Cl+ O OO AlCl 3ClCO 2 HO31 32 33 Cl^34CO 2 HO SC 6 H 5 SHResearch on the prostaglandins several decades ago revealed a second
pathway in the arichidonic acids cascade. Products from this alternate
route consisted of long-chain fatty acids instead of the cyclic prostanoids.
Subsequently, it was ascertained that these straight-chain acids, called eico-
sanoids, reacted with endogenous sulfur-containing oligopeptides, such as,
glutathione, to form a series of compounds called leukotrienes that elicited
allergic reactions. These were found to be the same as the previously
known slow-reacting substance of anaphylaxis (SRS-A). Drugs that coun-
teract this factor would provide an alternate means to antihistamines for
dealing with allergies. The majority of antagonists developed to date
consist of long-chain compounds that terminate in an acidic function.
This last comprises a tetrazole rather than a carboxylic acid in virtually
all compounds reported to date. A very recent entry interestingly terminates
in a carboxylic acid. The convergent synthesis starts with the alkylation of
the enolate from resorcinol monomethylether ( 35 ) with propyl iodide. The
use of aprotic conditions favors alkylation on carbon over oxygen to afford
( 36 ). The enolate from this product is then used to displace the halogen
atom in o-fluorobenzonitrile to give the aromatic ether. The nitrile is
then hydrolyzed to the corresponding acid with potassium hydroxide.
Treatment of that product with methanol in the presence of acid converts
the latter to its methyl ester. TheO-methyl ether in the product is then
cleaved with boron tribromide to afford the phenol ( 39 ). Synthesis of the
second half of the compound begins with the reduction of the acetyl
group in 40 to an ethyl group ( 41 ) with tirethylsilane. Bromination of
this intermediate with NBS proceeds, as expected at the position adjacent
to the benzyl ether to afford 42. The side chain that will connect the
two halves is then put in place by alkylating the free phenol group with
1-bromo-2-chloroethane ( 43 ). Reaction of the aromatic bromo function
in this last intermediate withp-fluorophenylboronic acid ( 44 ) leads to for-
mation of the biphenyl group and thus 45. The Finkelstein reaction, with
potassium iodide, leads to replacement of chlorine by the better leaving
group, iodine in 46. Alkylation of the enolate from the acid moiety
39 with iodide in 46 completes construction of the framework.
48 MONOCYCLIC AROMATIC COMPOUNDS