3.61 (t, J ) 8.0 Hz, 4H), 2.75-2.58 (m,
6H), 2.24-2.33 (m, 4H), 1.60-1.50 (m, 4H), 1.35-1.18 (m,
40H), 1.01 (s, 18H), 0.87 (t, J ) 6.4 Hz, 6H).
3-[N,N-Bis(2-hydroxyethyl)amino]-1,2-bis(tetradecanoyloxy)pro-
pane (16). Tetrabutylammonium fluoride trihydrate (0.50 g, 1.60
mmol) was added to an ice-cooled solution of 15 (0.43 g, 0.40
mmol) in THF (3 mL) under N2 atmosphere. The reaction
mixture was allowed to warm up to room temperature. It was
stirred overnight at room temperature, diluted with CH2Cl2 (30
mL), and washed sequentially with 5% NaHCO3 (10 mL), water
(10 mL), and saturated aqueous NaCl (10 mL). The organic
layer was dried (Na2SO4), filtered, and concentrated in Vacuo.
Purification by column chromatography (silica gel, elution with
2% methanol in CHCl3) furnished 16 (172 mg, 72%) as a wax.
1H NMR (CDCl3): δ 5.24-5.14 (m, 1H), 4.35 (dd, J ) 12.0,
3.2 Hz, 1H), 4.10 (dd, J ) 12.4, 6.4 Hz, 1H), 3.60 (t, J ) 5.2
Hz, 4H), 2.77-2.66 (m, 6H), 2.38-2.26 (m, 4H), 1.66-1.54
(m, 4H), 1.36-1.18 (m, 40H), 0.87 (t, J ) 6.0 Hz, 6H).
N,N-[Bis(2-tert-butyldiphenylsilyloxyethyl)]amine (12). To a
solution of diethanol amine (1.0 mL, 10.42 mmol), Et3N (3.56
mL, 25.52 mmol), and DMAP (127 mg, 1.04 mmol) in CH2Cl2
at 0 °C was added tert-butyldiphenylchlorosilane (6.75 mL,
26.05 mmol) dropwise. The reaction mixture was allowed to
warm to room temperature slowly. It was stirred for 20 h at
room temperature, diluted with CH2Cl2 (50 mL), and washed
sequentially with 5% NaHCO3 (30 mL), water (30 mL), and
saturated aqueous NaCl (30 mL). The organic layer was dried
(Na2SO4), filtered, and concentrated in Vacuo. Purification by
column chromatography (silica gel, elution with 2% methanol
in CHCl3) furnished 12 (5.45 g, 90%) as an oily liquid. 1H NMR
(CDCl3): δ 7.74-7.67 (m, 8H), 7.48-7.34 (m, 12H), 3.81 (t, J
) 5.2 Hz, 4H), 2.81 (t, J ) 5.2 Hz, 4H), 1.065 (s, 18H).
3-[N,N-Bis(2-tert-butyldiphenylsilyloxyethyl)amino]-1-(triphenyl-
methoxy)-2-propanol (13). To a solution of 12 (4.52 g, 7.78
mmol) and lithium perchlorate (2.27 g, 21.34 mmol) in ethanol
(30 mL) was added (R)-(+)-trityl glycidyl ether (2.95 g, 9.33
mmol) at room temperature. The reaction mixture was stirred
at 65 °C for 28 h, cooled to room temperature, diluted with
CH2Cl2 (100 mL), and washed with 5% NaHCO3 (40 mL)
followed by saturated aqueous NaCl (40 mL). The organic layer
was dried (Na2SO4), filtered, and concentrated in Vacuo.
Purification by column chromatography (silica gel, elution with
0.5% methanol in CHCl3) furnished 13 (6.48 g, 93%) as an
oily liquid. 1H NMR (CDCl3): δ 7.64-7.12 (m, 35H), 3.83-3.62
N,N-[Bis(2-hydroxyethyl)]-N-methyl-N[2,3-bis(tetradecanoyloxy)-
propyl]ammonium Iodide (3). A mixture of 16 (122 mg, 0.2 mmol)
and methyl iodide (1.5 mL) was taken in a 10 mL microwave
vial covered with a plastic cap. The reaction mixture was then
subjected to 150 W microwave irradiation at 80 °C for 3.5 h.
The reaction mixture was concentrated to dryness under high
vacuum. Purification of this crude product by column chroma-
tography (silica gel, elution with 8% MeOH in CHCl3) furnished
1
3 (120 mg, 81%) as a yellowish solid. H NMR (CDCl3): δ
5.73-5.64 (m, 1H), 4.47 (dd, J ) 12.0, 3.6 Hz, 1H), 4.32-3.74
(m, 11H), 3.37 (s, 3H), 2.42-2.30 (m, 4H), 1.66-1.53 (m, 4H),
1.37-1.18 (m, 40H), 0.87 (t, J ) 6.8 Hz, 6H); 13C NMR
(CDCl3) δ 173.60, 173.10, 65.84, 65.72, 65.18, 64.48, 63.54,
56.08, 56.03, 51.51, 34.52, 34.25, 32.16, 29.95, 29.91, 29.78,
29.75, 29.61, 29.54, 29.38, 29.34, 24.99, 24.91, 22.93, 14.37;
MS (ESI) m/z calculated: 615.0 [M+H]+, found: 615.2 [M+H]+.
3-[N,N-Bis(2-tert-butyldiphenylsilyloxyethyl)amino]-1-(triphenyl-
methoxy)-2-(tetradecanoyloxy)propane (17). To a solution of 13
(1.60 g, 1.78 mmol), Et3N (0.50 mL, 3.56 mmol), and DMAP