Anti-AIDS Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 5 669
substituted seselin compound (0.25 mmol) was added. The
mixture was stirred at 0 °C for 2-4 days. Na2S2O5 (excess),
water, and CHCl3 were added. After stirring for 0.5 h at room
temperature, the mixture was extracted with CHCl3 three
times. The combined organic layer was dried over MgSO4, then
solvent was removed. The residue was separated by TLC to
obtain the pure substituted (+)-cis-khellactone. However, the
substituted (+)-cis-khellactone could be directly acylated,
without further purification, with (S)-(-)-camphanic chloride
(excess) in Py/CH2Cl2 for 1-2 days at room temperature. The
mixture was diluted with EtOAc and washed with 10% aq HCl,
water and brine, successively. The organic phase was dried
over anhydrous MgSO4, filtered, and concentrated. The residue
was separated by TLC (eluant: hexane/EtOAc ) 7:3) and
afforded the appropriately substituted 3′,4′-di-O-(S)-campha-
noyl-(+)-cis-khellactone derivative.
2.24, and 2.52 (each 2H, m, CH2 in camphanoyl group), 1.80
(4H, m, 2 × CH2), 2.54 (2H, m, CH2), 2.72 (2H, m, CH2), 5.39
(1H, d, J ) 4.8 Hz, H-3′), 6.64 (1H, d, J ) 4.8 Hz, H-4′), 6.82
(1H, d, J ) 8.8 Hz, H-6), and 7.50 (1H, d, J ) 8.8 Hz, H-5);
75% d.e.; [R]D +9.00° (c 2.29, CHCl3). Anal. (C38H44O11‚1/2H2O)
C, H.
(3′R,4′R)-3′,4′-Di-O-(S)-ca m p h a n oyl-5-m eth oxy-4-m eth -
yl-(+)-cis-k h ella cton e (8): yield 44% (starting with 125 mg
of 16h ); mp 144-6 °C; UV λmax nm (ꢀ) 318 (7215), 257 (5225),
1
248 (5135), 215 (13440); H NMR δ 0.98-1.14 (15H, ms, 5 ×
CH3), 1.44, 1.57 and 2.14 (each 3H, s, CH3), 1.69, 1.97, 2.17,
and 2.52 (each 2H, m, CH2 in camphanoyl group), 2.64 (3H, s,
CH3-4), 3.89 (3H, s, CH3O-5), 5.36 (1H, d, J ) 4.8 Hz, H-3′),
5.95 (1H, s, H-3), 6.27 (1H, s, H-6), 6.58 (1H, d, J ) 4.8 Hz,
H-4′); 90% d.e.; [R]D -9.62° (c 0.52, CHCl3). Anal. (C36H42O12
‚
1/2H2O) C, H.
(3′R,4′R)-3,4-Dim et h yl-3′,4′-d i-O-(S)-ca m p h a n oyl-(+)-
cis-k h ella cton e (1): yield 64% (starting with 256 mg of 16a );
white solid; mp 118-20 °C; 1H NMR δ 0.93-1.12 (15H, ms, 5
× CH3), 1.27, 1.49, and 1.55 (each 3H, s, CH3), 1.73, 1.92, 2.20,
and 2.48 (each 2H, m, CH2 in camphanoyl group), 2.13 (3H, s,
CH3-3), 2.38 (3H, s, CH3-4), 5.40 (1H, d, J ) 4.8 Hz, H-3′),
6.66 (1H, d, J ) 4.8 Hz, H-4′), 6.63 (1H, d, J ) 8.8 Hz, H-6),
and 7.54 (1H, d, J ) 8.8 Hz, H-5); 88% d.e.; [R]D +6.14° (c 2.15,
CHCl3). Anal. (C36H42O11‚2H2O) C, H.
(3′R,4′R)-3′,4′-Di-O-(S)-cam ph an oyl-4-isopr opyl-5-m eth -
yl-(+)-cis-k h ella cton e (9): yield 36% (starting with 110 mg
of 16i); white solid; mp 218-20 °C; UV λmax nm (ꢀ) 300 (6392),
208 (14875); 1H NMR δ 0.96-1.15 and 1.27-1.30 (18H, ms, 6
× CH3), 1.50 and 1.57 (each 3H, s, CH3), 1.69, 1.94, 2.19, and
2.49 (each 2H, m, CH2 in camphanoyl group), 1.12 and 1.13
(each 3H, d, J ) 6.6 Hz, CH(CH3)2-4), 2.24 (3H, s, CH3-5), 3.12
(1H, m, J ) 6.6 Hz, CH(CH3)2-4), 5.39 (1H, d, J ) 4.8 Hz, H-3′),
6.28 (1H, s, H-3), 6.40 (1H, d, J ) 4.8 Hz, H-4′), 6.86 (1H, s,
(3′R,4′R)-4,5-Dim et h yl-3′,4′-d i-O-(S)-ca m p h a n oyl-(+)-
cis-k h ella cton e (2): yield 70% (starting with 256 mg of 16b);
white solid; mp 137-8 °C; UV λmax nm (ꢀ) 298 (6141), 215
H-6); 95% d.e.; [R]D -54.74° (c 0.38, CHCl3). Anal. (C38H46O11
)
C, H.
5,7-Dih yd r oxy-2,2-d im eth yl-4-ch r om a n on e (17). To a
mixture of 1,3,5-benzenetriol dihydrate (6.48 g, 40 mmol) and
3,3-dimethylacrylic acid (4.80 g, 48 mmol) was added 20 mL
of BF3‚Et2O at room temperature, and the mixture was heated
to 70 °C for 2.5 h, when the solution color changed to orange
from light yellow. After cooling to room temperature, the
reaction mixture was poured into ice-water and 10% aq KOH
added to pH 10. The solution was washed with EtOAc three
times. Then the aqueous solution was acidified by 10% aq HCl
and stirred for 10 min. The resulting precipitate was collected
by filtration, and washed with water until neutral. After
drying, 6.90 g of 17 was obtained: 83% yield; mp 189-90 °C;
1H NMR δ 1.46 (6H, s, 2 × CH3-2), 2.70 (2H, s, CH2-3), 5.37
(1H, br, OH-7), 5.88 and 5.94 (each 1H, d, J ) 2.1 Hz, ArH-6
and ArH-8), 12.04 (1H, s, OH-5, chelating with carbonyl at
C-4).
1
(12782); H NMR δ 0.96-1.15 (18H, ms, 6 × CH3), 1.50 and
1.56 (each 3H, s, CH3), 1.73, 1.93, 2.22, and 2.46 (each 2H, m,
CH2 in camphanoyl group), 2.24 (3H, s, CH3-4), 2.58 (3H, s,
CH3-5), 5.38 (1H, d, J ) 4.8 Hz, H-3′), 6.12 (1H, s, H-3), 6.41
(1H, d, J ) 4.8 Hz, H-4′), 6.83 (1H, s, H-6); 72% d.e.; [R]D
-70.77° (c 0.38, CHCl3). Anal. (C36H42O11‚H2O) C, H.
(3′R,4′R)-3,5-Dim et h yl-3′,4′-d i-O-(S)-ca m p h a n oyl-(+)-
cis-k h ella cton e (3): yield 82% (starting with 70 mg of 16c);
white solid; mp 98-100 °C; 1H NMR δ 0.93-1.12 (15H, ms, 5
× CH3), 1.27, 1.42, and 1.46 (each 3H, s, CH3), 1.69, 1.89, 2.20,
and 2.50 (each 2H, m, CH2 in camphanoyl group), 2.16 (3H, s,
CH3-3), 2.46 (3H, s, CH3-5), 5.36 (1H, d, J ) 4.8 Hz, H-3′),
6.61 (1H, d, J ) 4.8 Hz, H-4′), 6.65 (1H, s, H-6), and 7.61 (1H,
s, H-4); 80% d.e.; [R]D -4.47° (c 0.76, CHCl3). Anal. (C36H42O11
‚
1/2H2O) C, H.
(3′R,4′R)-4,6-Dim et h yl-3′,4′-d i-O-(S)-ca m p h a n oyl-(+)-
cis-k h ella cton e (4): yield 68% (starting with 400 mg of 16d );
white solid; mp 250 °C dec; 1H NMR δ 0.99-1.11 (18H, ms, 6
× CH3), 1.47, and 1.49 (each 3H, s, CH3), 1.65, 1.92, 2.20, and
2.45 (each 2H, m, CH2 in camphanoyl group), 2.25 (3H, s, CH3-
6), 2.98 (3H, s, CH3-4), 5.39 (1H, d, J ) 4.8 Hz, H-3′), 6.09
(1H, s, H-3), 6.65 (1H, d, J ) 4.8 Hz, H-4′), and 7.37 (1H, s,
7-Ben zyloxy-2,2-dim eth yl-5-h ydr oxy-4-ch r om an on e (18).
A mixture of compound 17 (624 mg, 3 mmol), benzyl bromide
(0.37 mL, 3 mmol), and K2CO3 (828 mg, 6 mmol) was refluxed
in acetone (20 mL) for 2 h. The solid was filtered, solvent was
removed, and the residue was recrystallized from 90% EtOH
to give white needle crystals of 18: 644 mg, 72%; mp 131-2
°C; 1H NMR δ 1.47 (6H, s, 2 × CH3-2), 2.70 (2H, s, CH2-3),
5.07 (2H, s, CH2Ph-7), 6.02 and 6.10 (each 1H, d, J ) 2.1 Hz,
ArH-6 and ArH-8), 7.39 (5H, m, PhH-7), 12.02 (1H, s, OH-5,
chelating with carbonyl at C-4).
2,2-Dim eth yl-5-h ydr oxy-7-m eth oxy-4-ch r om an on e (19).
A mixture of 17 (5.20 g, 25.0 mmol), K2CO3 (16.91 g, 50.0
mmol), and MeI (2.34 mL, 35 mmol) in acetone (50 mL) was
refluxed for 1 h. The reaction mixture was filtered and solvent
was removed in vacuo. The residue was extracted with hexane
several times. The hexane was removed to give 19: 4.11 g,
74%; mp 71-3 °C; 1H NMR δ 1.47 (6H, s, 2 × CH3-2), 2.70
(2H, s, CH2-3), 3.82 (3H, s, CH3O), 5.95 and 6.02 (each 1H, d,
J ) 2.1 Hz, ArH-6 and ArH-8), 12.03 (1H, s, OH-5, chelating
with carbonyl at C-4).
5-Ben zyloxy-4-m eth yl-3′,4′-d ih yd r oseselin (20). Com-
pound 18 (298 mg, 1 mmol) in THF (15 mL) was added
dropwise to NaBH4 (140 mg, 5 mmol) in THF (5 mL), then 1
mL of 10% aq KOH was added to completely solubilize the
NaBH4. The mixture was refluxed for 24 h. After cooling to
room temperature, the reaction mixture was poured into ice-
water, acidified with 10% aq HCl to neutral, and extracted
with Et2O three times. The organic phase was washed with
brine, and dried over anhydrous Na2SO4. After removal of the
solvent, crude product was dissolved in anhydrous CH2Cl2 (8
mL), and ethyl acetoacetate (0.8 mL, 0.67 mmol) and BF3‚Et2O
H-5); 86% d.e.; [R]D -2.00° (c 0.50, CHCl3). Anal. (C36H42O11
‚
H2O) C, H.
(3′R,4′R)-3-Ch lor o-3′,4′-d i-O-(S)-ca m p h a n oyl-4-m eth yl-
(+)-cis-k h ella cton e (5): yield 31% (starting with 69 mg of
16e); white solid; mp 203-4 °C; MS m/z (%) 670 (M+, 10), 672
(M + 2, 3); 1H NMR δ 0.99-1.13 (15H, ms, 5 × CH3), 1.28,
1.46, and 1.49 (each 3H, s, CH3), 1.72, 1.94, 2.23, and 2.52 (each
2H, m, CH2 in camphanoyl group), 2.64 (3H, s, CH3-4), 5.38
(1H, d, J ) 4.8 Hz, H-3′), 6.60 (1H, d, J ) 4.8 Hz, H-4′), 6.85
(1H, d, J ) 8.8 Hz, H-6), and 7.56 (1H, d, J ) 8.8 Hz, H-5);
76% d.e.; [R]D -343.2° (c 0.50, CHCl3). Anal. (C35H39O11Cl).
(3′R,4′R)-3′,4′-Di-O-(S)-ca m p h a n oyl-4-m eth yl-3-p h en yl-
(+)-cis-k h ella cton e (6): yield 61% (starting with 140 mg of
1
16f); white solid; mp 157-9 °C; H NMR δ 0.96-1.15 (15H,
ms, 5 × CH3), 1.27, 1.47, and 1.52 (each 3H, s, CH3), 1.71, 1.92,
2.20, and 2.52 (each 2H, m, CH2 in camphanoyl group), 2.29
(3H, s, CH3-4), 5.44 (1H, d, J ) 4.8 Hz, H-3′), 6.70 (1H, d, J )
4.8 Hz, H-4′), 6.88 (1H, d, J ) 8.8 Hz, H-6), 7.44 (5H, m, ArH-
3) and 7.62 (1H, d, J ) 8.8 Hz, H-5); 87% d.e.; [R]D +20.08° (c
2.58, CHCl3). Anal. (C41H44O11‚1/2H2O) C, H.
(3′R,4′R)-3′,4′-Di-O-(S)-cam ph an oyl-3,4-tetr ah ydr oben zo-
(+)-cis-k h ella cton e (7): yield 37% (starting with 141 mg of
1
16g); white solid; mp 160-3 °C; H NMR δ 0.96-1.12 (15H,
ms, 5 × CH3), 1.29, 1.44, and 1.48 (each 3H, s, CH3), 1.70, 1.92,