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Notes
J . Org. Chem., Vol. 61, No. 18, 1996 6423
comparison with the remaining two isomers prepared
earlier.8,9 Regiospecific oxidation of the olefinic moiety
of allyl group in the dienone 7 using Wacker conditions
(PdCl2, CuCl, O2, DMF, H2O)10 followed by purification
on a silica gel column furnished the diketone 8. In-
tramolecular aldol condensation transformed the dike-
tone 8 into the hydrindenone 5. The hydrindenone 5 was
converted into the radical precursor, bromoenone 9, by
employing a regiospecific bromoetherification reaction.11
Thus reaction of the hydrindenone 5 with N-bromosuc-
cinimide (NBS) in methanol-methylene chloride medium
furnished a diastereomeric mixture of the bromoenone
9. After different conditions were briefly explored, the
radical cyclization reaction of the bromoenone 9 was
carried out by slow addition of a benzene solution of a
mixture of tri-n-butyltin hydride (1.1 equiv) and a
catalytic amount of azobisisobutyronitrile (AIBN) to a
refluxing benzene solution of the bromoenone 9 (overall
concentration of nBu3SnH 0.01 M) to furnish an epimeric
mixture of the tricyclic ketones 10 and 11, which was
separated by silica gel column chromatography. The
gross structure of the cyclized products 10 and 11 were
derived from their comparable spectral data. The ab-
sence of olefinic proton and carbon resonances in the
NMR spectra, the shift in the carbonyl absorption band
to 1740 cm-1 in the IR spectra, and the downfield shift
of carbonyl carbon resonances to δ 218.3 and 218.55 ppm
in the 13C NMR spectra due to a cyclopentanone carbonyl
group clearly established the radical cyclization reaction.
The presence of three quaternary (δ 84.2, 50.9, and 44.7),
two methine (43.4 and 34.7), and five methylene (50.5,
48.9, 47.7, 33.2 and 32.5 ppm) aliphatic carbon atoms in
the 13C NMR spectrum (SEFT) on the product 11 (and
similarly for the ketone 10) established the regiospeci-
ficity in the cyclization as 5-exo mode, as the alternative
6-endo mode would have resulted in four each of methine
and methylene and two quaternary carbon atoms. The
stereochemical assignment at C-9 was derived from the
downfield shift of the C-9 methyl carbon resonance (δ 26)
in the ketone 10 when compared with that of the ketone
11 (17.5 ppm).
the present radical cyclization reaction, a trans-hydrin-
dane moiety was created in a stereospecific manner.13,14
Exp er im en ta l Section
Melting points are recorded in capillaries and are uncorrected.
1H and 13C chemical shifts (δ) and coupling constants (Hz) are
reported in the standard fashion with reference to either internal
1
tetramethylsilane (for H) or the central line (77.1 ppm) of CDCl3
(for 13C). Off-resonance multiplicities, when recorded, are given
in parentheses. Acme’s silica gel (100-200 mesh) was used for
column chromatography. Dry benzene was obtained by distil-
lation over sodium. Dry ether was obtained by washing with
ferrous sulfate followed by distillation over sodium. CuI, NBS,
nBu3SnH, PdCl2 were obtained from Fluka and used as re-
ceived: AIBN was recrystallized from methanol and stored in
the dark.
(2S,3R,5R)- a n d (2R,3R,5R)-2-Allyl-5-isop r op en yl-2,3-
d im eth ylcycloh exa n on es (7). To a cold (-10 °C), magneti-
cally stirred, solution of lithium dimethylcopper [prepared from
cuprous iodide (1.9 g, 10 mmol) and methyllithium in ether (20
mmol, 26 mL of 0.765 M)] was added a solution of (R)-carvone
(6, 1.0 g, 6.66 mmol) in dry ether (15 mL) over a period of 15
min. The reaction mixture was further stirred for 30 min at
room temperature, and a mixture of allyl bromide (8.0 g, 66.6
mmol, 5.8 mL) and HMPA (1.43 g, 8 mmol, 1.4 mL) was added
over 5 min. The reaction mixture was stirred for 24 h at room
temperature, quenched with 25% aqueous ammonia solution,
and extracted with ether (3 × 15 mL). The ether extract was
washed with brine and dried (Na2SO4). Evaporation of the
solvent and purification of the residue on a silica gel column,
using ethyl acetate-hexane (1:48) as eluent, furnished a 9:1
epimeric mixture of allyl product 7 (1.22 g, 89%) as pale yellow
oil. A small amount of major product was separated for the
spectral data. [R]24D: +37 (c 1.2, CHCl3). IR (neat): νmax 1705,
890 cm-1 1H NMR (200 MHz, CDCl3): δ 5.63 (1 H, t of dd, J )
.
17.5, 9.5 and 7.3 Hz), 5.07 (1 H, d, J ) 17.5 Hz), 5.07 (1 H, d, J
) 9.5 Hz), 4.79 (1 H, s), 4.72 (1 H, s), 2.3-2.7 (5 H, m), 1.9-2.2
(2 H, m), 1.6-1.7 (1 H, m), 1.75 (3 H, s), 1.0 (3 H, s), 0.91 (3 H,
d, J ) 7.2 Hz). 13C NMR (67.5 MHz, CDCl3): δ 215.6, 148.2,
134.3, 118.5, 110.9, 52.4, 43.5, 42.7, 41.1, 37.4, 33.4, 21.5, 19.6,
16.6. Mass: m/z 206 (M+, 10%). HRMS Calcd for C14H22
O
206.1671, found 206.1679.
(2S,3R,5R)-5-Isop r op en yl-2,3-d im eth yl-2-(2-oxop r op yl)-
cycloh exa n on e (8). A suspension of palladium chloride (61
mg, 0.34 mmol) and cuprous chloride (500 mg, 5 mmol) in DMF
(2.5 mL) and water (0.5 mL, 28.2 mmol) was magnetically stirred
in an oxygen atmosphere, created via evacuative displacement
of air using an oxygen balloon, for 1 h at room temperature. A
solution of allyl compound 7 (1.03 g, 5 mmol) in 1 mL of DMF
was then added, and the reaction mixture was stirred for 24 h
at room temperature in the oxygen atmosphere. Aqueous HCl
(3 N, 5 mL) was added to the reaction mixture, and it was
extracted with ether (3 × 10 mL). The ether layer was washed
with saturated aqueous sodium bicarbonate solution followed
by brine and dried (Na2SO4). Evaporation of the solvent and
careful chromatography of the residue on a silica gel column
using ethyl acetate-hexane (1:20 to 1:10) as eluent, furnished
the diketone 8 (775 mg, 70%) as a white solid, which was
recrystallized from hexane. mp 53-54 °C. [R]23D: +6.1 (c 1.14,
It was established12,6a that in the 6-methylbicyclo[3.2.1]-
octanes, the exo- and the endo methyl carbons resonate
in the range of δ24 and 15 ppm, respectively. The facile
formation of the tricyclic compounds 10 and 11 from the
bromide 9 is obviously due to the electrophilic nature of
the enone. The axial orientation of the side chain in the
preferred conformation of the intermediate radical might
have further facilitated the cyclization.
CHCl3). IR (nujol): νmax 1710, 1700, 895 cm-1
.
1H NMR (90
MHz, CDCl3): δ 4.83 (1 H, s), 4.75 (1 H, s), 2.78 (2 H, brs), 2.56
(2 H, brs), 2.2-2.5 (1 H, m), 2.12 (3 H, s), 1.65-1.85 (3 H, m),
1.72 (3 H, s), 1.02 (3 H, s), 0.88 (3 H, d, J ) 7.2 Hz. 13C NMR
(22.5 MHz, CDCl3): δ 211.8 (s), 205.5 (s), 146.3 (s), 109.6 (t),
49.4 (t), 49.1 (s), 41.1 (t), 39.5 (d), 34.4 (d), 31.7 (t), 30.2 (q), 20.0
(q), 17.8 (q), 14.4 (q). Anal. Calcd. for C14H22O2 C, 75.63; H,
9.97. Found C, 75.74; H, 10.19.
Me
Me
δ 24
δ
15
In conclusion, we have achieved the synthesis of chiral
tricyclo[6.2.1.01,5]undecanes via the stereospecific creation
of a spiro carbon atom adjacent to an existing stereogenic
quaternary carbon atom. It is worth mentioning that in
(13) There are only a very few reports in the literature on the
construction of trans-hydrindane moiety via radical cyclization reac-
tions,14 and in most of them, the cyclopentane moiety was created by
starting from 1,2-trans-substituted cyclohexanes, unlike the present
case where the ring junction stereochemistry is created in the radcial
cyclization reaction.
(11) Rodriguez, J .; Dulcere, J .-P. Synthesis 1993, 1177.
(12) J aggi, F. J .; Buchs, P.; Ganter, C. Helv. Chim. Acta 1980, 63,
872.
(14) Angoh, A. G.; Clive, D. L. J . J . Chem. Soc., Chem. Commun.
1985, 941 and 980. Bachi, M. D.; Bosch, E. Tetrahedron Lett. 1986,
27, 641.