Synthesis of α,ß-unsaturated epoxy ketones utilizing a bifunctional sulfonium/phosphonium ylide.

Herein, a new protocol for rapid synthesis of α,ß-unsaturated epoxy ketones utilizing a bifunctional sulfonium/phosphonium ylide is described. This approach comprises two sequential chemoselective reactions between sulfonium and phosphonium ylides and two distinct aldehydes, which allows for the rapid construction of a variety of unsymmetric α,ß-unsaturated epoxy ketones. This methodology allows the rapid construction of the core reactive functionality of a family of lipid peroxidation products, the epoxyketooctadecenoic acids, but can be further broadly utilized as a useful synthon for the synthesis of natural products, particularly those derived from oxidized fatty acids. Accordingly, a protocol utilizing this approach to synthesize the epoxyketooctadecenoic acid family of molecules is described.

Inter-relations between 3-hydroxypropionate and propionate metabolism in rat liver: relevance to disorders of propionyl-CoA metabolism.

Propionate, 3-hydroxypropionate (3HP), methylcitrate, related compounds, and ammonium accumulate in body fluids of patients with disorders of propionyl-CoA metabolism, such as propionic acidemia. Although liver transplantation alleviates hyperammonemia, high concentrations of propionate, 3HP, and methylcitrate persist in body fluids. We hypothesized that conserved metabolic perturbations occurring in transplanted patients result from the simultaneous presence of propionate and 3HP in body fluids. We investigated the inter-relations of propionate and 3HP metabolism in perfused livers from normal rats using metabolomic and stable isotopic technologies. In the presence of propionate, 3HP, or both, we observed the following metabolic perturbations. First, the citric acid cycle (CAC) is overloaded but does not provide sufficient reducing equivalents to the respiratory chain to maintain the homeostasis of adenine nucleotides. Second, there is major CoA trapping in the propionyl-CoA pathway and a tripling of liver total CoA within 1 h. Third, liver proteolysis is stimulated. Fourth, propionate inhibits the conversion of 3HP to acetyl-CoA and its oxidation in the CAC. Fifth, some propionate and some 3HP are converted to nephrotoxic maleate by different processes. Our data have implications for the clinical management of propionic acidemia. They also emphasize the perturbations of the liver intermediary metabolism induced by supraphysiological, i.e., millimolar, concentrations of labeled propionate used to trace the intermediary metabolism, in particular, inhibition of CAC flux and major decreases in the [ATP]/[ADP] and [ATP]/[AMP] ratios.