Base-catalyzed Claisen condensation forms the desired six-membered ring.
Heating that intermediate with base leads to saponification of the ester. The
beta ketoacid decarboxylates under reaction conditions to form 47.^5
Reductive amination of the carbonyl group in the ketone in this intermediate
with aniline would then lead to the substituted aniline ( 48 ). Treatment of 48
with chloroacetontrile in the presence of boron trichloride leads to acylation
on the benzene ring. The regiochemistry is attributable to the strongly acidic
reaction conditions that inactivate the pyridine moiety. Aqueous workup
then affords the chloroacetyl derivative ( 49 ). The ketone is then reduced
by means of sodium borohydride. On heating, the product undergoes
internal alkylation; the first formed compound then dehydrates to afford
the substituted indole ( 50 ).^6 The next step in the scheme involves construc-
tion of the pyrrolodione moiety. The required carbon atoms are added by
acylation of 50 with oxalyl chloride to afford 51. This compound isthen con-
densed with the imidate ( 52 ) from indole acetamide to afford an intermedi-
ate, such as 53. The reaction may be visualized as involving first formation
of an amide from imidate nitrogen with the acid chloride followed by
addition of the anion from the methylene group in 52 to the carbonyl. The
initially formed pyrroline is then dehydrated with strong acid.^7 Thus, the
PKC inhibitor 54 is obtained.
Leukotrienes, products from one branch of the arachidonic cascade, are
closely associated with symptoms of allergy, as well as asthma (see
Chapter 3, etalocib). The benzothiophene-based leukotriene antagonist,
zileuton, one of the first agents in this class, is now on the market. A
related compound, atreluton ( 60 ), that omits the fused benzene ring
present in the prototype, shows improved potency and duration of
action over its predecessor. Condensation of benzyl bromide ( 55 ) with
the anion from thiophene and butyllithium in the presence of the Heck
catalyst [tetrakis(triphenylphosphine) palladium(0) gives the coupling
product 56. Reaction with NBS leads to the bromothiophene ( 57 ).
Condensation of that intermediate with the methyl–ethynyl carbinol in
the presence of triphenylphosphine, Heck catalyst, and cupric iodide
leads to the coupling product 58. The requisite functionality is constructed
by first replacing the hydroxyl next to the acetylene by nitrogen.
Mitsonobu-like reaction withO,Nbis(phenyloxycarbonyl hydroxylamine)
in the presence of triphenylphosphine and DEAD affords 59. Reaction of
this intermediate with ammonia leads to displacement of both phenoxy
groups. This leads to formation of the free hydroxyl from the
O-carbonate and a urea from the phenoxy ester, yielding the leukotriene
antagonist 60.^8
90 FIVE-MEMBERED HETEROCYCLES