Organic Chemistry of Drug Synthesis. Volume 7

N

N O

O

O

HO

HNO 3

H 2 SO 4

N

N O

O

O

HO

O 2 N

114 115

The production by total synthesis of an analogue that incorporates an
additional fused ring, by way of contrast, includes a good many more
steps. The lengthy synthesis starts with the aluminum chloride-catalyzed
acylation of fluorotoluene ( 116 ) with succinic anhydride to afford the
acid ( 117 ). The ketone group is then reduced to methylene by means of
hydrogen over palladium; the acid is then esterified with methanol to
yield 118. Reaction with nitric acid proceeds in a straightforward manner
to afford the nitro derivative ( 119 ). The ester grouping is then saponified.
Heating the resulting acid in polyphosphoric acid results in ring closure
and thus formation of a tetralone ring ( 120 ). The next few steps establish
the requisite functionality in this newly added ring. This sequence includes
formal transfer of the carbonyl group to the alternate benzylic position.

O

O

O

HO

F

116

O

O

O

AlCl 3 F

CO 2 H

O

1. H 2


2. MeOHF

CO 2 CH 3

117 118

HNO 3

F

CO 2 CH 3

119

NO 2

1. NaOH


2. PPA

F NO 2

O

1. NaBH 4
   2. TsOH
   F NH 3. H^2
   121 2 120


2. Ac 2 O


3. KMnO 4
   F NHCOCH 3
   122

BuONO O

F NHCOCH 3

123

O

NOH

Zn/Ac 2 O

F NHCOCH 3

124

O

NHCOCH 3

1. OH2. CF–
   3 COCl
   F NH 2
   125

O

NHCOCF 3

O

O

O

HO

O

126

F

NHCOCF 3

base

127

tBuOK

N

N

N

3. COMPOUNDS WITH FIVE OR MORE FUSED RINGS: CAMPTOTHECINS 231