The carbinol ( 82 ) is then converted to the halide with thionyl chloride
apparently with retention of configuration ( 83 ). Displacement with pipera-
zine monoformamide leads to the alkylated product in which the groups are
now anti. Hydrolysis of the formamide grouping then affords secondary
amine 84. In a convergent sequence, 5-hydroxyquinoline ( 85 ) is allowed
to react with the tosyl derivative of chiral glycidol. The epoxy group in
the product ( 86 ) retains configuration. Condensation of piperazine ( 84 )
with the quinoline ( 86 ) opens the epoxide to afford 87. Configuration of
the alcohol is again retained as the reaction takes place at the nonchiral
terminal of the side-chain to be. Thus, 87 is obtained.^13
Most of the products from the arachidonic acid cascade exert deleterious
effects. Prostacylin ( 100 ) is a notable exception because of its vasodilatary
activity. The compound is destroyed far too quickly to be used as a drug.
An analogue in which a fused tetralin moiety replaces the furan and part of
the side chain is approved for use as a vasodilator for use in patients with
pulmonary hypertension. The lengthy complex synthesis starts with the
protection of the hydroxyl group in benzyl alcohol ( 88 ) by reaction with
tert-butyl dimethyl silyl (TMBDS) chloride ( 89 ). Alkylation of the
anion from 89 (butyllithium) with ally bromide affords 90. The protecting
group is then removed and the benzylic hydroxyl is oxidized with oxalyl
chloride in the presence of triethylamine to give the benzaldehyde ( 91 ).
The carbonyl group is then condensed with the organomagnesium deriva-
tive from treatment of chiral acetylene ( 92 ) with ethyl Grignard to afford
93. (The triple bond is not depicted in true linear form to simplify the
scheme.) The next few steps adjust the stereochemistry of the newly
formed alcohol in 93. This group is first oxidized back to a ketone with pyr-
idinium chlorochromate. Reduction with diborane in the presence of chiral
2-(hydroxyl-diphenylmethyl)pyrolidine affords the alcohol as a single
enantiomer. This compound is then again protected as its TMBDS ether.
Heating 94 with cobalt carbonyl leads to formation of the tricyclic
ring system ( 95 ). Mechanistic considerations aside, the overall sequence
to the product ( 95 ) involves eletrocylic formation of the six-membered
ring from the olefin and acetylenic bond, as well as insertion of the
elements of carbon monoxide to form the five-membered ring. Catalytic
hydrogenation of 95 leads to reduction of the double bond in the enone, as
well as hydrogenolysis of the benzylic TMBDS ether on the six-membered
ring ( 96 ). Reduction of the ketone then leads to the alcohol apparently as a
single enantiomer. Acid leads to loss of the tetrahydropyrany protecting
group to afford intermediate 97. The presence of labile groups in this com-
pound precludes the usual methods, such as hydrogen bromide or boron
tribromide, for cleaving the methyl ether. Instead, in an unusual sequence,
80 CARBOCYCLIC COMPOUNDS FUSED TO A BENZENE RING