HETEROCYCLES

Short Paper | Special issue | Vol. 88, No. 1, 2014, pp. 651-662
Received, 27th May, 2013, Accepted, 21st June, 2013, Published online, 25th June, 2013.
DOI: 10.3987/COM-13-S(S)19

■ Synthesis of Oxygen-Bridged Decahydroazulene Derivatives: Simplified Analogues of Biologically Active Natural Products

Hideki Abe, Akira Tezuka, Toyoharu Kobayashi, and Hisanaka Ito*

School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Abstract

Decahydroazulene derivatives having an ether bridge were synthesized. They are structurally simplified analogues of the biologically active guaiane sesquiterpenes englerin A and orientalol F.

Englerin A (1),1,2 isolated from the root and bark of Phyllanthus engleri in 2009, and orientalol F (2),3 isolated from the rhizome of Alisma orientalis in 2003, are biologically active guaiane sesquiterpenes sharing a common oxygen-bridged decahydroazulene skeleton as depicted in Figure 1. Englerin A (1) possesses selective inhibitory activity toward the growth of renal cancer cell lines at nanomolar levels. The structural complexities and biological activities of these compounds have fascinated synthetic researchers, resulting in many synthetic and biological studies of these sesquiterpenes to date.4–12 Although numerous analogues with various ester side chains of englerin A have been synthesized and tested for their biological activities,13–15 the pharmacophore of englerin A is not yet known. Therefore, synthesis of structurally simplified analogues 3 and 4 as target molecules is proposed in order to explore their structure–activity relationships. In this paper, we describe the synthesis of oxygen-bridged decahydroazulene derivatives via epoxide ring-opening and aldol condensation to construct the perhydroazulene skeleton.

Our synthetic plan for target molecules 3 and 4 is outlined in Scheme 1. Synthesis of these structurally simplified analogues would be accomplished by epoxide ring-opening and ether-cyclization of epoxyalcohols 5 and 6, which would be derived from decahydroazulenone derivatives 7 and 8. Bicyclic compounds 7 and 8 would be obtained through two-step operations involving aldol condensation of diketones 11 and 12, followed by hydrogenation of enones 9 and 10, accompanied by epimerization at H8a to form the trans-fused bicyclic system. Diketone derivatives 11 and 12 would be synthesized by 1,4-addition of cycloheptenone derivative 1316,17 to appropriate side chain units.

The investigation began with the preparation of decahydroazulenones 7 and 8 from γ-benzoyloxycycloheptenone 1316,17 as shown in Scheme 2. The 1,4-addition reaction of 13 with Grignard reagents, prepared from magnesium and 3-butenyl bromide or 3-methyl-3-butenyl bromide, gave the 3,4-trans adducts 14 or 15, respectively. The relative configurations at C3 and C4 of the adducts were confirmed by X-ray crystallographic analysis18 of the resulting diketone 12, which was obtained by ozonolysis of 15 as depicted in Scheme 2. Construction of the perhydroazulenone skeletons was achieved by intramolecular aldol condensation. After numerous attempts, the intramolecular aldol condensation of 11, obtained by ozonolysis of 14, was accomplished under acidic conditions [TsOH/THF, reflux] to give 9 in 69% yield. For the aldol condensation of 12, the azulenone derivative 10 was produced under basic conditions [t-BuOK/t-BuOH, rt] in 66% yield. Hydrogenation of 9 and 10 with palladium on carbon in EtOH gave 7 and 8 in 90% and 78% yields, respectively. The stereochemistry of the resulting 8 was determined by X-ray crystallographic analysis as 1R*,3aS*,4S*,8aS*.19 This result reveals that hydrogenation of the double bond of enone 10 occurred from the same face as the hydrogen atom at C3a. Subsequent epimerization at C8a of the resulting 16 was carried out to give trans-fused decahydroazulene derivative 8. When the reaction time was shortened, an inseparable mixture of cis-fused 16 and trans-fused 7 or cis-17 and trans-8 were obtained, respectively.

With the trans-fused decahydroazulenone derivatives in hand, we turned our attention to the construction of the oxygen-bridged moiety to complete the target molecules. Alkenes 20 and 21 were obtained in two-step procedures from 7 and 8, respectively, as shown in Scheme 3. Treatment of 7 or 8 with KHMDS and PhNTf2, followed by palladium-catalyzed reduction [Pd(OAc)2, dppp, Et3SiH] of the resulting enol triflates 18 or 19, afforded the alkenes 20 and 21 in good yields. After deprotection of 20 and 21, epoxidation of the resulting 22 and 23 with mCPBA afforded the precursors 5 and 6 in 51% or 54% yields, respectively. Finally, ether cyclization involving epoxide ring-opening to construct the oxygen-bridged decahydroazulene skeleton was achieved with TsOH in refluxing THF to produce the target molecules 3 and 4 in 64% and 59% yields.

To confirm the stereochemistry of the obtained target molecules, X-ray crystallographic analysis was carried out as shown in Scheme 4. After protection of the hydroxyl group of 3, recrystallization of the resulting p-bromobenzoate 24 gave a single crystal. The stereochemistry of 24 was determined as 3aR*,4R*,7S*,8S*,8aR*.20

In conclusion, we synthesized the very simplified analogues of biologically active guaiane sesquiterpenes, englerin A and orientalol F. Biological studies of these structurally simple analogues are now in progress.

EXPERIMENTAL
(1R*,2R*)-2-(But-3-en-1-yl)-4-oxocycloheptyl benzoate (14)
To a suspension of CuCN (156 mg, 1.74 mmol) in THF (17 mL) was added 3-butenylmagnesium bromide (0.5 M in THF, 3.48 mL) at –78 °C under Ar. After the resulting suspension was stirred for 15 min, a solution of enone 13 (200 mg, 0.869 mmol) in THF (2 mL) was added to this suspension. After stirred for 2 h at –78 °C, the reaction mixture was quenched with saturated NaHCO3 aqueous solution. The mixture was extracted with Et2O (3 x 50 mL), and the combined organic layers were washed with brine, dried over MgSO4. After the solvent was removed in vacuo, the resulted residue was purified by column chromatography (hexane/AcOEt, 20:1) to give 14 (183 mg, 74%) as colorless oil. IR (neat): 2932, 1712, 1638, 1601, 1451, 1314, 1272, 1175, 1111, 1070, 1026, 772, 712 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.31–1.58 (2H, m), 1.69–1.80 (1H, m), 1.88–2.28 (6H, m), 2.33–2.61 (3H, m), 2.96 (1H, dd, J = 13.4, 2.4 Hz), 4.95 (1H, d, J = 10.5 Hz), 5.02 (1H, dd, J = 17.1, 1.6 Hz), 5.22 (1H, ddd, J = 6.0, 6.0, 3.0 Hz), 5.74 (1H, dddd, J = 17.1, 10.5, 6.7, 6.7 Hz), 7.41–7.49 (2H, m), 7.53–7.60 (1H, m), 8.01–8.08 (2H, m); 13C NMR (75 MHz, CDCl3): δ 17.8, 30.4, 30.7, 31.2, 38.5, 42.6, 43.5, 75.8, 115.4, 128.4 (2C), 129.5 (2C), 130.3, 133.0, 137.5, 165.5, 213.0; HRESIMS calcd for C18H22O3Na [M+Na]+ 309.1467, found 309.1457.

(1R*,2R*)-2-[(2-Methyl)but-3-en-1-yl]-4-oxocycloheptyl benzoate (15)
To a suspension of CuCN (240 mg, 2.70 mmol) in THF (27 mL) was added 3-methyl-3-butenylmagnesium bromide (0.5 M in THF, 5.4 mL) at –78 °C under Ar. After the resulting suspension was stirred for 15 min, a solution of enone 13 (412 mg, 1.79 mmol) in THF (4 mL) was added to this suspension. After stirred for 2 h at –78 °C, the reaction mixture was quenched with saturated NaHCO3 aqueous solution. The mixture was extracted with Et2O (3 x 100 mL), and the combined organic layers were washed with brine, dried over MgSO4. After the solvent was removed in vacuo, the resulted residue was purified by column chromatography (hexane/AcOEt, 20:1) to give 15 (431 mg, 80%) as colorless oil. IR (neat): 2939, 2868, 1722, 1715, 1698, 1651, 1602, 1453, 1275, 1176, 1112, 1071, 1026, 890, 713 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.34–1.49 (1H, m), 1.53–1.84 (5H, m, including 3H, s, at δ 1.68), 1.93–2.23 (6H, m), 2.35–2.63 (3H, m), 2.97 (1H, dd, J = 13.4, 2.4 Hz), 4.69 (1H, s), 4.71 (1H, s), 5.23 (1H, ddd, J = 6.0, 6.0, 3.2 Hz), 7.42–7.49 (2H, m), 7.54–7.62 (1H, m), 8.01–8.09 (2H, m); 13C NMR (75 MHz, CDCl3): δ 17.9, 22.2, 29.4, 31.3, 34.3, 38.7, 42.7, 43.5, 75.9, 110.7, 128.5 (2C), 129.5 (2C), 130.4, 133.1, 144.7, 165.6, 213.2; HRESIMS calcd for C19H24O3Na [M+Na]+ 323.1623, found 323.1623.

(1R*,2R*)-4-Oxo-2-(3-oxopropyl)cycloheptyl benzoate (11)
Ozone gas was bubbled through a solution of 14 (164 mg, 0.572 mmol) in CH2Cl2 (12 mL) until a pale blue color persisted at –78 °C. Triphenylphosphine (299 mg, 1.14 mmol) was added to this mixture, and the mixture was stirred for 4 h at room temperature. After the solvent was removed in vacuo, the resulted residue was purified by column chromatography (hexane/AcOEt, 3:1) to give 11 (160 mg, 90%) as colorless oil. IR (neat): 2929, 1714, 1601, 1451, 1315, 1273, 1176, 1112, 1070, 1026, 713 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.47–1.64 (2H, m), 1.73–1.91 (2H, m), 1.96–2.19 (4H, m), 2.35–2.78 (4H, m), 2.98 (1H, dd, J = 13.2, 2.2 Hz), 5.15–5.23 (1H, m), 7.39–7.50 (2H, m), 7.51–7.64 (1H, m), 8.01–8.08 (2H, m), 9.78 (1H, s); 13C NMR (75 MHz, CDCl3): δ 17.8, 23.8, 31.3, 38.8, 40.7, 42.4, 43.5, 75.8, 128.5 (2C), 129.6 (2C), 130.4, 133.2, 165.5, 200.9, 213.0; HRESIMS calcd for C17H20O4­Na [M+Na]+ 311.1259, found 311.1270.

(1R*,2R*)-4-Oxo-2-(3-oxobutyl)cycloheptyl benzoate (12)
This compound was obtained as colorless needles (Mp 94–95 °C) in 76% yield from 15 (1.53 g, 5.01 mmol) in CH2Cl2 (50 mL), as descrived above for the preparation of 11. IR (KBr): 2944, 1716, 1654, 1560, 1451, 1364, 1315, 1274, 1175, 1113, 1071, 1026, 714 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.39–1.55 (1H, m), 1.69–1.85 (2H, m), 1.92–2.17 (7H, m, including 3H, s, at δ 2.11), 2.32–2.54 (4H, m), 2.55–2.71 (1H, m), 2.92 (1H, dd, J = 13.3, 2.2 Hz), 5.14–5.20 (1H, m), 7.41–7.49 (2H, m), 7.54–7.60 (1H, m), 8.02–8.08 (2H, m); 13C NMR (75 MHz, CDCl3): δ 17.7, 25.1, 29.9, 31.0, 38.7, 40.2, 42.4, 43.4, 75.7, 128.4 (2C), 129.5 (2C), 130.2, 133.1, 165.5, 207.6, 212.8; HRESIMS calcd for C18H22O4Na [M+Na]+ 325.1416, found 325.1407.

(3aR*,4R*)-8-Oxo-2,3,3a,4,5,6,7,8-octahydroazulen-4-yl benzoate (9)
A mixture of 11 (2.93 g, 10.2 mmol) and p-toluenesulfonic acid monohydrate (965 mg, 5.10 mmol) in THF (100 mL) was refluxed for 3 h. After the reaction was quenched with H2O, the mixture was extracted with Et2O (3 x 100 mL). The combined organic layers were washed with brine, and dried over MgSO4. After the solvent was removed in vacuo, the resulted residue was purified by column chromatography (hexane/AcOEt, 6:1) to give 9 (1.89 g, 69%) as colorless oil. IR (neat): 2927, 1716, 1677, 1603, 1560, 1315, 1270, 1112 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.42–1.59 (1H, m), 1.63–1.98 (3H, m), 2.11–2.59 (6H, m), 3.15–3.27 (1H, m), 4.81 (1H, ddd, J = 10.7, 10.7, 3.6 Hz), 6.91 (1H, s), 7.34–7.43 (2H, m), 7.45–7.54 (1H, m), 7.96–8.03 (2H, m); 13C NMR (75 MHz, CDCl3): δ 20.3, 28.6, 30.4, 36.0, 43.7, 49.4, 77.7, 128.1 (2C), 129.3 (2C), 130.1, 132.7, 142.5, 145.8, 165.5, 198.9; HRESIMS calcd for C17H18O3Na [M+Na]+ 293.1154, found 293.1167.

(3aR*,4R*)-1-Methyl-8-oxo-2,3,3a,4,5,6,7,8-octahydroazulen-4-yl benzoate (10)
To a solution of 12 (2.89 g, 9.56 mmol) in tert-BuOH (96 mL) was added potassium tert-butoxide (2.14 g, 19.1 mmol) at room temperature. After stirred for 0.5 h, the mixture was quenched with saturated NH4Cl aqueous solution at 0 °C. The mixture was extracted with Et2O (3 x 200 mL), and the combined organic layers were washed with brine, dried over MgSO4. After the solvent was removed in vacuo, the resulted residue was purified by column chromatography (hexane/AcOEt, 3:1) to give 10 (1.79 g, 66%) as colorless needles. Mp 102–103 °C; IR (KBr): 2936, 2864, 1715, 1672, 1602, 1451, 1315, 1272, 1178, 1112, 1070, 1026, 713 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.51–1.80 (3H, m), 1.89–2.16 (5H, m, including 3H, s, at δ 2.11), 2.25–2.40 (2H, m), 2.42–2.58 (3H, m), 3.20–3.37 (1H, m), 4.89 (1H, ddd, J = 10.5, 10.5, 3.8 Hz), 7.41–7.49 (2H, m), 7.52–7.61 (1H, m), 8.01–8.09 (2H, m); 13C NMR (75 MHz, CDCl3): δ 17.1, 20.7, 26.7, 36.3, 38.1, 44.8, 51.4, 77.5, 128.4 (2C), 129.6 (2C), 130.5, 132.9, 134.1, 159.9, 165.9, 201.7; HRESIMS calcd for C18H20O3Na [M+Na]+ 307.1310, found 307.1322.

(3aR*,4R*,8aR*)-8-Oxodecahydroazulen-4-yl benzoate (7)
To a solution of 9 (1.89 g, 6.98 mmol) in EtOH (70 mL) was added 10% palladium on carbon (377 mg), and the mixture was stirred for 24 h under H2 (1 atm) at room temperature. The catalyst was filtered off, and the solvent was removed in vasuo. The resulted residue was purified by column chromatography (hexane/AcOEt, 6:1) to give 7 (1.71 g, 90%) as colorless oil. IR (neat): 2943, 2873, 1710, 1694, 1450, 1314, 1272, 1116, 1070, 1024, 711 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.37–1.79 (5H, m), 1.84–2.12 (4H, m), 2.21–2.67 (4H, m), 2.84–2.97 (1H, m), 5.08 (1H, ddd, J = 10.3, 10.3, 4.1 Hz), 7.41–7.48 (2H, m), 7.52–7.60 (1H, m), 8.00–8.06 (2H, m); 13C NMR (75 MHz, CDCl3): δ 19.4, 23.7, 26.0, 32.6, 34.7, 43.0, 48.9, 51.8, 79.8, 128.4 (2C), 129.6 (2C), 130.5, 133.0, 165.9, 212.0; HRESIMS calcd for C17H20O3Na [M+Na]+ 295.1310, found 295.1319.

(1R*,3aS*,4S*,8aS*)-1-Methyl-8-oxodecahydroazulen-4-yl benzoate (8)
This compound was obtained as colorless needles (Mp 117–118 °C) in 78% yield from 10 (288 mg, 1.01 mmol) in EtOH (10 mL), as descrived above for the preparation of 7. IR (KBr): 2942, 2869, 1711, 1690, 1453, 1383, 1322, 1274, 1118, 1071, 1027, 960, 710 cm–1; 1H NMR (300 MHz, CDCl3): δ 0.97 (3H, d, J = 6.5 Hz), 1.20–1.35 (1H, m), 1.40–1.62 (3H, m), 1.74–2.18 (5H, m), 2.30–2.62 (4H, m), 5.05 (1H, ddd, J = 10.6, 10.6, 4.2 Hz), 7.41–7.48 (2H, m), 7.54–7.60 (1H, m), 7.99–8.05 (2H, m); 13C NMR (75 MHz, CDCl3): δ 19.3, 19.9, 29.7, 32.0, 34.3, 35.0, 43.4, 48.8, 59.7, 79.9, 128.4 (2C), 129.6 (2C), 130.4, 133.0, 165.9, 212.2; HRESIMS calcd for C18H22O3Na [M+Na]+ 309.1467, found 309.1469.

(3aR*,4R*,8aS*)-1,2,3,3a,4,5,6,8a-Octahydroazulen-4-yl benzoate (20)
To a solution of potassium hexamethyldisilazide (0.5 M in toluene, 3.64 mL, 1.82 mmol) in THF (12 mL) was added a solution of 7 (329 mg, 1.21 mmol) in THF (1.2 mL) at –78 °C under Ar. After stirred for 1 h at –78 °C, a solution of N-phenylbis(trifluoromethanesulfonamide) (648 mg, 1.82 mmol) in THF (2 mL) was added to the reaction mixture for 1 h at –78 °C. The reaction was quenched with saturated NaHCO3 aqueous solution, extracted with Et2O (3 x 50 mL), and dried over MgSO4. After the solvent was removed in vacuo, the resulted residue was purified by column chromatography (hexane/AcOEt, 20:1) to give 18 (438 mg, 89%) as white crystals. This compound was dissolved in DMF (11 mL), and palladium acetate (4.7 mg, 0.0209 mmol) and 1,3-bis(diphenylphosphino)propane (8.6 mg, 0.0209 mmol) were added to this solution at room temperature. After the reaction mixture was warmed to 60 °C, triethylsilane (0.418 mL, 304 mg, 2.62 mmol) was added dropwise to this mixture. After stirred for 0.5 h at 60 °C, the reaction mixture was quenched with saturated NaHCO3 aqueous solution, extracted with Et2O (3 x 50 mL). The combined organic layers were washed with brine, and dried over MgSO4. After the solvent was removed in vacuo, the resulted residue was purified by column chromatography (hexane/AcOEt, 50:1) to give 20 (241 mg, 85%) as colorless oil. IR (neat): 2944, 2871, 1715, 1602, 1585, 1451, 1314, 1270, 1176, 1113, 1070, 1026, 960, 710 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.17–1.71 (5H, m), 1.78–2.43 (7H, m), 5.04 (1H, ddd, J = 9.9, 9.9, 3.9 Hz), 5.69–5.85 (2H, m), 7.38–7.48 (2H, m), 7.51–7.58 (1H, m), 8.02–8.08 (2H, m); 13C NMR (75 MHz, CDCl3): δ 22.9, 23.4, 31.3, 32.3, 33.7, 41.5, 49.6, 81.6, 128.3 (2C), 129.5 (2C), 130.7, 130.9, 132.7, 135.9, 165.9; HRESIMS calcd for C17H20O2Na [M+Na]+ 279.1361, found 279.1365.

(1R*,3aS*,4S*,8aR*)-1-Methyl-1,2,3,3a,4,5,6,8a-octahydroazulen-4-yl benzoate (21)
This compound was obtained as colorless oil in 97% yield for two-step operations from 8 (100 mg, 0.349 mmol), as descrived above for the preparation of 20. IR (neat): 2951, 2869, 1715, 1602, 1444, 1314, 1270, 1112, 1070, 1026, 955, 884, 710 cm–1; 1H NMR (300 MHz, CDCl3): δ 0.97–1.09 (4H, m, including 3H, d, J = 5.5 Hz, at δ 1.04), 1.16–1.30 (1H, m), 1.39–1.61 (2H, m), 1.74–2.18 (6H, m), 2.23–2.33 (1H, m), 5.04 (1H, ddd, J = 9.2, 9.0, 3.8 Hz), 5.71–5.76 (1H, m), 5.82–5.90 (1H, m), 7.40–7.46 (2H, m), 7.49–7.59 (1H, m), 8.02–8.05 (2H, m); 13C NMR (75 MHz, CDCl3): δ 19.0, 23.4, 29.0, 31.9, 32.2, 41.2, 48.8, 49.5, 81.8, 128.3 (2C), 129.5 (2C), 131.0, 131.3, 132.7, 134.5, 165.9; HRESIMS calcd for C18H22O2Na [M+Na]+ 293.1517, found 293.1527.

(3aR*,4R*,8aS*)-1,2,3,3a,4,5,6,8a-Octahydroazulen-4-ol (22)
A mixture of 20 (159 mg, 0.622 mmol) and potassium carbonate (258 mg, 1.87 mmol) in MeOH (6 mL) was stirred for 3 h at 70 °C. After added H2O to this mixture, and this mixture was extracted with Et2O (3 x 50 mL). The combined organic layers were washed with brine, and dried over MgSO4. After the solvent was removed in vacuo, the resulted residue was purified by column chromatography (hexane/AcOEt, 7:1) to give 22 (90.3 mg, 95%) as white crystals. Mp 47 °C; IR (KBr): 3249, 3012, 2926, 2874, 1654, 1472, 1440, 1354, 1234, 1140, 1121, 1081, 1019, 966, 715 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.30–1.68 (6H, m), 1.86–2.24 (7H, m), 3.41–3.52 (1H, m), 5.61–5.77 (2H, m); 13C NMR (75 MHz, CDCl3): δ 22.9, 23.4, 31.3, 33.5, 35.2, 41.2, 52.1, 79.3, 130.6, 135.9; HRESIMS calcd for C10H16ONa [M+Na]+ 175.1099, found 175.1108.

(1R*,3aS*,4S*,8aR*)-1-Methyl-1,2,3,3a,4,5,6,8a-octahydroazulen-4-ol (23)
This compound was obtained as colorless oil in 52% yield from 21 (91.0 mg, 0.337 mmol) in MeOH (4 mL), as descrived above for the preparation of 22. IR (neat): 3351, 3017, 2950, 2916, 2869, 1715, 1652, 1445, 1376, 1353, 1016, 972, 712 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.00 (3H, d, J = 5.6 Hz), 1.15–2.16 (11H, m), 2.14–2.24 (1H, m), 3.49 (1H, ddd, J = 8.8, 8.8, 3.9 Hz), 5.63–5.69 (1H, m), 5.76–5.84 (1H, m); 13C NMR (75 MHz, CDCl3): δ 19.0, 23.4, 29.0, 32.0, 35.2, 41.0, 48.7, 52.0, 79.6, 131.3, 134.6; HRESIMS calcd for C11H18ONa [M+Na]+ 189.1255, found 189.1261.

(1aR*,4R*,4aR*,7aR*,7bS*)-Decahydroazuleno[4,5-b]oxiren-4-ol (5)
To a solution of 22 (14.9 mg, 0.0979 mmol) in CH2Cl2 (1 mL) was added m-chloroperbenzoic acid (29.0 mg, 0.118 mmol) at 0 °C under Ar. After stirred for 3 h at room temperature, the reaction was quenched with saturated NaHCO3 aqueous solution at 0 °C. The mixture was extracted with Et2O (3 x 10 mL), and the combined organic layers were washed with brine, dried over MgSO4. After the solvent was removed in vacuo, the resulted residue was purified by column chromatography (hexane/AcOEt, 5:1) to give 5 (8.4 mg, 51%) as colorless oil. IR (neat): 3401, 2944, 2869, 1453, 1092, 1040, 925, 842 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.18–1.76 (8H, m), 1.85–2.29 (5H, m), 2.80 (1H, dd, J = 6.0, 4.9 Hz), 2.96–3.05 (1H, m), 3.34 (1H, ddd, J = 9.7, 9.7, 3.9 Hz); 13C NMR (75 MHz, CDCl3): δ 24.2, 24.8, 30.9, 31.9, 32.3, 42.1, 51.4, 53.8, 59.0, 78.6; HRESIMS calcd for C10H16O2Na [M+Na]+ 191.1048, found 191.1054.

(1aR*,4R*,4aR*,7S*,7aR*,7bS*)-7-Methyldecahydroazuleno[4,5-b]oxiren-4-ol (6)
This compound was obtained as colorless oil in 54% yield from 23 (31.6 mg, 0.190 mmol) in CH2Cl2 (2 mL), as descrived above for the preparation of 5. IR (neat): 3395, 2950, 2869, 1722, 1455, 1378, 1351, 1268, 1169, 1095, 1056, 1023, 957, 898, 835, 744 cm–1; 1H NMR (300 MHz, CDCl3): δ 0.95–1.31 (7H, m, including 3H, d, J = 6.0 Hz, at δ 1.12), 1.37–1.58 (2H, m), 1.72–2.06 (5H, m), 2.15–2.27 (1H, m), 2.79 (1H, dd, J = 6.3, 4.9 Hz), 2.95–3.01 (1H, m), 3.33 (1H, ddd, J = 9.7, 9.7, 3.9 Hz); 13C NMR (75 MHz, CDCl3): δ 18.9, 24.7, 28.8, 32.1, 32.8, 41.5, 50.1, 50.7, 52.9, 57.9, 78.7; HRESIMS calcd for C11H18O2Na [M+Na]+ 205.1204, found 205.1204.

(3aR*,4R*,7S*,8S*,8aR*)-Decahydro-4,7-epoxyazulen-8-ol (3)
A mixture of 5 (14.1 mg, 0.0839 mmol) and p-toluenesulfonic acid monohydrate (7.9 mg, 0.0415 mmol) in THF (1 mL) was refluxed for 3 h. After the reaction was quenched with H2O, the mixture was extracted with Et2O (3 x 10 mL). The combined organic layers were washed with brine, and dried over MgSO4. After the solvent was removed in vacuo, the resulted residue was purified by column chromatography (hexane/AcOEt, 5:1) to give 3 (9.1 mg, 64%) as colorless needles. Mp 82–84 °C; IR (KBr): 3402, 2953, 1719, 1458, 1072, 1022 cm–1; 1H NMR (300 MHz, CDCl3): δ 0.95–1.30 (4H, m), 1.52–2.05 (9H, m), 3.54–3.60 (1H, m), 4.15–4.21 (1H, m), 4.31–4.37 (1H, m); 13C NMR (75 MHz, CDCl3): δ 21.4, 24.3, 25.0, 25.4, 27.2, 44.0, 48.8, 74.4, 77.3 (2C); HRESIMS calcd for C10H16O2Na [M+Na]+ 191.1048, found 191.1042.

(1R*,3aS*,4S*,7R*,8R*,8aS*)-1-Methyldecahydro-4,7-epoxyazulen-8-ol (4)
This compound was obtained as colorless oil in 59% yield from 6 (18.6 mg, 0.102 mmol) in THF (10 mL), as descrived above for the preparation of 3. IR (neat): 3436, 2950, 2870, 1720, 1654, 1468, 1377, 1232, 1133, 1079, 1025, 980, 908, 804, 774 cm–1; 1H NMR (300 MHz, CDCl3): δ 0.75–0.86 (1H, m), 1.10–1.25 (5H, m, including 3H, d, J = 6.4 Hz, at δ 1.14), 1.53–1.94 (9H, m), 3.64 (1H, dd, J = 9.7, 3.6 Hz), 4.10–4.16 (1H, m), 4.25–4.30 (1H, m); 13C NMR (75 MHz, CDCl3): δ 20.9, 24.2, 24.6, 25.0, 31.7, 37.8, 48.9, 50.0, 74.7, 77.4, 77.6; HRESIMS calcd for C11H18O2Na [M+Na]+ 205.1204, found 205.1197.

(3aR*,4R*,7S*,8S*,8aR*)-Decahydro-4,7-epoxyazulen-8-yl 4-bromobenzoate (24)
To a solution of 3 (18.6 mg, 0.111 mmol), triethylamine (46.2 µL, 33.6 mg, 0.332 mmol) and 4-dimethylaminopyridine (2.7 mg, 0.0221 mmol) in CH2Cl2 (1 mL) was added p-bromobenzoyl chloride (36.4 mg, 0.166 mmol) at room temperature. After stirred for 18 h, the reaction was quenched with H2O, and the mixture was extracted with CHCl3 (3 x 10 mL). The combined organic layers were washed with brine, and dried over MgSO4. After the solvent was removed in vacuo, the resulted residue was purified by column chromatography (hexane/AcOEt, 20:1) to give 24 (27.1 mg, 70%) as colorless needles. Mp 106–108 °C; IR (KBr): 2954, 2871, 1721, 1589, 1484, 1466, 1397, 1269, 1113, 1102, 1012, 755 cm–1; 1H NMR (300 MHz, CDCl3): δ 1.00–1.14 (1H, m), 1.22–1.35 (1H, m), 1.78–2.00 (10H, m), 4.40­–4.45 (2H, m), 4.93 (1H, dd, J = 10.1, 3.7 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.88 (2H, d, J = 8.5 Hz); 13C NMR (75 MHz, CDCl3): δ 21.3, 24.2, 25.4, 26.0, 27.6, 41.4, 49.0, 74.5, 76.4, 77.5, 128.0, 129.2, 131.1 (2C), 131.7 (2C), 165.1; HRESIMS calcd for C17H19BrO3Na [M+Na]+ 373.0415, found 373.0416.

ACKNOWLEDGEMENTS
This work was supported by Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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18. CCDC 934489 contains the supplementary crystallographic data of 12 for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
19. CCDC 934492 contains the supplementary crystallographic data of 8 for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.