The dehydration of the P-hydroxycyclopentanone, 11,16dihydroxy-16-methyl-9-oxo-13-trans-protenoic acid methyl ester, an analogue of prostaglandin El, proceeds with acid catalysis (pH < 3), by uncatalyzed routes (pH N 4 and N 7), and with base catalysis (pH N 5-6 and > 8). Deuterium from the solvent is not introduced a to the reactant keto function a t W O reaction at pH N 1, hut -30% exchange has occurred a t pH = 5,50% a t pH = 7, and 80% at pH N 9. The data are consistent with a mechanism in which the substrate is initially enolized with catalysis by acid, base, and water to a 1,3-enedioI, which looses water with catalysis by acid, base, and water. The first stage is rate determining in very acidic solution, while the second stage assumes the limitation of rate to an ever greater degree as the solution becomes more basic.
Keyphrases Prostaglandin El-P-hydroxycyclopentanone analogue, dehydration kinetics, mechanism u Kinetics-dehydration of the fl-hydroxycyclopentanone analogue of prostaglandin El, mechanism 0 Dehydration-P-hydroxycyclopentanone analogue of prostaglandin El, mechanism, kinetics
The prostaglandins are a structural class of compounds exhibiting the most diverse biological activities (1). Prostaglandin El (alprostadil, Ia) possesses, among other capacities, the potential for inhibiting gastric secretion in humans (2). The analogue of prostaglandin El (Ib) also possesses this activity and is in fact 30-fold more potent than the parent compound when administered orally (3).
E-type prostaglandins tend to undergo dehydration to yield the unsaturated A (11) and B (111) forms (4-6) (Scheme I). We report here some observations on the dehydration of Ib, which illuminate the mechanistic character of its degradation.
EXPERIMENTAL
Materials-Racemic mixtures of the 1601-and 16fl-hydroxy epimers and their respective antipodes for 11,16-dihydroxy-16-methyl-9-oxo-13-trans-protenoic acid methyl ester (Ih, SC-29333) and its dehydration products, IIb and IIIb, were used as supplied'.
Kinetics-The UV assay method developed by Monkhouse et al.
(5) was adopted to follow the dehydration kinetics of Ib. Stock solutions of