β-Santalol is an organic compound that is classified as a sesquiterpene. It comprises about 20% of the oil of sandalwood, the major component being α-santalol. As of 2002, about 60 tons of sandalwood oil are produced annually by steam distillation of the heartwood of Santalum album.
- Karl-Georg Fahlbusch, Franz-Josef Hammerschmidt, Johannes Panten, Wilhelm Pickenhagen, Dietmar Schatkowski, Kurt Bauer, Dorothea Garbe, Horst Surburg "Flavors and Fragrances" in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim: 2002. Published online: 15 January 2003; doi:10.1002/14356007.a11_141.
Alpha- (top) and beta-santalol are constituents of the prized East Indian sandalwood oil
A solution of butyllithium in hexanes (1.35 M, 11.7 ml, 15.8 mmol) was added over a 15 minutes period to a stirred suspension of ethyltriphenylphosphonium iodide (6.61g, 15.8 mmol) in THF (125 ml) at 00C. The resultant red solution was cooled to -78°C and 3-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propanal (2.55 g, 14.33 mmol) in solution in THF (16 ml) was added over a 15 minutes period. After further 5 minutes at -78°C, a solution of butyllithium in hexanes (1.35 M, 12.7 mL, 17.2 mmol) was added over a 5 minutes period and the mixture was further stirred for 20 minutes at -78°C before allowing to reach 00C in 2 hours. Dry paraformaldehyde (2.60 g, 86.0 mmol) was added in one portion to the deep red homogeneous solution and the mixture was stirred for 30 minutes at 00C and was allowed to reach room temperature. After 1 hour at room temperature the mixture was poured into 5.2 ml of saturated aqueous solution of NH4Cl and extracted twice with CH2Cl2. The organic layer was washed with water and brine, and dried with Na2SO4. The mixture was filtered through a short pad of silica gel with dichloromethane as eluent and solvents were removed under pressure to give a crude. Purification of crude compound was performed by flash chromatography on silica gel with cyclohexane/AcOEt 90/10) as eluent to give pure β-santalol as pale yellow oil. Further bulb to bulb distillation under reduced pressure afforded β-santalol in 50% yield (Z:E=95:5). 1H NMR (CDCl3, 400 MHz): 5.29 (t, J=7.5, IH), 4.73 (s, IH), 4.45 (s, IH), 4.14 (s, 2H), 2.66 (d, J=3.8, IH), 2.12-1.94 (m, 3H), 1.78 (d, J=I.2, 3H), 1.71-1.60 (m, 3H),
1.44-1.36 (m, 2H), 1.32 (br s, IH), 1.27-1.17 (m,3H), 1.04 (s, 3H). 13C NMR (CDCl3, 125 MHz): 166.2, 133.9, 129.0, 99.7, 61.6, 46.8, 44.7, 44.6, 41.5, 37.1, 29.7, 23.7, 23.2, 22.6, 21.2.
B) Preparation of β-santalol (via [1,4] hydrogenation) i) Preparation of a compound (V): 2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1] hept-exo-2-yl)-pent-2-enal
3-(2-Methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-propan-l-al (274.0 mg,
1.54 mmol) was dissolved in toluene (15.0 ml) at room temperature under nitrogen. The mixture was heated to reflux and propionaldehyde (0.4 ml, 1.96 mmol) and aqueous catalytic solution of hexamethyleneimine and benzoic acid (0.12 ml, 0.616 mmol) was separately added in one portion. Once that addition was finished, the mixture was further heated at reflux for 6 hours. The mixture was cooled down to room temperature and extracted twice with brine, the organic layer was dried over MgSθ2, filtered off and concentrated to give a crude which was further purified by flash chromatography with cyclohexane/ AcOEt (95/5) to afford the title compound in 80% yield.
1H NMR: 9.38 (s, IH), 6.48 (dt, J1=?^, J2=1.2, IH), 4.78 (s, IH), 4.49 (s, IH), 2.69 (d, J=3.9, IH), 2.40-2.29 (m, 2H), 2.12 (d, J=3.1, IH), 1.75 (s, 3H), 1.72-1.64 (m, 3H), 1.59-1.51 (m, IH), 1.47-1.36 (m, 2H), 130-1.21 (m, 2H), 1.09 (s, 3H). 13C NMR: 195.2, 165.5, 155.2, 139.1, 100.3, 46.8, 44.8, 44.7, 39.4, 37.1 , 29.6, 24.9, 23.7, 22.6, 9.1.
H) Preparation of a compound (IV): Acetic acid 2-methyl-5-(2-methyl-3-methylene- bicyclo[2.2.1]hept-2-exo-yl)-penta-l,3-dienyl ester To a stirred solution of 2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-yl)- pent-2-enal (268.0 mg, 1.23 mmol) in toluene (3.0 ml) were added Ac2O (0.35 ml, 3.70 mmol), Et3N (0.70 ml, 5.02 mmol), and a catalytic amount of DMAP (15.0 mg, 0.1 mmol). The resulting mixture was heated to reflux for 22 hours. The mixture was cooled down to room temperature and quenched with brine, extracted twice with Et2O, dried over MgSO4, filtered off and concentrated to give a crude which was further purified by flash chromatography with cyclohexane/AcOEt (98/2) to afford the title compound in 82% yield (E:Z=79:21). 1H NMR: 7.18 (s, IH), 5.99 (d, J=12.4, IH), 5.72 (dt, il=\2A, J2=6.1, IH), 4.76 (s, IH), 4.47 (s, IH), 2.68 (d, 3.4, IH), 2.17 (s, 3H), 2.12-2.01 (m, 2H), 1.81 (d, J=I.0, 3H), 1.73-1.63 (m, 3H), 1.43-1.39 (m, 2H), 1.27-1.18 (m, 2H), 1.02 (s, 3H).
13C NMR: 167.9, 165.5, 134.4, 130.6, 126.9, 120.7, 100.0, 46.9, 45.3, 45.0, 44.5, 37.0, 29.7, 23.6, 23.0, 20.8, 10.4.
Hi) Preparation of(2Z)-Acetic acid 2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1] hept-2-exo-yl)-pent-2-enyl ester (VII)
Acetic acid 2-methyl-5-(2-methyl-3-methylene-bicyclo[2.2.1]hept-2-exo-yl)-penta-l,3- dienyl ester (6.80 g, 93% pure; 24.3 mmol0.18 mmol) was treated with
[(Cp*)Ru(COD)]BF4 (52 mg, 0.122 mmol) and maleic acid (230 mg, 1.95 mmol) in dry and degassed acetone (20 ml) at 600C under 4 bars of H2 for 24 hours. The product was extracted with pentane/5% NaOH, washed twice with saturated aqueous NaCl, dried
(Na2SO4) and bulb-to-bulb distilled: 6.80 g (81% Z and 5% E by GC; 92%). 1H NMR: 5.38 (t, J=7.1, IH), 4.73 (s, IH), 4.59 (s, IH), 4.45 (s, IH), 2.66 (br s, IH),
2.12-2.04 (m, 4H), 2.07 (s, 3H), 1.73 (d, J= 1.0, 3H), 1.69-1.61 (m, 3H), 1.45-
1.37 (m, 2H), 1.27-1.17 (m, 3H), 1.04 (m, 3H).
13C NMR: 171.1, 166.1, 131.4, 129.4, 99.7, 63.2, 46.8, 44.7, 44.6, 41.2, 37.1, 29.7, 23.7,
23.4, 22.6, 21.5, 21.0.
|Jmol-3D images||Image 1|
|Molar mass||220.35 g mol−1|
|Boiling point||177 °C (351 °F; 450 K)|
|Solubility in water||Practically insoluble|
|Solubility in ethanol||Soluble|
|Solubility in diethyl ether||Soluble|
Chiral rotation ([α]D)
Refractive index (nD)
|Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)|
Biocatalyst mediated regio- and stereo-selective hydroxylation and epoxidation on (Z)-α-santalol were achieved for the first time, using a fungal strain Mucor piriformis. Four novel metabolites were characterized as 10,11-cis-β-epoxy-α-santalol, 5α-hydroxy-(Z)-α-santalol, 10,11-dihydroxy-α-santalol and 5α-hydroxy-10,11-cis-β-epoxy-α-santalol. Using Amano PS lipase from Burkholderia cepacia, α- and β-isomers of 10,11-cis-epoxy-α-santalol were resolved efficiently.