3346 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 10
Rønnest et al.
benzaldehyde (0.07 mL, 0.654 mmol) in CH2Cl2 (4 mL) was added
a solution of sodium triacetoxyborohydride (104 mg, 0.490 mmol)
in CH2Cl2 (4 mL) at 0 °C under nitrogen atmosphere. Acetic acid
(90% aq, 0.03 mL, 0.654 mmol) was added and the mixture was
stirred at 20 °C for 48 h. The mixture was washed with sat. aq
NaHCO3 (15 mL) and water (15 mL). The combined aqueous
phases were extracted with CH2Cl2 (3 × 30 mL). The combined
organic phases were dried (MgSO4) and concentrated. The residue
was purified by column chromatography (toluene:CH2Cl2:EtOAc
30:30:1) to afford the product 9. Yield: 26 mg (17%) (yellow
needles); Rf (EtOAc:heptane 5:2): 0.54; mp: 79-80 °C. IR (KBr,
(1H, s), 5.49 (1H, s), 4.06 (3H, s), 3.97 (3H, s), 3.95-3.84 (2H,
m), 3.02 (1H, dd, J ) 16.5, 13.5 Hz), 2.89-2.75 (3H, m), 2.40
(1H, dd, J ) 16.5, 4.6 Hz), 0.94 (3H, d, J ) 6.7 Hz). 13C NMR
(75 MHz, CDCl3) 197.0, 192.5, 169.8, 169.5, 164.5, 157.6, 137.2,
128.8 (2C), 128.3 (2C), 126.4, 105.1, 105.0, 97.1, 90.7, 89.4, 69.9,
57.0, 56.3, 39.9, 36.1, 34.7 14.1. HRMS (ESI+) calcd for
[C24H24ClO6] 443.1261, found 443.1264.
(2S,6′R)-(7-Chloro-4,6-dimethoxy-benzofuran-3-one)-2-spiro-1′-(6′-
methyl-2′-(4-methylbenzyloxy)-cyclohex-2′-ene-4′-one) (23). Yield: 201
mg (54%) (white crystals); Rf (EtOAc:heptane 5:1): 0.45; mp:
1
176-178 °C. IR (KBr, cm-1) 1709, 1664. H NMR (300 MHz,
1
cm-1) 1709, 1664. H NMR (CDCl3) δ 7.31-7.18 (5H, m), 5.52
CDCl3) δ 7.11-7.04 (4H, m), 6.09 (1H, s), 5.58 (1H, s), 4.87 (1H,
d, J ) 12.2 Hz), 4.76 (1H, d, J ) 12.2 Hz), 4.01 (3H, s), 3.95 (3H,
s), 3.04 (1H, dd, J ) 16.5, 13.4 Hz), 2.85 (1H, ddq, J ) 13.2, 4.5,
6.6 Hz), 2.41 (1H, dd, J ) 16.4, 4.4 Hz), 2.30 (3H, s), 0.97 (3H,
d, J ) 6.6 Hz). 13C NMR (75 MHz, CDCl3) δ 197.1, 192.7, 169.9,
169.8, 164.7, 157.9, 138.2, 131.8, 129.5 (2C), 127.0 (2C), 106.2,
105.8, 97.1, 91.0, 89.7, 71.0, 57.2, 56.6, 40.2, 36.7, 21.4, 14.5.
HRMS (ESI+) calcd for [C24H24ClO6]+ 443.1261, found 443.1273.
(1H, s), 4.30 (2H, s), 3.90 (3H, s), 3.86 (3H, s), 3.60 (3H, s), 2.93
(1H, dd, J ) 16.1, 13.3 Hz), 2.85-2.75 (1H, m), 2.40 (1H, dd, J
) 16.1, 4.1 Hz), 0.89 (3H, d, J ) 6.5 Hz). 13C NMR (CDCl3) δ
196.8, 194.1, 171.1, 163.9, 156.8, 146.6, 140.2, 128.8 (2C), 128.2
(2C), 127.6, 110.2, 106.2, 105.2, 105.1, 90.1, 62.6, 60.5, 57.0, 51.5,
40.2, 36.8, 14.5. HRMS (ESI+) calcd for [C24H25ClNO6]+ 458.1370,
found 458.1371.
General Procedure for the Synthesis of Enol Ethers by Solvoly-
sis (16 and 17). CSA (0.1 mmol, 0.1 equiv) was added to a solution
of griseofulvic acid (0.6 mmol, 1 equiv), the appropriate alcohol
(3 mmol, 5 equiv), and 1,4-dioxane (3 mL). The mixture was stirred
at 100 °C for 6 h and then cooled to 20 °C. EtOAc (20 mL) was
added to the solution, and the mixture was washed with sat.
NaH2PO4 (20 mL) and then water (20 mL). The combined aqueous
phases were extracted with EtOAc (3 × 20 mL), dried (MgSO4),
and then concentrated. The residue was purified by column
chromatography (toluene:CH2Cl2:EtOAc 7:7:1) to afford the desired
product and the isomer. When possible the product was recrystal-
lized from EtOAc/Heptane.
(2S,6′R)-(7-Chloro-4,6-dimethoxy-benzofuran-3-one)-2-spiro-1′-(2′-
(4-biphenylmethoxy)-6′-methyl-cyclohex-2′-ene-4′-one) (24). Yield: 54
mg (19%); Rf (toluene:CH2Cl2:heptane 2:2:1): 0.32. IR (KBr, cm-1
)
1
1704, 1662. H NMR (300 MHz, CDCl3) δ 7.58-7.50 (4H, m),
7.46-7.40 (2H, m), 7.37-7.31 (1H, m), 7.28-7.23 (2H, m), 6.10
(1H, s), 5.63 (1H, s), 4.97 (1H, d, J ) 12.4 Hz), 4.85 (1H, d, J )
12.4 Hz), 4.01 (3H, s), 3.96 (3H, s), 3.07 (1H, dd, J ) 16.5, 13.4
Hz), 2.88 (1H, ddq, J ) 13.4, 4.6, 6.6 Hz), 2.45 (1H, dd, J ) 16.5,
4.6 Hz), 1.00 (3H, d, J ) 6.6 Hz). 13C NMR (50 MHz, CDCl3) δ
197.0, 192.4, 169.5 (2C), 164.5, 157.7, 141.0, 140.4, 133.6, 128.7
(4C), 127.2, 127.0 (4C), 105.9, 105.3, 97.2, 90.7, 89.4, 70.4, 56.9,
56.3, 40.0, 36.3, 14.2. HRMS (ESI+) calcd for [C29H26ClO6]+
505.1418, found 505.1421.
(2S,6′R)-(7-Chloro-4,6-dimethoxy-benzofuran-3-on)-2-spiro-1′-(2′-
cyclopropylmethoxy-6′-methyl-cyclohex-2′-en-4′-one) (16). Yield: 86
mg (4%) (white crystals); Rf (EtOAc:heptane 5:1): 0.51; mp:
(2S,6′R)-(7-Chloro-4,6-dimethoxy-benzofuran-3-one)-2-spiro-1′-
(2′-(1-adamantylmethoxy)-6′-methyl-cyclohex-2′-ene-4′-one) (25).
Yield: 5 mg (2%); Rf (toluene:CH2Cl2:EtOAc 3:3:1): 0.16. 1H NMR
(300 MHz, CDCl3) δ 6.05 (1H, s), 5.37 (1H, s), 3.96 (3H, s), 3.91
(3H, s), 3.26 (1H, d, J ) 9.2 Hz), 3.13 (1H, d, J ) 9.2 Hz), 3.03
(1H, dd, J ) 16.6, 13.6 Hz), 2.87-2.71 (1H, m), 2.36 (1H, dd, J
) 16.6, 4.8 Hz), 1.83-175 (3H, m), 1.63-1.50 (4H, m), 1.45-1.28
(6H, m), 1.20-1.13 (2H, m), 0.95 (3H, d, J ) 6.7 Hz). 13C NMR
(50 MHz, CDCl3) δ 197.1, 192.8, 170.3 (2C), 164.5, 157.7, 104.2
(2C), 97.4, 91.3, 89.3, 78.6, 57.0, 56.4, 40.3, 38.8 (3C), 36.8 (3C),
35.7, 33.5, 27.9 (3C), 14.3. HRMS (ESI+) calcd for [C27H32ClO6]+
487.1887, found 487.1888.
1
190-191 °C. IR (KBr, cm-1) 1704, 1659, 1608. H NMR(500
MHz, CDCl3) δ 6.13 (1H, s), 5.47 (1H, s), 4.03 (3H, s), 3.98 (3H,
s), 3.65 (2H, d, J ) 6.5 Hz), 3.03 (1H, dd, J ) 16.7, 13.5 Hz),
2.83 (1H, ddq, J ) 13.5, 4.7, 6.6 Hz), 2.41 (1H, dd, J ) 16.7, 4.7
Hz), 1.05-0.98 (1H, m), 0.96 (3H, d, J ) 6.6 Hz), 0.50-0.43 (2H,
m), 0.22-0.13 (2H, m). 13C NMR (50 MHz, CDCl3) δ 197.0, 192.5,
169.9, 169.6, 164.4, 157.6, 105.0 (2C), 97.1, 90.8, 89.3, 73.2, 56.9,
56.3, 39.9, 36.2, 14.2, 9.0, 2.7 (2C). HRMS (ESI+) calcd for
[C20H22ClO6]+ 393.1105, found 393.1108. Anal. (C20H21ClO6): C,
H.
(2S,6′R)-(7-Chloro-4,6-dimethoxy-benzofuran-3-on)-2-spiro-1′-
(2′-cyclopentoxy-6′-methyl-cyclohex-2′-en-4′-one) (17). Yield: 50 mg
(2S,6′R)-(7-Chloro-4,6-dimethoxy-benzofuran-3-one)-2-spiro-1′-
(2′-benzyloxy-6′-methylcyclohex-2′-ene-4′-one-4′-oxime) (29). To a
solution of 20 (0.20 mmol, 1.0 equiv) in EtOH (5 mL, 0.03M) and
DMSO (2.5 mL, 0.03M) was added hydroxylamine hydrochloride
(0.70 mmol, 3.5 equiv) and sodium acetate (0.86 mmol, 4.3 equiv).
The mixture was stirred at 75 °C for 24 h, allowed to reach 20 °C,
and diluted with CH2Cl2 (20 mL). The mixture was washed with
distilled water (2 × 15 mL) and then brine (15 mL). The organic
phase was dried (MgSO4) and concentrated. The crude mixture was
purified by column chromatography (toluene:CH2Cl2:EtOAc 2:2:
1) to afford the desired product.
(4%) (yellow oil); Rf (EtOAc:heptane 5:1): 0.50. IR (KBr, cm-1
)
1
1705, 1652, 1615. H NMR (500 MHz, CDCl3) δ 6.11 (1H, s),
5.49 (1H, s), 4.56-4.51 (1H, m), 4.03 (3H, s), 3.97 (3H, s), 3.03
(1H, dd, J ) 16.7, 13.5 Hz), 2.82 (1H, ddq, J ) 13.5, 4.8, 6.7 Hz),
2.40 (1H, dd, J ) 16.7, 4.8 Hz), 1.79-1.72 (2H, m), 1.72-1.64
(2H, m), 1.58-1.44 (4H, m), 0.95 (3H, d, J ) 6.7 Hz). 13C NMR
(50 MHz, CDCl3) δ 197.1, 192.6, 169.6, 169.0, 164.3, 157.5, 105.8,
105.1, 97.0, 90.9, 89.2, 81.6, 56.8, 56.3, 39.8, 36.1, 32.1 (2C), 23.7
(2C) 14.2. HRMS (ESI+) calcd for [C21H24ClO6]+ 407.1261, found
407.1262.
General Procedure for the Synthesis of Enol Ethers by
Addition-Elimination (19-25). To a solution of 18 (0.65 mmol,
1 equiv) in 1,4-dioxane (3 mL, 0.2 M) was added the desired alcohol
(1.30 mmol, 2 equiv) and DBU (1.63 mmol, 2.5 equiv). The mixture
was heated to 100 °C and stirred for 12 h. The mixture was then
cooled to 20 °C, and excess reagent was quenched with sat. aq
NH4Cl (30 mL). The aqueous phase was extracted with EtOAc (3
× 30 mL) and the combined organic phases were dried (MgSO4)
and then concentrated. The residue was purified by column
chromatography (heptane:EtOAc 3:2) affording the product. When
possible the product was recrystallized from EtOAc/heptane.
(2S,6′R)-(7-Chloro-4,6-dimethoxy-benzofuran-3-on)-2-spiro-1′-
(6′-methyl-2′-(2-phenylethoxy)-cyclohex-2′-en-4′-one) (22). Yield:
Yield: 167 mg (82%) (white needles); Rf (EtOAc:heptane 5:1):
1
0.39 and 0.36; mp: 139-141 °C. IR (KBr, cm-1) 1706, 1614. H
NMR (300 MHz, CDCl3) δ 8.63 (1H, s), 7.30-7.13 (5H, m), 6.36
(0.5H, s), 6.07 (1H, s), 6.68 (0.5H, s), 4.99-4.71 (2H, m), 3.99
(3H, s), 3.93 (3H, s), 3.14 (0.5H, dd, J ) 16.6, 4.7 Hz), 3.04 (0.5H,
dd, J ) 15.0, 13.2 Hz), 2.73 (0.5H, dd, J ) 16.6, 13.0 Hz),
2.69-2.51 (1H, m), 2.42 (0.5H, dd, J ) 15.0, 4.2 Hz), 0.98 (1.5H,
d, J ) 6.6 Hz), 0.97 (1.5H, d, J ) 6.8 Hz). 13C NMR (75 MHz,
CDCl3) δ 194.0 (0.5C), 193.8 (0.5C), 169.5, 164.2, 159.8 (0.5C),
157.4, 157.2 (0.5C), 155.1 (0.5C), 151.8 (0.5C), 135.7 (0.5C), 135.5
(0.5C), 128.3 (2C), 127.7 (0.5C), 127.6 (0.5C), 126.6, 126.5, 105.7,
100.3 (0.5C), 97.0, 93.7 (0.5C), 91.5 (0.5C), 91.4 (0.5C), 89.1, 70.0
(0.5C), 69.7 (0.5C), 56.9, 56.2, 36.4 (0.5C), 35.2 (0.5C), 30.9 (0.5C),
25.5 (0.5C), 14.4 (0.5C), 14.3 (0.5C). HRMS (ESI+) calcd for
[C23H23ClNO6]+ 444.1214, found 444.1204.
1
199 mg (86%); Rf (toluene:CH2Cl2:EtOAc 1:1:1): 0.50. H NMR
(300 MHz, CDCl3) δ 7.20-7.12 (3H, m), 7.03-6.95 (2H, m), 6.13