134 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Sevillano et al.
N-[(1S,7a R)-7a -Met h yl-5-oxo-2,3,5,6,7,7a -h exa h yd r o-
1H-in d en -1-ylm eth yl]p h th a lim id e (14). To a suspension of
red HgO (325 mg, 1.50 mmol) in THF/H2O 85:15 (9,2 mL), BF3‚
OEt2 (0.49 mL, 4.00 mmol) was added under argon, followed
by a 0.02 M solution of compound 12 (400 mg, 1.00 mmol) in
THF. The resulting mixture was stirred at room temperature
for 1 h. Then, it was diluted with CH2Cl2 and filtered, and the
filtrate was washed with aqueous Na2CO3 (saturated solution)
and brine, dried (Na2SO4), and evaporated. The residue was
chromatographed (hexane/ethyl acetate 2:1) to provide depro-
after crystallization from MeOH. Mp 220-221 °C. [R]23D +10.2°
(c 0.47, H2O); 1H NMR (D2O), δ: 0.73 (s, 3H); 1.58 (s, 3H);
7.35 (d, 1H, J ) 6.0). MS m/z (%): 304 (M+, 70). HRMS (FAB+)
m/z: calcd, 305.2203 (MH+); found, 305.2247. Anal. (C14H24N8‚
2HCl‚H2O) C, H, N.
(1R,7a R)-4,7a -Dim et h yl-5-oxo-2,3,5,6,7,7a -h exa h yd r o-
1H-in d en e-1-ca r ba ld eh yd e Bis(a m id in oh yd r a zon e) (22).
Following method B, 22 (39%) was obtained as a white solid
after crystallization from MeOH. Mp 256 °C. [R]23 +4.8° (c
D
0.40, H2O). 1H NMR (CD3OD), δ: 0.50 (s, 3H); 1.36 (s, 3H);
7.15 (d, 1H, J ) 6.0). HRMS (FAB+) m/z: calcd, 305.2203
(MH+); found, 305.2176. Anal. (C14H24N8.2HCl‚H2O) C, H, N.
tected ketone 14 (130 mg, 42%) as a white foaming oil. [R]23
D
-31.8° (c 0.62, CHCl3). 1H NMR (CDCl3), δ: 1.22 (s, 3H); 3.71
(dd, 1H, J ) 13.9, 8.0); 3.85 (dd, 1H; J ) 13.9, 6.6); 5.76 (s,
1H); 7.75 (dd, 2H, J ) 5.5, 3.3); 7.87 (dd, 2H, J ) 5.5, 3.9). MS
m/z (%): 309 (M+, 22).
(3a R,7a R)-3a -Hyd r oxy-7a -m eth ylp er h yd r oin d en e-1,5-
d ion e (23). To a solution of the triketone (6.0 g, 33 mmol)
obtained from methylvinyl ketone and 2-methylcyclopentane-
1,3-dione in 33 mL of dried DMF, a total of 113.5 mg of R-(+)-
proline was added. The mixture was stirred at room temper-
ature for 24 h under Ar. Then it was filtered and evaporated,
and the residue was chromatographed (hexane/EtOAc 1:1),
N-[(1S,7a R)-5-Am id in oh yd r a zon o-7a -m eth yl-2,3,5,6,7,-
7a-h exah ydr o-1H-in den -1-yl-m eth yl]ph th alim ide (15). Fol-
lowing method A, compound 15, a white foaming solid, was
obtained (6:1 ∆5(N) E/Z, 98%) and crystallized from MeOH/
ether. [R]23D -61.5° (c 0.47, MeOH). 1H NMR (CD3OD), δ: 0.98
(s, 3H) (major); 1.05 (s, 3H) (minor); 3.57 (dd, 1H, J ) 13.7,
8.0); 3.73 (dd, 1H, J ) 13.7, 6.5); 5.84 (s, 1H) (major); 6.73 (s,
1H) (minor); 7.50-7.70 (m, 4H). HRMS (FAB+) m/z: calcd,
366.1930 (MH+); found, 366.1902. Anal. (C20H23N5O2‚HCl) C,
H, N.
yielding the diketone 23 (5.46 g, 91%). Mp 108-110 °C (CH2-
1
Cl2). [R]23 -57.6° (c 0.80, CHCl3). H NMR (CDCl3), δ: 1.25
D
(s, 3H). MS m/z (%): 182 (M+, 53).
(7a R)-7a -Meth yl-2,3,5,6,7,7a -h exa h yd r o-1H-in d en e-1,5-
d ion e (24). To a solution of diketone 23 (6.6 g, 36.3 mmol) in
66 mL of dry benzene, 100 mg (0.5 mmol) of p-TsOH were
added. The mixture was heated to reflux for 1 h under Ar. It
was then diluted with EtOAc and washed with sodium
bicarbonate and brine, and the organic solvent was dried and
evaporated to dryness under reduced pressure, yielding 24 (5.4
g, 91%). Mp 61-63 °C (CH2Cl2). [R]23D -315.4° (c 1.05, toluene).
1H NMR (CDCl3), δ: 1.33 (s, 3H); 5.98 (d, 1H, J ) 2.2). MS
m/z (%): 164 (M+, 100).
(1S,7a R)-1-Am in om eth yl-2,3,5,6,7,7a -h exa h yd r o-1H-in -
d en -5-on e Am id in oh yd r a zon e (16). 16 was obtained from
15 as described for compound 13 (96 mg, 0.26 mmol). For
purification, the precipitate was removed by filtration and the
filtrate was dried with anhydrous Na2CO3 to obtain 48 mg
1
(78%) of 16 (6:1 ∆5(N) E/Z) as a white foaming solid. H NMR
(CD3OD), δ: 0.50 (s, 3H) (major); 0,57 (s, 3H) (minor); 2.52
(dd, 1H, J ) 12.5, 10.0); 2.79 (dd, 1H, J ) 12.5, 3.7); 5.44 (d,
1H, J ) 2.0) (major); 5.55 (s, 1H) (minor). HRMS (FAB+) m/z:
calcd, 238.2034 (M3H+); found, 238.2053. Anal. (C12H21N5‚
2HCl) C, H, N.
[(7aR)-7a-Meth yl-1-oxo-2,3,5,6,7,7a-h exah ydr o-1H-in den -
5-on e]p r op ylen ic Th ioa ceta l (25). To a solution of 24 (2.9
g, 17.7 mmol) in 9 mL of CHCl3, 2.7 mL (26.8 mmol) of
propane-1,3-dithiol and 0.5 mL of TMSCl (5.4 mmol) were
added, and then the mixture was stirred under Ar at room
temperature for 3 h. NaOH (4%) aqueous solution was then
added. The mixture was diluted with EtOAc, extracted, and
washed with brine. The organic layer was dried and evapo-
rated to give a residue that was purified by precipitation with
(1S,3a S,4S,7a R)-3a -H yd r oxy-4,7a -d im et h yl-5,5-et h yl-
en d ioxyp er h yd r oin d en e-1-ca r ba ld eh yd e (17) a n d (1R,-
3a S ,4S ,7a R )-3a -H yd r oxy-4,7a -d im e t h yl-5,5-e t h yle n d i-
oxyp er h yd r oin d en e-1-ca r ba ld eh yd e (21). Aldehydes 17
(88%) and 21 (72%) were obtained by pyridinium chlorochro-
mate (PCC) oxidation of the corresponding alcohols, which
were prepared in 63% overall yield (1:1 mixture) from (3aS,4S,-
7aS)-3a-hydroxy-4,7a-dimethylperhydroindene-1,5-dione35 fol-
lowing the procedure described in previous papers.19,20,30,31
17: 1H NMR (CDCl3), δ: 0.99 (d, 3H, J ) 6.9); 1.10 (s, 3H);
3.82-4.04 (m, 4H); 9.73 (d, 1H, J ) 4.0). MS m/z (%): 254
hexane, yielding 4.9 g (90%) of 25. [R]23 -299.6° (c 0.71,
D
1
3
CHCl ). H NMR (CDCl3), δ: 1.16 (s, 3H); 5.75 (s, 1H). MS m/z
(%): 254 (M+, 100).
[(7a S)-7a -Meth yl-1-m eth ylen e-2,3,5,6,7,7a -h exa h yd r o-
1H-in d en -5-on e]p r op ylen ic Th ioa ceta l (26). To a suspen-
sion of 15.9 g (39.4 mmol) of methyltriphenylphosphonium
iodide in 265 mL of dry benzene under Ar, a diluted solution
of 4.5 N NaOtAm (1.3 equiv, 8.2 g, 39.4 mmol) in benzene was
added at room temperature; the bright-yellow phosphorane
was immediately formed. The mixture was heated to reflux,
and a solution of 25 (7.7 g, 30.3 mmol) in 55 mL of benzene
was added and the mixture was gently refluxed for 45 min.
After cooling and filtration, the solution was diluted with
EtOAc and washed with brine. The residue was purified by
chromatography (hexane/EtOAc 9:1), yielding 26 (5.2 g, 67%)
1
(M+, 35). 21: H NMR (CDCl3), δ: 0.98 (d, 3H, J ) 6.8); 1.29
(s, 3H); 1.96 (c, 1H, J ) 6.8); 2.99 (dt, 1H, J ) 8.5, 2.1); 3.83-
4.03 (m, 4H); 9.80 (d, 1H, J ) 2.1). MS m/z (%): 254 (M+, 25).
Meth yl (E)-[(1R,3aS,4S,7aR)-3-(3a-Hydr oxy-4,7a-dim eth -
yl-5,5-eth ylen d ioxyp er h yd r oin d en -1-yl)]a cr yla te (18). A
solution of 17 (187 mg, 0.74 mmol) in dry benzene (3.0 mL)
was added to a suspension of methoxycarbonylmethylentri-
phenylphosphorane (379 mg, 1.11 mmol) in dry benzene (2.0
mL). The mixture was stirred at reflux under Ar for 7 h. The
solvent was then evaporated, and the residue was chromato-
graphed through a silica gel column (hexane/ethyl acetate 6:4)
to yield ester 18 (215 mg, 94%) as a colorless oil, which was
purified by crystallization from CH2Cl2/hexane. Mp: 95 °C
(CH2Cl2/hexane). [R]23D +1.8° (c 0.60, CHCl3). 1H NMR (CDCl3),
δ: 0.92 (s, 3H); 0.99 (d, 3H, J ) 6.9); 1.92 (q, 1H, J ) 6.9);
3.71 (s, 3H); 3.82-4.04 (m, 4H); 5.64 (d, 1H, J ) 15.7); 7.17
(dd, 1H, J ) 15.7, 10.6). MS m/z (%): 292 (M+-H2O, 1).
Meth yl (E)-[(1R,7aR)-5-Am idin oh ydr azon o-4,7a-dim eth -
yl-2,3,5,6,7,7a-h exah ydr o-1H-in den -1-yl)]acr ylate (19). Fol-
lowing method B, 19 (28%) was obtained as a white solid after
recrystallization from MeOH/ether.1H NMR (CD3OD), δ: 0.80
(s, 3H); 1.72 (s, 3H); 3.62 (s, 3H); 5.82 (d, 1H, J ) 15.7); 6.88
(dd, 1H, J ) 15.7, 8.0). HRMS (FAB+) m/z: calcd, 305.1977
(MH+); found, 305.1987. Anal. (C16H24N4O2.HCl) C, H, N.
(1S,7a R)-4,7a -Dim et h yl-5-oxo-2,3,5,6,7,7a -h exa h yd r o-
1H-in d en e-1-ca r ba ld eh yd e Bis(a m id in oh yd r a zon e) (20).
Following method B, 20 (54%) was obtained as a white solid
as a white solid. Mp 113 °C (CH2Cl2). [R]23 -186.4° (c 0.96,
D
1
3
CHCl ). H NMR (CDCl3), δ: 1.11 (s, 3H); 4.77 (s, 2H); 5.51 (s,
1H). MS m/z (%): 252 (M+, 81).
[(1R ,7a S )-1-H yd r oxym e t h yl-7a -m e t h yl-2,3,5,6,7,7a -
h exa h yd r o-1H-in d en -5-on e]p r op ylen ic Th ioa ceta l (27).
To a solution of 9-BBN (4.9 g, 40.4 mmol) in 40 mL of dry THF,
a total of 5.1 g (20.2 mmol) of 26 was added at room temp-
erature under Ar. The mixture was stirred for 1 h 10 min.
The solution was then cooled to 0 °C, and 6 N NaOH (15 equiv)
and 30% H2O2 (10 equiv) were added sequentially. The reaction
mixture was heated to 50 °C for 1 h. Then, it was allowed to
reach room temperature, diluted with EtOAc, and washed with
brine. The residue was purified by column chromatography
(hexane/EtOAc 3:1), yielding a mixture (88%) of alcohol 27 and
21
its epimer
/
ratio. [R]23 -90.9° (c 0.92, CHCl3). 1H NMR
1
D
(CDCl3 400 MHz), δ: 0.92 (s, 3H); 3.63 (dd, 1H, J ) 10.7, 7.1);
3.73 (dd, 1H, J ) 10.7, 7.1); 5.45 (d, 1H, J ) 1.9). MS m/z (%):
270 (M+, 94).