Total Synthesis of the Eupomatilones
purified by flash chromatography (30% EtOAc/hexane) to afford
the corresponding primary alcohol (0.10 g, 98%) as a syrup: 1H
NMR (CDCl3, 500 MHz) δ 6.82 (s, 1H), 6.40 (d, 1H, J ) 1.7 Hz),
6.36 (d, 1H, J ) 1.7 Hz), 5.97 (ABq, 2H, J ) 1.4 Hz, ∆ν ) 14.6
Hz), 4.78 (d, 1H, J ) 1.5 Hz), 3.85 (s, 3H), 3.84 (s, 3H), 3.83 (s,
3H), 3.82 (s, 3H), 3.42 (ABX, 2H, JAB ) 10.7 Hz, JAX ) 4.0 Hz,
JBX ) 5.9 Hz, ∆ν ) 57.7 Hz), 1.57-1.38 (m, 1H), 1.31-1.26 (m,
2H), 0.92 (s, 9H), 0.81 (d, 3H, J ) 6.9 Hz), 0.47 (d, 3H, J ) 6.9
Hz), -0.08 (s, 3H), -0.15 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 153.2, 153.1, 147.8, 140.6, 137.8, 137.3, 135.3, 132.0, 125.6,
108.9, 106.5, 102.8, 100.9, 71.5, 66.1, 60.9, 60.0, 56.2, 56.1, 42.4,
37.6, 26.0, 18.2, 14.9, 9.1, -3.9, -4.7; IR (neat) νmax 3436, 2931,
1618, 1583, 1508, 1472, 1423, 1409, 1306, 1234, 1127, 1080, 1047,
834, 773, 736 cm-1; HRMS (ESI, m/z calcd for C29H44O8SiNa
571.2697, found 571.2722.
A solution of n-Bu4NF (12 mg, 0.04 mmol) in THF (2 mL) was
added to a solution of the above primary alcohol (25 mg, 0.04
mmol) in THF at 25 °C and the reaction mixture was stirred for
2 h at this temperature. The volatiles were removed and the residue
was dissolved in EtOAc (10 mL), and then washed with water and
saturated aqueous NaCl. The organic layer was dried (Na2SO4) and
concentrated, and the residue was purified by flash chromatography
(40% EtOAc/hexane) to afford the diol 19 (18 mg, 94%): 1H NMR
(CDCl3, 500 MHz) δ 6.91 (s, 1H), 6.44 (d, 1H, J ) 1.7 Hz), 6.36
(d, 1H, J ) 1.7 Hz), 5.97 (s, 2H), 4.69 (d, 1H, J ) 2.2 Hz), 3.89
(s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.35 (ABX, 2H,
JAB ) 10.9 Hz, JAX ) 9.1 Hz, JBX ) 4.7 Hz, ∆ν ) 29.8 Hz), 2.92
(br s, 1H), 1.64-1.59 (m, 2H), 1.49-1.46 (m, 1H), 0.79 (d, 3H, J
) 7.2 Hz), 0.66 (d, 3H, J ) 7.2 Hz); 13C NMR (CDCl3, 125 MHz)
δ 153.1, 152.9, 148.3, 140.9, 137.2, 137.0, 135.7, 132.0, 126.4,
108.3, 106.9, 101.3, 101.1, 73.7, 64.2, 60.9, 60.1, 56.2, 56.1, 43.7,
39.9, 16.9, 5.7; IR (neat) νmax 3354, 2962, 1617, 1583, 1507, 1469,
1409, 1305, 1271, 1236, 1169, 1126, 1080, 1050, 1008, 972, 930,
844, 736 cm-1; HRMS (ESI), m/z calcd for C23H30O8Na 457.1832,
found 457.1824.
Eupomatilone 4 (1d). A solution of diol 19 (12 mg, 0.03 mmol),
TEMPO (1.0 mg), and n-Bu4NI (15 mg, 0.04 mmol) in CH2Cl2 (2
mL) and 2 mL of 0.5 M aqueous NaHCO3 and 0.05 M K2CO3
(1:1) was vigorously stirred at room temperature for 5 min.
N-Chlorosuccinimide (10 mg, 0.08 mmol) was added and the
reaction mixture was stirred for 1 h at this temperature. The reaction
mixture was diluted with CH2Cl2 (10 mL) and washed with water
and saturated aqueous NaCl. The organic layer was dried (Na2-
SO4) and concentrated, and the residue was purified by flash
chromatography (30% EtOAc/hexane) to afford eupomatilone 4 (1d,
11.8 mg, 98%): 1H NMR (CDCl3, 500 MHz) δ 6.76 (s, 1H), 6.43
(d, 1H, J ) 1.7 Hz), 6.30 (d, 1H, J ) 1.7 Hz), 6.00 (s, 2H), 5.28
(d, 1H, J ) 5.0 Hz), 3.93 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.83
(s, 3H), 2.71 (app quintet, 1H, J ) 7.3 Hz), 2.18 (qd, 1H, J ) 7.3,
5.2 Hz), 1.11 (d, 3H, J ) 7.3 Hz), 0.59 (d, 3H, J ) 7.3 Hz); 13C
NMR (CDCl3, 125 MHz) δ 178.5, 153.3, 153.1, 148.8, 141.0, 137.3,
136.3, 131.2, 129.0, 126.2, 107.7, 106.3, 101.3, 101.1, 80.4, 60.9,
60.0, 56.3, 56.2, 40.6, 39.1, 9.9, 9.8; IR (neat) νmax 2972, 2940,
2837, 1773, 1618, 1582, 1505, 1477, 1425, 1410, 1378, 1338, 1310,
1278, 1239, 1172, 1126, 1093, 1061, 1022, 975, 929, 839, 733
cm-1; HRMS (ESI) m/z calcd for C23H26O8Na 453.1519, found
453.1519.
1-((1S*,2R*)-1-(tert-Butyldimethylsilyl)oxy-2,3-dimethyl-3-
butenyl)-2-bromo-3,4,5-trimethoxybenzene (20). Following the
procedure for the preparation of 11, to a solution of (E)-2-methyl-
2-butene-1-ylmagnesium bromide in THF (0.3 M, 28 mL, 8.5
mmol) was added o-bromotrimethoxybenzaldehyde (1.91 g, 7.7
mmol) to afford syn and anti isomers (1:1) (2.4 g, 90%) as a syrup.
Syn isomer: 1H NMR (CDCl3, 500 MHz) δ 6.97 (s, 1H), 5.12 (app
t, 1H, J ) 2.4 Hz), 4.98 (s, 1H), 4.89 (s, 1H), 3.90 (s, 3H), 3.89 (s,
3H), 3.88 (s, 3H), 2.75-2.70 (m, 1H), 1.99 (d, 1H, J ) 2.1 Hz),
1.95 (s, 3H), 0.90 (d, 3H, J ) 7.1 Hz); 13C NMR (CDCl3, 125
MHz) δ 152.5, 150.5, 148.1, 142.1, 136.9, 111.7, 107.9, 107.2,
72.4, 61.1, 61.0, 56.1, 43.8, 22.3, 11.3; IR (neat) νmax 3472, 2969,
2937, 1642, 1568, 1481, 1448, 1426, 1394, 1324, 1194, 1162, 1105,
1037, 1009, 893, 817, 738 cm-1; HRMS (ESI) m/z calcd for C15H21-
BrO4Na 367.0521, found 367.0512. Anti isomer: 1H NMR (CDCl3,
500 MHz) δ 6.87 (s, 1H), 5.05 (d, 1H, J ) 9.1 Hz), 4.99 (s, 2H),
3.89 (s, 9H), 2.50 (qd, 1H, J ) 7.1, 9.0 Hz), 2.27 (br s, 1H), 1.80
(s, 3H), 0.92 (d, 3H, J ) 7.1 Hz); 13C NMR (CDCl3, 125 MHz) δ
153.2, 150.3, 147.2, 142.6, 137.4, 113.7, 110.5, 106.6, 73.7, 61.1,
61.0, 56.2, 50.5, 18.8, 15.6; IR (neat) νmax 3421, 2966, 2941, 1642,
1482, 1394, 1324, 1238, 1195, 1162, 1104, 1011, 886, 824 cm-1
;
HRMS (ESI) m/z calcd for C15H21BrO4Na 367.0521, found
367.0553.
Following the procedure for the preparation of 13, 2,6-lutidine
(0.3 mL, 2.6 mmol) and BuMe2SiOTf (0.44 mL, 1.9 mmol) were
added to a solution of the preceding syn isomer (0.6 g, 1.7 mmol)
to afford 20: 1H NMR (CDCl3, 500 MHz) δ 6.93 (s, 1H), 5.07 (d,
1H, J) 3.1 Hz), 4.82 (s, 1H), 4.77 (s, 1H), 3.89 (s, 3H), 3.88 (s,
3H), 3.85 (s, 3H), 2.40-2.35 (m, 1H), 1.86 (s, 3H), 0.97 (d, 3H, J
) 6.9 Hz), 0.89 (s, 9H), 0.03 (s, 3H), -0.21 (s, 3H); 13C NMR
(CDCl3, 500 MHz) δ 152.1, 150.0, 147.2, 141.8, 139.2, 111.8,
108.0, 107.9, 74.7, 61.1, 61.0, 56.0, 45.7, 25.9, 22.2, 18.2, 12.0,
-4.8, -5.2; IR (neat) νmax 3053, 2985, 2856, 1480, 1422, 1395,
1324, 1265, 1195, 1162, 1106, 1039, 1010, 895, 737, 704 cm-1
;
HRMS (ESI) m/z calcd for C21H35BrO4SiNa 481.1386, found
481.1360.
3-epi-Eupomatilone 6 (26). Following the previously described
procedure for the preparation of the eupomatilone 4 diol 19, a
solution of n-Bu4NF (18 mg, 0.07 mmol) in THF (2 mL) was added
to a solution of alcohol (30 mg, 0.06 mmol) to afford the
corresponding diol (22 mg, 95%): 1H NMR (CDCl3, 500 MHz) δ
6.99 (s, 2H), 6.87 (d, 1H, J ) 7.6 Hz), 6.86 (d, 1H, J ) 7.9 Hz),
6.72 (d, 2H, J ) 1.5 Hz), 6.70 (d, 1H, J ) 1.5 Hz), 6.68 (br s, 3H),
6.62 (dd, 1H, J ) 7.9, 1.5 Hz), 6.02 (d, 2H, J ) 1.3 Hz), 6.00 (br
s, 2H), 4.81 (d, 1H, J ) 2.0 Hz), 4.74 (d, 1H, J ) 2.0 Hz), 3.93 (s,
6H), 3.90 (s, 3H), 3.89 (s, 3H), 3.64 (s, 3H), 3.63 (s, 3H), 3.42 (td,
1H, J ) 2.1, 10.9 Hz), 3.35 (dd, 1H, J ) 4.5, 10.9 Hz), 2.32 (br,
2H), 1.67-1.60 (m, 2H), 1.55-1.50 (m, 2H), 1.30-1.22 (m, 2H),
0.81 (d, 3H, J ) 7.3 Hz), 0.79 (d, 3H, J ) 7.3 Hz), 0.69 (d, 6H,
J ) 7.1 Hz); IR (neat) νmax 3355, 2935, 1597, 1571, 1479, 1401,
1321, 1267, 1230, 1125, 1081, 1038, 935, 810, 737 cm-1; HRMS
(ESI) m/z calcd for C22H28O7SiNa 427.1733, found 427.1734.
Following the procedure for the preparation of eupomatilone 4,
N-chlorosuccinimide (10 mg) was added to a solution of the
preceding diol (15 mg, 0.04 mmol), TEMPO (1.0 mg), and n-Bu4-
NI (19 mg, 0.05 mmol) in CH2Cl2 (2 mL) and 2 mL of 0.5 M
aqueous NaHCO3 and 0.05 M K2CO3 (1:1) to afford 26 (two
atropisomers) (14 mg, 93%): 1H NMR (CDCl3, 500 MHz) δ 6.88
(d, 1H, J ) 7.9 Hz), 6.87 (d, 1H, J ) 7.9 Hz), 6.83 (s, 1H), 6.82
(s, 1H), 6.73 (d, 1H, J ) 1.4 Hz), 6.70 (dd, 1H, J ) 1.4, 7.9 Hz),
6.62 (d, 1H, J ) 1.4 Hz), 6.57 (dd, 1H, J ) 1.4, 7.9 Hz), 6.05 (dd,
2H, J ) 1.1, 4.3 Hz), 6.03 (m, 2H), 5.40 (d, 1H, J ) 4.9 Hz), 5.32
(d, 1H, J ) 4.9 Hz), 3.91 (s, 6H), 3.90 (s, 6H), 3.66 (s, 3H), 3.65
(s, 3H), 2.74 (app sextet, 2H, J ) 7.0 Hz), 2.20-2.10 (m, 2H),
1.12 (d, 6H, J ) 7.3 Hz), 0.56 (d, 3H, J ) 7.3 Hz), 0.54 (d, 3H,
J ) 7.3 Hz); 13C NMR (CDCl3, 125 MHz) δ 178.7, 152.9, 151.5,
147.7, 147.6, 147.0, 146.9, 141.6, 130.2, 129.2, 129.1, 126.3, 126.2,
123.5, 122.4, 110.6, 109.6, 108.5, 108.2, 105.0, 104.9, 101.2, 101.1,
80.6, 80.5, 61.2, 61.1, 60.8, 56.2, 40.7, 38.9, 38.6, 29.7, 9.9, 9.8,
9.7; IR (neat) νmax 2972, 2938, 1775, 1598, 1482, 1458, 1436, 1402,
1360, 1340, 1323, 1273, 1226, 1173, 1127, 1092, 1057, 1038, 1006,
970, 934, 910, 859, 810, 734 cm-1; HRMS (ESI) m/z calcd for
C22H24O7Na 423.1420, found 423.1416.
Eupomatilone 6 (1f). Pyridinium dichromate (15 mg, 0.07
mmol) was added to a solution of alcohol 27 (30 mg, 0.06 mmol)
in CH2Cl2 (1 mL) at 25 °C. The reaction mixture was stirred at
this temperature for 2 h, diluted with Et2O (15 mL), and washed
with water and saturated aqueous NaCl. The organic layer was dried
(Na2SO4) and concentrated to afford corresponding aldehyde (25
mg, 85%), which was used without further purification.
J. Org. Chem, Vol. 72, No. 23, 2007 8733