of the quinolone ( 85 ). Reaction of 85 with 2-methylpiperazine leads to a
second displacement of fluorine, in this case by the less hindered of the
basic nitrogen atoms on the piperazine. Saponification of the ester then
affordsgatifloxacin( 86 ).^16
Replacing one of the protons on the cyclopropyl group by fluorine intro-
duces an element of asymmetry into that moiety. A significant portion of
the synthesis ofsitaloxacin( 98 ) is consequently devoted to the preparation
of that substituent in chiral form. Reaction of the chiral auxiliary amino-
alcohol ( 87 ) with phosgene closes the ring to afford the oxazolidone
( 88 ). This compound is then treated with the methyl acetal from acet-
aldehyde; the ring amide nitrogen displaces one of the methoxy groups
to give the corresponding carbinolamine derivative 89. Heating 89 leads
to loss of methanol to yield the vinyl amine ( 90 ). Addition of fluoromethy-
lene carbene, generated from fluoromethyl iodide and diethyl zinc leads to
formation of the cyclopropyl group ( 91 ). The reaction proceeds to afford
C 6 H 5HO
H 2 N
87COCl 2
NHO C 6 H 5
C 6 H 5O88(CH 3 O) 2 CHCH (^3) N
O C^6 H^5
C 6 H 5
O
89
CH 3 O CH 3
Heat O C 6 H 5
C 6 H 5
O ICHEt^2 F
2 Zn N
O C^6 H^5
C 6 H 5
O
F
NH 2
F
92
CO 2 C 2 H 5
O
F
F
Cl
CO 2 C 2 H (^5) F
O
F
F
Cl
F NH
F
NaH
CO 2 C 2 H 5
O
F
F
Cl
F
N
93
(^9594)
NH
NHOCOtBu
CO 2 C 2 H 5
O
F
Cl
F
N
97
N
tBuO 2 CNH
CO 2 H
O
F
Cl
F
N
98
N
NH 2
- TFA
- NaOH
90
91
H 2OC 2 H 596NC 6 H 5the chiral cis isomer due to the steering influence of the proximate chiral
auxiliary. Catalytic hydrogenation leads to scission of the benzyl–nitrogen
and benzyl–oxygen bonds; the transient carbonate disintegrates on work
up to afford chiralcis-amine ( 92 ). The scheme then proceeds much as
that above though details differ. Thus, reaction of 92 with the ethoxymethy-
lene intermediate ( 93 ) leads the amine to replace the ethoxy group to afford
174 SIX-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING