Organic Chemistry of Drug Synthesis. Volume 7

NH

CO 2 P

NH 2

+

29

HO 2 C

CO 2 P''

NHP'

30

NH

CO 2 H

HN CO 2 H

O

31

The substrate arachidonic acid, which often leads to formation of
inflammatory prostaglandins, is stored in tissues as one of a number of
phospholipids; these compounds, as the name indicates, comprise
complex phosphate-containing esters. The antiinflammatory corticoste-
roids inhibit the action of the enzyme, phospholipase A 2 , that frees arachi-
donic acid. The many undesired effects of those steroids has led to the
search for non-steroidal inhibitors of that enzyme. A highly substituted
indole derivative has shown good activity as a phospholipase A 2 inhibitor.
Alkylation of the anion from treatment of indole ( 32 ) with benzyl
chloride affords the corresponding N-benzylated derivative ( 33 ). The
methyl ether at the 4 position is then cleaved by means of boron tribromide
to yield 34. Alkylation of the enolate from reaction of the phenol with
sodium hydride with tert-butylbromoacetate affords the corresponding

NH

CH 3 O

32

NaH

C 6 H 5 CH 2 Cl

N

CH 3 O

BBr 3

N

HO

33 34

BrCH 2 CO 2 tBu

NaH

N

O

35

CO 2 tBu

Cl

O Cl

N O

O

36

CO 2 tBu

O

O

Cl

1. NH 3


2. H+

N

O

37

CO 2 H
O
O

NH 2

1. COMPOUNDS WITH ONE HETEROATOM 143