Neoclerodane Diterpenes as a Novel Scaffold
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15 4769
(1H, ddd, J ) 3.2, 7.5, 11.2 Hz, H-2), 5.28 (1H, d, J ) 10.5 Hz,
H-12), 6.39 (1H, dd, J ) 0.9, 1.8 Hz, H-14), 7.40 (1H, dd, J )
1.5, 1.8 Hz, H-15), 7.42 (1H, dd, J ) 0.9, 1.5 Hz, H-16).
(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(Benzoyloxy)-2-(3-fura-
nyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-
[2,1-c]pyran-7-carboxylic Acid Methyl Ester (13). 13 was
synthesized as described for 9 from 8a using benzoyl chloride
to afforded 0.06 g (98%) of 13 as a white solid, mp 165-170
°C. 1H NMR (CDCl3): δ 1.18 (3H, s, H-19), 1.47 (3H, s, H-20),
1.50-1.75 (4H, m, H-6â, H-7R,â and H-11â), 1.84 (1H, ddd, J
) 3.0, 3.0, 9.9 Hz, H-6R), 2.11 (1H, dd, J ) 2.4, 10.8 Hz, H-8),
2.26 (1H, s, H-10), 2.47 (2H, m, H-3R,â), 2.55 (1H, dd, J ) 5.1,
13.5 Hz, H-11R), 2.84 (1H, dd, J ) 6.9, 9.9 Hz, H-4), 3.75 (3H,
s, CO2CH3), 5.40 (1H, dd, J ) 9.6, 10.5 Hz, H-2), 5.52 (1H, dd,
J ) 2.1, 11.7 Hz, H-12), 6.39 (1H, dd, J ) 0.9, 1.8 Hz, H-14),
7.40 (1H, dd, J ) 1.5, 1.8 Hz, H-15), 7.42 (1H, dd, J ) 0.9, 1.5
Hz, H-16), 7.48 (2H, dt, J ) 7.2, 7.5 Hz, Ar-m-H), 7.60 (1H, tt,
J ) 1.2, 7.5 Hz, Ar-p-H), 8.09 (2H, dt, J ) 1.2, 7.2 Hz, Ar-o-
H). Anal. (C28H30O8): C, H.
Nicotinic Acid (2S,4aR,6aR,7R,9S,10aS,10bR)-7-Car-
bomethoxy-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-
4,10-dioxo-2H-naphtho[2,1-c]pyran-9-yl Ester (14). 14 was
synthesized as described for 13 from 8a using nicotinoyl
chloride hydrochloride to afford 0.03 (56%) of 14 as a white
solid, mp 200-204 °C. 1H NMR (CDCl3): δ 1.18 (3H, s, H-19),
1.47 (3H, s, H-20), 1.50-1.72 (4H, m, H-6â, H-7R,â and H-11â),
1.84 (1H, ddd, J ) 3.0, 3.0, 9.9 Hz, H-6R), 2.11 (1H, dd, J )
2.4, 10.5 Hz, H-8), 2.27 (1H, s, H-10), 2.49 (2H, m, H-3R,â),
2.54 (1H, dd, J ) 5.1, 13.2 Hz, H-11R), 2.85 (1H, dd, J ) 6.2,
10.7 Hz, H-4), 3.76 (3H, s, CO2CH3), 5.41 (1H, dd, J ) 10.1,
10.1 Hz, H-2), 5.53 (1H, dd, J ) 5.1, 11.7 Hz, H-12), 6.39 (1H,
d, J ) 0.9 Hz, H-14), 7.42 (3H, m, H-15, H-16 and Ar-H), 8.34
(1H, ddd, J ) 1.5, 3.9, 7.8 Hz, Ar-H), 8.82 (1H, ddd, J ) 1.8,
3.9 Hz, Ar-H), 9.27 (1H, d, J ) 1.5 Hz, Ar-H). Anal. (C27H29-
NO8‚0.25H2O): C, H, N.
(2S,4aS,6aR,7R,9S,10aS,10bR)-9-(Propionyloxy)-2-(3-
furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-
naphtho[2,1-c]pyran-7-carboxylic Acid Methyl Ester (9).
A solution of 8a (0.05 g, 0.13 mmol), propionic anhydride (0.09
g, 0.66 mmol), and a catalytic amount of DMAP in CH2Cl2 (20
mL) was stirred at room temperature overnight. Absolute
MeOH (15 mL) was added and the solvent was removed under
reduced pressure. CH2Cl2 (25 mL) was added to the residue
and the solution was washed with 10% HCl (3 × 20 mL) and
saturated NaCl (3 × 20 mL) and dried (Na2SO4). Removal of
the solvent under reduced pressure afforded 0.04 g (78%) of 9
as a white solid, mp 217-221 °C. 1H NMR (CDCl3): δ 1.12
(3H, s, H-19), 1.18 (3H, t, J ) 7.5 Hz, CH3CH2CO2), 1.46 (3H,
s, H-20), 1.47-1.70 (4H, m, H-6â, H-7R,â and H-11â), 1.80 (1H,
ddd, J ) 3.0, 3.0, 9.9 Hz, H-6R), 2.07 (1H, dd, J ) 3.0, 11.1
Hz, H-8), 2.17 (1H, s, H-10), 2.30 (2H, q, J ) 7.5 Hz, CH3CH2-
CO2), 2.47 (2H, m, H-3R,â), 2.53 (1H, dd, J ) 5.4, 13.2 Hz,
H-11R), 2.76 (1H, dd, J ) 8.1, 8.7 Hz, H-4), 3.73 (3H, s,
CO2CH3), 5.16 (1H, dd, J ) 9.9, 10.5 Hz, H-2), 5.53 (1H, dd, J
) 5.4, 11.7 Hz, H-12), 6.38 (1H, dd, J ) 0.6, 1.8 Hz, H-14),
7.39 (1H, dd, J ) 1.5, 1.8 Hz, H-15), 7.41 (1H, dd, J ) 0.6, 1.5
Hz, H-16). Anal. (C24H30O10‚0.25H2O): C, H, O.
(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(Isobutyryloxy)-2-(3-
furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-
naphtho[2,1-c]pyran-7-carboxylic Acid Methyl Ester (10).
10 was synthesized as described for 9 from 8a using isobutyryl
chloride to afford 0.04 g (62%) of 10 as a white solid, mp 209-
211 °C. 1H NMR (CDCl3): δ 1.13 (3H, s, H-19), 1.24 (3H, d, J
) 6.9 Hz, CH3CH(CH3)CO2), 1.26 (3H, d, J ) 6.9 Hz CH3CH-
(CH3)CO2), 1.46 (3H, s, H-20), 1.52-1.78 (3H, m, H-7R,â and
H-11â), 1.80 (1H, ddd, J ) 3.0, 3.0, 9.9 Hz, H-6R), 2.12 (2H,
m, H-3R and H-8), 2.20 (1H, s, H-10), 2.25-2.35 (2H, m, H-3â
and H-6â), 2.51 (1H, dd, J ) 5.1, 13.2 Hz, H-11R), 2.68 (1H,
sept, J ) 6.9 Hz, CH3CH(CH3)CO2), 2.77 (1H, dd, J ) 8.4, 8.4
Hz, H-4), 3.74 (3H, s, CO2CH3), 5.15 (1H, dd, J ) 9.9, 10.3 Hz,
H-2), 5.52 (1H, dd, J ) 5.3, 11.9 Hz, H-12), 6.39 (1H, dd, J )
0.9, 1.5 Hz, H-14), 7.40 (1H, dd, J ) 1.5, 1.5 Hz, H-15), 7.42
(1H, dd, J ) 0.9, 1.5 Hz, H-16). Anal. (C25H32O8‚0.25H2O): C,
H, O.
(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(2-Methylacryloyloxy)-
2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-
2H-naphtho[2,1-c]pyran-7-carboxylic Acid Methyl Ester
(11). 11 was synthesized as described for 9 from 8a using
methacrylic anhydride to afford 0.03 g (56%) of 11 as a white
solid, mp 196-199 °C. 1H NMR (CDCl3): δ 1.15 (3H, s, H-19),
1.47 (3H, s, H-20), 1.50-1.75 (4H, m, H-6â, H-7R,â and H-11â),
1.82 (1H, ddd, J ) 3.0, 3.0, 10.2 Hz, H-6R), 1.99 (3H, s, CH2d
C(CH3)CO2), 2.04-2.21 (2H, m, H-3R and H-8), 2.23 (1H, s,
H-10), 2.40 (1H, m, H-3â), 2.53 (1H, dd, J ) 5.1, 13.5 Hz,
H-11R), 2.80 (1H, dd, J ) 8.4, 8.4 Hz, H-4), 3.75 (3H, s,
CO2CH3), 5.22 (1H, dd, J ) 9.9, 9.9 Hz, H-2), 5.53 (1H, dd, J
) 5.1, 11.7 Hz, H-12), 5.69 (1H, d, J ) 1.5 Hz, H-CHdC(CH3)-
CO2), 6.24 (1H, d, J ) 1.5 Hz, H-CHdC(CH3)CO2), 6.39 (1H,
dd, J ) 0.9, 1.5 Hz, H-14), 7.41 (1H, dd, J ) 1.5, 1.5 Hz, H-15),
7.42 (1H, dd, J ) 0.9, 1.5 Hz, H-16). Anal. (C25H30O8‚
0.25H2O): C, H, O.
(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(Methanesulfonyloxy)-
2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-
2H-naphtho[2,1-c]pyran-7-carboxylic Acid Methyl Ester
(15). A solution of 8a (0.05 g, 0.13 mmol), methanesulfonyl
chloride (1 mL, 12.9 mmol), and NEt3 (2 mL, 14.3 mmol) in
CH2Cl2 (30 mL) was stirred at room temperature overnight
and then the mixture was washed with saturated NaHCO3
(20 mL) and saturated NaCl (2 × 15 mL) and dried (Na2SO4).
The solvent was removed under reduced pressure. The result-
ing crude solid was purified by column chromatography (eluent
EtOAc/n-hexanes) to afford 0.02 g (32%) of 15 as a white solid,
1
mp 147-150 °C. H NMR (CDCl3): δ 1.14 (3H, s, H-19), 1.47
(3H, s, H-20), 1.50-1.70 (3H, m, H-7R,â and H-11â), 1.81 (1H,
m, H-6R), 2.11 (1H, dd, J ) 2.9, 11.3 Hz, H-8), 2.16 (1H, s,
H-10), 2.19 (1H, m, H-6â), 2.42 (1H, dd, J ) 13.2, 13.2 Hz,
H-3R), 2.50 (1H, m, H-3â), 2.52 (1H, dd, J ) 4.8, 13.2 Hz,
H-11R), 2.75 (1H, dd, J ) 3.6, 13.2 Hz, H-4), 3.25 (3H, s, CH3-
SO2), 3.74 (3H, s, CO2CH3), 5.07 (1H, dd, J ) 8.0, 12.2 Hz,
H-2), 5.55 (1H, dd, J ) 5.1, 11.7 Hz, H-12), 6.41 (1H, dd, J )
0.9, 1.8 Hz, H-14), 7.42 (1H, dd, J ) 1.8, 1.8 Hz, H-15), 7.45
(1H, br d). Anal. (C22H28O9S): C, H, O.
(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(Trimethylsilanyloxy)-
2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-
2H-naphtho[2,1-c]pyran-7-carboxylic Acid Methyl Ester
(16). A solution of 8a (0.08 g, 0.20 mmol), NEt3 (0.1 mL, 0.72
mmol), and chlorotrimethylsilane (0.1 mL, 0.79 mmol) in CH2-
Cl2 (30 mL) was stirred at room temperature overnight. The
mixture was washed with saturated NaHCO3 (2 × 10 mL) and
H2O (50 mL) and dried (Na2SO4), and the solvent was removed
under reduced pressure. The resulting crude solid was purified
by column chromatography (eluent EtOAc/n-hexanes) to afford
OxalicAcid(2S,4aR,6aR,7R,9S,10aS,10bR)-7-Carbometh-
oxy-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-
2H-naphtho[2,1-c]pyran-9-yl Methyl Diester (12). 12 was
synthesized as described for 9 from 8a using methyl chlo-
rooxoacetate to afford (26%) of 12 as a white solid, mp 241-
1
1
0.06 g (68%) of 16 as a white solid, mp 197-200 °C. H NMR
244 °C. H NMR (CDCl3): δ 1.16 (3H, s, H-19), 1.47 (3H, s,
(CDCl3): δ 0.14 (9H, s, (CH3)3SiO), 1.11 (3H, s, H-19), 1.48
(3H, s, H-29), 1.50-1.73 (3H, m, H-7R,â and H-11â), 1.79 (1H,
ddd, J ) 3.0, 3.0, 10.5 Hz, H-6R), 2.03 (1H, dd, obscured, H-8),
2.06 (1H, s, H-10), 2.10-2.38 (3H, m, H-3R,â and H-6â), 2.57
(1H, dd, J ) 5.1, 10.5 Hz, H-11R), 2.69 (1H, dd, J ) 3.9, 12.9
Hz, H-4), 3.72 (3H, s, CO2CH3), 4.12 (1H, dd, J ) 7.5, 11.7 Hz,
H-2), 5.56 (1H, dd, J ) 5.1, 11.4 Hz, H-12), 6.38 (1H, dd, J )
0.8, 1.7 Hz, H-14), 7.40 (1H, m, H-15), 7.42 (1H, m, H-16). Anal.
(C24H34O7Si): C, H.
H-20), 1.56-1.81 (4H, m, H-3R, H-6â, H-7â and H-11â), 1.84
(1H, ddd, J ) 3.0, 3.0, 10.1 Hz, H-6R), 2.11 (1H, dd, J ) 3.0,
11.3 Hz, H-8), 2.19 (1H, m, H-7R), 2.22 (1H, s, H-10), 2.46 (1H,
dd, J ) 4.5, 8.1 Hz, H-3â), 2.52 (1H, dd, J ) 5.6, 12.8 Hz,
H-11R), 2.79 (1H, dd, J ) 5.1, 12.0 Hz, H-4), 3.76 (3H, s,
CO2CH3), 3.96 (3H, s, COCO2CH3), 5.26 (1H, dd, J ) 8.5, 11.9
Hz, H-2), 5.54 (1H, dd, J ) 5.1, 11.7 Hz, H-12), 6.39 (1H, dd,
J ) 0.9, 1.5 Hz, H-14), 7.42 (2H, m, H-15 and H-16). Anal.
(C24H28O10‚0.25H2O): C, H.