5918 J . Org. Chem., Vol. 61, No. 17, 1996
Abad et al.
(1′S)-3-(1′,2′,2′-t r im et h ylcyclop en t yl)-2-cycloh exen -1-
on e (12). A solution of ketone 11 (433.2 mg, 1.93 mmol) in a
mixture of methanol (7.8 mL) and 3.3% aqueous potassium
hydroxide (1.6 mL) was heated at 150 °C in a sealed tube for
5 h. The mixture was poured into water and extracted with
ether. Workup as usual afforded an oily residue, which was
purified by chromatography using pentane-ether 8:2 as eluent
In summary, we have established a general synthetic
route for the enantioselective synthesis of cuparane-type
sesquiterpenoids, which allowed the preparation of two
representatives members of this family, (-)-cuparene (2)
and (-)-δ-cuparenol (3), to be completed in 47% and 27%
overall yield, respectively, from â-cyclogeraniol. This
strategy is distinctively different from previous ap-
proaches and should also allow, with minor modifications,
the preparation of related herbertane-type sesquiterpe-
noids.16 These studies are being pursued in our labora-
tory and will be reported on in due course.
to provide the enone 12 (369 mg, 93%) as a colorless oil: [R]20
D
-56.6° (c 4.8, CHCl3); IR (KBr) 1680, 1615, 1270, 970, 900
1
cm-1; H NMR δ 5.95 (1H, br s, H-2), 2.35 (4H, m, H2-4 and
H2-6), 1.93 (2H, m, H2-5), 1.07 (3H, s, CH3-1′), 1.04 and 0.80
(6H each, each s, 2 × CH3-2′); MS (EI) m/ z 207 (M+ + 1, 6),
206 (M+, 35), 191 (7), 163 (6), 150 (62), 137 (100); HRMS calcd
for C14H22O 206.1671, found 206.1674.
(1′S,6RS)-6-Met h yl-3-(1′,2′,2′-t r im et h ylcyclop en t yl)-2-
cycloh exen -1-on e (13). To a solution of 12 (100 mg, 0.485
mmol) in THF (5 mL) was added dropwise a solution of LDA
in THF (0.750 mL of a 0.7 M solution, 0.525 mmol) at -50 °C.
The mixture was stirred for 30 min, and HMPA (0.26 mL) and
MeI (0.3 mL, 4.82 mmol) were successively added. The
solution was allowed to warm gradually to -20 °C over 1 h,
and saturated aqueous NH4Cl solution was added. Usual
workup afforded the crude product, which was purified by
chromatography using pentane-ether 8:2 as eluent to give the
methyl ketone 13 (102 mg, 96%) as a 1:1 mixture of epimers
at C-6 (1H NMR analysis): IR (KBr) 1660, 1610, 1370, 1215,
Exp er im en ta l Section
Gen er a l P r oced u r es. For general experimental informa-
tion see ref.17 1H and 13C NMR assignments were made on the
basis of a combination of DEPT and inverse-detected hetero-
nuclear multiple quantum coherence (HMQC) and NOE
experiments. Spectroscopic data and experimental details for
the preparation of â-cyclogeraniol (5), epoxy alcohol 6, tert-
butyldimethylsilyl ether 7, and R-siloxy ketone 4, which were
partially given in ref 3, are included in the supporting
information.
(1′S,2RS)-2-[(ter t-Bu tyld im eth ylsilyl)oxy]-1-(1′,2′,2′-tr i-
m eth ylcyclop en tyl)-1,5-h exa n ed ion e (10). A stirred solu-
tion of the R-siloxy ketone 4 (1.11 g, 3.89 mmol) in anhyd THF
(2.5 mL) containing a few crystals of anhydrous phenanthro-
line was treated dropwise with a stock solution of lithium
diisopropylamide in THF at -78 °C until persistence of the
characteristic rust color of LDA-phenanthroline (approxi-
mately 6 mL, 0.7 M, 4.2 mmol). The stirring was continued
at the same temperature for 2 h. 3-(Trimethylsilyl)-3-buten-
2-one (0.66 mL, 3.99 mmol) was then added dropwise at -78
°C, and the resulting solution was allowed to warm slowly to
rt. After a few min, water was added and the mixture was
extracted with pentane. Workup as usual afforded an oily
residue (a mixture of 9 and 10, as shown by 1H NMR analysis),
which was dissolved in a mixture of methanol (12.5 mL) and
4% aqueous potassium hydroxide (2.5 mL). After being stirred
at rt for 6 h, the reaction mixture was poured into water and
extracted with pentane. Workup as usual gave a residue that
was purified by chromatography using pentane-ether 8:2 as
eluent to afford, in order of elution, starting material 4 (39.6
mg, 4%) and diketone 10 (1.139 g, 83%) as a 7:1 mixture of
diastereomers.
1
880 cm-1; H NMR δ 5.93 (1H, br s, H-2 of both epimers at
C-6), 1.12 and 1.11 (3H, each d, J ) 6.8 Hz, CH3-6 of both
epimers at C-6), 1.061 and 1.058 (3H, each s, CH3-1′ of both
epimers at C-6), 1.037 and 1.033 (3H, each s, CH3-2′ of both
epimers at C-6), 0.79 (3H, s, CH3-2′ of both epimers at C-6);
EM (EI) m/ z 221 (M+ + 1, 9), 220 (M+, 48), 205 (11), 192 (5),
177 (7), 164 (60), 151 (100); HRMS calcd for C15H24O 220.1827,
found 220.1825.
(1RS,1′S,6RS)-6-Meth yl-3-(1′,2′,2′-tr im eth ylcyclopen tyl)-
2-cycloh exen -1-ol (14). The mixture of epimeric R-methyl
ketones 13 (83.7 mg, 0.38 mmol) in THF (2.4 mL) was treated
with DIBALH (0.95 mL of a 1 M solution in cyclohexane, 0.95
mmol) at -78 °C. The solution was stirred for 80 min, water
(1.5 mL) was added and the solution was extracted with ether.
Workup as usual gave a residue, which was purified by
chromatography using pentane-ether 8:2 as eluent to afford
alcohol 14 (81 mg, 96%) as a mixture of four diastereomers:
1
IR (film) 3300, 3020, 1630, 1360, 1015, 880 cm-1; H NMR δ
5.61 and 5.41 (1H, each m), 4.00 and 3.76 (1H, each m), 1.02-
0.94 (9H, m), 0.76 (3H, m).
(1′S)-1 -Met h yl-4-(1′, 2′,2′-t r im et h ylcyclop en t yl)b en -
zen e [(-)-Cu p a r en e (2)]. Hexamethyldisiloxane (0.45 mL,
2.13 mmol) was added to a stirred suspension of P2O5 (153
mg, 1.08 mmol) in CCl4 (0.75 mL).12 The resulting solution
was heated at reflux for 2 h until a homogeneous solution was
formed. Then SeO2 (76.6 mg, 0.69 mmol) was added followed
by a solution of the above-obtained mixture of diastereomeric
alcohols 14 (66.5 mg, 0.3 mmol) in CCl4 (1.5 mL). The
resulting reaction mixture was heated at reflux overnight and
poured into water. Extraction with pentane and workup as
usual afforded an oil, which was purified by chromatography,
using pentane as eluent, to give cuparene (2) (57 mg, 93%):
Spectroscopic data of 10: IR (film) 1705, 1370, 1260, 835,
755 cm-1; H NMR (only signals corresponding to the major
1
diastereomer are given) δ 4.58 (1H, dd, J 6.6, 4.8 Hz, H-2),
2.60 (1H, ddd, J ) 18.5, 8.0, 7.4 Hz, H-4), 2.40 (1H, ddd, J )
18.5, 4.1, 2.8 Hz, H′-4), 2.11 (3H, s, H3-6), 1.07 (6H, s, CH3-1′
and CH3-2′), 0.87 (3H, s, CH3-2′), 0.88 (9H, s, SiC(CH3)3), 0.04
and 0.01 (3H each, each s, SiC(CH3)3).
(1′S)-1-(1′,2′,2′-Tr im e t h ylcyclop e n t yl)h e xa n e -1,5-d i-
on e (11). A solution of 10 (1.139 g, 3.21 mmol) in a mixture
of anhyd THF (10 mL) and MeOH (3.2 mL) was treated with
a solution of SmI2 in THF (40 mL of a 0.2 M solution in THF,
8 mmol) at -78 °C. The reaction mixture was kept at the same
temperature for 30 min, and then it was allowed to warm
slowly to rt over 3 h. The resulting dark greenish mixture
was diluted with pentane and washed with brine. Chroma-
tography of the residue left after evaporation of the solvent
(gradient elution, from 90 to 70% pentane in ether) furnished
the diketone 11 as a colorless oil (713.6 mg, 99%): [R]20D -17.5°
[R]20 -59.6° (c 1.9, CHCl3) (lit.14 [R]D -63°); IR (film) 1510,
D
1460, 1370, 810 cm-1; H NMR δ 7.25 (2H, d, J ) 8 Hz, H-3
1
and H-5), 7.09 (2H, d, J ) 8 Hz, H-2 and H-6), 2.48 (1H, m,
H-5′), 2.31 (3H, s, CH3-1), 1.25, 1.05 and 0.55 (3H each, each
s, CH3-1 and 2 × CH3-2); MS (EI) m/ z 203 (M+ + 1, 5), 202
(M+, 30), 187 (6), 159 (8), 146 (10), 145 (38), 132 (100); HRMS
calcd for C15H22 202.1721, found 202.1721.
(c 6.0, CHCl3); IR (film) 1715, 1700, 1460, 1370, 1160 cm-1
;
(1′S)-2-Meth yl-5-(1′, 2′,2′-tr im eth ylcyclop en tyl)p h en ol
[(-)-δ-Cu p a r en ol (3)]. Triethylamine (0.095 mL, 0.69 mmol)
was added to a solution of diastereomeric ketones 13 (55.4 mg,
0.251 mmol) in CH2Cl2 (1.2 mL) was added triethylamine
(0.095 mL, 0.69 mmol) and TMS triflate (0.066 mL, 0.34 mmol)
at -78 °C. The reaction mixture was stirred at the same
temperature for 3 h and then poured into water and extracted
with ether. Workup as usual afforded an oily residue, which
was taken up in CH3CN (0.70 mL) and treated with palladium
(II) acetate (64 mg, 0.28 mmol). The resulting mixture was
stirred overnight at rt, poured into water, and extracted with
1H NMR δ 2.58-2.3 (5H, m, H-5′+ H2-2 + H2-4), 2.10 (3H, s,
H3-6), 1.08 (3H, s, CH3-1′), 1.04 and 0.80 (3H each, each s, 2 ×
CH3-2′); MS (EI) m/ z 225 (M+ + 1, 0.7), 224 (M+, 0.8), 168
(1.5), 155 (16), 115 (17), 113 (47), 111 (100); HRMS calcd for
C14H24O2 224.1776, found 224.1773.
(16) Connolly, J . D.; Hill, R. A. In Dictionary of Terpenoids, 1st ed.;
Chapman and Hall: London, 1991; Vol. 1, pp 299-300.
(17) Abad, A.; Agullo´, C.; Arno´, M.; Cun˜at, A. C.; Zaragoza´, R. J . J .
Org. Chem. 1992, 57, 50.