Arachidonic Acid Analogues
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(sextet, J=7.2 Hz, 2H; 17-H), 1.71 (quintet, J=7.8 Hz, 2H; 3-H), 2.02–
2.09 (m, 2H; 16-H), 2.11 (dt, J=6.8, 6.8 Hz, 2H; 4-H), 2.32 (t, J=7.8 Hz,
2H; 2-H), 2.75–2.84 (ddd and t overlapping, 3H; 10-H and 7-H; including
2.80, t, J=6.6 Hz, 2H; 7-H), 2.87 (ddd, J=15.6, 7.5, 6.5 Hz, 1H; 10-H),
3.46 (ddq as sextet, J=7.5 Hz, 1H; 13-H), 3.67 (s, 3H; COOCH3), 5.20–
5.30 (m, 4H; 11-H, 12-H, 14-H, 15-H), 5.43–5.32 ppm (m, 4H; 5-H, 6-H,
8-H, 9-H); 13C NMR (CDCl3, 150 MHz): d=14.03 (C-20), 22.01 (C-13-
CH3), 22.56 (C-19), 24.76 (C-3), 25.59 (C-7), 25.81 (C-10), 26.53 (C-4),
27.48 (C-16), 29.44 (C-17), 30.50 (C-13), 31.55 (C-18), 33.42 (C-2), 51.48
(-OCH3), 125.61 (C-11), 128.07 (C-15), 128.24 (C-5), 128.35 (C-9), 128.84
(C-8 or C-6), 128.88 (C-6 or C-8), 134.12 (C-14), 135.02 (C-12),
174.00 ppm (C=O); MS (EI): m/z (%): 332 [M]+ (9), 248 (16), 217 (12),
164 (13), 147 (11), 133 (23), 119 (29), 107 (43), 93 (100), 91 (44), 81 (58);
MS (ESI): m/z (%): 355 [M+Na]+ (100), 333 [M+H]+ (64), 217 (48), 199
(43), 170 (36); HRMS (EI): m/z calcd for C22H36O2: 332.2715 [M]+;
found: 332.2722.
yield) as
a
colorless oil. [a]D20 =À8.89 (c=0.0009 gmLÀ1 in CHCl3);
1H NMR (CDCl3, 600 MHz): d=0.89 (t, J=6.9 Hz, 3H; 20-H), 1.02 (d,
J=7.2 Hz, 3H; CH-CH3), 1.24–1.33 (m, 4H; 18-H, 19-H), 1.35 (sextet,
J=7.2 Hz, 2H; 17-H), 1.73 (quintet, J=7.2 Hz, 2H; 3-H), 2.06 (nonet,
J=6.3 Hz, 2H; 16-H), 2.12 (dt, J=7.2, 7.2 Hz, 2H; 4-H), 2.22 (t, J=
7.6 Hz, 2H; 2-H), 2.54 (brs, 1H; OH), 2.76–2.84 (ddd and t, overlapping,
3H; 10-H and 7-H, including 2.81, t, J=6.0 Hz, 2H; 7-H), 2.87 (ddd, J=
15.0, 7.5, 6.3 Hz, 1H; 10-H), 3.42 (dt, J=5.2, 5.2 Hz, 2H, CH2N), 3.46
(sextet, J=7.5 Hz, 1H; 13-H), 3.73 (t, J=5.2 Hz, 2H; CH2O), 5.20–5.31
(m, 4H; 11-H, 12-H, 14-H, 15-H), 5.44–5.32 (m, 4H; 5-H, 6-H, 8-H, 9-
H), 5.88 ppm (brs, 1H; NH); 13C NMR (CDCl3, 150 MHz): d=14.09 (C-
20), 22.04 (C-13-CH3), 22.59 (C-19), 25.44 (C-3), 25.61 (C-7), 25.84 (C-
10), 26.61 (C-4), 27.51 (C-16), 29.46 (C-17), 30.50 (C-13), 31.57 (C-18),
35.92 (C-2), 42.48 (NH-CH2), 62.70 (-CH2-OH), 125.61 (C-11), 128.10 (C-
9), 128.26 (C-15), 128.43 (C-6), 128.84 (C-5), 129.02 (C-8), 134.12 (C-14),
135.10 (C-12), 174.16 ppm (C=O); MS (EI): m/z (%): 361 [M]+ (2), 328
(12), 218 (9), 178 (14), 125 (20), 103 (33), 85 (100); HRMS (EI): m/z
calcd for C23H39NO2: 361.2981 [M]+ ; found: 361.2973; elemental analysis
calcd (%) for C23H39NO2: C 76.40, H 10.87, N 3.87; found: C 76.15, H
10.59, N 4.16.
Method B (from aldehyde 11): The synthesis was carried out as described
for 24, using phosphonium salt 20 (167 mg, 0.31 mmol), KHMDS (58 mg,
0.29 mmol), and aldehyde 11 (53 mg, 0.34 mmol). The reaction was com-
pleted in 2.5 h at À98–08C to give 27 (25 mg, 22% yield).
Compound 28: A 1m aqueous solution of LiOH (0.2 mL) was added to a
stirred solution of 27 (34 mg, 0.102 mmol) in dry THF (1 mL) at room
temperature, under an argon atmosphere. Stirring was continued for 24 h,
then the reaction mixture was acidified with a 5% aqueous solution of
HCl to pH 3, and lipophilic products were extracted with Et2O. The com-
bined organic extracts were washed with brine, and dried (Na2SO4). Con-
centration in vacuo at 37–398C gave acid 28 as a colorless oil (28 mg,
86% yield), which was used in the next step without further purification.
1H NMR (CDCl3, 600 MHz): d=0.89 (t, J=6.6 Hz, 3H; 20-H), 1.01 (d,
J=7.2 Hz, 3H; CH-CH3), 1.24–1.33 (m, 4H; 18-H, 19-H), 1.36 (sextet,
J=7.2 Hz, 2H; 17-H), 1.72 (quintet, J=7.8 Hz, 2H; 3-H), 2.01–210 (m,
2H; 16-H), 2.14 (dt, J=7.2, 7.2 Hz, 2H; 4-H), 2.37 (t, J=7.8 Hz, 2H; 2-
H), 2.76–2.85 (ddd and t overlapping, 3H; 10-H and 7-H; including 2.81,
t, J=6.3 Hz, 2H; 7-H), 2.86 (ddd, J=15.7, 7.5, 6.5 Hz, 1H; 10-H), 3.46
(ddq as sextet, J=7.2 Hz, 1H; 13-H), 5.20–5.31 (m, 4H; 11-H, 12-H, 14-
H, 15-H), 5.32–5.45 (m, 4H; 5-H, 6-H, 8-H, 9-H), 10.55 ppm (brs, 1H;
COOH); MS (EI): m/z (%): 318 [M]+ (4), 248 (6), 220 (15), 191 (9), 164
(12), 133 (23), 119 (38), 107 (46), 93 (100), 81 (67); HRMS (EI): m/z
calcd for C21H34O2: 318.2559 [M]+; found: 318.2551.
Compound 33: The synthesis was carried out as described for 24, using
phosphonium salt 23 (217 mg, 0.41 mmol), KHMDS (75 mg, 0.38 mmol),
and aldehyde 3 (94 mg, 0.29 mmol) in anhydrous THF (0.8 mL). The re-
action was completed in 2.5 h at À98–08C to give 33 (84 mg, 58% yield).
[a]D20 =À29.6 (c=0.00550 gmLÀ1 in CHCl3). 1H NMR (CDCl3, 300 MHz):
d=0.98 (d, J=6.6 Hz, 3H; CH-CH3), 1.04 (s, 9H; Si(Ph)2CACHTNUGTRNEUNG(CH3)3), 1.80
(quintet, J=7.2 Hz, 2H; 3-H), 2.23 (tt, J=6.9, 2.4 Hz, 2H; 4-H), 2.42 (t,
J=7.5 Hz, 2H; 2-H), 2.63 (m, 1H; 13-H), 2.74–2.86 (m, 1H; 10-H), 2.86–
2.98 (m, 1H; 10-H), 3.08 (quintet, J=2.4 Hz, 2H; 7-H), 3.45 (d, J=
6.3 Hz, 2H; 14-H), 3.67 (s, 3H; COOCH3), 5.24 (tdd, J=10.8, 9.6, 0.9 Hz,
1H; 12-H), 5.41 (dtd, J=10.8, 6.3, 0.5 Hz, 1H; 11-H), 7.33–7.46 (m, 6H;
3-H, 4-H, 5-H, ArH), 7.68–7.62 ppm (m, 4H; 2-H, 6-H, ArH); 13C NMR
(CDCl3, 75 MHz): d=9.7, 17.2, 17.4, 18.2, 19.3, 23.9, 26.8, 26.9, 32.8, 34.7,
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51.5 (OCH3), 68.3 (CH2O), 74.2 (C C), 75.3 (C C), 78.8 (C C), 79.1 (C
C), 124.7, 127.6, 129.5, 133.8, 134.3, 135.6, 173.6 ppm (C=O); MS (ESI):
m/z (%): 523 [M+Na]+ (100), 423 (6), 270 (14).
Compound 34: Acetic acid (0.1 mL) and TBAF (0.73 mL, 0.73 mmol, 1m
solution in THF) were added sequentially to a stirred solution of 33
(81 mg, 0.16 mmol) in dry THF (3.2 mL), at 08C under an argon atmos-
phere. Stirring was continued for 10 min at 08C and for 20 h at room
temperature. The reaction mixture was quenched by the addition of a sa-
turated aqueous solution of NH4Cl at 08C, then extracted with AcOEt.
The combined organic extracts were washed with a saturated aqueous so-
lution of NaHCO3 and brine, dried (Na2SO4), and concentrated in vacuo
at 378C. Purification by flash column chromatography on silica gel (40%
ethyl acetate in hexane) gave 34 as a colorless viscous liquid (32 mg,
76% yield). [a]2D0 =+10.57 (c=0.00265 gmLÀ1 in CHCl3); 1H NMR
(CDCl3, 300 MHz): d=0.96 (d, J=6.9 Hz, 3H; CH-CH3), 1.80 (quintet,
J=7.2 Hz, 2H; 3-H), 2.22 (tt, J=6.9, 2.4 Hz, 2H; 4-H), 2.42 (t, J=
7.2 Hz, 2H; 2-H), 2.70 (m, 1H; 13-H), 2.96 (m as d, J=7.2 Hz, 2H; 10-
H), 3.10 (quintet, J=2.4 Hz, 2H; 7-H), 3.36 (dd, J=10.5, 8.1 Hz, 1H; 14-
H), 3.50 (dd, J=10.5, 5.7 Hz, 1H; 14-H), 3.67 (s, 3H; COOCH3), 5.23
(tdd, J=10.9, 9.5, 0.9 Hz, 1H; 12-H), 5.57 ppm (dtd, J=10.9, 6.3, 0.5 Hz,
1H; 11-H); 13C NMR (CDCl3, 75 MHz): d=9.7, 16.7, 17.5, 18.2, 23.8,
Compound 31: A mixture of acid 28 (22 mg, 0.069 mmol), and fresh car-
bonyldiimidazole (23 mg, 0.138 mmol) in dry THF (1 mL) was stirred for
2 h at room temperature under an argon atmosphere. A solution of pro-
tected ethanolamine 30 (62 mg, 0.208 mmol) in THF (0.5 mL) was added.
The reaction mixture was stirred for 1 h and then diluted with water and
ethyl acetate. The organic layer was separated and the aqueous layer was
extracted with AcOEt. The combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated in vacuo. The crude product was
purified by flash column chromatography on silica gel (25% acetone in
hexane) to give 31 as a colorless oil (37 mg, 91% yield). 1H NMR
(CDCl3, 600 MHz): d=0.88 (t, J=6.9 Hz, 3H; 20-H), 1.02 (d, J=6.6 Hz,
3H; CH-CH3), 1.07 (s, 9H; CACHTNUTRGNEU(GN CH3)3), 1.24–1.31 (m, 4H; 18-H, 19-H),
1.35 (sextet, J=7.2 Hz, 2H; 17-H), 1.69 (quintet, J=7.2 Hz, 2H; 3-H),
2.02–2.09 (m, 2H; 16-H), 2.12 (dt, J=7.2, 7.2 Hz, 2H; 4-H), 2.13 (t, J=
7.6 Hz, 2H; 2-H), 2.75–2.84 (ddd and t overlapping, 3H; 10-H and 7-H;
including 2.81, t, J=6.0 Hz, 2H; 7-H), 2.86 (ddd, J=15.7, 7.5, 6.5 Hz,
1H; 10-H), 3.40 (dt, J=5.4, 5.4 Hz, 2H; CH2-NH), 3.45 (sextet, J=
7.5 Hz, 1H; 13-H), 3.75 (t, J=5.4 Hz, 2H; CH2-OTBDPS), 5.18–5.31 (m,
4H; 11-H, 12-H, 14-H, 15-H), 5.32–5.44 (m, 4H; 5-H, 6-H, 8-H, 9-H),
5.73 (brs, 1H; NH), 7.39 (t, J=7.8 Hz, 4H; 3-H, 5-H, ArH), 7.44 (t, J=
7.8 Hz, 2H; 4-H, ArH), 7.64 ppm (d, J=7.8 Hz, 4H; 2-H, 6-H, ArH);
MS (EI): m/z (%): 599 [M]+ (3), 542 (100), 296 (15), 276 (9), 242 (38),
199 (89), 164 (35), 91 (24); HRMS (EI): m/z calcd for C39H57NO2Si:
599.4159 [M]+ ; found: 599.4165.
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32.8, 34.9, 51.5 (OCH3), 67.5 (CH2O), 74.5 (C C), 75.2 (C C), 78.5 (C
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C), 79.2 (C C), 126.3 (CH=CH), 133.9 (CH=CH), 173.7 ppm (C=O); MS
(ESI): m/z (%): 285 [M+Na]+ (40), 263 [M+H]+ (12), 202 (100), 186
(24).
Compound 35: The synthesis was carried out as described for 26, using
alcohol 34 (32 mg, 0.12 mmol) and Dess–Martin periodinane (155 mg,
0.37 mmol) in anhydrous CH2Cl2 (2.4 mL). The reaction was completed
in 2 h at 08C, and the sensitive aldehyde 35 was used in the next step
without further purification. 1H NMR (CDCl3, 300 MHz): d=1.18 (d, J=
6.6 Hz, 3H; CH-CH3), 1.80 (quintet, J=7.2 Hz, 2H; 3-H), 2.22 (tt, J=
6.9, 2.4 Hz, 2H; 4-H), 2.42 (t, J=7.2 Hz, 2H; 2-H), 2.82 (m, 1H; 13-H),
2.98 (m as d, J=7.1 Hz, 2H; 10-H), 3.10 (quintet, J=2.4 Hz, 2H; 7-H),
3.25–3.52 (m, 2H; 14-H), 3.67 (s, 3H; COOCH3), 5.32 (dd, J=10.8,
Compound 32: The synthesis was carried out as described for 18, using
31 (32 mg, 0.053 mmol) and TBAF (0.07 mL, 0.07 mmol, 1m solution in
THF) in dry THF (2 mL). The reaction was completed in 1 h and the re-
sulting crude oil was purified by flash column chromatography on silica
gel (57:40:3 ethyl acetate/hexane/MeOH) to afford 32 (17 mg, 88%
Chem. Eur. J. 2010, 16, 4091 – 4099
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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