Valencene

Wilson, C. W. et al., J. Agric. Food Chem., 1978, 26, 1430-1432 Oxidation of the sesquiterpene valencene to the 4-en-3-one proceeds explosively when at sub-ambient temperatures [1], A safer alternative oxidation procedure is detailed [2],... 

Orange oil was investigated because the Hedfly is attracted to oranges. When a sesquiterpene cut from orange oil was tested, it was indeed active. It was hoped that valencene would be the active material because it is the major sesquiterpene in orange oil, and it is commercially available. However, valencene is not active. It was found that (+)-a-copaene, a contaminant in the valencene cut, is the active material. 

The allylic oxidation of the sesquiterpenoid (+)-valencene has been performed using f-BuOOH as the oxidant and BiCl3 as catalyst. Nootkatone was the major product, isolated in 35% yield by flash chromatography (ethyl acetate - light petroleum, boiling point 40-60 °C) (Scheme 17) [87, 88]. 

Scheme 17 BiCl3-catalyzed allylic oxidation of (+)-valencene using /-BuOOH...

Valanone B 69 (+)-Valencene 49, 69 Valerian oil 223 Vanilla extract 134, 223 Vanillin 134, 178, 213, 223 Vanoris 19 Veloutone 84 Velvione 88 Veramoss 141 Veratraldehyde 136 Verbenone 216 Verdantiol 125... 

Nootkatone can be prepared by oxidation of valencene, a sesquiterpene hydrocarbon isolated from orange oils. 

Nootkatone is an important constituent from grapefruit flavour. It is synthesised by oxidation of valencene, which is obtained and isolated from orange peel oil where it occurs at a maximum level of 0.4% [9]. 

For the oxidation of valencene to nootkatone, strong oxidation agents like oxygen in the presence of metal salts, peroxides or chromate compounds are required. There are also several patents on the bioconversion of valencene to nootkatone which results in natural nootkatone (Scheme 13.9) [10,11]. 

Franssen et al. [24] pointed out an alternative method of production of nootkatone from valencene catalysed by (-i-)-germacrene A hydroxylase, an enzyme of the cytochrome P450 monooxygenase type that was isolated from chicory roots. In general, this enzyme appeared to accept a broad range of sesquiterpenes and hydroxylates exclusively at the side-chain s isopropenyl group. Valencene is an exception it was not hydroxylated at the side chain, but -nootkatol was formed in the first step (Scheme 22.5) it is not yet clear if the second step is enzyme-catalysed. 

Scheme 22.5 Production of nootkatone from valencene catalysed by (+)-germacrene A hydroxylase [81]...

In the last few years, sesquiterpene synthase from different plants has raised attention. In 2004, Schalk and Clark [88] described a process (patented by Fir-menich, Switzerland) that makes it possible to obtain sesquiterpene synthase and to produce various aliphatic and oxygenated sesquiterpenes from farnesyl diphosphate. For instance, valencene can be obtained in this way. 

Scheme 23.12 Biotransformation of (+)-valencene to (+)-nootkatone via a-nootkatol and/or fi-nootkatol...

Recently, an industrial process development for nootkatone production from valencene by microbial transformation (bacteria, fungi) was mentioned [199, 200]. Although no details were given, the author claimed the development of an in situ product-removal technique by which an extremely selective recovery of nootkatone from the reaction mixture and the excess precursor during the proceeding production was achieved and which was said to be essential for an economically viable bioprocess. 

The same rational P450cam mutants which have already been described for limonene and pinene oxyfunctionalisations were also successfully applied to valencene. In whole-cell biotransformations -nootkatol and nootkatone formed as main products with up to 25% overall yield, corresponding to activities of up to 9.9 nmol (nmol P450) min [201]. Higher activities (up to 43 min ) but lower selectivities than those with P450cam were obtained with mutants derived from Bacillus megaterium P450 BM3. 

Valencene (5), a sesquiterpene hydrocarbon isolated from orange oils is used as starting material for the synthesis of nootkatone (6), which is used for flavouring beverages [26] and which is a much sought-after aromatic substance [131]. 

Two bacterial strains, one from soil and the other from infected local beer, which utilised calarene as the sole source of carbon and energy have been isolated by enrichment culture techniques [149]. Both these bacteria were adapted to grow on valencene as the sole carbon source. Fermentations of valencene (5) by these bacteria of the genus Enterobacter in a mineral salts medium yielded several neutral metabolic products dihydro alpha-agarofuran (200) (7.5%), nootkatone (6) (12%), another ketone (201) (18%) and a-cyperone (202) (8%), Fig. (40). 

Very recently, the chemoenzymatic preparation of nootkatone from valencene was described [150]. Nootkatone was prepared from valencene by copper(I) iodide catalysed oxidation with tert-butyl hydroperoxide and hydroxylated at C-9 by Mucor plumbeus and Cephalosporium aphidicola. 

However, the most notable difference between orange oils is the percentage of valencene. Valencene is a sesquiterpene hydrocarbon. In cold-pressed Valencia oil, it is 10 to 20 times higher than other orange oils (Coleman et al., 1969). 

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