A. Srikrishna, D. B. Ramachary / Tetrahedron Letters 43 (2002) 2765–2768
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of triethylamine, furnished only the bicyclic ketoketal†7
15, mp 61°C, in 65% yield, contrary to the expected
acid chloride. To overcome this problem, the ketal
moiety in 11 was hydrolysed to furnish the keto-acid
16, which was converted into diazoketone 17 via the
corresponding acid chloride. Stereospecific intramolecu-
lar cyclopropanation8 of the diazoketone 17 with a
mixture of copper powder and anhydrous copper sul-
phate in refluxing cyclohexane furnished the tricyclic
dione 18,† mp 198–200°C, in 74% yield. After accom-
plishing the synthesis of the tricyclic dione 18 contain-
ing three contiguous quaternary carbon atoms,
differentiation of the two ketones in 18 was addressed
and for this purpose the preferred reduction of cyclo-
hexanones when compared to cyclopentanones was
exploited.9 Thus, regio- and stereoselective reduction of
the dione 18 with one equivalent of sodium borohy-
dride in methanol furnished a 19:1 mixture of the
hydroxy-ketones 19a and 19b in quantitative yield, via
preferred approach of the hydride from the less hin-
dered equatorial side,10 and which were separated by
column chromatography on silica gel. Etherification of
the hydroxy-ketone 19a with sodium hydride and
methyl iodide in the presence of a catalytic amount of
tetrabutylammonium iodide (TBAI) in dimethylfor-
mamide (DMF) and THF furnished the methoxy-
ketone† 20 in 94% yield, which on reaction with lithium
in liquid ammonia11 furnished the bicyclic ketone 21
(Scheme 4). The equatorial stereochemistry of the
methoxy group in 21 was assigned on the basis of the
coupling constants (11.0 and 3.3 Hz) of the axial proton
attached to the methoxy bearing carbon, thus confirm-
ing the stereostructures of hydroxy-ketones 19a and
19b.
Next attention was turned towards the conversion of
the methoxyketone 21 into thapsane, which requires the
introduction of one carbon each at the C-8 and C-9
positions. To overcome the regiochemical problem, the
methyl group was introduced prior to the cleavage of
the cyclopropane ring. Thus, alkylation of the tricyclic
ketone 20 with LDA and methyl iodide in THF and
HMPA furnished the methylated ketone 22, mp 80–
82°C, in 87% yield, in a highly stereoselective manner,12
which on regioselective cyclopropane ring cleavage11
with lithium in liquid ammonia and THF furnished a
2:1 mixture of the bicyclic ketone 23, mp 62°C, and the
alcohol 24, mp 93°C, in 81% yield, which were sepa-
rated by column chromatography on silica gel. PCC
oxidation transformed the alcohol 24 into the ketone
23.12 Finally, reaction of the ketone 23 with methylene-
triphenylphosphorane in benzene at room temperature
furnished 3-methoxythaps-8(11)-ene† 25 in 84% yield,
which on isomerisation with a catalytic amount of
MeO
Li-liq. NH3
O
MeO
73%
MeO
O
O
20
21
Scheme 4.
† All the compounds exhibited spectral data consistent with the structures. Selected spectral data for the ketoketal 15: IR (thin film): wmax 1728,
1646, 878 cm−1 1H NMR (300 MHz, CDCl3+CCl4): l 4.91 (1H, br s), 4.87 (1H, br s), 4.10–3.75 (4 H, m), 2.77 (1H, d, J 16.5 Hz), 2.55 (1H,
.
d, J 19.0 Hz), 2.47 (1H, m), 2.43 (1H, m of d, J 16.5 Hz), 1.85 (1H, d, J 19.0 Hz), 1.05 (3H, s), 0.96 (3H, s), 0.94 (3H, s). 13C NMR (75 MHz,
CDCl3+CCl4): l 210.1 (C), 148.1 (C), 110.8 (C), 108.0 (CH2), 64.9 (CH2), 64.4 (CH2), 54.2 (CH), 46.9 (CH2), 45.0 (C), 43.5 (C), 28.4 (CH2), 21.6
(CH3), 19.9 (CH3), 17.2 (CH3). For the dione 18: mp: 198–200°C. IR (thin film): wmax 1728, 1706 cm−1 1H NMR (300 MHz, CDCl3): l 2.88
.
(1H, dt, J 14.0 and 7.5 Hz), 2.47 (1H, dt, J 14.4 and 5.7 Hz), 2.26 (1H, ddd, J 13.5, 5.7 and 2.0 Hz), 2.11 (1H, d, J 18.0 Hz), 2.08 (1H, dd, J
7.8 and 2.4 Hz), 1.87 (1H, dd, J 18.0 and 1.0 Hz), 1.62 (1H, ddd, J 13.5, 7.8 and 1.5 Hz), 1.19 (3H, s), 1.09 (1H, dd, J 5.1 and 3.0 Hz), 1.07
(3H, s), 0.98 (3H, s), 1.00–0.90 (1H, m). 13C NMR (75 MHz, CDCl3+CCl4): l 213.0 (C), 211.2 (C), 51.8 (C), 46.9 (C), 43.0 (CH2), 37.0 (CH),
35.5 (2 C, C and CH2), 28.5 (CH2), 23.2 (CH3), 20.1 (CH3), 19.0 (CH3), 16.7 (CH2). For the methoxyketone 20: IR (neat): wmax 1726 cm−1 1H
.
NMR (300 MHz, CDCl3+CCl4): l 3.30 (3H, s), 2.94 (1H, br s), 2.31 (1H, dt, J 14.0 and 5.1 Hz), 2.02 (1H, d, J 18.0 Hz), 1.90–1.70 (4 H, m),
1.64 (1H, d, J 18.0 Hz), 1.27 (3H, s), 1.04 (1H, dd, J 5.0 and 2.7 Hz), 0.96 (3H, s), 0.87 (3H, s), 0.95–0.75 (1H, m). 13C NMR (75 MHz,
CDCl3+CCl4): l 213.7 (C), 86.8 (CH), 57.5 (CH3), 45.4 (CH2), 42.7 (C), 40.8 (C), 37.0 (C), 36.97 (CH), 24.9 (CH3), 22.9 (CH2), 22.5 (CH3), 21.6
(CH2), 21.2 (CH3), 17.7 (CH2). For the tricyclic ketone 22: IR (thin film): wmax 1723 cm−1 1H NMR (300 MHz, CDCl3+CCl4): l 3.31 (3H, s),
.
2.96 (1H, br s), 2.32 (1H, dt, J 14.0 and 5.7 Hz), 2.12 (1H, q, J 8.0 Hz), 1.84 (1H, br d, J 9 Hz), 1.85–1.65 (3H, m), 1.21 (3H, s), 1.02 (3H, d,
J 8.0 Hz), 0.92 (3H, s), 0.90–0.80 (1H, m), 0.85 (3H, s), 0.74 (1H, dd, J 9.0 and 5.4 Hz). 13C NMR (75 MHz, CDCl3+CCl4): l 216.9 (C), 87.2
(CH), 57.6 (CH3), 47.3 (CH), 44.5 (C), 41.9 (C), 37.1 (C), 36.9 (CH), 24.8 (CH3), 23.4 (CH2), 22.3 (CH3), 21.5 (CH2), 17.4 (CH2), 17.3 (CH3),
16.5 (CH3). For the bicyclic ketone 23: IR (thin film): wmax 1737 cm−1 1H NMR (300 MHz, CDCl3+CCl4): l 3.34 (3H, s), 3.05 (1H, m of d,
.
J 8 Hz), 2.56 (1H, q, J 7.2 Hz), 2.22 (1H, d, J 18.3 Hz), 1.90 (1H, dd, J 18.3 and 1.5 Hz), 1.85–1.75 (1H, m), 1.55–1.40 (3H, m), 1.22 (3H, s),
1.10 (3H, d, J 7.2 Hz), 0.98 (3H, s), 0.94 (3H, s), 0.91 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): l 219.8 (C), 84.4 (CH), 57.6 (CH3), 53.4 (CH2),
49.7 (C), 49.0 (CH), 41.8 (C), 39.8 (C), 35.6 (CH2), 24.9 (CH3), 23.0 (CH3), 22.6 (CH2), 18.0 (CH3), 13.8 (CH3), 13.4 (CH3). For
3-methoxythaps-8(11)-ene 25: IR (neat): wmax 1650, 880 cm−1 1H NMR (300 MHz, CDCl3+CCl4): l 4.82 (1H, m), 4.77 (1H, m), 3.33 (3H, s),
.
3.04 (1H, dd, J 11.4 and 4.0 Hz), 2.82–2.70 (1H, m), 2.38 (1H, qd, J 16.0 and 2.7 Hz), 1.84 (1H, d, J 16.0 Hz), 1.80–1.60 (1H, m), 1.60–1.15
(3H, m), 1.08 (3H, d, J 6.6 Hz), 1.06 (3H, s), 0.96 (3H, s), 0.86 (3H, s), 0.79 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4): l 156.3 (C), 106.3 (CH2),
84.8 (CH), 57.6 (CH3), 51.0 (C), 49.1 (CH2), 42.6 (C), 42.58 (CH), 41.7 (C), 34.6 (CH2), 24.7 (CH3), 23.1 (CH3), 22.8 (CH2), 18.4 (CH3), 17.7
1
(CH3), 13.4 (CH3). For 3-methoxythaps-8-ene 26: H NMR (300 MHz, CDCl3+CCl4): l 3.25 (3H, s), 2.81 (1H, dd, J 6.0 and 3.0 Hz), 2.18 (1H,
d, J 15.3 Hz), 1.70–1.50 (3H, m), 1.55 (3H, s), 1.54 (3H, s), 1.40–1.20 (2 H, m), 0.94 (3H, s), 0.90 (3H, s), 0.86 (3H, s), 0.77 (3H, s). 13C NMR
(75 MHz, CDCl3+CCl4): l 137.2 (C), 129.8 (C), 86.5 (CH), 57.0 (CH3), 55.6 (C), 51.4 (CH2), 43.2 (C), 41.8 (C), 30.0 (CH2), 29.0 (CH3), 26.6
(CH3), 24.5 (CH3), 20.9 (CH2), 17.1 (CH3), 14.5 (CH3), 13.6 (CH3).