D.A. Foley et al. / Tetrahedron 69 (2013) 1778e1794
1791
C(8a)CH3], 1.04 [3H, d, J 6.8, one of CH(CH3)2]}, 1.14e1.28 (1H, m),
1.32e1.47 (2H, m), 1.72e1.91 (2H, m), 2.25 (1H, dd, J 14.7, 7.7),
2.52e3.02 {4H, m, containing, 2.57 (br d), 2.66 [1H, d, A of ABq, J 22.2,
one of C(2)H2], 2.91 [1H, septet, J 7.0, CH(CH3)2], 2.96 [1H, d, B of ABq,
J 22.2, one of C(2)H2]}; dC (75.5 MHz, CDCl3) 21.2 (2ꢂ CH3), 23.9
(CH2), 24.0, 24.5 (2ꢂ CH3), 26.2 (CH), 33.6, 34.6 (2ꢂ CH2), 38.4 (CH),
38.9, 39.1 (2ꢂ CH2), 56.9 [C, C(8a)], 136.1, 140.7 [2ꢂ C, C(3), C(3a)],
0.90 [6H, 2ꢂ d, J 7.0, 6.0, one of CH(CH3)2, C(6)CH3], 1.00 [3H, d, J 7.0,
one of CH(CH3)2], 1.07 [3H, s, C(3a)CH3], 1.15e1.29 (1H, m),
1.33e1.86 [6H, m, containing 1.69 (1H, br t, J 13.4, one of CH2)],
2.07e2.18 (1H, m), 2.51 (1H, ddd, J 13.7, 5.8, 2.3, one of CH2), 2.69
[1H, septet, J 7.0, CH(CH3)2], 2.76e2.92 [2H, m, C(2)H2], 3.11e3.37
(4H, m, SCH2CH2S); dC (75.5 MHz, CDCl3) 20.8, 21.4 [2ꢂ CH3, one of
CH(CH3)2, C(6)CH3], 23.9 [CH3, one of CH(CH3)2], 24.7 (CH2), 26.0
[CH3, C(8a)CH3], 26.3 [CH, CH(CH3)2], 36.0, 36.0, 37.7, 37.8 (4ꢂ CH2),
38.3 [CH, C(6)H], 38.7 (CH2), 50.7 [CH2, C(2)H2], 56.0 [C, C(8a)], 80.9
[C, C(1)], 139.6, 141.9 (2ꢂ C); HRMS (ESþ): exact mass calculated for
C17H29S2 [MþH]þ, 297.1705. Found 297.1702.
221.4 (C, C]O); HRMS (ESþ): exact mass calculated for C15H25
[MþHꢀH2O]þ, 221.1900. Found 221.1900.
O
4.1.17. (3aR*,6R*,8aR*)-3-Isopropyl-6,8a-dimethyl-4,5,6,7,8,8a-hex-
ahydroazulen-1(3aH)-one 28. (6R*,8aR*)-3-Isopropyl-6,8a-dimethyl-
4,5,6,7,8,8a-hexahydroazulene-1(2H)-one 27 (1.50 g, 6.81 mmol)
was dissolved in an ethanol/toluene (20:80) mixture (80 mL) and
rhodium trichloride trihydrate (3.00 mg, 0.2 mol %) was added. The
reaction mixture was heated under reflux, while stirring under an
atmosphere of nitrogen for 24 h. Evaporation of the solvent mixture,
followed by purification of the residue by flash chromatography on
In another experiment a pure sample of 32 was isolated and
characterised, which aided the spectral assignments.
4.1.19. (3aS*,6R*,8aS*)-3-Isopropyl-6,8a-dimethyl-1,3a,4,5,6,7,8,8a-
octahydroazulene 31. A mixture of (6R*,8aR*)-3-isopropyl-6,8a-di-
methyl-4,5,6,7,8,8a-hexahydro-3aH-spiro[azulene-1,20-[1,3]dithio-
lane 30 and (6R*,8aR*)-3-isopropyl-6,8a-dimethyl-4,5,6,7,8,8a-
hexahydro-2H-spiro[azulene-1,20-[1,3]dithiolane]32 (3:1) (0.90 g,
3.04 mmol) were dissolved in ethanol (15 mL) and RaneyÒ nickel
(10.5 g, weighed as a slurry in water) was added. The suspension
was then heated under reflux for 15 min. The reaction mixture was
filtered through a plug of CeliteÒ to remove the catalyst and washed
several times with ethanol. The filtrate was then concentrated
under reduced pressure to give the crude product as a colourless
oil. A 1H NMR spectrum of the crude reaction mixture showed the
presence of a number of products, with the alkene 31 as the major
component of the mixture, along with dienes 33 and 34 in a ratio of
1:0.55:0.37. Purification by flash chromatography on silica gel
eluted with hexane gave the pure alkene 31 (0.26 g, 42%) as a col-
ourless oil: nmax/cmꢀ1 (film) 2956, 2914, 2869, 1458, 1379; dH
(300 MHz, CDCl3) 0.78e1.25 {14H, m, containing 0.85 [3H, d, J 6.6,
C(6)CH3], 0.95 [3H, d, J 6.9, one of CH(CH3)2], 1.01 [3H, s, C(8a)CH3],
1.09 [3H, d, J 6.9, one of CH(CH3)2]}, 1.27e1.75 (7H, m), 1.83e2.01
[1H, m, one of C(1)H2], 2.03e2.22 [1H, m, CH(CH3)2], 2.24e2.43 [2H,
m, one of C(1)H2, C(3a)H], 5.23 [1H, d, J 2.1, C(2)H]; dC (75.5 MHz,
CDCl3)21.1, 22.0 [2ꢂ CH3, CH(CH3)2], 22.6 [CH3, br, C(6)CH3], 25.8
(CH2), 27.2 [CH, CH(CH3)2], 32.6 [CH3, C(8a)CH3], 32.9, 33.8 (2ꢂ
CH2), 35.2 [CH, br, C(6)H], 37.4 (CH2), 43.6 [C, C(8a)], 45.5 [CH2, C(1)
H2], 56.5 [CH, C(3a)H], 119.0 [CH, C(2)H], 152.5 [C, C(3)].
silica gel, eluting with ethyl acetate/hexane (5:95) gave the pure a,b-
unsaturated ketone 28 (1.02 g, 68%) as a colourless oil: nmax/cmꢀ1
(film) 2960, 2871, 1701, 1611, 1457; dH (300 MHz, CDCl3) 0.60e0.95
{5H, m, containing 0.79 [3H, d, J 6.6, C(6)CH3]}, 1.04 [3H, s, C(8a)CH3],
1.12 [3H, d, J 7.0, one of CH(CH3)2], 1.23 [3H, d, J 6.6, one of CH(CH3)2],
1.30e1.59 [4H, m, C(6)H], 1.80 [1H, ddd, J 14.9, 11.2, 3.6, one of C(4)
H2], 1.89e2.06 [2H, m, one of C(4)H2], 2.55 [1H, d septets, J 6.9, 0.9,
CH(CH3)2], 2.77 [1H, overlapping ddd, J 5.2, 3.5,1.7, C(3a)H], 6.02 [1H,
s, C(2)H]; dC (75.5 MHz, CDCl3) 20.3 [CH3, one of CH(CH3)2], 21.4 [CH3,
one of CH(CH3)2], 23.1 [CH3, C(6)CH3], 26.2 [CH2, C(4)H2], 28.0 [CH3,
C(8a)CH3], 29.0 [CH, CH(CH3)2], 33.3, 34.3, 34.9 [3ꢂ CH2, C(5)H2, C(6)
H2, C(7)H2], 37.0 [CH, br, C(6)H], 51.8 [C, C(8a)], 54.1 [CH, C(3a)H],
127.1 [CH, C(2)H], 190.1[C, C(3)], 215.7 (C, C]O); HRMS (ESþ): exact
mass calculated for C15H25O [MþH]þ, 221.1905. Found 221.1904.
4.1.18. (6R*,8aR*)-3-Isopropyl-6,8a-dimethyl-4,5,6,7,8,8a-hexahy-
dro-3aH-spiro[azulene-1,20-[1,3]dithiolane 30 and (6R*,8aR*)-3-
isopropyl-6,8a-dimethyl-4,5,6,7,8,8a-hexahydro-2H-spiro[azulene-
1,20-[1,3]dithiolane] 32. 1,2-Ethanedithiol (3.48 mL, 41.4 mmol) was
added to a solution of (3aR*,6R*,8aR*)-3-isopropyl-6,8a-dimethyl-
4,5,6,7,8,8a-hexahydroazulen-1(3aH)-one 28 (1.30 g, 5.91 mmol)
in dichloromethane (80 mL), while stirring at 0 ꢁC under an at-
mosphere of nitrogen. Titanium tetrachloride (17.8 mL, 1 M in
dichloromethane, 17.7 mmol), was then added slowly, and the
reaction mixture was allowed to warm to room temperature over
30 min. The solution was heated under reflux for 6 h and was then
cooled to room temperature, and washed with potassium hy-
droxide (1 M, 3ꢂ80 mL), water (80 mL) brine (80 mL), dried and
concentrated under reduced pressure to give the crude thioketal
30 as a pink oil. Purification by flash chromatography on silica gel
eluted with ethyl acetate/hexane (20:80), gave the thioketal 30
(1.34 g, 76%), containing 25e30% of a minor compound 32 as
a colourless oil with a pungent sulfur odour: nmax/cmꢀ1 (film)
2958, 2922, 1455, 1380; dH (300 MHz, CDCl3) 0.98, 1.00 [6H, 2ꢂ d, J
6.8, 6.8, one of CH(CH3)2, C(6)CH3], 1.09 [3H, d, J 6.7, one of
CH(CH3)2], 1.18 [3H, s, C(8a)CH3], 1.24e1.71 (7H, m), 1.93e2.08 [1H,
m, C(6)H], 2.10e2.29 [2H, m, containing 2.14 (1H, d, J 10.5), 2.21
(1H, septet, J 6.9, CH(CH3)2), 2.44e2.59 (1H, m), 2.89e2.91 (1H, m,
one of SCH2CH2S), 3.08e3.33 (3H, m, SCH2CH2S), 5.37 [1H, s, C(2)
H]; dC (75.5 MHz, CDCl3) 19.7, 20.8 [2ꢂ CH3, one of CH(CH3)2, C(6)
CH3], 21.7 [CH3, one of CH(CH3)2], 24.8 (CH2), 26.7 (CH2), 27.0 (CH),
27.5 [CH3, C(8a)CH3], 29.8 (CH2), 30.3 [CH, C(6)H], 36.0 (CH2),
37.8 (C), 39.4, 40.1 [2ꢂ CH2, C(40)H2, C(50)H2], 57.9 [CH, CH(CH3)2],
84.3 [C, C(1)], 127.4 [CH, C(2)H], 152.8 [C, C(3)]; HRMS (ESþ):
exact mass calculated for C17H29S2 [MþH]þ, 297.1705. Found
297.1705.
The dienes 33 and 34 were isolated as a mixture following
chromatography as a clear oil (0.20 g, 33%) in a ratio of 0.55:0.45.
The endo-diene 33 displayed characteristic signals in the 1H NMR
spectrum dH (300 MHz, CDCl3) 2.72 [1H, septet, J 6.8, CH(CH3)2],
6.02 [1H, d, J 5.3, one of C(1)H or C(2)H], 6.26 [1H, d, J 5.3, one of
C(1)H or C(2)H].
The exo-diene 34 displayed characteristic signals in the 1H NMR
spectrum dH (300 MHz, CDCl3) 1.77, 1.70 [2ꢂ 3H, 2ꢂ s, CH(CH3)2],
5.60 [1H, d, J 5.8, one of C(1)H or C(2)H], 6.26 [1H, d, J 5.3, one of
C(1)H or C(2)H].
4.1.20. (1R*,2S*,3aS*,6R*,8aS*)-1-Isopropyl-3a,6-dimethyldecahydroa
zulene-1,2-diol 6 and (1S*,2R*,3aS*,6R*,8aS*)-1-isopropyl-3a,6-
dimethyldecahydroazulene-1,2-diol 36
4.1.20.1. Method (a). Osmium tetroxide (0.150 mL, 4% solution
in water, 0.024 mmol) was added to a solution of the alkene 31
(100 mg, 0.485 mmol) and NMO (74.0 mg, 0.631 mmol) in acetone
(10 mL) and water (2 mL). The reaction mixture was stirred at room
temperature for 3 h. The progress of the reaction was monitored by
TLC and the presence of more polar products was observed. The
reaction mixture was worked up at this stage, following the pro-
cedure described below, and a sample taken for 1H NMR analysis,
which only showed starting material. The alkene was re-exposed to
osmium tetroxide (0.150 mL, 4% solution in water, 0.024 mmol) and
NMO (74 mg, 0.631 mmol) in acetone (10 mL) and water (2 mL). The
reaction mixture was stirred at room temperature for two weeks.
This sample also contained a small amount (25e30%) of a minor
compound, which was identified as 32: dH (300 MHz, CDCl3) 0.89,