reason, been assigned nonproprietary names. By way of a reminder, the
quinolones act by interfering with the bacterial enzyme, DNA gyrase.
An important step in cell replication involves reading the genome in
order to generate a corresponding RNA strand. The sheer size of the
genome requires that it be cut in order to gain access to the relevant
section. Gyrases and related topoisomerases temporarily hold the cut ends
during transcription; other enzymes reconnect those ends when the
process is complete. Topoisomerase inhibitors cause the formation of
covalent bonds so that the genome is frozen in the cut position and as a con-
sequence can no longer function. Cell replication is thus brought to a halt.
The synthesis of one of the agents begins with nucleophilic aromatic
displacement of bromine by cyanide in the highly fluorinated compound
78. Acid hydrolysis of the nitrile ( 79 ), followed by esterification of the
newly formed acid, affords ester 80. Base-catalyzed condensation of the
intermediate with diethyl malonate leads to the tricarbonyl derivative 81.
F
F
OCH 3Br
F78CuCN F
F
OCH 3CN
F79- H 2 SO 4
- C 2 H 5 OH
F
F
OCH 3CO 2 C 2 H 5F80CO 2 CH 3
CO 2 CH 3
NaOC 2 H 5F
F
OCH 3FO81F
F
OCH 3FCO 2 CH 3OTSA82F
F
OCH 3FCO 2 CH 3O83CH(OC 2 H 5 ) 3
OC 2 H 5F
F
OCH 3FCO 2 CH 3O84NHNH 2NaFF
F
OCH 3CO 2 CH 3ON85HN NHH 3 CHNH 3 CF
N
OCH 3CO 2 HON861.- NaOH
CO 2 CH 3
CO 2 CH 3This loses one of the carboxylates on heating in the presence of toluene-
sulfonic acid to afford theb-ketoester ( 82 ). Reaction of this intermediate
with ethylorthoformate then adds a carbon atom to the activated methylene.
Heating that compound with cyclopropylamine in effect exchanges the
ethoxy group with the amine to afford enamine ( 84 ). Treatment 84 with
sodium fluoride leads to displacement of one of the ring fluoro groups
by the basic nitrogen on the side chain. This step concludes the formation
- COMPOUNDS WITH ONE HETEROATOM 173