Prostaglandin endoperoxides. 14. Solvent-induced fragmentation of prostaglandin endoperoxides. New aldehyde products from PGH2 and a novel intramolecular 1,2-hydride shift during endoperoxide fragmentation in aqueous solution

Abstract

product is not thiocyanate but either the product of its further reaction with BrCN according to eq 1 or a further decomposition product of S(CN)2.BrCN + -SCN -Br + S(CN)2(1)The reactions of ADPaS and ATP0S are not useful for synthesizing adenosine 5'-[180]diphosphates or -triphosphates with chiral Pa or Pd because of the oxygen rearrangements in the polyphosphate systems described herein. These can be prevented by protecting the terminal phosphoryl groups with removable alkyl substituents, as demonstrated by the reactions of the RF and SP epimers of /3-(cyanoethyl)-ADPaS with BrCN in H2180 to produce high yields of the SP and RF epimers of 6-(cyanoethyl)-[a-180]ADP.22 The displacement of thiocyanate by H2180 proceeded with inversion of configuration at Pa, and the /3-cyanoethyl groups were easily removed by treatment with base to produce the SP and Rf epimers of [a-180]ADP.22Eckstein and Lowe and their collaborators have been able to desulfurize nucleoside phosphorothioates with electrophilic brominating agents in acidic solutions with inversion of configuration and without rearrangements in polyphosphates.19c•23 At neutral pHs these reactions also involved rearrangements, suggesting that our observations do not represent an isolated phenomenon observable only in the special case of reactions of BrCN with ADPaS or ATP/3S. This paper and our earlier communication4 provide the first evidence for involvement of cyc/o-diphosphates in chemical reactions. Dimeric phenylphosphonic anhydride is the only fourmembered ring organophosphorus compound reported in the literature that has two P-O-P bonds.24•25 Recently a cyclic phosphoric acid anhydride was postulated as a possible inter- (22)

Metabolite-initiated protein misfolding may trigger Alzheimer's disease

“…4B). Salomon and coworkers (38) have shown that the prostaglandin endoperoxide 10 undergoes a solventinduced fragmentation in phosphate buffer (0.2 M sodium phosphate, pH 7.9) at 37°C to give 9 in 22% yield. Fig.…”

Formation of Highly Reactive γ-Ketoaldehydes (Neuroketals) as Products of the Neuroprostane Pathway

“…Recently, we reported that IsoP endoperoxide intermediates also undergo rearrangement to form highly reactive ␥-ketoaldehyde levuglandin-like compounds (4). 2 We propose to term these nonenzymatically generated ␥-ketoaldehydes isoketals (IsoKs) to distinguish them from levuglandins formed by rearrangement of the cyclooxygenase endoperoxide intermediate, PGH 2 (5). These extremely reactive molecules form covalent adducts with lysine residues on proteins at a rate that exceeds that of 4-hydroxy-2-nonenal (4-HNE) by orders of magnitude, which is considered to be one of the most reactive aldehydes generated as a product of lipid peroxidation (6).…”

Oxidized phospholipids, isolevuglandins, and atherosclerosis

“…Inspired by the model studies, we then showed that rearrangement of PGH 2 in neutral aqueous solution not only generates PGD 2 and PGE 2 but also two levulinaldehyde derivatives with prostaglandin side chains, which we named levuglandin (LG) E 2 and LGD 2 ( Fig. 1) [5]. We confirmed the structures of LGE 2 and LGD 2 by total syntheses [6,7].…”

“…1) is involved since hydrogen bonding by protic solvents accelerates the reaction by two orders of magnitude over the rate in aprotic solvents of similar polarity [4]. Isotopic labeling and kinetics experiments showed that water promotes intramolecular migration of a bridgehead hydride in concert with cleavage of C -C and O -O bonds [5]. These observations led us to predict that as yet unknown products should be readily formed by rearrangements of PGH 2 .…”