Endoperoxides, reduction

Radical-anion complexes Scope of this review 91 Thermodynamic and kinetic methodologies Voltammetric methods 92 Homogeneous redox catalysis 94 Convolution analysis 98 Laser flash photolysis 102 Photoacoustic calorimetry 103 Thermochemical estimates 105 Fleduction of C—O and O O bonds 106 Reduction of ethers 107 Reduction of peroxides and endoperoxides Reduction of S—S and C—S bonds 136 Reduction of disulfides 137 Reduction of sulfides 150 Concluding remarks 157 Fleferences 160... 

This group is prepared by the reaction of the anion of 9-hydroxyanthracene and the tosylate of an alcohol. Since the formation of this group requires an S 2 displacement on the alcohol to be protected, it is best suited for primary alcohols. The group is cleaved by a novel singlet oxygen reaction followed by reduction of the endoperoxide with hydrogen and Raney nickel. 

F.a.b.-m.s. has contributed to a detailed analysis of the high-mannose carbohydrate chains of prostaglandin endoperoxide synthase from sheep. Oligosaccharides released by hydrazinolysis were analyzed after N-re-acetylation and reduction. The f.a.b. data defined the compositions of the oligosaccharides, and showed that hydrazinolysis had effected a partial fission of the chitobiose core. 

GL 24] [R 1] [P 26] The feasibility of safely carrying out the oxidation of cyclopentadiene by singlet oxygen to 2-cyclopentene-l, 4-diol was demonstrated [40]. The explosive intermediate endoperoxide was generated and without isolation used onsite for a subsequent hydration reaction. By reduction with thiourea the pharmaceutically important product 2-cyclopentene-l,4-diol was so obtained. 

Since the corresponding endoperoxide precursors are all too unstable for isolation, the diimide reduction constitutes an important chemical structure confirmation of these elusive intermediates that are obtained in the singlet oxygenation of the respective 1,3-dienes. However, the aza-derivative 14 and the keto-derivative 15 could not be prepared,17> because the respective endoperoxides of the pyrroles 18) and cyclopentadienones suffered complex transformations even at —50 °C, so that the trapping by the diimide reagent was ineffective. 

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). 

In addition to the parent compound 2, the derivatives 2a, b, the benzo-system 16, the lactone-peroxides 17, and the fused polycyclic derivatives 18 and 19 could be prepared via the singlet oxygen-diimide route. For example, the parent system 2 was obtained in ca. 40% yield by diimide reduction of the stable 1,3-cyclohexadiene endoperoxide in MeOH at 0 °C27,28). Dihydroascaridole 2a and dihydroergosterol endoperoxide... 

The benzo-derivative 16 is accessible through 1,4-dimethylnaphthalene, which on singlet oxygenation leads to the thermally labile naphthalene-1,4-endoperoxide. This endoperoxide expels singlet oxygen at ca. 10 °C, but diimide reduction below 0 °C in MeOH affords the stable dihydro derivative 16 (Eq. 11). 

The lactone-peroxides 17 are derived from the corresponding ot-pyrones. Singlet oxygenation at low temperature affords the unstable a-pyrone endoperoxides which, on warming up, readily decarboxylate into 1,2-diacylethylenes. However, subambient diimide reduction leads to the desired lactone peroxides 17 (Eq. 12)29). 

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). 

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 keto-derivative 21 is of interest because the relatively unreactive 3,5-cyclo-heptadienone substrate, which towards most dienophiles reacts with double bond isomerization, affords the desired endoperoxide (Eq. 16)33). Diimide reduction proceeds smoothly, leading to the keto-peroxide 21 in over 90% yield. 

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>. 

The diimide reduction again proceeds sluggishly and several recycles are essential to achieve complete conversion. The doubly unsaturated endoperoxide is the major product in the singlet oxygenation of 1,3,5-cyclooctatriene (Eq. 14). 

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... 

The keto endoperoxide 90 has been synthesised from 1,4-cyclohexadiene through its photooxygenation, reduction of the resulting diastereoisomeric mixture of endoperoxides 89 and subsequent oxidation (Scheme 60). Some chemistry of 90 is described . 

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>. 

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... 

A sequence of transformations involving diastereoselective singlet oxygen photooxygenation of TBS-protected 3,5-cycloheptadienol 525 to predominantly 5yw-endoperoxide syn-526 and some anti-526, followed by reduction into the all-ci5 triol 527 as described in Scheme 146, was used by Johnson for synthesis of enantiopure methyl 2,4-dideoxyhexa-pyranosides D-528 and L-5284°5.406... 

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