Synthesis of the (E)FGH Ring System of Ciguatoxin
J . Org. Chem., Vol. 67, No. 10, 2002 3309
1
72.9, 72.5, 71.5, 70.9, 69.82, 69.77, 68.4, 67.7, 63.0, 36.6, 35.3,
27.7, 25.0, 18.31, 18.27, 13.0; HRMS (FAB) calcd for C52H72O8-
SiSNa m/z 907 ((M + Na)+) 907.4615, found 907.4629.
1496, 1454, 1362, 1284, 1208, 1094, 918, 738 cm-1; H NMR
(CDCl3, 500 MHz) δ 7.34-7.21 (m, 15H), 4.85 (d, J ) 11.3 Hz,
1H), 4.69-4.52 (m, 6H), 4.41 (d, J ) 11.3 Hz, 1H), 4.03 (dd, J
) 7.3, 6.7 Hz, 1H), 3.90 (m, 1H), 3.78-3.57 (m, 10H), 3.41-
3.18 (m, 9H), 2.42 (dd, J ) 15.3, 7.3 Hz, 1H), 2.32 (dd, J )
15.3, 6.7 Hz, 1H), 2.24 (ddd, J ) 14.0, 6.4, 3.1 Hz, 1H), 1.79
(dd, J ) 13.4, 11.3 Hz, 1H), 1.59-1.52 (m, 2H), 1.26 (s, 3H),
1.12 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 170.9, 139.4, 138.5,
138.2, 128.3, 128.23, 128.21, 128.1, 127.7, 127.61, 127.56,
127.4, 127.2, 96.9, 80.4, 80.0, 79.8, 79.4, 78.6, 73.7, 73.6, 73.4,
73.3, 73.1, 72.0, 70.9, 70.4, 67.7, 67.5, 55.3, 51.6, 39.6, 32.7,
32.0, 29.8, 25.1, 9.3; HRMS (FAB) calcd for C43H56O11Na ((M
+ Na)+) 771.3720, found 771.3733.
Olefin 26. To a solution of oxepane 6 (33.3 mg, 0.0445
mmol) in CH2Cl2 (1 mL) at -78 °C was added diisobutyl-
aluminum hydride (1.0 M solution in toluene, 70 µL, 0.070
mmol). The resultant solution was stirred at -78 °C for 1 h
before the reaction was quenched with saturated aqueous
potassium sodium tartrate (2 mL). The mixture was extracted
with ethyl acetate (20 mL), and the extracts were washed with
saturated aqueous NH4Cl, dried over Na2SO4, filtered, and
concentrated in vacuo, to give the crude aldehyde.
Alcoh ol 18b. To a solution of mixed thioacetal 17b (141.8
mg, 0.160 mmol) in CH2Cl2 (10 mL) were added diisopropyl-
ethylamine (140 µL, 0.804 mmol) and chloromethyl methyl
ether (40 µL, 0.53 mmol). The resultant solution was stirred
at room temperature for 22 h. The mixture was diluted with
ethyl acetate (50 mL), washed with water and brine, dried over
Na2SO4, and concentrated in vacuo. The residue was dissolved
in THF (10 mL) and treated with TBAF (1.0 M solution in
THF, 0.65 mL, 0.65 mmol), and the resultant solution was
stirred at room temperature for 1 h. The solvent was removed
in vacuo, and the residue was purified by flash chromatogra-
phy on silica gel (35-60% ethyl acetate/hexanes) to give alcohol
18b (123.1 mg, 99% for the two steps) as a colorless oil: IR
(film) 3499, 3061, 3030, 2942, 2878, 1718, 1583, 1496, 1454,
1439, 1362, 1328, 1281, 1211, 1102, 966, 918, 866, 787, 739
1
cm-1; H NMR (CDCl3, 500 MHz) δ 7.48 (m, 2H), 7.35-7.19
(m, 18H), 5.24 (dd, J ) 7.3, 6.1 Hz, 1H), 4.66 (d, J ) 9.0 Hz,
2H), 4.58 (d, J ) 11.2 Hz, 1H), 4.51 (d, J ) 12.4 Hz, 1H), 4.50
(m, 2H), 4.47 (d, J ) 12.1 Hz, 1H), 4.39 (d, J ) 11.5 Hz, 1H),
3.87 (m, 3H), 3.78-3.72 (m, 2H), 3.68 (dd, J ) 10.6, 1.6 Hz,
1H), 3.61-3.54 (m, 3H), 3.37 (ddd, J ) 11.5, 9.7, 4.6 Hz, 1H),
3.35 (s, 3H), 3.33 (ddd, J ) 9.4, 7.0, 2.5 Hz, 1H), 3.26 (ddd, J
) 10.9, 8.2, 2.2 Hz, 1H), 3.10 (s, 1H), 2.39 (ddd, J ) 14.8, 7.3,
6.1 Hz, 1H), 2.34 (ddd, J ) 12.1, 4.9, 4.6 Hz, 1H), 2.21 (ddd, J
) 14.8, 6.5, 6.1 Hz, 1H), 1.98 (m, 1H), 1.57 (ddd, J ) 12.1,
11.5, 11.5 Hz, 1H), 1.47-1.38 (m, 2H), 1.32 (s, 3H), 1.14 (m,
1H); 13C NMR (CDCl3, 125 MHz) δ 138.4, 138.1, 137.8, 134.5,
132.4, 128.9, 128.49, 128.47, 128.4, 128.3, 127.9, 127.72,
127.69, 127.6, 127.5, 127.2, 96.9, 84.2, 84.0, 79.7, 73.5, 73.3,
72.7, 72.4, 70.9, 70.6, 69.9, 67.9, 67.6, 67.0, 55.2, 37.5, 33.2,
27.9, 24.8, 14.8; HRMS (FAB) calcd for C45H56O9SNa ((M +
Na)+) 795.3543, found 795.3553.
To a suspension of methyltriphenylphosphonium bromide
(25.1 mg, 0.0703 mmol) in THF (0.5 mL) at 0 °C was added
sodium bis(trimethylsilyl)amide (1.0 M solution in THF, 65
µL, 0.065 mmol). After 30 min, to the ylide solution was added
the above aldehyde in THF (0.2 mL). The resultant solution
was stirred at 0 °C for 30 min before the reaction was quenched
with acetone (1 mL). The mixture was extracted with ethyl
acetate (20 mL), and the extracts were washed with water and
brine, dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by flash chromatography on silica gel (20-40%
ethyl acetate/hexanes) gave olefin 26 (24.5 mg, 77% for the
two steps) as a colorless oil: IR (film) 3064, 3030, 2937, 2856,
1732, 1641, 1495, 1454, 1358, 1281, 1209, 1084, 918, 739 cm-1
;
â-Alk oxya cr yla te 7b. To a solution of alcohol 18b (108.5
mg, 0.140 mmol) in CH2Cl2 (6 mL) were added methyl
propiolate (40 µL, 0.45 mmol) and N-methylmorpholine (25 µL,
0.23 mmol). The resultant solution was stirred at room
temperature for 19.5 h. Additional methyl propiolate (25 µL,
0.28 mmol) and N-methylmorpholine (8 µL, 0.07 mmol) were
added, and the stirring was continued for a further 19 h. The
mixture was concentrated in vacuo, and the residue was
purified by flash chromatography on silica gel (20-60% ethyl
acetate/hexanes) to give â-alkoxyacrylate 7b (105.0 mg, 88%):
[R]D26 ) +47.1° (c 1.7, CHCl3); IR (film) 3030, 2947, 1713, 1642,
1623, 1496, 1454, 1438, 1362, 1329, 1285, 1191, 1140, 1102,
1045, 918, 836, 739 cm-1; 1H NMR (CDCl3, 500 MHz) δ 7.42-
7.20 (m, 21H), 5.22 (d, J ) 12.5 Hz, 1H), 5.08 (dd, J ) 10.4,
2.6 Hz, 1H), 4.68 (d, J ) 8.0 Hz, 2H), 4.61 (d, J ) 11.9 Hz,
1H), 4.58-4.55 (m, 3H), 4.51 (d, J ) 11.6 Hz, 1H), 4.41 (d, J
) 11.0 Hz, 1H), 4.19 (dd, J ) 11.9, 5.0 Hz, 1H), 3.90 (m, 1H),
3.85 (dd, J ) 11.0, 2.0 Hz, 1H), 3.78 (ddd, J ) 10.4, 9.5, 4.1
Hz, 1H), 3.70 (s, 3H), 3.70-3.54 (m, 5H), 3.46 (ddd, J ) 11.6,
9.5, 4.7 Hz, 1H), 3.37 (s, 3H), 3.34-3.28 (m, 2H), 2.45 (ddd, J
) 11.9, 5.0, 4.7 Hz, 1H), 2.31 (ddd, J ) 14.9, 9.5, 2.6 Hz, 1H),
2.08 (ddd, J ) 14.9, 10.4, 2.0 Hz, 1H), 1.95 (m, 1H), 1.66 (ddd,
J ) 11.9, 11.9, 11.6 Hz, 1H), 1.49 (m, 2H), 1.16 (s, 3H), 1.09
(m, 1H); 13C NMR (CDCl3, 125 MHz) δ 167.9, 160.8, 138.8,
138.4, 137.8, 133.5, 133.3, 128.8, 128.4, 128.30, 128.27, 128.25,
127.8, 127.7, 127.6, 127.54, 127.47, 127.3, 127.1, 98.2, 96.9,
82.6, 79.8, 78.8, 77.0, 73.4, 73.0, 72.0, 71.9, 71.3, 70.4, 69.4,
67.7, 67.6, 53.2, 51.0, 37.8, 30.8, 27.7, 24.8, 13.1; HRMS (FAB)
calcd for C49H60O11SNa ((M + Na)+) 879.3754, found 879.3751.
O-Lin k ed Oxep a n e 6. To a solution of â-alkoxyacrylate 7b
(18.4 mg, 0.0215 mmol) and 2,2′-azobis(isobutyronitrile) (1.7
mg, 0.010 mmol) in toluene (1 mL) heated at 80 °C was added
dropwise a solution of tri-n-butyltin hydride (55 µL, 0.20 mmol)
in toluene (1 mL) via syringe pump over 3.5 h. After the
addition, the resultant solution was stirred at the same
temperature for a further 1 h. The mixture was cooled to room
temperature and concentrated in vacuo. Purification by flash
column chromatography on silica gel (25-50% ethyl acetate/
hexanes) gave oxepane 6 (13.7 mg, 85%) as a colorless oil:
[R]D26 ) +69.9° (c 1.3, CHCl3); IR (film) 3030, 2947, 1739, 1642,
1H NMR (CDCl3, 500 MHz) δ 7.34-7.19 (m, 15H), 5.75 (dddd,
J ) 17.0, 11.0, 8.0, 6.2 Hz, 1H), 5.04 (dd, J ) 11.0, 1.1 Hz,
1H), 5.03 (dd, J ) 17.0, 1.1 Hz, 1H), 4.86 (d, J ) 11.9 Hz, 1H),
4.68 (d, J ) 11.3 Hz, 1H), 4.65-4.59 (m, 4H), 4.54 (d, J ) 11.9
Hz, 1H), 4.42 (d, J ) 11.3 Hz, 1H), 3.89 (m, 1H), 3.77-3.72
(m, 2H), 3.67-3.61 (m, 2H), 3.58 (dd, J ) 10.4, 5.3 Hz, 1H),
3.38 (ddd, J ) 11.3, 9.5, 5.0 Hz, 1H), 3.34 (s, 3H), 3.36-3.25
(m, 4H), 3.19 (ddd, J ) 8.9, 5.3, 2.0 Hz, 1H), 3.13 (ddd, J )
11.3, 8.9, 4.4 Hz, 1H), 2.26 (ddd, J ) 11.9, 5.0, 5.0 Hz, 1H),
2.18 (ddd, J ) 14.6, 7.4, 6.2 Hz, 1H), 2.03 (ddd, J ) 14.6, 8.0,
5.9 Hz, 1H), 1.93 (m, 1H), 1.86 (ddd, J ) 14.3, 6.5, 2.9 Hz,
1H), 1.79 (ddd, J ) 14.3, 11.0, 1.4 Hz, 1H), 1.63 (ddd, J ) 11.9,
11.3, 11.3 Hz, 1H), 1.55 (m, 2H), 1.28 (s, 3H), 1.13 (m, 1H);
13C NMR (CDCl3, 125 MHz) δ 139.5, 138.6, 138.3, 134.4, 128.4,
128.3, 128.2, 128.1, 127.7, 127.65, 127.60, 127.4, 127.2, 117.6,
96.9, 82.9, 80.6, 80.1, 79.7, 78.7, 73.7, 73.45, 73.43, 73.41, 73.2,
72.1, 70.9, 70.5, 67.8, 67.6, 55.3, 39.5, 32.8, 32.3, 29.9, 25.2,
9.4; HRMS (FAB) calcd for C43H56O9Na ((M + Na)+) 739.3822,
found 739.3803.
Alcoh ol 27. To a solution of olefin 26 (16.7 mg, 0.0233
mmol) in CH2Cl2 (1.5 mL) at 0 °C were added dimethyl sulfide
(0.15 mL, 2.0 mmol) and boron trifluoride etherate (10 µL,
0.079 mmol). The resultant solution was stirred at room
temperature for 1 h before the reaction was quenched with
saturated aqueous NaHCO3 (0.5 mL). The mixture was
extracted with ethyl acetate (20 mL), and the extracts were
washed with saturated aqueous NaHCO3 and brine, dried over
Na2SO4, filtered, and concentrated in vacuo. Purification by
flash chromatography on silica gel (20-40% ethyl acetate/
hexanes) gave alcohol 27 (13.0 mg, 83%) as a colorless oil:
27
[R]D ) +66.3° (c 0.27, CHCl3); IR (film) 3468, 3063, 3030,
2938, 2862, 1641, 1496, 1453, 1361, 1281, 1209, 1088, 1029,
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985, 914, 737 cm-1; H NMR (CDCl3, 500 MHz) δ 7.34-7.19
(m, 15H), 5.75 (dddd, J ) 17.4, 11.4, 8.1, 6.3 Hz, 1H), 5.05
(dd, J ) 17.4, 1.8 Hz, 1H), 5.04 (dd, J ) 11.4, 1.8 Hz, 1H),
4.86 (d, J ) 12.0 Hz, 1H), 4.68 (d, J ) 12.0 Hz, 1H), 4.61 (d,
J ) 11.1 Hz, 1H), 4.60 (d, J ) 12.0 Hz, 1H), 4.54 (d, J ) 12.0
Hz, 1H), 4.42 (d, J ) 11.1 Hz, 1H), 3.87 (m, 1H), 3.79-3.70
(m, 3H), 3.67-3.58 (m, 4H), 3.54 (dd, J ) 6.6, 1.5 Hz, 1H),
3.38 (ddd, J ) 11.4, 9.6, 4.8 Hz, 1H), 3.32-3.27 (m, 2H), 3.14-