Endoperoxide fragmentation

Antimalarial drug artemisinine, sesquiterpenic 8-lactone with 1,2,5-trioxane (endoperoxide) fragment 98CSR273. 

Salomon, R.G., Miller, D.B., Zagorski, M.G., and Coughlin, D.J. Solvent Induced Fragmentation of Prostaglandin Endoperoxides. New Aldehyde Products from PGH2 and Novel Intramolecular 1,2-Hydride Shift During Endoperoxide Fragmentation in Aqueous Solution. J Am Chem Soc 106 (1984) 6049-6060. 

Isotopically labeled DHPN Oa was also used as a source of [ Oa] to provide further support for the proposed structure. It was thus confirmed that Oa-mediated oxidation of melatonin yields AFMK through the intermediary of a transient endoperoxide as inferred from the fragmentation pattern of the [ 0]-labeled oxidation product. The deformyla-tion product of AFMK, namely A -acetyl-5-methoxykynuramine, was also shown to be produced. 

In addition to the CIEEL mechanism, peroxides and endoperoxides are key intermediates in a number of chemical and biological processes. There are a growing number of examples where ET to the 0-0 bond in these systems is accepted as an important step in their activity. For example, it is now generally agreed that the first step in the bioactivity of the recently discovered potent antimalarial, artemisinin, involves an ET from Fe-heme to the 0-0 bond, leading to fragmentation and a number of psytotoxic radical intermediates. " In contrast to the enormous amount of literature on the thermal and photochemical reactivity of peroxides, there is relatively little known about their ET chemistry. It is this lack of kinetic data on ET to peroxides and endoperoxides and the possible relationship of this data to Saveant s model for dissociative ET that initiated our own interest in this chemistry.22 23 2 - - - ... 

In water, however, the endoperoxide is exclusively transformed by SN2 reaction with the solvent into the corresponding ring-opened hydroperoxide (Eq. 55), which then undergoes intramolecular fragmentation to the desired product [12]. Limitations in the choice of the solvent may in turn restrict the choice of the sensitizer for reasons of solubility and photochemical (and thermal) stability. As a result, experimental conditions for an optimal chemical yield may call for a sensitizer exhibiting a relatively small d>A. 

Evidence for adiabatic photolytic cycloreversions at room temperature has been obtained more frequently in recent years [121,122], The adiabatic generation of singlet oxygen by photochemical cycloreversion of the anthracene and 9,10-dimethylanthracene endoperoxides 105 and 106 proceeds with wavelength-dependent quantum yields of 0.22 and 0.35, respectively, and involves the second excited singlet state of the endoperoxides [123]. Photodissociation of the 1,4-endoperoxide from l,4-dimethyl-9,10-diphenylanthracene was found to yield both fragments, i.e., molecular oxygen and l,4-dimethyl-9,10-diphenylanthracene, in their electronically excited state [124]. 

Rtd.ll)-Catalyzed reactions of endoperoxides,3 Although the Ru(ll)-catalyzed reaction of endoperoxides usually results in complex mixtures, the reaction of the prostaglandin endoperoxide (I) is a remarkably clean fragmentation to the triene 2, as the only isolablc product. Endoperoxides containing a double bond undergo useful isomcri/ations todiepoxides (equations 1 and 11). 

In the series of hydroxycyclohexadienylperoxyl radicals, one encounters the competition between the H02-/02- elimination leading to phenol [reactions (9) and (14)/(15)] and fragmentation of the ring (Pan et al. 1993). That latter has been attributed to an intramolecular addition of the peroxyl radical function to a diene double bond [reaction (24)]. This reaction is reversible [reaction (-24)], but when 02 adds to the newly created carbon-centered radical the endoperoxidic function is locked in [reaction (25)]. In analogy to reaction (24), the first step of the trichloromethylperoxyl-radical-induced oxidation of indole is its addition to the indole C(2)-C(3) double bond (Shen et al. 1989). 

Reactions of 1,4-epiperoxides and Ru(II).3 1,4-Epiperoxides (endoperoxides) in the presence of this complex can undergo fragmentation, reduction, and disproportionation, reactions which differ from those induced by thermolysis or reaction with Fe(II) salts. Although several products are usually formed, fragmentation can lead to single products. 

The highly unstable endoperoxides of imidazoles, sometime spectroscopically detected [81a], rearrange to dioxetanes or hydroperoxides or rapidly fragment or polymerize so that from the synthetic perspective, the reaction has a poor scope [54,67,81]. One interesting application has been pointed out by Lipshutz as a general asymmetric synthesis of TV-protected amino acids/dipeptides via appropriately substituted imidazoles (Sch. 48) [82],... 

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