Analogues of Diacylglycerol
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 18 5745
with BCl3 (1 M in CH2Cl2, 4.5 mL). After 20 min at -78 °C,
the reaction was quenched with a saturated aqueous NaHCO3
solution (20 mL) and the mixture was immediately partitioned
between CH2Cl2 (15 mL) and the aqueous NaHCO3 solution.
The organic layer was washed with water and brine, dried
(MgSO4), and concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel with EtOAc/
hexanes (1:4) as eluant to give 24 as an oil (530 mg, 86%): 1H
NMR (CDCl3) δ 6.84 (s, 4 H, PhOCH3), 6.23-6.28 (tt, 1H, J )
7.6, 2.2 Hz, >CdCH), 4.00 (AB q, 2 H, J ) 9.5, Hz, OCH2-
PhOCH3), 3.80 (br AB q, 2 H, J ) 12.1, Hz, CH2OH), 3.76 (s,
3 H, OCH3), 2.98 (d of irr quartets, 1 H, J ) 16.4 Hz, H-4a),
2.89 (d of irr quartets, 1 H, J ) 16.4 Hz, H-4b), 2.62-2.74 (m,
2 H, >CHdCHCH2), 2.16 (br s, 1 H, CH2OH), 1.57-1.71
(overlapping septet and quintet, 3 H, 2 × CHMe2, CH(i-Bu)2),
1.10 (irr t, 4 H, 2 × CH2CHMe2), 0.83-0.88 (m, 12 H, 4 × CH3);
13C NMR (CDCl3) δ 169.1, 154.5, 152.6, 144.7, 125.0, 115.8,
114.8, 83.0, 70.3, 65.5, 55.9, 44.1, 33.4, 32.2, 25.3, 23.2, 22.9,
22.8; FABMS m/z (relative intensity) 405 (MH+, 57.3), 404
(M•+, 100). Anal. (C24H36O5) C, H.
(Z)-{2-[(4-Methoxyphenoxy)methyl]-4-[5-methyl-3-(2-
methylpropyl)hexylidene]-5-oxo-2-2,3-dihydrofuryl}-
methyl Methylsulfonate (26). A solution of 24 (510 mg, 1.3
mmol) in CH2Cl2 (5 mL) was cooled to 0 °C, treated with
triethylamine (0.54 mL, 3.9 mmol) and methanesulfonyl
chloride (0.15 mL, 1.95 mmol), and stirred for 10 min while
slowly warming to room temperature. The reaction mixture
was concentrated in vacuo and the residue was purified by
flash column chromatography on silica gel with EtOAc/hexanes
(1:10) as eluant to give 26 as an oil (640 mg, 100%): 1H NMR
(CDCl3) δ 6.82 (s, 4 H, PhOCH3), 6.29-6.34 (tt, 1 H, J ) 7.6,
2.3 Hz, >CdCH), 4.43 (s, 2 H, CH2SO2CH3), 4.01 (AB q, 2 H,
J ) 9.7, Hz, OCH2PhOCH3), 3.76 (s, 3 H, OCH3), 3.04 (s, 3 H,
SO2CH3), 3.02 (d of irr quartets, 1 H, J ) 16.6 Hz, H-3a), 2.96
(d of irr quartets, 1 H, J ) 16.6 Hz, H-3b), 2.62-2.75 (m, 2 H,
>CHdCHCH2), 1.58-1.71 (m, 3 H, 2 × CHMe2, CH(i-Bu)2),
1.04-1.16 (m, 4 H, 2 × CH2CHMe2), 0.80-0.89 (m, 12 H, 4 ×
CH3); 13C NMR (CDCl3) δ 168.1, 154.8, 152.1, 145.9, 123.5,
115.8, 114.9, 80.3, 70.3, 70.0, 55.8, 44.1, 37.8, 33.7, 33.4, 32.3,
25.3, 23.2, 22.9, 22.8; FABMS m/z (relative intensity) 483
(MH+, 71.5), 482 (M•+, 100). Anal. (C25H38O7S) C, H.
(Z)-{2-(Hydroxymethyl)-4-[5-methyl-3-(2-methylpro-
pyl)hexylidene-5-oxo-2-2,3-dihydrofuryl}methyl Methyl-
sulfonate (28). A solution of 26 (618 mg, 1.28 mmol) in
CH3CN/H2O (4:1, 8 mL) was cooled to 0 °C and treated with
ammonium cerium(IV) nitrate (2.1 g, 3.84 mmol). After 30 min
of being stirred at the same temperature, the reaction mixture
was diluted with EtOAc (10 mL). The organic layer was
washed with water and brine, dried (MgSO4), and concentrated
in vacuo. The residue was purified by flash column chroma-
tography on silica gel with EtOAc/hexanes (1:4) as eluant to
give 28 as an oil (453 mg, 93%): 1H NMR (CDCl3) δ 6.28-
6.33 (tt, 1 H, J ) 7.6, 2.3 Hz, >CdCH), 4.36 (AB q, 2 H, J )
11.1 Hz, CH2SO2CH3), 3.69-3.76 (m, 2 H, CH2OH), 3.07 (s, 3
H, SO2CH3), 2.85 (br AB q, 2 H, J ) 17.1 Hz, H-3), 2.65-2.71
(m, 2 H, >CHdCHCH2), 2.18 (br s, 1 H, CH2OH), 1.60-1.71
(m, 3 H, 2 × CHMe2, CH(i-Bu)2), 1.02-1.15 (m, 4 H, 2 ×
CH2CHMe2), 0.85-0.87 (m, 12 H, 4 × CH3); 13C NMR (CDCl3)
δ 168.5, 146.0, 123.7, 81.8, 69.8, 64.6, 44.1, 37.7, 33.4, 33.0,
32.3, 25.3, 23.2, 23.1, 22.8; FABMS m/z (relative intensity) 377
(MH+, 100.0). Anal. (C18H32O6S) C, H.
(1:10) as eluant to give 10 (59 mg, 30%) as an oil: 1H NMR
(CDCl3) δ 6.01 (t, 1 H, J ) 7.2 Hz, >CdCH), 3.86 (AB q, 2 H,
J ) 10.7, Hz, CH2OCH2C(CH3)3), 3.71 (dd, 1 H, J ) 12.3, 4.9
Hz, CHHOH), 3.64 (dd, 1 H, J ) 12.3, 7.8 Hz CHHOH), 2.83
(d, 1 H, J ) 4.7 Hz, H-4a), 2.68 (s, 2 H, OCH2C(CH3)3), 2.66
(d, 1 H, J ) 4.7 Hz, H-4b), 2.46 (irr t, 2 H, J ≈ 6.6 Hz, >CHd
CHCH2), 1.98-2.01 (br dd, J ≈ 8.0, 5.2 Hz, 1 H, CH2OH),
1.54-1.66 (m, 3 H, 2 × CHMe2, CH(i-Bu)2), 1.06-1.10 (m, 4
H, 2 × CH2CHMe2), 0.98 (s, 9 H, OCH2C(CH3)3), 0.87 (br s, 6
H, 2 × CH3), 0.85 (br s, 6 H, 2 × CH3); 13C NMR (CDCl3) δ
171.4, 168.5, 145.6, 127.0, 74.4, 63.5, 59.4, 49.7, 44.2, 36.4, 34.5,
33.4, 31.5, 26.8, 25.3, 23.2, 23.2, 22.9; FABMS m/z (relative
intensity) 369 (MH+, 100.0). Anal. Calcd for C22H40O4‚
0.8H2O: C, 69.00; H, 10.95. Found: C, 68.82; H, 10.28.
(E)-5-(Hydroxymethyl)-5-[(4-methoxyphenoxy)methyl]-
3-[5-methyl-3-(2-methylpropyl)hexylidene]-4,5-dihydro-
furan-2-one (23). Starting from 21 (592 mg, 1.2 mmol) and
following the same procedure as for 24, compound 23 was
obtained as an oil (360 mg, 74%): 1H NMR (CDCl3) δ 6.82 (s,
4 H, PhOCH3), 6.78-6.84 (m, 1H, >CdCH), 4.04 (AB q, 2 H,
J ) 9.6 Hz, OCH2Ph), 3.87 (dd, 1 H, J ) 12.3, 7.2 Hz,
CHHOH), 3.78 (dd, 1 H, J ) 12.3, 6.4 Hz, CHHOH), 3.77 (s, 3
H, OCH3), 2.92 (dm, 1 H, J ) 16.7 Hz, H-4a), 2.78 (dm, 1 H,
J ) 16.7 Hz, H-4b), 2.13-2.16 (irr t, 2 H, >CHdCHCH2), 1.98
(br t, 1 H, J ≈ 7 Hz, CH2OH), 1.72 (irr quintet, 1 H, CH(i-
Bu)2), 1.64 (irr septet of doublets, 2 H, 2 × CHMe2), 1.05-
1.16 (m, 4 H, 2 × CH2CHMe2), 0.79-0.89 (m, 12 H, 4 × CH3);
13C NMR (CDCl3) δ 170.1, 154.6, 152.6, 141.1, 127.1, 115.8,
114.8, 83.7, 70.4, 65.6, 55.9, 44.0, 34.9, 33.0, 30.3, 25.4, 23.1,
22.8; FABMS m/z (relative intensity) 405 (MH+, 53.8), 404 (M+,
100). Anal. (C24H36O5‚0.2H2O) C, H.
(E)-{2-[(4-Methoxyphenoxy)methyl]-4-[5-methyl-3-(2-
methylpropyl)hexylidene]-5-oxo-2-2,3-dihydrofuryl}-
methyl Methylsulfonate (25). Starting from 23 (347 mg,
0.86 mmol) and following the same procedure as for 26,
compound 25 was obtained as an oil (415 mg, 100%): 1H NMR
(CDCl3) δ 6.79 (s, 4 H, PhOCH3), 6.76-6.84 (m, 1H, >CdCH),
4.41 (s, 2 H, CH2SO2CH3), 3.98 (AB q, 2 H, J ) 9.7 Hz,
OCH2Ph), 3.72 (s, 3 H, OCH3), 3.01 (s, 3 H, SO2CH3), 2.90 (dm,
1H, J ) 16 Hz, H-3a), 2.82 (dm, 1 H, J ) 16 Hz, H-3b), 2.09-
2.14 (m, 2 H, >CHdCHCH2), 1.68 (quintuplet, 1 H, CH(i-Bu)2),
1.59 (m, 2 H, 2 × CHMe2), 1.00-1.13 (m, 4 H, 2 × CHCH2-
CHMe2), 0.76-0.88 (m, 12 H, 4 × CH3); 13C NMR (CDCl3) δ
169.1, 154.8, 152.1, 142.3, 125.6, 115.8, 114.9, 80.9, 70.4, 70.2,
55.8, 44.0, 37.9, 35.1, 33.0, 30.7, 25.4, 23.1, 22.8, 22.7; FABMS
m/z (relative intensity) 483 (MH+, 62.0), 482 (M•+, 100). Anal.
(C25H38O7S) C, H.
(E)-{2-(Hydroxymethyl)-4-[5-methyl-3-(2-methylpro-
pyl)hexylidene-5-oxo-2-2,3-dihydrofuryl}methyl Methyl-
sulfonate (27). Starting from 25 (415 mg, 0.86 mmol) and
following the same procedure as for 28, compound 27 was
obtained as an oil (271 mg, 84%): 1H NMR (CDCl3) δ 6.72-
6.77 (m, 1 H, >CdCH), 4.30 (AB q, 2 H, J ) 11.1 Hz,
CH2SO2CH3), 3.68 (br s, 2 H, CH2OH), 3.03 (s, 3 H, SO2CH3),
2.94 (br s, 1 H, CH2OH), 2.71 (m, 2 H, H-3), 2.07 (m, 2 H,
>CHdCHCH2), 1.66 (irr quintet, 1 H, CH(i-Bu)2), 1.57 (irr
septet, 2 H, 2 × CHMe2), 0.97-1.10 (m, 4 H, 2 × CH2CHMe2),
0.75-0.85 (m, 12 H, 4 × CH3); 13C NMR (CDCl3) δ 169.7, 142.3,
126.0, 82.7, 70.0, 64.7, 44.0, 37.7, 35.1, 32.9, 29.9, 25.4, 23.1,
22.8, 22.7; FABMS m/z (relative intensity) 377 (MH+, 100.0).
Anal. (C18H32O6S) C, H.
(Z)-5-[(2,2-Dimethylpropoxy)methyl)-5-(hydroxy-
methyl)-3-[5-methyl-3-(2-methylpropyl)hexylidene]-4,5-
dihydrofuran-2-one (10). A cooled solution of neopentyl
alcohol (190 mg, 2.2 mmol) in DMF (5 mL) at 0 °C was treated
with triethylamine (0.23 mL, 1.62 mmol). The cooling bath was
removed, and after 30 min of stirring at room temperature, a
solution of 28 (204 mg, 0.54 mmol) in DMF (5 mL) was added.
The resulting solution was stirred for 1 h, and the reaction
was quenched by the slow addition of water (5 mL). Following
several extractions with EtOAc (40 mL), the combined organic
layers were washed with water and brine, dried (MgSO4), and
concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel with ethyl ether/hexanes
(E)-5-[(2,2-Dimethylpropoxy)methyl)-5-(hydroxy-
methyl)-3-[5-methyl-3-(2-methylpropyl)hexylidene]-4,5-
dihydrofuran-2-one (9). Starting from 27 (147 mg, 0.39
mmol) and following the same procedure as for 10, compound
9 (100 mg, 70%) was obtained as an oil: 1H NMR (DMSO) δ
6.78 (t, 1 H, J ) 7.2 Hz, >CdCH), 4.81 (t, 1 H, J ) 6.0 Hz,
CH2OH), 3.71 (AB q, 2 H, J ) 10.5, Hz, CH2OCH2C(CH3)3),
3.43 (dd, 1 H, J ) 11.9, 5.8, CHHOH), 3.32 (dd, 1 H, J ) 11.9,
6.0 Hz, CHHOH), 2.67 (AB q, 2 H, J ) 14.2, Hz, OCH2C(CH3)3),
2.51 (d, 1 H, J ) 5.1 Hz, H-4a), 2.28 (d, 1 H, J ) 5.1 Hz, H-4b),
2.09 (irr t, 2 H, J ≈ 6.7 Hz, >CHdCHCH2), 1.48-1.61 (m, 3
H, 2 × CHMe2, CH(i-Bu)2), 0.93-1.05 (irr t, J ≈ 7.0 Hz, 4 H,
2 × CH2CHMe2), 0.86 (s, 9 H, OCH2C(CH3)3), 0.77-0.79