550 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4
Ceruti et al.
epoxidic CH), 3.73 (s, 3 H, COOCH3), 5.00-5.16 (m, 4 H, vinylic
CH), 5.86 [t, J ) 7.3 Hz, 1 H, CHdC(COOCH3)]; IR (liquid
film) 2960, 2925, 2855, 1715 (CO), 1440, 1380 cm-1; CIMS
(isobutane) m/z 471 (100), 453 (65), 439 (14), 315 (70), 291 (18),
273 (34); HRMS 470.3762 (calcd for C31H50O3 470.3760). Anal.
(C31H50O3) C, H, O.
(18), 153 (23), 135 (55), 109 (52), 81 (80), 69 (100); HRMS
440.3655 (calcd for C30H48O2 440.3654). Anal. (C30H48O2) C,
H, O.
(18Z)-29-MOS: (6Z,10E,14E,18E)-22,23-Ep oxy-2,10,15,-
19,23-p e n t a m e t h yl-6-vin yl-2,6,10,14,18-t e t r a cosa p e n -
ta en e (31). Methyltriphenylphosphonium bromide (10 equiv,
810 mg, 2.27 mmol) in anhydrous THF (10 mL) was left at
-20 °C, under nitrogen, with stirring. n-Butyllithium (1.6 M
solution in hexane, 10 equiv, 1.4 mL, 2.27 mmol) was added;
the color progressively turned to yellow and then to orange.
It was allowed to stand for 30 min at -20 °C and then placed
in another acetone bath at -80 °C. Z-Enal 30 (100 mg, 0.227
mmol) was dissolved in anhydrous THF (50 mL) and cooled
to -80 °C. The orange solution of the ylide at -80 °C was
slowly transferred with a glass syringe into the solution of
Z-enal 30 at -80 °C under dry nitrogen. After 30 min of
stirring at -80 °C, it was left at room temperature for 30 min.
The mixture was poured into saturated iced NH4Cl/diethyl
ether, 1:1 (100 mL), upon which the orange-yellow color
disappeared. The mixture was then extracted with diethyl
ether (3 × 40 mL). The combined extracts were washed with
saturated brine (2 × 30 mL), dried with anhydrous sodium
sulfate, and evaporated in vacuo. The resulting oil was
purified by flash chromatography with petroleum ether/diethyl
ether, 99:1, to remove impurities, then 98:2, finally 97:3,
affording 87 mg (88% yield from Z-enal 30) of (18Z)-29-MOS
(31) as a colorless oil. 1H NMR analysis showed pure Z-
isomerism in the conjugated system. On TLC it had identical
Rf to 2,3-oxidosqualene: 1H NMR (CDCl3) δ 1.256 and 1.301
(2 s, 6 H, epoxidic CH3), 1.56-1.69 (m, 17 H, allylic CH3 and
CH2-epoxide), 1.98-2.28 (m, 18 H, allylic CH2), 2.70 (t, J )
6.2 Hz, 1 H, epoxidic CH), for (H1)(H2)CdC(H3)(R): H1 cis to
H,3 5.08 [broad d, J 1,3 ) 11.1 Hz, 1 H, (H1)(H2)CdC(H3)(R)],
5.05-5.19 (m, 4 H, non conjugated vinylic CH), 5.24 [broad d,
J 2,3 ) 17.4 Hz, 1 H, (H1)(H2)CdC(H3)(R)], 5.37 [broad t, J )
7.3 Hz, 1 H, CHdC(R)-CHdCH2], 6.68 [dd, J 3,1 ) 11.1 Hz and
J 3,2 ) 17.4 Hz, 1 H, (H1)(H2)CdC(H3)(R)]; IR (liquid film) 2925,
2855, 1665, 1595, 1450, 1380 cm-1; EIMS m/z 438 (1.4), 410
(0.6), 395 (2.3), 377 (2), 351 (1), 337 (1), 309 (2), 271 (9), 243
(7), 215 (15), 203 (20), 173 (20), 161 (38), 149 (63), 135 (47), 93
(100); HRMS m/z 438.3865 (calcd for C31H50O 438.3862). Anal.
(C31H50O) C, H, O.
(2E,6E,10E,14E)-18,19-Ep oxy-6,11,15,19-tetr a m eth yl-2-
(4-m eth yl-3-pen ten yl)-2,6,10,14-icosatetr aen -1-ol (32). Com-
pound 32 was obtained from E-acetate 28 following the same
method and purification as compound 29, with 90% yield: 1H
NMR (CDCl3) δ 1.258 and 1.299 (2 s, 6 H, epoxidic CH3), 1.43-
1.68 (m, 17 H, allylic CH3 and epoxide-CH2), 1.99-2.27 (m,
18 H, allylic CH2), 2.70 (t, J ) 6.2 Hz, 1 H, epoxidic CH), 3.54
(m, 1 H, OH), 4.03 (broad s, 2 H, CH2OH), 5.00-5.20 (m, 4 H,
vinylic CH), 5.41 [t, J ) 6.7 Hz, 1 H, CHdC(CH2OH)]; IR
(liquid film) 3450, 2960, 2925, 2855, 1450, 1380 cm-1; CIMS
(isobutane) m/z 443 (15), 427 (35), 425 (100), 407 (30); HRMS
442.3806 (calcd for C30H50O2 442.3811). Anal. (C30H50O2) C,
H, O.
(2E,6E,10E,14E)-18,19-Ep oxy-6,11,15,19-tetr a m eth yl-2-
(4-m eth yl-3-p en ten yl)-2,6,10,14-icosa tetr a en a l (33). Com-
pound 33 was obtained from E-alcohol 32 following the same
method and purification as compound 30, with 87% yield: 1H
NMR (CDCl3) δ 1.256 and 1.300 (2 s, 6 H, epoxidic CH3), 1.56-
1.68 (m, 17 H, allylic CH3 and epoxide-CH2), 2.00-2.52 (m,
18 H, allylic CH2), 2.70 (t, J ) 6.2 Hz, 1 H, epoxidic CH), 5.05-
5.23 (m, 4 H, vinylic CH), 6.44 [t, J ) 7.2 Hz, 1H, CHdC-
(CHO)], 9.35 (s, 1 H, CHO); IR (liquid film) 2960, 2925, 2855,
1690 (CO), 1455, 1375 cm-1; CIMS (isobutane) m/z 441 (100),
423 (70), 407 (6), 383 (10); HRMS 440.3658 (calcd for C30H48O2
440.3654). Anal. (C30H48O2) C, H, O.
1
28: H NMR (CDCl3) δ 1.257 and 1.299 (2 s, 6 H, epoxidic
CH3), 1.58-1.69 (m, 17 H, allylic CH3 and epoxide-CH2), 1.98-
2.14 (m, 14 H, allylic CH2), 2.29 [m, 4 H, CH2CHdCCH2-
(COOCH3)], 2.70 (t, J ) 6.2 Hz, 1 H, epoxidic CH), 3.72 (s, 3
H, COOCH3), 5.00-5.20 (m, 4 H, vinylic CH), 6.74 [t, J ) 7.4
Hz, 1 H, CHdC(COOCH3)]; IR (liquid film) 2960, 2925, 2850,
1720 (CO), 1440, 1375 cm-1; CIMS (isobutane) m/z 471 (100),
453 (71), 439 (13), 333 (15), 319 (87), 291 (34), 273 (59); HRMS
470.3754 (calcd for C31H50O3 470.3760). Anal. (C31H50O3) C,
H, O.
(2Z,6E,10E,14E)-18,19-Ep oxy-6,11,15,19-tetr a m eth yl-2-
(4-m eth yl-3-p en ten yl)-2,6,10,14-icosa tetr a en -1-ol (29). Li-
AlH4, washed with pentane before use (5 equiv, 61 mg, 1.60
mmol), was added to dry diethyl ether (10 mL) with stirring
and cooled to -30 °C under argon. Z-Ester 27 (1 equiv, 150
mg, 0.32 mmol) in dry diethyl ether (1 mL) was added with
vigorous stirring. After 30 min, the reaction was stopped, as
no more ester was present. Saturated aqueous NH4Cl (100
µL) was added with a syringe to the mixture at -30 °C, under
argon, whereupon effervescence appeared. A very small
amount of anhydrous sodium sulfate was added with stirring,
and the suspension was filtered on a syntherized porous
septum and evaporated to dryness. A flash chromatography
column was preeluted with petroleum ether/diethyl ether/
isopropylamine, 98:1:1, until basic eluate and then with
petroleum ether/diethyl ether/isopropylamine, 98.9:1:0.1 (300
mL). The crude product was eluted with petroleum ether/
diethyl ether/isopropylamine, 98.9:1:0.1, to remove impurities,
then petroleum ether/diethyl ether/isopropylamine, 94.9:5:0.1,
finally 89.9:10:0.1, to obtain 133 mg (94% yield from 27) of
compound 29 as a colorless oil: 1H NMR (CDCl3) δ 1.258 and
1.300 (2 s, 6 H, epoxidic CH3), 1.58-1.70 (m, 17 H, allylic CH3
and epoxide-CH2), 2.00-2.27 (m, 18 H, allylic CH2), 2.70 (t, J
) 6.2 Hz, 1 H, epoxidic CH), 4.11 (broad s, 2 H, CH2OH), 5.03-
5.23 (m, 4 H, vinylic CH), 5.31 [t, J ) 7.2 Hz, 1 H, CHdC(CH2-
OH)]; IR (liquid film) 3450, 2960, 2925, 2855, 1450, 1380 cm-1
;
CIMS (isobutane) m/z 443 (24), 425 (100), 407 (23), 291 (77),
273 (69), 221 (44), 207 (47); HRMS 442.3813 (calcd for C30H50O2
442.3811). Anal. (C30H50O2) C, H, O.
(2Z,6E,10E,14E)-18,19-Ep oxy-6,11,15,19-tetr a m eth yl-2-
(4-m eth yl-3-p en ten yl)-2,6,10,14-icosa tetr a en a l (30). Z-
Alcohol 29 (120 mg, 0.27 mmol) dissolved in n-hexane (40 mL)
was left at +5 °C under nitrogen, with stirring. Na2CO3 (50
equiv, 1.43 g, 13.5 mmol) and activated MnO2 (20 equiv, 85%
purity, 552 mg, 5.4 mmol) were added. After 2 h of reaction
at +5 °C, additional Na2CO3 (25 equiv, 715 mg, 6.75 mmol)
and activated MnO2 (10 equiv, 85% purity, 276 mg, 2.7 mmol)
were added, and the mixture was allowed to react for a further
2 h. The reaction mixture was filtered on a porous septum
and evaporated to dryness. A flash chromatography column
was preeluted with petroleum ether/isopropylamine, 99:1, until
basic eluate, followed by petroleum ether/isopropylamine, 99.9:
0.1 (300 mL). The crude product was quickly eluted with
petroleum ether/diethyl ether/isopropylamine, 98.9:1:0.1, to
remove impurities, then petroleum ether/diethyl ether/isopro-
pylamine, 96.9:3:0.1, to give 105 mg (88% yield from 29) of
pure Z-enal 30 as a colorless oil. As the crude product is
essentially pure (1H NMR and TLC analysis), it may be used
directly in the next step: 1H NMR (CDCl3) δ 1.258 and 1.300
(2 s, 6 H, epoxidic CH3), 1.56-1.69 (m, 17 H, allylic CH3 and
epoxide-CH2), 1.98-2.25 (m, 18 H, allylic CH2), 2.70 (t, J )
6.2 Hz, 1 H, epoxidic CH), 5.00-5.18 (m, 4 H, vinylic CH), 6.46
[t, J ) 8.1 Hz, 1H, CHdC(CHO)], 10.09 (s, 1 H, CHO); IR
(18E)-29-MOS: (6E,10E,14E,18E)-22,23-Ep oxy-2,10,15,-
19,23-p e n t a m e t h yl-6-vin yl-2,6,10,14,18-t e t r a cosa p e n -
ta en e (34). (18E)-29-MOS (34) was obtained from E-aldehyde
33 following the same method and purification as compound
31, with 85% yield. 1H NMR analysis showed pure E-
isomerism in the conjugated system: 1H NMR (CDCl3) δ 1.258
and 1.301 (2 s, 6 H, epoxidic CH3), 1.59-1.70 (m, 17 H, allylic
(liquid film) 2960, 2925, 2855, 1678 (CO), 1455, 1380 cm-1
;
CIMS (isobutane) m/z 441 (100), 423 (92); EIMS m/z 440 (3),
422 (8), 407 (2), 371 (4), 353 (3), 289 (5), 271 (4), 217 (8), 203