I. V. Ivanov et al. / Bioorg. Med. Chem. 10 (2002) 2335–2343
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sphere. Methyl 5-hexynoate (9) (0.46 g, 3.68 mmol) was
added at once to the suspension followed by bromide 8
(1.42 g, 3.68 mmol). The reaction mixture was vigor-
ously stirred overnight at rt, quenched with satd aq
NH4Cl (200 mL). The lipophilic products were extracted
with Et2O (4ꢃ100 mL). The combined organic extracts
were washed with satd aq NaCl (2ꢃ150 mL). After dry-
ing over Na2SO4 the ethereal solution was concentrated
in vacuum. The crude residue was purified by silica gel
flash chromatography (hexane/Et2O, 3:1) under argon
atmosphere to give pure 10 as yellow oil; yield 1.28 g
(81%). TLC: Rf=0.39 (hexane/Et2O, 1:1). IR (neat)/
cmꢀ1: 2240 (CꢁC), 1740, 1725 (C¼O), 1115 (C–O), 710
(Ph). 1H NMR (200 MHz, CDCl3) d 8.01 (m, 2H, o-Bz),
7.49 (m, 3H, (m+p)-Bz), 5.55 (tt, 1H, J=1.5 and
6.5 Hz, 16-CH), 3.61 (s, 3H, OCH3), 3.11 (m, 6H, 7-, 10-
and 13-CH2), 2.40 (t, 2H, J=7.0 Hz, 2-CH2), 2.19 (m,
2H, 4-CH2), 1.75 (m, 4H, 3- and 17-CH2), 1.20–1.40 (m,
4H, 18- and 19-CH2), 0.85 (t, 3H, J=6.8 Hz, CH3). 13C
NMR (50 MHz, CDCl3) d 173.56, 165.66, 133.09,
130.39, 129.89 (2C), 128.46 (2C), 79.99, 79.66, 78.37,
75.23, 74.92 (2C), 74.29, 74.18, 64.96, 51.50, 34.89,
33.05, 27.39, 24.12, 22.39, 18.38, 13.98, 10.01, 9.86 (2C).
Anal. calcd for C28H30O4: C, 78.11; H, 7.02. Found: C,
78.18; H, 7.29.
(m, 2H, 3-CH2), 1.25–1.45 (m, 4H, 18- and 19-CH2),
0.88 (t, 3H, J=6.8 Hz, CH3). 13C NMR (50 MHz,
CDCl3) d=174.97, 165.73, 133.02, 130.67, 130.05,
129.94 (2C), 129.24, 128.91, 128.47 (2C), 127.62, 124.57
(2C), 84.36, 78.04, 65.29, 51.43, 35.15, 33.64, 27.47,
26.81, 25.77 (2C), 25.00, 22.43, 17.43, 14.01. EIMS m/z
(%):314
(1.48)
[M+ꢀBzCOO],
285
(0.27)
[M+ꢀBzCOO–CH3O], 257 (0.59) [M+ꢀBzCOO–
C4H9). Anal. calcd for C28H36O4: C, 77.03; H, 8.31.
Found: C, 77.12; H, 8.21.
Methyl (16R,5Z,8Z,11Z,14Z)-(13a) and methyl (16S,
5Z,8Z,11Z,14Z)-16-hydroxyeicosa-5,8,11,14-tetraenoate
(13b). A methanol solution of NaOMe (0.1 M, 8 mL)
was added to a solution of racemic 11 (70.1 mg,
0.16 mmol) in dry methanol (10 mL) under argon atmo-
sphere. The resulting mixture was stirred at rt for 18 h.
After the reaction was completed, methanol was partly
removed by evaporation under reduced pressure, the
residue was acidified to pH 4 using 1 MHCl and the
lipophilic products were extracted with Et2O
(3ꢃ30 mL). Combined organic extracts were dried over
Na2SO4, concentrated under vacuum and the crude
residue was purified by silical gel column chromato-
graphy (hexane/Et2O, 1:1) to give pure racemic 13
(39.5 mg, 74%). Enantiomers were separated by chiral
HPLC (solvent system n-hexane/MeOH, 98:2) to yield
20.7 mg of the pure 13a and 17.8 mg of 13b.
Methyl rac-(5Z,8Z,11Z,14Z)-16-(benzoyloxy)eicosa-5,8,
11,14-tetraenoate (11). Into a 250-mL Erlenmeyer flask
containing Lindlar’s catalyst (1.60 g) dry benzene
(30 mL) was added. The mixture was saturated with H2
at rt and cooled to 10 ꢂC. Then quinoline (1.6 mL) and a
solution of 10 (1.01 g, 2.35 mmol) in benzene (70 mL)
were added to the catalyst suspension and the reaction
mixture was stirred for 1 h at 10 ꢂC. The mixture was
filtered, washed with 2 MHCl (2 ꢃ30 mL) and the sol-
vent was evaporated. RP-HPLC of the crude residue
revealed two products, which were separated by pre-
parative RP-HPLC (solvent system MeOH/H2O, 95:5)
to yield 0.48 g (48.6%) of the pure tetraenoate 11 and
0.28 g (27.4%) of the corresponding monoacetylenide
12. Analytical data for 11: TLC: Rf=0.54 (hexane/
Et2O, 1:1). RP-HPLC: RT=7.17 min. 1H NM
(200 MHz, CDCl3) d 8.05 (m, 2H, o-Bz), 7.44 (m, 3H,
(m+p)-Bz), 5.79 (m, 1H, 16-CH), 5.25–5.45 (m, 8H,
CH¼CH), 3.44 (s, 3H, OCH3), 3.01 (m, 2H, 13-CH2),
2.77 (m, 4H, 7- and 10-CH2), 2.29 (t, 2H, J=7.0 Hz, 2-
CH2), 2.09 (m, 2H, 4-CH2), 1.75 (m, 4H, 3- and 17-
CH2), 1.25–1.40 (m, 4H, 18- and 19-CH2), 0.90 (t, 3H,
J=6.8 Hz, CH3). 13C NMR (50 MHz, CDCl3) d 174.04,
166.03, 132.80, 132.10, 131.15, 129.93, 129.75 (2C),
129.09 (2C), 128.98 (2C), 128.43 (2C), 128.24, 127.77,
71.20, 51.50, 34.78, 33.64, 27.47, 26.81, 26.58, 25.85
(2C), 25.00, 22.73, 14.09. EIMS m/z (%): 316 (3.33)
[M+ꢀBzCOO], 287 (0.37) [M+ꢀBzCOO–CH3O], 259
(1.48)) [M+ꢀBzCOO–C4H9]. Anal. calcd for C28H38O4:
C, 76.68; H, 8.73. Found: C, 76.97; H, 8.85. Analytical
data for 12: TLC: Rf=0.54 (hexane/Et2O, 1:1). RP-
HPLC: RT=5.91 min. 1H NMR (200 MHz, CDCl3)
d:=8.05 (m, 2H, o-Bz), 7.42 (m, 3H, (m+p)-Bz), 5.55
(tt, 1H, J=6.4 and 1.7 Hz, 16-CH), 5.25–5.45 (m, 6H,
CH=CH), 3.61 (s, 3H, OCH3), 2.93 (m, 2H, 13-CH2),
2.74 (m, 4H, 7- and 10-CH2), 2.27 (t, 2H, J=7.0 Hz, 2-
CH2), 2.05 (m, 2H, 4-CH2), 1.83 (m, 2H, 17-CH2), 1.65
Analitical data for 13a: [a]2D1 +6 (c 0.23, acetone). CP-
HPLC: RT=11.36 min. RP-HPLC: RT=8.45 min.
TLC: Rf=0.49 (hexane/Et2O, 1:1). 1H NMR (200 MHz,
CDCl3) d 5.25–5.52 (m, 8H, CH¼CH), 4.45 (m, 2H, 16-
CH), 3.61 (s, 3H, OCH3), 2.80 (m, 6H, 7-, 10- and 13-
CH2), 2.29 (t, 2H, J=7.0 Hz, 2-CH2), 2.08 (m, 2H, 4-
CH2), 1.65 (m, 2H, 3-CH2), 1.25–1.35 (m, 6H, 17-, 18-
and 19-CH2), 0.89 (t, 3H, J=6.8 Hz, CH3). 13C NM R
(50 MHz, CDCl3) d 174.71, 133.12, 130.41, 129.09,
128.79, 128.55 (2C), 128.13, 127.94, 68.04, 51.52, 37.37,
33.45, 27.67, 26.72, 26.32, 25.90 (2C), 24.82, 22.79,
14.08. EIMS m/z (%): 316 (2.1) [M+ꢀH2O], 245 (1.6)
[M+ꢀMeOH–C4H9]. HRMS calcd for C21H34O3 [M+]:
334.2508. Found 334.1312. Analytical data for 13b: [a]D21
ꢀ6 (c 0.23, acetone). CP-HPLC: RT=22.33 min. Other
analytical data are identical to those obtained for 13a.
R
Methyl (16R,5Z,8Z,11Z)-(14a) and methyl (16S,5Z,
8Z,11Z)-16-hydroxyeicosa-5,8,11-trien-14-ynoate (14b).
Enantiomers of 14 (14a and 14b) were prepared from
methyl (5Z,8Z,11Z)-rac-16-(benzoyloxy)eicosa-5,8,11-
trien-14-ynoate (12) (47.9 mg, 0.11 mmmol) by an ana-
logues procedure as described for 13a and 13b and
yielded 16.2 mg of pure 14a and 15.9 mg of 14b.
Analytical data for 14a: [a]2D1 +12 (c 0.32, acetone). CP-
HPLC: RT=16.69 min. RP-HPLC: RT=7.05 min.
TLC: Rf=0.49 (hexane/Et2O, 1:1). 1H NMR (200 MHz,
CDCl3) d 5.25–5.45 (m, 6H, CH¼CH), 4.31 (tt, 1H,
J=1.7 and 7.4 Hz, 16-CH3), 3.61 (s, 3H, OCH3), 2.95
(m, 2H, 13-CH2), 2.74 (m, 4H, 7- and 10-CH2), 2.33 (t,
2H, J=7.0 Hz, 2-CH2), 2.09 (m, 2H, 4-CH2), 1.65 (m,
4H, 3- and 17-CH2), 1.25–1.40 (m, 4H, 18- and 19-
CH2), 0.88 (t, 3H, J=6.8 Hz, CH3). 13C NMR (50 MHz,