P.C. Andrews et al. / Tetrahedron 64 (2008) 9197–9202
9201
OCH2CHCH2O), 5.26–5.42 (m, 13H, 12ꢂCH alkene and
CH2CHOCH2). 13C NMR (50 MHz, CDCl3)
14.22 (CH3), 14.37 (CH3),
1654 w, 1442 m, 1391 m, 1266 m, 1161 m, 1120 m, 1053 m, 988 m,
d
928 m, 792 w, 708 s cmꢀ1. MS calculated for C25H38O4Naþ¼425.3;
20.68 (CH2), 22.81 (CH2), 24.98 (CH2), 25.66 (CH2), 25.75 (CH2),
29.24 (CH2), 29.39 (CH2), 29.49 (CH2), 29.60 (CH2), 29.82 (CH2),
32.05 (CH2), 34.15 (CH2), 62.14 (OCH2), 69.24 (OCH), 127.14 (CH
alkene), 127.76 (CH alkene), 127.98 (CH alkene), 128.09 (CH al-
kene), 128.19 (CH alkene), 128.38 (CH alkene), 128.45 (CH alkene),
128.68 (CH alkene), 129.57 (CH alkene), 132. 11 (CH alkene),
172.20 (C]O, 1C, 2-DHA), 173.32 (C]O, 2C, 1,3-stearic). IR (neat)
nmax 3012 w, 2961 m, 2914 s, 2849 m, 1733 s, 1471 s, 1255 m,
1255 w, 1195 w, 1179 w, 1156 w, 1106 w cmꢀ1. MS calculated for
found: 425.5. HRMS calculated for
found: 425.2667.
C
25H38O4Naþ¼425.2668;
4.2.7. Synthesis of 1,2-didodecanoylgylcerol-(3,6,9,12,15,18-
docosahexaenoyl)glycerol (LaLaD) (10)
To a solution of 1-(3,6,9,12,15,18-docosahexaenoyl)glycerol 9
(56 g, 140 mmol) in CH2Cl2 (200 mL) were added dodecanoic acid
(lauric acid) (68 g, 336 mmol), N,N-dimethylaminopyridine (6.8 g,
56 mmol) and N-ethyl-N0-(3-dimethylaminopropyl) carbodiimide
hydrochloride (64.4 g, 336 mmol). The solution was stirred at room
temperature overnight before being purified by passage through
a plug of silica (diameter 13 cm, height 7 cm, 2 L CH2Cl2 eluent) to
give the title compound (LaLaD) 10 as a white/yellow solid (99.8 g,
C
C
61H106O6Naþ¼957.8; found: 957.5. HRMS calculated for
61H106O6Naþ¼957.7887; found: 957.7883.
4.2.5. Synthesis of 1,2-acetonide-3-(3,6,9,12,15,18-
docosahexaenoyl)glycerol (8)
93%). Mp 37–41 ꢁC. 1H NMR (400 MHz, CDCl3)
d 0.86 (apparent t,
To a solution of 1,2-acetonide glycerol (7) (16 g, 121 mmol) in
CH2Cl2 (200 mL) were added docosahexaenoic acid (43 g,
131 mmol), N,N-dimethylaminopyridine (3.2 g, 26.2 mmol) and
N-ethyl-N0-(3-dimethylaminopropyl) carbodiimide hydrochloride
(25.1 g, 131 mmol). The solution was stirred at room temperature
overnight before the crude material was purified by passage
through a plug of silica (diameter 13 cm, height 7 cm, 2 L CH2Cl2
eluent) to obtain the title compound 8 as a colourless oil (51.9 g,
6H, J 7.0 Hz, 2ꢂlauric CH3), 0.97 (t, 3H, J 7.5 Hz, DHA CH3), 1.21–1.47
(m, 36H, 18ꢂCH2), 1.58–1.65 (m, 4H, 2ꢂlauric O2CCH2CH2CH2),
2.04–2.11 (m, 2H, DHA CH]CHCH2CH2), 2.29 (t, 2H, J 7.7 Hz, lauric
O2CCH2CH2), 2.31 (t, 2H, J 7.4 Hz, lauric O2CCH2CH2), 2.38 (d, 2H, J
2.8 Hz, O2CCH2CH]CH2) 2.80–2.86 (m,10H, DHA 5ꢂC]CCH2C]C),
4.13–4.18 (m, 2H, one each of OCH2CHCH2O), 4.29 (dd, 2H, J 4.3,
11.9 Hz, one each of OCH2CHCH2O), 5.26–5.42 (m, 13H, 12ꢂCH al-
kene and CH2CHOCH2). 13C NMR (50 MHz, CDCl3)
d 14.25 (CH3),
97%). 1H NMR (300 MHz, CDCl3)
1.37 (s, 3H, CH3 acetonide), 1.43 (s, 3H, CH3 acetonide), 2.00–2.12
(m, 4H, CH]CHCH2CH2CH3), 2.41 (d, 2H, 4.9 Hz, DHA
d
0.97 (t, 3H, J 7.5 Hz, DHA CH3),
14.41 (CH3), 20.70 (CH2), 22.83 (CH2), 22.87 (CH2), 25.06 (CH2),
25.09 (CH2), 25.74 (CH2), 25.78 (CH2), 25.83 (CH2), 29.27
(CH2), 29.31 (CH2), 29.46 (CH2), 29.53 (CH2), 29.66 (CH2), 29.81
(CH2), 32.10 (CH2), 34.10 (CH2), 34.24 (CH2), 34.40 (CH2), 62.80
(OCH2), 62.47 (OCH2), 69.06 (OCH), 127.22 (CH alkene), 127.85 (CH
alkene), 128.06 (CH alkene), 128.18 (CH alkene), 128.28 (CH al-
kene),128.46 (CH alkene), 128.51 (CH alkene), 128.75 (CH alkene),
129.67 (CH alkene), 132.20 (CH alkene), 172.71 (C]O, 1C, 3-DHA),
173.04 (C]O, 1C, 2-lauric), 173.43 (C]O, 1C, 1-lauric). IR (neat)
nmax 3012 m, 2955 s, 2919 s, 2851 s, 1741 s, 1647 m, 1551 m, 1454
m, 1377 m, 1146 s, 1110 m, 1034 m, 719 w cmꢀ1. MS calculated
J
O2CCH2C]CH2), 2.80–2.90 (m, 10H, DHA 5ꢂCH]CHCH2CH]C),
3.73 (dd, J 6.1, 8.4 Hz, 1H, one of OCH2CHCH2O), 4.04–4.20 (m, 3H,
three of OCH2CHCH2O), 4.21–4.29 (m, 1H, CH2CHOCH2), 5.29–5.44
(m, 12H, alkene CH). 13C NMR (75 MHz, CDCl3)
d 14.4 (CH3), 20.7
(CH2), 22.9 (CH2), 25.5 (CH3), 25.7 (CH2), 25.7 (CH2), 25.8 (CH2),
25.8 (CH2), 26.8 (CH3), 34.1 (CH2), 64.8 (OCH2), 66.5 (OCH2), 73.8
(OCH), 110.0 (O2C(CH3)2 acetonide), 127.2 (CH alkene), 127.2 (CH
alkene), 127.9 (CH alkene), 128.0 (CH alkene), 128.2 (CH alkene),
128.3 (CH alkene), 128.4 (CH alkene), 128.5 (CH alkene), 128.7 (CH
alkene), 129.6 (CH alkene), 132.2 (CH alkene), 173.0 (C]O DHA).
IR (neat) nmax 3013 s, 2964 s, 2933 s, 1715 s, 1654 w, 1455 m, 1380
s, 1371 s, 1258 s, 1215 s, 1157 s, 1084 s, 1058 s, 990 m, 928 m, 843
m, 792 w, 711 s cmꢀ1. MS calculated for C28H42O4Naþ¼465.3;
for
C
C
49H82O6Hþ¼767.6; found: 766.6. HRMS calculated for
49H82O6Hþ¼767.6190; found: 767.6192.
4.2.8. Synthesis of 1,2-dihexadecanoyl-3-(3,6,9,12,15,18-
docosahexaenoyl)glycerol (PPD) (11)
found: 465.3. HRMS calculated for
found: 465.2977.
C
28H42O4Naþ¼465.2981;
To a solution of 1-(3,6,9,12,15,18-docosahexaenoyl)glycerol 9
(41 g, 104 mmol) in CH2Cl2 (200 mL) were added hexadecanoic
acid (palmitic acid) (64 g, 250 mmol), N,N-dimethylaminopyridine
(3 g, 12.5 mmol) and N-ethyl-N0-(3-dimethylaminopropyl) carbo-
diimide hydrochloride (48 g, 250 mmol). The solution was stirred
at room temperature overnight before being purified by passage
through a plug of silica (diameter 13 cm, height 7 cm, 2 L CH2Cl2
eluent) to give the title compound (PPD) 11 as a white/yellow solid
4.2.6. Synthesis of 3-(3,6,9,12,15,18-docosahexaenoyl)glycerol (9)
To a solution of 1,2-acetonide-3-(3,6,9,12,15,18-docosahexa-
enoyl)glycerol
8 (38 g, 86 mmol) in HPLC grade methanol
(300 mL) was added Amberlyst-Hþ resin (5 g). The mixture was
stirred at room temperature for 33 h before the resin was filtered
off and solvent removed under the reduced pressure. The residual
oil was then purified by passage through a plug of silica (di-
ameter 13 cm, height 7 cm, 2 L of 3:2 EtOAc/hexane eluent) to
yield the title compound 9 as clear oil (31 g, 90%). 1H NMR
(87.8 g, 96%). Mp 22–25 ꢁC. 1H NMR (800 MHz, CDCl3)
d 0.88 (ap-
parent t, 6H, J 7.2 Hz, 2ꢂpalmitic CH3), 0.97 (t, 3H, J 7.3 Hz, DHA
CH3), 1.22–1.34 (m, 50H, 25ꢂCH2), 1.58–1.63 (m, 4H, 2ꢂpalmitic
O2CCH2CH2CH2), 2.06–2.10 (m, 2H, DHA CH]CHCH2CH2), 2.31 (t,
2H, J 7.4 Hz, palmitic O2CCH2CH2), 2.32 (t, 2H, J 7.3 Hz, palmitic
O2CCH2CH2), 2.38 (d, 2H, J 2.8 Hz, O2CCH2CH]CH2) 2.80–2.87 (m,
10H, DHA 5ꢂC]CCH2C]C), 4.14 (m, 2H, one each of OCH2CH-
CH2O), 4.29 (dd, 2H, J 4.2, 11.9 Hz, one each of OCH2CHCH2O), 5.26–
5.43 (m, 13H, 12ꢂCH alkene and CH2CHOCH2). 13C NMR (200 MHz,
(300 MHz, CDCl3)
d 0.97 (t, 3H, J 7.5 Hz, DHA CH3), 2.02–2.12 (m,
2H, CH]CHCH2CH2CH3), 2.26 (br s, 1H, OH), 2.39–2.45 (m, 4H,
DHA O2CCH2C]CH2 and CH]CHCH2CH2CH3), 2.68 (br s, 1H, OH),
2.79–2.89 (m, 10H, DHA 5ꢂCH]CHCH2CH]C), 3.58 (dd, 1H, J 5.8,
11.5 Hz, one of OCH2CHCH2O), 3.68 (dd, 1H, J 3.9, 11.5 Hz, one of
OCH2CHCH2O), 3.88–3.95 (m, 1H, one of OCH2CHCH2O), 4.08–4.23
(m, 2H, one of OCH2CHCH2O and OCH2CHCH2O), 5.28–5.45 (m,
CDCl3)
d 14.26 (CH3), 14.42 (CH3), 20.71 (CH2), 22.77 (CH2), 22.85
(CH2), 25.02 (CH2), 25.05 (CH2), 25.70 (CH2), 25.75 (CH2), 25.79 (CH2),
29.24 (CH2), 29.28 (CH2), 29.43 (CH2), 29.44 (CH2), 29.52 (CH2), 29.64
(CH2), 29.66 (CH2), 29.78 (CH2), 29.80 (CH2), 29.82 (CH2), 29.85 (CH2),
32.0 (CH2), 34.05 (CH2), 34.20 (CH2), 34.37 (CH2), 62.24 (OCH2),
62.44 (OCH2), 68.99 (OCH), 127.17 (CH alkene), 128.14 (CH alkene),
128.03 (CH alkene), 128.15 (CH alkene), 128.24 (CH alkene),128.26
(CH alkene), 128.41 (CH alkene), 128.43 (CH alkene), 128.54 (CH
alkene), 128.73 (CH alkene), 129.63 (CH alkene), 132.19 (CH alkene),
12H, alkene CH). 13C NMR (75 MHz, CDCl3)
d 13.2 (CH3), 19.5
(CH2), 21.7 (CH2), 24.5 (CH3), 24.6 (CH2), 24.6 (CH2), 33.0 (CH2),
62.3 (OCH2), 64.3 (OCH2), 69.2 (OCH), 126.0 (CH alkene), 126.7
(CH alkene), 126.9 (CH alkene), 126.9 (CH alkene), 127.1 (CH al-
kene), 127.3 (CH alkene), 127.3 (CH alkene), 127.4 (CH alkene),
127.6 (CH alkene), 128.6 (CH alkene), 131.0 (CH alkene), 172.5
(C]O DHA). IR (neat) nmax 3045 s, 3013 s, 2963 s, 2932 s, 1740 s,