2670 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14
Xie et al.
room temperature, the mixture was extracted with CHCl3
three times. The combined organic layer was dried over
MgSO4, and then solvent was removed. The residue was
separated by TLC to obtain the pure substituted (+)-cis-
khellactone.
3′,4′-Di-O-(S)-(-)-ca m p h a n oyl-5-m eth yl-(+)-cis-k h ella c-
ton e (9): yield 66.5% (starting with 60 mg of 45), white solid;
mp 163-4 °C; 1H NMR δ 0.97-1.13 (12H, m.s., 4 × CH3), 1.27,
1.50, 1.69, and 2.41 (each 3H, s, CH3), 1.71, 1.91, 2.22, and
2.48 (each 2H, m, CH2 in camphanoyl group), 2.43 (3H, s, CH3-
5), 5.36 (1H, d, J ) 4.8 Hz, H-3′), 6.23 (1H, d, J ) 9.8 Hz,
H-3), 6.62 (1H, d, J ) 4.8 Hz, H-4′), 6.67 (1H, s, H-6), and
7.80 (1H, d, J ) 9.8 Hz, H-4); 81% d.e.; [R]D +18.92° (c 0.37,
CHCl3). Anal. (C35H40O11‚11/2H2O) C, H.
3′,4′-Di-O-(S)-(-)-ca m p h a n oyl-6-m eth yl-(+)-cis-k h ella c-
ton e (10): yield 28% (starting with 80 mg of 46), white solid;
mp 206-7 °C; 1H NMR δ 0.92-1.12 (15H, m.s., 5 × CH3), 1.47,
1.49, and 2.05 (each 3H, s, CH3), 1.66, 1.92, 2.23, and 2.48 (each
2H, m, CH2 in camphanoyl group), 2.23 (3H, s, CH3-6), 5.39
(1H, d, J ) 4.8 Hz, H-3′), 6.22 (1H, d, J ) 9.8 Hz, H-3), 6.66
(1H, d, J ) 4.8 Hz, H-4′), 7.26 (1H, s, H-5), and 7.58 (1H, d, J
) 9.8 Hz, H-4); 87% d.e.; [R]D +8.45° (c 0.97, CHCl3). Anal.
(C35H40O11‚H2O) C, H.
However, the substituted (+)-cis-khellactone could be di-
rectly acylated, without further purification, with (S)-(-)-
camphanic chloride (greater than 0.5 mmol) in Py/CH2Cl2 for
1-2 days at room temperature. The mixture was diluted with
EtOAc and washed with 10% aqueous 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-(-)-camphanoyl-(+)-cis-
khellactone derivative.
3′,4′-Di-O-(S)-(-)-ca m p h a n oyl-3-m eth oxy-(+)-cis-k h el-
la cton e (3): yield 47% (starting with 103 mg of 39), white
+
solid, mp 149-50 °C; MS (Cl-NH3) m/z (%) 670 (M + NH4
,
1
3′,4′-Di-O-(S)-(-)-ca m p h a n oyl-4-p r op yl-(+)-cis-k h ella c-
ton e (11): yield 26% (starting with 70 mg of 47), white crystals
from EtOH; mp 270-1 °C; 1H NMR δ 0.99-1.12 (15H, m.s., 5
× CH3), 1.46, 1.50, and 1.56 (each 3H, s, CH3), 1.65, 1.91, 2.24,
and 2.51 (each 2H, m, CH2 in camphanoyl group), 1.06 (3H, t,
J ) 7.5 Hz, CH3 of propyl group at 4-position), 1.73 (2H, six,
J ) 7.5 Hz, CH2 of propyl group at 4-position), 2.70 (2H, t, J
) 5 Hz, CH2 of propyl group at 4-position), 5.40 (1H, d, J )
4.8 Hz, H-3′), 6.11 (1H, s, H-3), 6.66 (1H, d, J ) 4.8 Hz, H-4′),
6.84 (1H, d, J ) 8.8 Hz, H-6), and 7.57 (1H, d, J ) 8.8 Hz,
100); H NMR δ 0.93-1.12 (15H, m.s., 5 × CH3), 1.43, 1.47,
and 1.55 (each 3H, s, CH3), 1.69, 1.92, 2.22, and 2.48 (each
2H, m, CH2 in camphanoyl group), 3.88 (3H, s, CH3O-3), 5.39
(1H, d, J ) 4.8 Hz, H-3′), 6.64 (1H, d, J ) 4.8 Hz, H-4′), 6.78
(1H, s, H-4), 6.83 (1H, d, J ) 8.8 Hz, H-6), and 7.34 (1H, d, J
) 8.8 Hz, H-5); 80% d.e.; [R]D +12.87° (c 0.72, CHCl3). Anal.
(C35H40O12‚1/2H2O) C, H.
3′,4′-Di-O-(S)-(-)-ca m p h a n oyl-4-m eth oxy-(+)-cis-k h el-
la cton e (4): yield 60% (starting with 103 mg of 40), white
+
solid; mp 174-6 °C; MS (Cl-NH3) m/z (%) 670 (M + NH4
,
H-5); 100% d.e.; [R]D +17.95° (c 0.39, CHCl3). Anal. (C37H44O11
C, H.
)
75); 1H NMR δ 0.93-1.14 (18H, m.s., 6 × CH3), 1.45, and 1.49
(each 3H, s, CH3), 1.68, 1.92, 2.24, and 2.48 (each 2H, m, CH2
in camphanoyl group), 3.97 (3H, s, CH3O-4), 5.38 (1H, d, J )
4.8 Hz, H-3′), 5.53 (1H, s, H-3), 6.64 (1H, d, J ) 4.8 Hz, H-4′),
6.81 (1H, d, J ) 8.8 Hz, H-6), and 7.74 (1H, d, J ) 8.8 Hz,
3′,4′-Di-O-(S)-(-)-ca m p h a n oyl-4-isop r op yl-(+)-cis-k h el-
la cton e (12): yield 41% (starting with 110 mg of 48), white
crystals from EtOH; mp 260-1 °C; 1H NMR δ 0.97-1.11 (15H,
m.s., 5 × CH3), 1.33, 1.45, and 1.49 (each 3H, s, CH3), 1.65,
1.91, 2.20, and 2.50 (each 2H, m, CH2 in camphanoyl group),
1.30 (6H, d, J ) 6.6 Hz, 2 × CH3 at 4-position), 3.32 (1H, five,
J ) 6.6 Hz, at 4-position), 5.38 (1H, d, J ) 4.8 Hz, H-3′), 6.14
(1H, s, H-3), 6.64 (1H, d, J ) 4.8 Hz, H-4′), 6.84 (1H, d, J )
8.8 Hz, H-6), and 7.61 (1H, d, J ) 8.8 Hz, H-5); 100% d.e.;
[R]D +19.00° (c 0.60, CHCl3). Anal. (C37H44O11) C, H.
3′,4′-Di-O-(S)-(-)-ca m p h a n oyl-4-p h en yl-(+)-cis-k h ella c-
ton e (13): yield 52% (starting with 120 mg of 49), isomer
mixture with a ratio of 3′R,4′R:3′S,4′S ≈ 50:50. The pair of
diastereoisomers was separated by TLC with an eluant of 40:2
CH2Cl2/acetone to obtain the product with lower Rf value as a
white solid with mp 148-50 °C: 1H NMR δ 1.00-1.15 (12H,
m.s., 4 × CH3), 1.27, 1.48, 1.52, and 1.56 (each 3H, s, CH3),
1.72, 1.95, 2.24, and 2.54 (each 2H, m, CH2 in camphanoyl
group), 5.43 (1H, d, J ) 4.8 Hz, H-3′), 6.21 (1H, s, H-3), 6.71
(1H, d, J ) 4.8 Hz, H-4′), 6.78 (1H, d, J ) 8.8 Hz, H-6), 7.44
(1H, d, J ) 8.8 Hz, H-5), 7.42 and 7.54 (5H, d.m. ArH at
4-position); 65% d.e.; [R]D +4.36° (c 0.55,CHCl3). Anal.
(C40H42O11‚H2O) C, H.
3′,4′-Di-O-(S)-(-)-ca m p h a n oyl-4-t r iflu or om et h yl-(+)-
cis-k h ella cton e (14): yield 29% (starting with 37 mg of 50),
white solid; mp 232-4 °C; MS (EI) m/z (%) 690 (M+, 1), 477
(30), 281 (80); 1H NMR δ 0.98-1.13 (12H, m.s., 4 × CH3), 1.28,
1.48, 1.51, and 2.16 (each 3H, s, CH3), 1.72, 1.94, 2.21, and
2.51 (each 2H, m, CH2 in camphanoyl group), 2.64 (s, CF3),
5.40 (1H, d, J ) 4.8 Hz, H-3′), 6.63 (1H, s, H-3), 6.64 (1H, d, J
) 4.8 Hz, H-4′), 6.92 (1H, d, J ) 9.0 Hz, H-6), and 7.67 (1H, d,
J ) 9.0 Hz, H-5); >86% d.e.; [R]D +17.00° (c 0.33, CHCl3).
4-Meth yl-(+)-cis-k h ella cton e (63): yield 62% (starting
with 890 mg of 44), white solid; mp 196-7 °C; 1H NMR δ 1.42
and 1.47 (each 3H, s, 2′-CH3 × 2), 2.42 (3H, s, 4-CH3), 3.27
and 4.15 (each 1H, br, OH × 2), 3.87 (1H, d, J ) 4.8 Hz, 3′-
CH), 5.21 (1H, d, J ) 4.8 Hz, 4′-CH), 6.16 (1H, s, 3-H), 6.83
(1H, d, J ) 8.8 Hz, 6-H), 7.48 (1H, d, J ) 8.8 Hz, 5-H); 73%
e.e., with was determined by 1H NMR spectrum of 7; [R]D
+46.86° (c 0.70, CHCl3). Anal. (C15H16O5) C, H.
H-5); 73% d.e.; [R]D +2.34° (c 0.69, CHCl3). Anal. (C35H40O12
‚
1/2H2O) C, H.
3′,4′-Di-O-(S)-(-)-ca m p h a n oyl-5-m eth oxy-(+)-cis-k h el-
la cton e (5): yield 50% (starting with 103 mg of 41), white
+
solid; mp 168-70 °C; MS (Cl-NH3) m/z (%) 670 (M + NH4
,
60), 652 (M+, 7); 1H NMR δ 0.98-1.14 (15H, m, 5 × CH3), 1.44,
1.50, and 1.55 (each 3H, s, CH3), 1.71, 1.90, 2.22, and 2.49 (each
2H, m, CH2 in camphanoyl group), 3.90 (3H, s, CH3O-5), 5.40
(1H, d, J ) 4.8 Hz, H-3′), 6.27 (1H, d, J ) 9.8 Hz, H-3), 6.65
(1H, d, J ) 4.8 Hz, H-4′), 6.25 (1H, s, H-6), and 7.97 (1H, d, J
) 9.8 Hz, H-4); 86% d.e.; [R]D -4.44° (c 0.45, CHCl3). Anal.
(C35H40O12‚1/2H2O) C, H.
3′,4′-Di-O-(S)-(-)-ca m p h a n oyl-6-m eth oxy-(+)-cis-k h el-
la cton e (6): yield 61% (starting with 65 mg of 42), white solid;
mp 262-4 °C; MS (EI) m/z (%) 652 (M+, 20); 1H NMR δ 0.98-
1.14 (15H, m.s., 7 × CH3), 1.52 (3H, s, CH3), 1.72, 1.97, 2.10,
and 2.48 (each 2H, m, CH2 in camphanoyl group), 3.92 (3H, s,
CH3O-6), 5.40 (1H, d, J ) 4.8 Hz, H-3′), 6.27 (1H, d, J ) 9.8
Hz, H-3), 6.65 (1H, d, J ) 4.8 Hz, H-4′), 6.90 (1H, s, H-5), and
7.60 (1H, d, J ) 9.8 Hz, H-4); >90% d.e.; [R]D -18.26° (c 0.46,
CHCl3). Anal. (C35H40O12‚21/2H2O) C, H.
3′,4′-Di-O-(S)-(-)-ca m p h a n oyl-3-m eth yl-(+)-cis-k h ella c-
ton e (7): yield 47% (starting with 113 mg of 43), white solid;
mp 143-5 °C; 1H NMR δ 0.96-1.15 (15H, m.s., 5 × CH3), 1.45,
1.49, and 2.19 (each 3H, s, CH3), 1.69, 1.92, 2.25, and 2.48 (each
2H, m, CH2 in camphanoyl group), 2.16 (3H, s, CH3-3), 5.40
(1H, d, J ) 4.8 Hz, H-3′), 6.66 (1H, d, J ) 4.8 Hz, H-4′), 6.80
(1H, d, J ) 8.8 Hz, H-6), 7.35 (1H, d, J ) 8.8 Hz, H-5) and
7.43(1H, s, H-4); >90% d.e.; [R]D +21.08° (c 0.37, CHCl3). Anal.
(C35H40O11‚H2O) C, H.
3′,4′-Di-O-(S)-(-)-ca m p h a n oyl-4-m eth yl-(+)-cis-k h ella c-
ton e (8): yield 50% (starting with 60 mg of 44), white solid;
mp 264-7 °C; MS m/z (%) 636 (M+, 7), 423 (100), and 227 (82);
1H NMR δ 0.98-1.14 (12H, m.s., 4 × CH3), 1.27, 1.50, 1.69,
and 2.41 (each 3H, s, CH3), 1.71, 2.04, 2.21, and 2.46 (each
2H, m, CH2 in camphanoyl group), 2.41 (3H, s, CH3-4), 5.40
(1H, d, J ) 4.8 Hz, H-3′), 6.13 (1H, s, H-3), 6.67 (1H, d, J )
4.8 Hz, H-4′), 6.85 (1H, d, J ) 8.8 Hz, H-6), and 7.54 (1H, d,
J ) 8.8 Hz, H-5); 84% d.e.; [R]D +8.4° (c 0.50, CHCl3). Anal.
(C35H40O11‚21/2H2O) C, H.
Gen er a l P r oced u r e of Acyla tion for Syn th esizin g
4-Meth yl-(+)-cis-k h ella cton es Der iva tives (15-26). To a
solution of 63 (50 mg, 0.18 mmol) in CH2Cl2 (2 mL) and
pyridine (1 mL) was added excess acylating agent at 0 °C. The