Synthesis and chiroptical characterization of prostacyclin diastereomers

Prostaglandins
De BiswanathW D Johnson

Abstract

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 e...Continue Reading

References

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