Peroxyl Radical Cyclization

Other silanes led to an increase in the formation of alcohols 341 and free hydroperoxides 340b. Tokuyasu et al. extended the investigations to Co-catalyzed tandem radical peroxidation/peroxyl radical cyclization sequences to give oxygenated endoperoxides, such as 342 [378]. 

The transformation of 3 to hydroperoxide 2 proceeds by sequential oxygenation and peroxyl radical cyclization-oxygen entrapment (Scheme 4). The overall cascade accomplishes the formation of three C-O bonds and three stereocenters in a single... 

Several 1,2-dioxolanes [7, 75-76] and polycyclic peroxides [7, 77[ have been obtained in modest yields from unsaturated hydroperoxides by peroxyl radical cyclization-oxygenation pathways under initiation with DBPO or DTBN (cf. Scheme 43) [76a, 77[. In general, there is a strong bias for exo cyclization [7a, 75b], although an exception has been noted [78]. Moreover, when there is a choice, the... 

A short synthesis of the antimalarial peroxide yingzhaosu C, which allowed the relative stereochemistry of the natural product to be assigned as cis, has been achieved by means of tandem peroxyl radical cyclization-oxygen entrapment... 

Beckwith pioneered the use of a Thiol-Oxygen-Co-Oxidation (TOCO) process for the transformation of 1,4-dienes and 1,3,6-trienes to 1,2-dioxolanes [90], As illustrated by the example in Scheme 51 [90a], this process involves phenylthio radical addition to the least substituted double bond, oxygen entrapment, peroxyl radical cyclization, oxygen entrapment and hydrogen atom transfer from the thiol. In accord with the Beckwith-Houk transition state model [91, 92], cyclization provides preferentially the c/s-3,5-disubstituted 1,2-dioxolanes. 

Only the Cy6 compound (77) is obtained from hydroperoxide (76), again in nearly pure form and in good yield (Scheme 40). This is a remarkable result when one considers that Cy6/Cy7 cyclizations generally give poor yields with carbon radicals and fail with alkoxyl radicals. This discovery led Porter to test the peroxyl radical cyclization mechanism leading to intermediate... 

The discovery made by Porter that peroxyl radicals easily add intramolecularly to double bonds (Section VIII.2.D, Schemes 39 and 40) led this author to test the peroxyl radical cyclization mechanism proposed for the biosynthesis of prostaglandins (Scheme 152). This scheme involved formation of 432 from the unsaturated fatty acid 431, cyclization of 432 (in a Cy5/Cy6 case) to the (Cy 5) radical 433, followed by a second cyclization of the carbon-centered radical 433 (also in a Cy5/Cy6 case) to the (Cy 5) radical 434. The radical 434 would now be oxidized to the endoperoxide 435, which would decompose to prostaglandin PGFj (436). 

In the case of the hematin-catalyzed reaction we have proposed that peroxyl radicals are the epoxidizing agents (40). The mechanism is illustrated in Figure 8. Hematin reduces the hydroperoxide to an alkoxyl radical that cyclizes to the adjacent double bond. 

As in the case of linear peroxidation products, the initiation step of the formation of isoprostanes is the abstraction of a hydrogen atom from unsaturated acids by a radical of initiator. Initiation is followed by the addition of oxygen to allylic radicals and the cyclization of peroxyl radicals into bicyclic endoperoxide radicals, which form hydroperoxides reacting with hydrogen donors. 

The arachidonic acid cascade is a biological free radical oxidation of unsaturated fatty acids leading to formation of the prostaglandins (equation 102). Cyclization of a peroxy radical intermediate 66 leading to endoperoxide 67 was proposed as a pathway for this process, and this was demonstrated in chemical model systems, in which the peroxyl radical 66 was generated by hydrogen abstraction from the hydroperoxide corresponding to 66. 

The autoxidation of polyunsaturated fatty acids (cf. Porter et al. 1981) is usually monitored by the formation of malonaldehyde using the 2-thiobarbituric acid essay. This is carried out under rather severe conditions which decomposes its precursor. This malonaldehyde-like product is obviously formed via a cycliza-tion reaction of a peroxyl radical, followed by other processes such as further cyclization and hydroperoxide formation [reactions (21)-(23)]. The resulting hydroperoxides may eliminate malonaldehyde upon a homolytic cleavage of the endoperoxidic intermediate (Pryor and Stanley 1975). 

Vitamin E is effective as an antioxidant in arachidonate autoxidation, trapping the kinetic peroxyl radical product before cyclization can occur. Adding vitamin E in arachidonate autoxidation results in reducing radical cyclization products and forming the kinetic product distribution, six simple trans, cis diene hydroperoxides. 

This has two consequences (1) most importantly, direct initiation of radicals in lipids bound to the heme, and (2) assurance of lipid release as LOO rather than LOOH. Chain propagation may proceed through LOO directly or through epoxyallylic peroxyl radicals from LOO cyclization. 

Cyclization requires the presence of a c/i-double bond homoallylic to a hydroperoxide (230, 269), as shown in Reaction 45. In addition, cyclization of peroxyl radicals at internal positions is considerably faster than secondary oxidations of hydroperoxides at either external position. About 25% of peroxyl radicals in lino-lenic acid and 33% of peroxyl radicals in arachidonic acid are internal (Table 4). Thus, linolenic and arachidonic acids are particularly prone to formation of cyclic peroxides. These factors together make intramolecular cyclization 4—6 fold faster than p-scission in higher polyunsaturated fatty acids (247). 

Studies on prostaglandin biosynthesis in the early 1970s have shown that molecular oxygen is incorporated into polyunsaturated lipids. It was shown that autoxidation of polyunsaturated species leads to peroxyl radical intermediates that can undergo yff-scission, H-atom abstraction, and allylic rearrangement or/and cyclization. Beckwith looked into the oxygenation of dienes initiated by phenylthiyl radicals... 

With the increasing frequency of isolation of cyclic peroxides from natural sources [39] and the demonstrable antiparasitic and many other biological properties possessed by both the natural products and their analogs, there is currently considerable interest in the synthesis of such compounds [5]. In particular, the opportunity of exploiting the facile conversion of enols or enolates into peroxyl radicals and then inducing cyclization of the peroxyl radical (or hydroperoxide) by addition to a distal carbonyl group is apparent. 

As an alternative to 5-exo cyclization the peroxyl radical may also undergo 4-exo cyclization to form 1,2-dioxetanyl carbinyl radicals. Such reactions appear to only be favored if there are no double bonds appropriately positioned for 5-exo cyclization. Dioxetanes have been postulated to serve as precursors to lipid aldehydes by fragmentation reactions. 

Fatty acid peroxyl radical 1,2-Dioxetanyl radical 4- xo cyclization of a peroxyl radical to a 1,2-dioxetanyl radical... 

The new radical thus formed can undergo further reactions, such as cyclization and polymerizations (Chapter 4). Ally lie peroxyl radicals (ROO ) can thus add to an unsaturated fatty acid to produce a peroxide-linked dimer (5). 

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