Hydroxylation 1,8-cineole

Duffy JE, Hay ME (2001) The ecology and evolution of marine consumer-prey interactions. In Bertness MD, Gaines SD, Hay ME (eds) Marine community ecology. Sinauer, Sunderland, pp 131-158 Duisken M, Sandner F, Blomeke B, Hollender J (2005) Metabolism of 1,8-cineole by human cytochrome P450 enzymes identification of a new hydroxylated metabolite. Biochim Biophys Acta 1722 304-311... 

Mono- and bi-cyclic monoterpenes containing sites of unsaturation tend to be hydroxylated at the allylic position, (more examples of allylic hydroxylation are discussed in Section 1.4.5.2) with regio-isomers occurring if more than one allylic position is accessible. Some illustrative examples of reported hydroxylations are shown in Scheme 10. " The hydroxylation of 1,4-cineole (42) is illustrative of the enantioselectivity that may be achieved in such transformations. Bacillus cereus gives a 1 7 mixture of 2R)-exo- and (25)-e/tdo-monohydroxy-1,4-cineole, both with essentially 100% enantiomeric purity. ... 

This constitution is supported also by the conversion of terpineol into terpin and vice versa. When terpin loses a molecule of water, not from the two hydroxyl groups, as in the preceding conversion into cineol, but in such a way as to leave one hydroxyl group present, we obtain terpineol. 

Preliminary characterization of the partially purified cineole synthetase indicated that the enzyme, like other monoterpene synthetases, exhibited a pH optimum on the acid side of neutrality, was inhibited by thiol-directed reagents, and required a divalent cation for catalysis (Mn + was preferred) (Croteau and Karp, 1977a). A single protein appeared to be involved in conversion of the acyclic precursor to 1,8-cineole, and no free intermediates could be discerned in the reaction. A mechanism for the formation of 1,8-cineole was proposed that involved the hydration of a double bond of an enzyme-bound monocyclic intermediate, followed by displacement of the enzyme by the hydroxyl group to form the heterocyclic ring and simultaneously release the product (Croteau and Karp, 1977a). 

The production of new materials for the aroma and fragrance industry was the powerful driving force in the research on the hydroxylation of terpenes [924, 1105-1107]. For instance, 1,4-cineole, a major constituent of eucalyptus oil, was regioselectively hydroxylated by Streptomyces griseus to give 8-hydroxycineole as the major product along with minor amounts of exo- and cnJo-2-hydroxy derivatives, with low optical purity (Scheme 2.151) [1108]. On the other hand, when Bacillus cereus was used, (2R)-exo- and (2/ )-en o-hydroxycineoles were exclusively formed in a ratio of 7 1, both in excellent enantiomeric excess [1109]. 

Cineole is a avor constituent of Citrus aurantifolia and Piper cubeba (Bornscheuer et al., 2014). In vitro and in vivo animal studies demonstrated extensive biotransformation of this mono-terpene strongly suggesting biotransformation in the human body too. After oral application to rabbits, four neutral and one acidic metabolite could be isolated from urine (Asakawa et al., 1988). Using rat and human liver microsomes, however, only 2-hydroxylation could be observed indicating species related differences in 1,4 cineole metabolism (Miyazawa et al., 2001a) (Figure 9.8). 

Miyazawa, M M. Shindo, and T. Shimada, 2001a, Roles of cytochrome P450 3A enzymes in the 2-hydroxyl-ation of 1,4 cineole, a monoterpene cyclic ether, by rat and human liver microsomes, 31 ... 

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