Prostaglandins endoperoxide model

To the best of our knowledge, no direct connection exists between this thermal behaviour of the model bicyclo[2.2.1] system 9 and prostaglandin endoperoxide 4,... 

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. 

Coughlin, D.J. and Salomon, R.G. (1977) Synthesis and thermal reactivity of some 2,3-dioxabicyclo[2.2.1]heptane models of prostaglandin endoperoxides. Journal of the American Chemical Society, 99 (2), 655-657. 

Selective reduction of unsaturated endoperoxides. 2,3-Dioxabicyclo[2.2.1]-heptane (3) serves as a model of the prostaglandin endoperoxide (PGG2), involved in the biosynthesis of prostaglandins and also of thromboxanes and PGl2 (prostacyclin). One successful synthesis of 3 involved sensitized photooxygena-lion of cyclopentadiene to give the unstable heat-sensitive endoperoxide 2, which... 

Figure 6.3 Effect of two structurally distinct thromboxane A2/prostaglandin endoperoxide receptor antagonists, L636,499 and SQ29,548, on the time to coronary occlusion in the canine model of coronary thrombosis following electrically-induced endothelial injury...

Figure 6.5 Percent change in thromboxane A2 and prostacyclin biosynthesis, measured as excretion of their urinary metabolites, 2,3-dinor-thromboxane (Tx) 82 and 2,3-dinor-6-keto-prostaglandin (PG) respectively, in response to a thromboxane A2/prostaglandin endoperoxide receptor antagonist (L636,499) alone and in combination with a thromboxane synthase inhibitor (U63,557A) in the chronic canine model of coronary thrombosis. (Note that occlusion did not occur in dogs treated with the combination therapy)...

Therefore, these model systems are applicable to a systematic study of radical cyclization leading to a prostaglandin endoperoxide intermediate. 

This study of endoperoxide-Cu reactivity demonstrates how the examination of simple endoperoxide model systems can help to clarify the chemistry of the naturally-occurring PCH and PCG molecules and it seems likely that more model studies of thj.s type will provide additional information about the reactivity of prostaglandins, thromboxanes, and prostacyclin. 

The current interest in the prostaglandin endoperoxides has led Adam and his colleagues to study the chemistry of 1,2-dioxolans as models of the natural products. The compounds are readily prepared from cyclopropanes as shown in Scheme 16. Yields are in the range 71—96%. 

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. 

Bowers, R., Ellis, E., Brigham, K. and Oates, J. (1983). Effects of prostaglandin cyclic endoperoxides on the lung circulation of sheep. J. Clin. Invest., 63, 131-137 Short, B.L., Miller, M.K., Stround, C.Y. and Fletcher, J.R. (1983). Comparison of the thromboxane inhibitors to cyclooxygenase inhibitors on survival in a newborn rat model for group B-streptococcal sepsis. In Samuelsson, B., Paoletti, R. and Ramwell, P. (eds.) Advances in Prostaglandin, Thromboxane and Leukotriene Research, Vol. 12, pp. 113-116. (New York Raven Press)... 

Since peroxyl radicals add so easily to double bonds (see Sections VIII.2.D and XI.4.B.a) 3-cyclopentenyl peroxyl radicals appeared to be attractive models for prostaglandin bicyclic endoperoxide formation, by analogy with the cycliza-tion discussed in Scheme 116. Under the conditions used, however, disproportionation was preferred to intramolecular cyclization. ... 

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