Ascochlorin Derivatives as Ligands for Receptors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4119
Hz), 5.46 (1H, t, J ) 7.0 Hz), 5.89 (1H, d, J ) 16.0 Hz), 10.42
Com p ou n d 6. 3-Ch lor o-4,6-d im eth oxy-2-m eth yl-5-
[(2E,4E)-3-m eth yl-5-((1R,2R,6R)-1,2,6-tr im eth yl-3-oxocy-
cloh exyl)-2,4-p en t a d ien yl]ben zoic Acid . NaH2PO4‚2H2O
(0.155 g, 0.993 mmol) and water (2.6 mL) were added to 32
(0.428 g, 0.989 mmol). tert-Butyl alcohol (10.4 mL), 2-methyl-
2-butene (0.460 mL, 4.34 mmol), and 90% sodium chlorite
(0.305, 3.04 mmol) were added to the mixture, which was then
stirred for 15 min at room temperature. The reaction mixture
was diluted with water and extracted with CH2Cl2. The organic
layer was washed with brine, dried (MgSO4), and evaporated
in vacuo to give 0.396 g of crude product. The product was
purified by silica gel column chromatography (CH2Cl2-MeOH)
to give 6 (0.384 g, 87%) as a colorless gum. IR (KBr disk): 3440,
1712 cm-1. NMR (CD3OD, 500 MHz): 0.70 (3H, s), 0.79
(3H, d, J ) 6.8 Hz), 0.82 (3H, d, J ) 6.8 Hz), 1.61 (1H, qd, J
) 13.4, 4.7 Hz), 1.92 (3H, s), 1.92-2.10 (2H, m), 2.24-2.29
(1H, m), 2.33 (3H, s), 2.50-2.62 (2H, m), 3.53 (2H, d, J )
7.0 Hz), 3.80 (3H, s), 3.81 (3H, s), 5.46 (1H, t, J ) 7.0 Hz),
5.48 (1H, d, J ) 15.8 Hz), 5.93 (1H, d, J ) 15.8 Hz). Anal.
(C25H33Cl O5) C, H.
(1H, s). Anal. (C28H37Cl O6) C, H.
Com p ou n d 9. {2-Ch lor o-4-for m yl-5-m eth oxy-3-m eth yl-
6-[(2E,4E)-3-m eth yl-5-((1R,2R,6R)-1,2,6-tr im eth yl-3-oxo-
cycloh exyl)-2,4-p en ta d ien yl]p h en oxy}a cetic Acid . A 20%
aqueous potassium carbonate solution (1 mL, 1.45 mmol) was
added to a solution of 8 (0.207 g, 0.409 mmol) in methanol,
and the mixture was stirred for 2 h at room temperature. The
reaction mixture was acidified to pH 2 with a 3 N aqueous
HCl solution and extracted with ether. The extract was washed
with water and brine, dried (MgSO4), and evaporated in vacuo.
The residue was purified by silica gel column chromatography
(CH2Cl2-MeOH) to give 9 as a colorless gum (0.122 g, 63%).
1
IR (film): 1715, 1696 cm-1. H NMR (CDCl3, 500 MHz): 0.70
(3H, s), 0.81 (3H, d, J ) 6.8 Hz), 0.83 (3H, d, J ) 6.8 Hz), 1.62
(1H, qd, J ) 13.5, 6.0 Hz), 1.91 (3H, br s), 1.91-1.97 (2H, m),
2.34-2.45 (3H, m), 2.63 (3H, s), 3.62 (2H, d, J ) 6.9 Hz), 3.84
(3H, s), 4.65 (2H, s), 5.42 (1H, d, J ) 16.0 Hz), 5.43 (1H, t, J
) 6.9 Hz), 5.89 (1H, d, J ) 16.0 Hz), 10.42 (1H, s). Anal.
(C26H33ClO6) C, H.
Com p ou n d s 18 a n d 19. 6-Ch lor o-5-h yd r oxy-2,7-d i-
m et h yl-2-[2-((1R,2R,6R)-1,2,6-t r im et h yl-3-oxocycloh ex-
yl)vin yl]ch r om a n -8-ca r b a ld eh yd e a n d 8-Ch lor o-5-h y-
dr oxy-2,7-dim eth yl-2-[2-((1R,2R,6R)-1,2,6-tr im eth yl-3-oxo-
cycloh exyl)vin yl]ch r om a n -6-ca r ba ld eh yd e. Compound 1
(400 mg, 0.989 mmol) was dissolved in concentrated H2SO4
(16 mL) and was left standing for 30 min at room temperature.
The reaction mixture was poured into ice water and extracted
with EtOAc. The organic layer was washed with water and
brine successively, dried (MgSO4), and concentrated in vacuo.
The residue was subjected to silica gel column chromatography
(hexane-acetone, 95:5-9:1) to give 18 and 19, which were
crystallized to 18 (80 mg, 20%) from hexane-acetone (9:1) and
to 19 (130 mg, 33%) from hexane-acetone (95:5), respectively.
Compound 18: mp 65 °C. IR (film): 1710, 1635 cm-1. 1H NMR
(CDCl3, 500 MHz): 0.55 (1.5H, d, J ) 7.0 Hz), 0.59 (1.5H, d,
J ) 7.0 Hz), 0.66 (3H, s), 0.79 (1.5H, d, J ) 7.0 Hz), 0.82 (1.5
H, d, J ) 7.0 Hz), 1.49 (3H, s), 1.54-1.63 (1H, m), 1.69-1.76
(0.5H, m), 1.82-1.95 (2.5H, m), 1.96-2.02 (1H, m), 2.19 (0.5H,
q, J ) 7.0 Hz), 2.30-2.41 (2.5H, m), 2.50-2.57 (1H, m), 2.66
(1.5H, s), 2.67 (1.5H, s), 2.76 (0.5H, t, J ) 5.0 Hz), 2.79 (0.5H,
t, J ) 5.0 Hz), 5.316 (0.5H, d, J ) 16.0 Hz), 5.323 (0.5H, d, J
) 16.0 Hz), 5.364 (0.5H, d, J ) 16.0 Hz), 5.370 (0.5H, d, J )
16.0 Hz), 6.183 (0.5H, s), 6.185 (0.5H, s), 10.592 (0.5H, s),
10.595 (0.5H, s). Anal. (C23H29ClO4) C, H. Compound 19: mp
Com p ou n d 10. 2-Ch lor o-4-for m yl-5-m eth oxy-3-m eth yl-
6-[(2E,4E)-3-m eth yl-5-((1R,2R,6R)-1,2,6-tr im eth yl-3-oxo-
cycloh exyl)-2,4-p en ta d ien yl]p h en yl P yr id in e-4-ca r box-
yla te. Isonicotinoyl chloride hydrochloride (71.7 mg, 0.403
mmol) was added to a solution of 7 (61.3 mg, 0.146 mmol) in
dry pyridine (1 mL). The reaction mixture was stirred for 3 h
at room temperature, water was added, and the solution was
stirred for an additional 30 min. The resulting mixture was
extracted with EtOAc, and the extract was washed with
aqueous CuSO4 solution, water, saturated aqueous NaHCO3
solution, and brine successively, dried (MgSO4), and concen-
trated in vacuo. The residue was subjected to silica gel column
chromatography (hexanes-EtOAc) to produce 10 (69.3 mg,
1
90%) as a colorless gum. IR (film): 1760, 1710, 1700 cm-1. H
NMR (CDCl3, 500 MHz): 0.69 (3H, s), 0.76-0.83 (6H, br),
1.59-1.64 (1H, m), 1.65 (3H, br s), 1.85-1.96 (2H, m), 2.32-
2.45 (3H, m), 2.67 (3H, s), 3.39-3.50 (1H, br), 3.50-3.63 (1H,
br), 3.88 (3H, s), 5.29 (1H, d, J ) 16.0 Hz), 5.34 (1H, t, J ) 7.0
Hz), 5.82 (1H, d, J ) 16.0 Hz), 7.79-7.99 (2H, m), 8.87 (2H,
m), 10.49 (1H, s). Anal. (C30H34ClNO5) C, H, N.
2,4-Di-O-m eth ylascoch lor in (32).3-Ch lor o-4,6-dim eth oxy-
2-m eth yl-5-[(2E,4E)-3-m eth yl-5-((1R,2R,6R)-1,2,6-tr im eth yl-
3-oxocycloh exyl)-2,4-p en ta d ien yl]ben za ld eh yd e. MeI (2
mL, 32.1 mmol) and potassium carbonate (2 g, 14.5 mmol) were
added to a solution of 1 (400 mg, 0.989 mmol) in acetone (20
mL). The mixture was heated at reflux for 3 h and filtered.
The filtrate was concentrated in vacuo and crystallized from
hexane to afford 32 (380 mg, 89%); mp 101 °C. IR (film): 1732,
1690 cm-1. 1H NMR (CDCl3, 500 MHz): 0.70 (3H, s), 0.81 (3H,
d, J ) 7.0 Hz), 0.83 (3H, d, J ) 7.0 Hz), 1.57-1.67 (1H, m),
1.93 (3H, br s), 1.91-1.97 (2H, m), 2.34-2.46 (3H, m), 2.64
(3H, s), 3.55 (2H, d, J ) 7.0 Hz), 3.83 (3H, s), 3.88 (3H, s),
5.41 (1H, d, J ) 16.0 Hz), 5.47 (1H, t, J ) 7.0 Hz), 5.89 (1H,
d, J ) 16.0 Hz), 10.42 (1H, s). Anal. (C25H33ClO4) C, H.
Com pou n d 16. 3-Ch lor o-4,6-dim eth oxy-2-m eth yl-5-[(E)-
2,3-ep oxy-3-m et h yl-5-((1R,2R,6R)-1,2,6-t r im et h yl-3-oxo-
cycloh exyl)-4-p en ten yl]ben za ld eh yd e. NaHCO3 (0.111 mg)
and m-chloroperbenzoic acid (70%, 157 mg, 0.637 mmol) were
added to a solution of 32 (229 mg, 0.530 mmol) in CH2Cl2 (7
mL). The mixture was stirred for 3 h in an ice bath, diluted
with water, and extracted with ether. The organic layer was
washed with 10% sodium thiosulfate aqueous solution, satu-
rated NaHCO3 aqueous solution, and brine, dried over
Na2SO4, and concentrated in vacuo. The residue was subjected
to silica gel column chromatography (hexanes-EtOAc, 5:1) to
give 16 (39 mg, 16%). IR (film): 1715, 1696, 1553, 1458, 1379,
1309, 1228, 1100 cm-1. 1H NMR (CDCl3, 500 MHz): 0.67 (3H,
s), 0.78 (1.5H, d, J ) 7.0 Hz), 0.804 (1.5H, d, J ) 7.0 Hz), 0.806
(1.5H, d, J ) 7.0 Hz), 0.83 (1.5 H, d, J ) 7.0 Hz), 1.557 (1.5H,
s), 1.562 (1.5H, s), 1.56-1.65 (1H, m), 1.87-1.95 (2H, m), 2.32-
2.44 (3H, m), 2.65 (3H, s), 2.97-3.00 (2H, m), 3.00-3.05 (1H,
m), 3.87 (3H, s), 3.93 (3H, s), 5.24 (0.5H, d, J ) 16.0 Hz), 5.25
(0.5H, d, J ) 16.0 Hz), 5.53 (0.5H, d, J ) 16.0 Hz), 5.5.54 (0.5H,
d, J ) 16.0 Hz), 10.42 (1H, s). Anal. (C25H33ClO5) C, H.
99 °C. IR (film): 1710, 1635 cm-1 1H NMR (CDCl3, 500
.
MHz): 0.52 (1.5H, d, J ) 7.0 Hz), 0.57 (1.5H, d, J ) 7.0 Hz),
0.66 (3H, s), 0.80 (1.5H, d, J ) 7.0 Hz), 0.83 (1.5 H, d, J ) 7.0
Hz), 1.53 (3H, s), 1.54-1.63 (1H, m), 1.68-1.76 (0.5H, m),
1.79-1.96 (2.5H, m), 1.97-2.03 (1H, m), 2.20 (0.5H, q,
J ) 7.0 Hz), 2.30-2.40 (2.5H, m), 2.40-2.50 (1H, m), 2.61
(1.5H, s), 2.63 (1.5H, s), 2.74 (0.5H, t, J ) 5.0 Hz), 2.78 (0.5H,
t, J ) 5.0 Hz), 5.304 (0.5H, d, J ) 16.0 Hz), 5.311 (0.5H, d, J
) 16.0 Hz), 5.346 (0.5H, d, J ) 16.0 Hz), 5.359 (0.5H, d, J )
16.0 Hz), 10.13 (0.5H, s), 10.14 (0.5H, s), 12.75 (1H, s). Anal.
(C23H29ClO4) C, H; C: calcd, 68.22; found, 68.70.
Com p ou n d 4. 2-Ch lor o-4-for m yl-5-h yd r oxy-3-m eth yl-
6-[(2E,4E)-3-m eth yl-5-((1R,2R,6R)-1,2,6-tr im eth yl-3-oxo-
cycloh exyl)-2,4-p en ta d ien yl]p h en yl P yr id in e-3-ca r box-
yla te. Nicotinoyl chloride hydrochloride (242 mg, 1.42 mmol)
was added to a solution of 1 (0.150 g, 0.358 mmol) in dry
pyridine (1.5 mL). The reaction mixture was stirred for 2 h at
room temperature, after which time water was added and the
solution was stirred for an additional 30 min. The resulting
mixture was extracted with ether. The extract was washed
with aqueous CuSO4 solution, water, saturated aqueous
NaHCO3 solution, and brine successively, dried (MgSO4), and
concentrated in vacuo. The residue was subjected to silica gel
column chromatography (hexanes-EtOAc, 3:1) to give 4
(242 mg, 39%). 1H NMR (CDCl3, 500 MHz): 0.68 (3H, s),
0.79 (3H, d, J ) 7.0 Hz), 0.81 (3H, d, J ) 7.0 Hz), 1.56-1.66
(1H, m), 1.71 (3H, s), 1.86-1.95 (2H, m), 2.30-2.44 (3H,
m), 2.69 (3H, s), 3.33-3.48 (1H, br), 3.48-3.63 (1H, br), 5.30
(1H, d, J ) 16.0 Hz), 5.39 (1H, t, J ) 7.0 Hz), 5.83 (1H, d,