Peroxide bridging

Chemistry and biological activity of artemisinin (sesquiterpene y-lactone with oxepane fragment and transannular peroxide bridge) and related antimalari-als 99H(51)1681. 

As the first isolable intermediate in the bioconversion of arachidonic acid into prostaglandins and thromboxanes (Eq. 3), PGG2 is a bicyclic peroxide of immense biological importance. It is difficult to obtain pure from natural sources and the presence of the 15-hydroperoxide group adds a further dimension of chemical lability to that associated with the 9,11-peroxide bridge. The chemical synthesis of PGG2 is thus a landmark in prostaglandin chemistry. It also represents a pinnacle of success for the silver-salt route to bicyclic peroxides. 

Baldwin, M. J., P. K. Ross, J. E. Pate, Z. Tyeklar, K. D. Karlin, and E. I. Solomon. 1991. Spectroscopic and Theoretical Studies of an End-On Peroxide-Bridged Coupled Binuclear Cooper(II) Model Complex of Relevance to Active Sites in Hemocyanin and Tyrosinase. J. Am. Chem. Soc. 113, 8671. 

The formation of peroxyl radicals with peroxide bridges are very important for the degradation of this polymer (see later). 

The mechanism of PIP degradation appeared to be principally different. PIP has double bonds and oxidizes through intramolecular peroxyl radical addition to the double bond with formation of peroxide bridges. 

Dichloroaluminium hydride in ether or sodium borohydride in TEA can lead to formation of ethers from ozonides by reductive cleavage of the two C—O bonds of the peroxide bridge (Equation (19)) <85JOC275>. 

One of the most important peroxo complexes synthesized after 1983 is the rhenium species formed from methyltrioxorhenium (MTO) precursor. The synthesis of this complex is achieved in the way indicated in equation 2, by reacting hydrogen peroxide with MTO . The isolated peroxo complex 1 contains in the coordination sphere two /7 -peroxide bridges, a direct metal carbon bond and a molecule of water. The crystal structure of the peroxo rhenium derivative, however, was obtained by substitution of the water molecule with other ligands " more details on this aspect are enclosed in the structural characterization paragraph. 

In 1972, Chinese researchers isolated, by extraction at low temperature from a plant, a crystalline compound that they named qinghaosu [the name artemisinin (la) is preferred by Chemical Abstracts, RN 63968-64-9]. The plant source of artemisinin is a herb, Artemisia annua (Sweet wormwood), and the fact that artemisinin is a stable, easily crystallizable compound renders the extraction and purification processes reasonably straightforward. The key pharmacophore of this natural product is the 1,2,4-trioxane unit (2) and, in particular, the endoperoxide bridge. Reduction of the peroxide bridge to an ether provides an analogue, deoxyartemisinin 3, that is devoid of antimalarial activity. ... 

Haynes and Vonwiller reported that artemisinin displayed multifarious reactivity in the presence of heme and non-heme iron(II) and also iron(III) °. The THF product 21 and artennuin D 13 were generally observed in varying ratios that were dependent upon the conditions used. Other products were also formed and the authors concluded that it was not possible to assign the parasiticidal species. However, they proposed an alternative mechanism of action that did not involve reductive ring opening of the peroxide bridge (Scheme 17). 

The action of the artemisinin derivatives is based on an unique mechanism. Haem or Fe in the parasite catalyzes the opening of the peroxide bridge in artemisinin, leading to the formation of free radicals which are lethal (see Fig. 1). 

Fig. 1. Mechanism of action of artemisinin. By the reduction of the peroxide bridge two radical anions can be formed which will both lead to alkylation of proteins and parasite death. (From van Agtmael et al. Trends Pharmacol Sci 1999 20 199, reproduced with permission from Elsevier Science.)...

The allylic alcohol 176, prepared by the hydrolysis of allylic bromide 173 <2004JME1423>, was oxidized with MnOz to the corresponding aldehyde 177, which reacted easily with allyl bromide in the presence of zinc under Barbier s conditions to give the adduct 178 (Scheme 25). Of particular note is the fact that the peroxide bridge was not sensitive to Zn under these reaction conditions <20050L5219>. 

Completely different results from those obtained in the photooxidation of 2.4.6-tri-tert-butyl-X phosphorin 24 (p. 54) are obtained in the photooxidation of 1.1-dimethoxy-2.4.6-tri-tert-butyl-X -phosphorin 183, as Schaffer has found. In this case the 2-hydroxy-endoxy-phosphinic acid methyl ester 213 can be isolated in about 20% yield. Its formation can be explained by assuming normal 1.4-addition to 212 as the primary product which is transformed to 213 by hydrolytic ring cleavage of the peroxide bridge, followed by loss of methanol. 

Similar reactions have been reported (161) for cobaltocene with nitric oxide (NO). (See Scheme 13.) In this case, however, rather than producing the peroxide-bridged structure 63, the more stable ether-linked species 64 was produced. Complex 64 was crystallographically characterized, its reactions were studied, and a mechanism for its formation was proposed. 

In this mechanism, the peroxide anion of the substrate makes a nucleophilic attack on the carbonyl carbon of a-ketoglutarate so that a peroxide bridge is formed between the two compounds. In this way, one atom each of molecular oxygen is incorporated into the substrate and a-ketoglutarate to form the product and succinate, The incorporation of molecular oxygen into succinate has been shown in most of the reactions that require a-ketoglutarate. 

Within the CoMFA electrostatic map, red contours are displayed in areas where negative charge is associated with increased activity of the database analogues. Red contours are visible near the peroxide bridge, supporting the important role the peroxide plays in activity and near 0-11 (or N-l 1). There are also red contours in... 

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