Synthesis of oxygenated cineole derivatives from cineole: utility of cytochrome P450cin as an enantioselective catalyst

The oxidation of cineole to (1R)-6β-hydroxycineole by cytochrome P450cin (CYP176A) is utilised as the initial step in the synthesis of a range of compounds, both novel and ones previously known only as racemates. The potential of P450cin to provide useful, enantiopure building blocks is thus demonstrated. In particular, hydroxylation by this enzyme was used as the initial step in the synthesis of a range of functionalised cineole derivatives that could be used as mechanistic probes to elucidate the effect of substrate structure on the transformations mediated by P450cin.

Figure optionsDownload as PowerPoint slide

(1R)-6-KetocineoleC10H16O2
• 100% ee
• [α]D24 = −68.4 (c 0.3, ethanol)
• Source of chirality: Enantiopure starting material
• Absolute configuration: 1R, 4S

(1R)-5α-Bromo-6-ketocineoleC10H15O2Br
• 100% ee
• [α]D24 = −15.7 (c 1.0, ethanol)
• Source of chirality: Enantiopure starting material
• Absolute configuration: 1R, 4R, 5R

(1R)-5α-Methyl-6-ketocineoleC11H18O2
• 100% ee
• [α]D24 = +22.0 (c 0.36, ethanol)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4S,5R)

(1R)-5α-Fluoro-6-ketocineoleC10H15O2F
• 100% ee
• [α]D24 = +44.0 (c 1.0, ethanol)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4R,5R)

(1R)-5β-Fluoro-6-ketocineoleC10H15O2F
• 100% ee
• [α]D24 = −10.1 (c 1.0, ethanol)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4R,5S)

5,5-Dimethyl-(4S)-(3-oxobutyl)dihydrofuran-2-oneC10H16O3
• 100% ee
• [α]D24 = +63.1 (c 0.3, chloroform)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (4S)

(1R)-5,6-DiketocineoleC10H14O3
• 100% ee
• [α]D24 = −14.5 (c 0.1, chloroform)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4R)

(1R)-Cineolic acid, dimethyl esterC12H20O5
• 100% ee
• [α]D24 = −5.7 (c 1.0, ethanol)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4R)

(1R)-5β,6β-DihydroxycineoleC10H18O3
• 100% ee
• [α]D24 = −24.3 (c 0.76, ethanol)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4S,5S,6S)

(1R)-5β,6α-DihydroxycineoleC10H18O3
• 100% ee
• [α]D24 = −5.9 (c 1.0, ethanol)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4S,5S,6R)

(1R)-5α,6β-DihydroxycineoleC10H18O3
• 100% ee
• [α]D24 = −33.6 (c 1.0, ethanol)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4S,5R,6S)

(1R)-5β,6β-Dihydroxycineole acetonideC13H22O3
• 100% ee
• [α]D24 = +9.1 (c 1.0, ethanol)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4S,5S,6S)

(1R)-5α,6α-Dihydroxycineole acetonideC13H22O3
• 100% ee
• [α]D24 = −45.9 (c 1.0, dichloromethane)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4S,5R,6R)

(1R)-5-(1,3-Dioxolan-2-yl)-6-ketocineoleC12H18O4
• 100% ee
• [α]D24 = −92.2 (c 1.0, ethanol)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4R)

(1R)-6-(1,3-Dioxolan-2-yl)-5-ketocineoleC12H18O4
• 100% ee
• [α]D24 = –14.5 (c 0.1, ethanol)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4R)

(1R)-5β-(t-Butyldimethylsilyl)-6-ketocineoleC16H30O3Si
• 100% ee
• [α]D24 = −59.7 (c 1.0, dichloromethane)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4S,5S)

(1R)-5β-Hydroxy-6-ketocineoleC10H16O3
• 100% ee
• [α]D24 = −5.5 (c 1.9, dichloromethane)
• Source of chirality: Enantiopure starting material
• Absolute configuration: (1R,4S,5S)