Endoperoxide bicyclic

The pyrazine I reacts with singlet oxygen to yield the endoperoxide 2, which is converted into the 1,3,6-oxadiazepine 4 on treatment with triphenylphosphanc. It is thought that the reaction involves deoxygenation to the bicyclic oxirane 3 as the key intermediate.320... 

Of the substrates that have worked well, let us first illustrate the 7-alkylidene-2,3-dioxabicyclo[2.2.1]heptane system 10. It was known that fulvenes react with singlet oxygen at low temperatures to afford the corresponding endoperoxides however, attempts to isolate these labile compounds led to decomposition, although NMR identification was possible at —70 °C 19>. When reduction of the singlet oxygenates with diimide was performed at —50 °C, the bicyclic peroxides 10 were obtained in high yield (Eq. 7) 20). 

The bicyclic peroxide 11 was prepared via diimide reduction of the endoperoxide derived from spirocyclopentadiene (Eq. 8)21>. As before, at elevated temperature the labile endoperoxide rearranges into diepoxide and ketoepoxide,22) but diimide reduction at —78 °C allows trapping leading to the highly strained bicyclic peroxide 11. 

A number of the bicyclic ozonides 12 were prepared in good yield (45-65 %) by diimide reduction of furan singlet oxygenates (Eq. 9) 23>. Again, low temperature were essential because the furan endoperoxides readily transform into 1,2-diacyl-ethylenes. Of course, the bicyclic ozonides 12 can alternatively be prepared via ozonolysis of the appropriate 1,2-disubstituted cyclobutene 24). 

Similarly, the cyclobutane-fused bicyclic peroxide 19 was prepared by diimide reduction of the corresponding bicyclic endoperoxide derived from 1,3,5-cyclooctatriene (Eq. 14)31a). 

Again, the bicyclic valence isomer coexists in sufficient concentration, that the bicyclic peroxide 19 was readily accessible in ca. 20% yield. Alternatively, the thermally labile bicyclic valence isomer of cyclooctatetraene, namely bicyclo[4.2.0]-octa-2,4,7-triene, was converted into the corresponding endoperoxide on low temperature singlet oxygenation and reduced with diimide to yield 19. 

Alternatively, the (2 + 4)-tropilidene endoperoxide, which is the major product in the singlet oxygenation of cycloheptatriene 30 a) affords on diimide reduction the desired bicyclic peroxide 20. The double bond in the two-carbon bridge is reduced selectively, but on exhaustive treatment with excess diimide, the fully saturated substance is obtained. A number of substituted derivatives have been prepared in this way30). 

The strained dienic endoperoxide is readily reduced by diimide, leading to the relatively stable bicyclic peroxide in high yield. Again, aprotic solvents such as CH2C12 or CFClj are essential for the diimide reduction, because in MeOH complex rearrangements take place 30d e>. 

Doubtless attempts will now be made to prepare more sophisticated model compounds that more closely resemble the natural prostaglandin endoperoxides. Thus the influence of endo-5-allyl and/or cxo-6-vinyl groups upon the chemistry of the [2.2.1] system is clearly of interest. However, it seems likely that the next major effort in this area will involve a thorough and systematic investigation of the reactions of the first generation of bicyclic peroxides that has now been obtained. 

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. 

As follows from the above mechanism, to form stable trihydroxy compounds, bicyclic endoperoxides must be reduced. It was found that glutathione may be an efficient reductant... 

Studies on the mode of activity of the antimalarials related to artemisinin have centred on simpler 1,2,4-trioxanes, 1,2,4,5-tetraoxanes and bicyclic endoperoxides <00H(52)1345 00JCS(P1)1265 00JMC2753 00TL3145>. The chemical and electro-chemical reduction of artemisinin has been reported <00JCS(P1)4279>. 

Acid-catalyzed dimerization and oligomerization of 1,2,4-trioxolanes will be covered in Section 4.16.5.2.1. In general, ozonides are not prone to spontaneous polymerization. Polymeric products can be obtained from the ozonolysis of alkenes but most likely arise from reaction of the primary ozonide. Bicyclic 1,2,4-trioxolanes such as 2,5-dimethylfuran endoperoxide can dimerize on warming in CCI4 (Section 4.16.5.1.1). 1,2,4-Trithiolane tends to polymerize at room temperature especially if left open to air, whilst more highly substituted ring systems are stable. 

The only examples of 1,2,4-trioxolanes containing A-linked substituents arise from photooxygenation of oxazoles. The endoperoxides thus produced are bicyclic, with a 1,2,4-trioxolane ring bridged by an imine moiety and are unstable at ambient temperature. They have been characterized at low temperature and thermal rearrangement is described in Section 4.16.5.1.1. 

However, thermolysis of the same compound 31 at 60 °C under oxygen gave, in addition to the major products 34 (68%), a small amount (7%) of the fused bicyclic 8-membered endoperoxide 35, which derives from mesomeric diradical 36 . 

More recently, Bachi and coworkers extended and adapted the TOCO reaction to the synthesis of 2,3-dioxabicyclo[3.3.1]nonane derivatives hke 228 (Scheme 52) ° ° . As detailed in Scheme 53a, the bridged bicyclic hydroperoxide-endoperoxides hke 229 are obtained, from (S )-limonene (227), in a 4-component one-operation free-radical domino reaction in which 5 new bonds are sequentially formed. Particular experimental conditions are required in order to reduce the formation of by-products 230 and (PhS)2, and to favor the critical 6-exo-ring closure of peroxy-radical 231 to carbon-centered radical 232206 chemoselective reduction of bridged bicyclic hydroperoxide-endoperoxides... 

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