Front Matter

For other applications of P450s, readers are referred to a number of books and

reviews (Juchau, 1990; Gonzalez and Gelboin, 1994; Ortiz de Montellano, 1995;

Durst and O’Keefe, 1995; Lewis, 1996; Juchau et al., 1998).

18.2 Hydroxylation of fatty acids, by monooxygenases

Hydroxylated fatty acids have various (potential) applications as polymer building

blocks, as intermediates in antibiotic synthesis (Schneider et al., 1998) or in medical

fields. In lactonized form they can serve as perfume ingredients.

The hydroxylation of nonactivated -C–H bonds is one of the most useful biotrans-

formations (Johnson, 1978; Kieslich, 1980; Mansuy and Battione, 1989) because the

reactivity profile of enzymes in hydroxylations of -C–H bonds declines in the order

secondary>tertiary>primary (Faber, 1997), in contrast to the reactivity in che-

mical radical reactions (tertiary>secondary>primary). Moreover, enzymatic hy-

droxylations often occur with high regio- and stereoselectivity. On the other hand,

they can only compete with chemical syntheses, if the latter are more expensive or

not feasible. Several chemical methods for the hydroxylation of fatty acids are well-

known. For instance, the formation ofx-hydroxy fatty acids is achieved by oxidation

of cyclic ketones using the Baeyer – Villiger reaction followed by alkaline ring

opening. Until now, the Baeyer – Villiger oxidation via transition metal catalysts

has been limited to cyclobutanone (Phillips and Romao, 1999), cyclopentanone

and cyclohexanone and their derivatives (Strukul, 1998; Paneghetti et al., 1999).

A more general pathway of synthesis starts from dihalogen alkanes, followed by

the conversion to hydroxyhalogen alkanes and a Grignard reaction to introduce

the carboxyl group (Becker et al., 1993). Remarkable progress has been achieved

in catalytic chemistry in the past few years allowing regioselective hydroxylations

of primary nonactivated -C–H bonds. For instance, the use of an aluminophosphate

(AlPO 4 -18) matrix containing Co2+and Mn2+ions and molecular oxygen as oxidant

resulted in mainly terminal hydroxylation ofn-alkanes (Hartmann and Ernst, 2000).

For the stereoselective synthesis of hydroxylated fatty acids at in-chain positions

only a few laborious pathways – mainly for thex-1 position of C 12 to C 18 fatty

acids – were described (Voss and Gerlach, 1983; Villemin et al., 1984). These re-

ports include multistep syntheses and require protecting group chemistry.

Readers who are interested in learning more about the physiological roles of hy-

droxy fatty acids and their further metabolism are referred to a range of reviews

describing for example P450 enzymes involved in the formation of arachidonate

metabolites in the regulation of blood pressure (Hercule and Oyekan, 2000;

McGiff, 1991, Oyekan et al., 1998; McGiff et al., 1991), in brain biochemistry

(Yehuda et al., 1999) and peroxisome profileration (Bocos et al., 1995).

18.2 Hydroxylation of fatty acids, by monooxygenases 395