Synthesis and chiroptical characterization of prostacyclin diastereomers.
In the mercuri- and halo-cyclizations of PGF2 alpha methyl ester and its 11,15-bis(alpha- ethoxyethyl)-ether (or other protected forms) the exo-PGI1 derivative predominates independent of reagent and degree of protection of the PGF2 alpha sample used. Diastereomerically pure samples of exo- and endo-PGI1 and prostacycline (PGI2) were prepared. PGI0 epimers were prepared: catalytic hydrogenation of PGI2 Me ester provides exclusively the endo isomer. PGI2 methyl ester was found to be stable to extensive chromatography on silica, and to storage for at least a year in anhydrous ethanol at -20 degrees C. At pH 7.4 in 2:1 H2O:EtOH, the ester has a half-life in excess of 5 hr at 25 degrees C. A reproducible small scale (0.4-3 mg) synthesis of prostacyclin uses a modification of Whittaker's iodocyclization followed by DBN treatment. This procedure, developed with 15-3H-PGF2 alpha, proved widely applicable to PGF2 alpha analogs and diastereomers. The following prostacyclins (in the Me ester and Na salt forms) bearing the 5-en-6-yl ether unit were prepared in this way: ent-PGI2, rac-PGI2, 15-epi-PGI2, ent-15-epi-PGI2, 11-epi-PGI2, 8,9,12-epi-PGI2, E-PGI2, 13,14-dihydro-PGI2, and 13,14-dihydro-15-epi-PGI2. NMR comparisons for the methyl esters reveal that of the resonances (H-5,9,UU, 15) that appear at delta 4.0 +/- 0.6 ppm, the most deshielded is H-9 so long as the 5.6-olefin is Z. The 8R,9S-6,9-oxido-Z-5,6-ene unit is most readily characterized by its strong positive dichroic absorption at 210-230 nm. CD spectroscopy not only serves to confirm the presence of this unit in analogs, but also can be used for quantitative analysis of PGI2 solutions and for monitoring the rate of hydrolytic cleavage of these enol ethers.
D003500:Cyclization; D011464:Epoprostenol / Q000138:chemical synthesis*; D008722:Methods; D011453:Prostaglandins / Q000138:chemical synthesis*; D011458:Prostaglandins E / Q000138:chemical synthesis; D013237:Stereoisomerism
D011453:Prostaglandins; D011458:Prostaglandins E; D011464:Epoprostenol