Stereospecific formation hydroperoxides

Fig. 11. Metabolism of arachidonic acid by 12- and 15-lipoxygenase pathways with corresponding stereospecific formation of hydroperoxyeicosatetraenoic acids (HpETE). Subsequent reduction of these hydroperoxides leads to the corresponding HETE at either carbon-12 or -15, which are thought to mediate biological activities of these enzymatic pathways.

Another route to a methyl-branched derivative makes use of reductive cleavage of spiro epoxides ( ). The realization of this process was tested in the monosaccharide series. Hittig olefination of was used to form the exocyclic methylene compound 48. This sugar contains an inherent allyl alcohol fragmenC the chiral C-4 alcohol function of which should be idealy suited to determine the chirality of the epoxide to be formed by the Sharpless method. With tert-butvl hydroperoxide, titanium tetraisopropoxide and (-)-tartrate (for a "like mode" process) no reaction occured. After a number of attempts, the Sharpless method was abandoned and extended back to the well-established m-chloroperoxybenzoic acid epoxida-tion. The (3 )-epoxide was obtained stereospecifically in excellent yield (83%rT and this could be readily reduced to give the D-ribo compound 50. The exclusive formation of 49 is unexpected and may be associated with a strong ster chemical induction by the chiral centers at C-1, C-4, and C-5. 

Figure C4.2.1 Lipoxygenase (LOX)-catalyzed transformation of linoleic or linolenic acid (R = CH3(CH2)4-, linoleic acid R = CH3CH2CH=CHCH2-, linolenic acid) showing oxidation by molecular oxygen and formation of conjugated diene hydroperoxides. These events give the basis for measurement of activity by either oxygen uptake or UV absorption at 234 nm. Also shown is the usual preference for (S)-stereospecificity of oxidation.

Fig. 6. Three irnportam oxidative pathways for the metabolism of polyunsaturated fatty acids. A. The principal steps in the formation of prostaglandin endoperoxides from arachidonic acid. B. Likely mechanism for the formation of hydroperoxy cis.trans conjugated fatly acids by autooxidalion or by lipoxygena.sc.s. In the latter case, positional as well as stereospecificity arc normally found. The formed hydroperoxides may then be enzymatically transformed into leukotrienes (not shown) or to hydroxy acids. C. The enzymatic sequence in cytochrome P-450 mediated oxygenation. The first electron is donated from NADPH via the f lavoprotein (Fp) NADPH-cytochrome-P-450-reductase. while the second electron comes either from NADPH or NADH. In this way the monooxygenase enzymes inlrrxluce one oxygen from air into the substrate.

The single and double dioxygenations of polyenoic fatty acids. The LOX activity is commonly abundant in higher plant species. Usual substrates of LOX are methylene-interrupted polyenoic fatty acids, in plants presumably linoleic and linolenic acids. Most of LOX act regio-and stereospecifically [1,2]. Like soybean LOX, many of plant enzymes convert linoleic and linolenic acids into corresponding 13(5)-hydroperoxides. At the same time, many plant tissues, in particular, potato tubers and tomatoes, possess the activity of 9-LOX. Such enzymes are able to form double hydroperoxide of a-linolenic acid via intermediary formation of 9(iS)-HPOT [3]. The double dioxygenation of linolenate occurs in potato tubers [3], rice and wheat seeds and in other tissues, exhibiting the 9-LOX activity. 

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