Synthesis of Lysophosphatidylcholines and Related DeriVatiVes
3.56 (m, 1H), 3.81-3.89 (m, 1H), 4.03-4.10(m, 2H), 4.12-4.18
(m, 2H), 4.22-4.26 (m, 2H), 4.28-4.36 (m, 1H), 4.78 (m, 1H);
13C NMR (50 MHz, CDCl3) δ 14.0, 19.0, 22.6, 24.9, 25.3, 29.1,
29.3, 29.4, 29.6, 30.4, 31.9, 34.1, 59.3, 62.1, 63.1, 64.2, 69.6, 71.7,
97.9, 170.0, 173.4; Rf (hexane/EtOAc 3:1) ) 0.49. Anal. Calcd for
C27H50O7: C, 66.63: H, 10.36. Found: C, 66.68; H, 10.33. FAB-
MS [M + Na+] calcd 509.3454, found 509.3471.
at room temperature. The white solid (Et3N‚HCl) was filtered, and
the solvent was evaporated. The oily residue was dissolved in 30
mL of anhydrous acetonitrile and was transferred to a pressure
bottle. The solution was cooled in a dry ice-acetone bath below
-10 °C, and 1 mL of precooled trimethylamine was added. The
pressure bottle was sealed and kept at 65 °C with stirring for 24 h.
The solution was then cooled to 0 °C, and the resulting white
precipitate was filtered and purified by silica gel column chroma-
tography using chloroform/methanol/water (65:25:4) to yield the
phospholipids 11a isolated as a white powder after freeze-drying
from benzene (0.51 g, 61%). IR (CHCl3) 1732 cm-1; 1H NMR (200
MHz, CDCl3) δ 0.78 (t, J ) 6.8 Hz, 3H), 1.15 (br s, 24H), 1.27-
1.30 (m, 4H), 1.41-1.44 (m, 4H), 2.22 (dt, J ) 7.5, 2.6 Hz, 2H),
3.14 (s, 9H), 3.55 (m, 2H), 3.80-3.95 (m, 4H), 4.12-4.38 (m,
4H), 4.62 (m, 1H, 4.74 (m, 1H); 13C NMR (50 MHz, CDCl3) δ
13.9, 20.0, 22.6, 24.8, 25.1, 29.0, 29.2, 29.3, 29.4, 29.5, 29.6, 30.7,
31.8, 34.0, 48.3, 62.12, 63.62, 64.8, 67.4, 68.2, 69.4, 98.1, 174.2;
Rf (CHCl3/CH3OH/H2O 65:25:4) ) 0.29. Anal. Calcd for C29H58-
NO8P: C, 60.08; H, 10.08; N, 2.42; P, 5.34. Found: C, 59.87; H,
10.40; N, 2.41; P, 5.32. FAB-MS [M + H+] calcd 580.3978, found
580.3986.
1-(12′-N-[2′′-Naphthylacetyl]aminolauroyl-2-tetrahydropyra-
nyl-3-methoxyacetyl-sn-glycerol (9b). To a solution of 8b (2.20
g, 3.16 mmol) in 10 mL of anhydrous acetonitrile was added 50
mL of 0.6 M tetraethyammonium methoxyacetate solution in
acetonitrile. The acetonitrile solutions were dried over 3 Å molecular
sieves. The reaction mixture was stirred at room temperature for
72 h. The solvent was evaporated to dryness, and the residue was
chromatographed on a silica gel column with cyclohexane/ethyl
acetate (2:3) to give the product 9b, as a clear oily liquid (1.63 g,
1
84% yield). IR (CHCl3) 1660, 1732 cm-1; H NMR (200 MHz,
CDCl3) δ 1.19-1.58 (m, 24H), 2.26-2.33 (t, J ) 7.7 Hz, 2H),
3.17-3.20 (m, 2H), 3.41 (s, 3H), 3.45-3.56 (m, 1H), 3.74 (s, 2H),
3.75-3.89 (m, 1H) 4.06-4.32 (m, 7H), 4.75-476 (m, 1H), 5.60-
5.75 (m, 1H), 7.32-7.47 (m, 3H), 7.68-7.82 (m, 4H); 13C NMR
(50 MHz, CDCl3) δ 19.0, 24.5, 24.8, 25.5, 26.6, 29.0, 33.9, 39.7,
44.1, 48.8, 62.1, 64.3, 66.4, 67.6, 97.8, 126.0, 126.4, 127.1, 127.4,
128.1, 128.5, 132.4, 133.2, 169.9,170.7, 173.7; Rf (cyclohexane/
ethyl acetate 3:2) ) 0.24. Anal. Calcd for C35H51NO8: C, 68.49;
H, 8.38; N, 2.28. Found: C, 68.33; H, 8.29; N, 2.51; FAB-MS
[M + Na+] calcd for C35H51NNaO8 636.3507, found 636.3524.
1-Palmitoyl-2-tetrahydropyranyl-sn-glycerol (10a).26 To a
solution of 9a (0.680 g, 1.4 mmol) in 10 mL of chloroform/methanol
(1:4) was added tert-butylamine (1.73 mL, 16.4 mmol) at 0 °C,
and the reaction mixture was stirred at 0-10 °C for 1 h. The solvent
was reduced to one-half of its original volume and passed through
a silica gel column (EtOAc/hexane 1:3) to give a fluffy white
product 10a (0.569 g, 98%). IR (CHCl3) 1732 cm-1; 1H NMR (200
MHz, CDCl3) δ 0.86 (t, J ) 6.8 Hz, 3H), 1.24 (s, 24H), 1.50-
1.58 (m, 6H), 1.59-1.61 (m, 2H), 2.26-2.31 (dt, J ) 7.7, 2.7 Hz,
2H), 3.58-3.68 (m, 3H), 3.88-3.98 (m, 2H) , 4.13-4.35 (m, 2H),
4.59 (m, 0.5H), 4.78 (m, 0.5H); 13C NMR (50 MHz, CDCl3) δ
14.0, 19.0, 22.6, 24.9, 25.3, 29.1, 29.2, 29.3, 29.4, 29.6, 30.4, 31.7,
34.2, 58.6, 62.1, 64.2, 70.0, 97.9, 173.4; Rf (hexane/EtOAc 3:1) )
0.37. Anal. Calcd for C24H46O5: C, 69.52; H, 11.38. Found: C,
69.66; H, 11.58. FAB-MS [M + NH4+] calcd 432.3689, found
432.3698.
1-Palmitoyl-sn-glycero-3-phosphocholine (12a).17 Compound
11a (0.300 g, 0.53 mmol) was dissolved in 7 mL of 0.15 M HCl
in dioxane/water. The solution was stirred at room temperature for
2 h. Then 10 mL of dioxane was added, and the mixture was freeze-
dried overnight. The crude solid was chromatographed on silica
gel using chloroform/methanol/water 65:25:4 and freeze-dried from
benzene to give analytically pure 12a (0.250 g, 98%) as a white
solid. IR (CHCl3) 1732 cm-1; 1H NMR (200 MHz, CDCl3) δ 0.88
(t, J ) 6.8 Hz, 3H), 1.26-1.45 (br s, 26H), 2.22 (t, J ) 7.7 Hz,
2H), 3.35 (s, 9H), 3.90-4.50 (m, 9H); Rf (CHCl3/CH3OH/H2O 65:
1
25:4) ) 0.13. The H NMR spectrum corroborates exactly with
that reported in the literature17 and that of an authentic sample
(Avanti).
1-(12′-N-[2′′-Naphthylacetyl]aminolauroyl)-2-tetrahydropy-
ranyl-sn-glycero-3-phosphocholine (11b). To a solution of 10b
(0.7503 g, 1.38 mmol) in 30 mL of benzene, cooled in an ice-
water bath, was added 2-chloro-2-oxo-1,3,2-dioxaphospholane (0.25
mL, 2.76 mmol) followed by triethylamine (0.39 mL, 2.76 mmol),
dropwise. The ice bath was removed, and the reaction mixture was
stirred at room temperature for 9 h. The white precipitate of Et3N‚
HCl was filtered and washed with benzene. The combined solvent
was evaporated, and the oily residue was dissolved in 30 mL of
CH3CN. The solution was transferred to a pressure bottle and frozen
at -10 °C. To this solution was added NMe3 (3 mL), and the
pressure bottle was sealed and kept at 65 °C for 36 h. The pressure
bottle was then cooled in an ice bath, whereupon most of the product
precipitated. This solid, combined with the oily residue obtained
from evaporation of the solvent, was purified on a silica gel column
with CHCl3/MeOH/H2O (65:25:4). The fractions containing the
product were collected, the solvent was evaporated, and the residue
was freeze-dried from benzene to give 11b (0.576 g, 58%) as white/
1-(12′-N-[2′′-Naphthylacetyl]aminolauroyl)-2-tetrahydropy-
ranyl-sn-glycerol (10b). To a stirred solution of 9b (1.63 g, 2.66
mmol) in 20 mL of chloroform/methanol (1:4) was added tert-
butylamine (3.29 mL, 31.2 mmol) at 0 °C, and the reaction mixture
was stirred at 0 °C for 1 h. The solvent was then evaporated to
one-third volume, and the solution was passed through a silica gel
column using cyclohexane/ethyl acetate (3:2) to remove the
impurities, followed by ethyl acetate to elute the product. The
solvent was evaporated, and the product was freeze-dried from
benzene to give 10b (1.32 g, 92%) as a fluffy white solid. IR
1
pale yellow solid. IR (CHCl3) 1735 cm-1; H NMR (CDCl3, 200
1
(CHCl3) 1660, 1732 cm-1; H NMR (200 MHz, CDCl3) δ 1.19-
MHz) δ 1.24 (br s, 16H), 1.66 (m, 10H), 2.29 (br t, 2H), 3.18 (t,
2H, J ) 7.2 Hz), 3.32 (br s, 9H), 3.70 (br s, 2H), 3.90 (m, 3H),
3.99 (br m, 4H), 4.26 (m, 2H), 4.72 (m, 1H), 5.72 (m, 1H), 7.35-
7.83 (m, 7H); 13C NMR (CDCl3, 50 MHz) δ 18.9, 19.8, 24.8, 24.9,
26.7, 29.1, 29.8, 30.8, 34.2, 39.7, 43.9, 54.2, 59.2, 61.6, 63.1, 64.3,
65.1, 66.2, 72.8, 74.22, 96.8, 99.5, 125.9, 126.3, 127.3, 127.6, 128.1,
128.6, 132.4, 133.5, 170.8, 173.7; 31P NMR (CDCl3, 160 MHz,
pyrophosphate ext ref) δ -1.79. Rf (CHCl3/CH3OH/H2O 65:25:4)
) 0.39. Anal. Calcd. for C37H59N2O9P‚5/2H2O: C, 59.10; H, 8.58;
N, 3.73. Found: C, 59.55; H, 8.79; N, 3.75. FAB-MS [M + H+]
calcd 707.4036, found 707.4074.
1.64 (m, 24H), 2.26-2.36 (t, J ) 7.7 Hz, 2H), 3.17-3.20 (m, 2H),
3.45-3.59 (m, 1H), 3.74 (s, 2H), 3.78-3.84 (m, 1H), 4.06-4.32
(m, 5H), 4.52 (m, 0.5H), 4.81 (m, 0.5H), 5.4-5.6 (m, 1H), 7.32-
7.47 (m, 3H), 7.68-7.82 (m, 4H); 13C NMR (50 MHz, CDCl3) δ
19.0, 24.5, 24.8, 26.6, 29.0, 33.9, 39.7, 44.1, 62.1, 64.3, 66.4, 67.6,
97.8, 126.0, 126.4, 127.1, 127.4, 128.1, 128.5, 132.4, 133.2, 170.7,
173.7; Rf (cyclohexane/ethyl acetate 2:3) ) 0.42. Anal. Calcd for
C32H47NO6‚1/2H2O: C, 69.79; H, 8.78; N, 2.54. Found: C, 69.86;
H, 8.52; N, 2.55. FAB-MS [M + Na+] calcd 564.3296, found
564.3275.
1-Palmitoyl-2-tetrahydropyranyl-sn-glycero-3-phosphocho-
line (11a).26 To a solution of 10a (0.610 g, 1.47 mmol) in 25 mL
of freshly distilled benzene was added triethylamine (0.31 mL, 2.21
mmol), followed by 2-chloro-2-oxo-1,3,2-dioxaphospholane (0.2
mL, 2.21 mmol) at 0 °C. The reaction mixture was stirred overnight
1-(12′-N-[2′′-Naphthylacetyl]aminolauryl)-sn-glycero-3-phos-
phocholine (12b). To a cloudy solution of 11b (0.401 g, 0.56mmol)
in 45 mL of 1,4-dioxane was added 0.15 mL of 12 N aqueous HCl,
and the reaction mixture was stirred for 2 h at room temperature.
After addition of 30 mL more dioxane the mixture was freeze-
J. Org. Chem, Vol. 72, No. 5, 2007 1697