US EPA

8711709 

Journal Article 

Solvent-Induced Fragmentation of Prostaglandin Endoperoxides. New Aldehyde Products from PGH2and a Novel Intramolecular 1,2-Hydride Shift during Endoperoxide Fragmentation in Aqueous Solution 

Salomon, RG; Miller, DB; Zagorski, MG; Coughlin, DJ 

1984 

Yes 

Journal of the American Chemical Society
ISSN: 0002-7863
EISSN: 1520-5126 

106 

20 

6049-6060 

English 

10.1021/ja00332a049 

The prostaglandin (PG) endoperoxide nucleus, 2,3-dioxabicyclo[2.2.1]heptane, is three orders of magnitude less stable in aqueous vs. cyclohexane solution. Water-induced fragmentation of 2,3-dioxabicyclo[2.2.1]heptane-1-d1exhibits a deuterium kinetic isotope effect kH/kD=1.5. Although rate-determining cleavage of a C-D bond occurs, deuterium is not lost to the protic solvent. Rather, the bridgehead deuterium migrates intramolecularly to the incipient methyl group of the levulinaldehyde product. Dimethyl sulfoxide (Me2SO) also induces rapid decomposition of the PG endoperoxide nucleus at 37∘C. However, a different mechanism is suggested by kH/kD= 3.3 for the fragmentation reaction induced by Me2SO. The PG endoperoxide PGH2[9α, 11 α-epidioxy-15(S)-hydroxy-5(Z),13(E)-prostadienoic acid] rearranges spontaneously at 37 ∘C in Me2SO or aqueous solution to form levulinaldehyde derivatives, levuglandin (LG) E2[8(R)-acetyl-9(R)-formyl-12(S)-hydroxy-5(Z),10(E)-heptadecadienoic acid] and LGD2[9(R)-acetyl-8(R)-formyl-12(S)-hydroxy-5(Z),10(E)-heptadecadienoic acid]. The Me2SO-induced fragmentation affords levuglandins in 70 to 80% yield according to 1H NMR analysis of the decomposition product mixture while the yield of levuglandins in aqueous solution is about 22% at pH 7.9. 1984, American Chemical Society. All rights reserved.