drugs that had emerged from manipulation of the structure of the steroid
hormones provided at least some of the impetus for research on the pros-
taglandins. The expectation of major classes of new drugs was to some
extent dispelled by the findings in the late 1960s that prostaglandins and
other products derived from arachidonic acid tended to mediate injurious
responses, such as inflammation rather than hormonal effects. In spite of
this, several compounds based on this structure have found uses in the
clinic. These include, for example, misoprostol, a drug based on the ben-
eficial effect of this class of compounds on the mucous lining of the
stomach. This compound differs from the naturally occurring prostaglandin
E (PGE) by the removal of the side chain hydroxyl to one carbon furthest
from the cyclopentane and presence of an additional methyl group on that
position. Other compounds based on this structure provide several ophthal-
mic products. These topical prostaglandins are used to lower intraocular
pressure in glaucoma patients. They are believed to cause the outflow
of fluid within the eye by binding to specific intraocular receptors. These
compounds are classed as PGFs. Since both ring oxygens comprise
alcohols.
OHO CH 3CO 2 HOHMisoprotolThe first two agents, both used to lower intraocular pressure due to glau-
coma, differ from natural prostaglandins by the presence of an aromatic
ring at the end of the neutral side chain. Construction of the terminal
group on travoprost ( 9 ) starts with the reaction of the anion from
methyl dimethoxyphophonate with the aryloxy acid chloride ( 1 ).
Displacement of halogen affords product 2. Treatment of 2 with strong
base leads to formation of the corresponding ylide. A key intermediate
for the synthesis of many prostaglandins is the so-called Corey lactone.
This compound, shown as its dibenzylcarboxylic ester ( 3 ), provides func-
tionality for immediate attachment of the neutral side chain as well as, in
latent form a junction point for the addition of the carboxylic acid
bearing side chain. Reaction of this reactive species from 2 with 3 leads
to the condensation product of the ylide with the aldehyde. The trans
22 ALICYCLIC COMPOUNDS