Glycosylation of Fluoroquinolones
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19 3907
app t, J ) 7.4 Hz), 3.70-3.74 (1H, m), 3.39-3.43 (1H, m), 3.25
(4H, app t, J ) 4.5 Hz), 2.65-2.67 (6H, m), 2.14 (3H, s), 2.05
(3H, s), 2.03 (3H, s), 1.97 (3H, s), 1.27-1.32 (2H, m), 0.09-
1.13 (2H, m). HRMS FAB (m/e) calcd for C36H45FN3O13 (M +
H)+ 746.293642, found 746.294192.
[(â-glu cofu r a n osyl)oxy]p r op yl)p ip er a zin yl]-4-oxoqu in o-
lin e-3-ca r boxyla te 2′,5′,6′-Tr ia ceta te, 21. To a solution of
acetobromoglucose 12a (452 mg, 1.1 mmol) in 1,2-dichloro-
ethane (5.0 mL, 0.2 M) were added the 3-hydroxypropyl
ciprofloxacin allyl ester (20) (430 mg, 1.0 mmol), 4 Å molecular
sieves (∼30 mg), and silver carbonate (303.3 mg, 1.1 mmol).
The reaction mixture was heated at 50-60 °C under an argon
atmosphere for 12 h in the dark. The solids were filtered off
and the filtrate was concentrated in vacuo to give a crude
residue. Flash column chromatography (95:5 chloroform-
methanol) of this crude residue gave the unexpected gluco-
furanose product 21 (561 mg, 74%). 1H NMR (400 MHz, CDCl3)
δ: 8.52 (1H, s), 8.01 (1H, d, J ) 13.3 Hz), 7.25 (1H, d, J ) 6.6
Hz), 6.05 (1H, ddt, J ) 17.1, 10.5, 5.1 Hz), 5.71 (1H, d, J ) 5.2
Hz), 5.46 (1H, dd, J ) 17.2, 1.4 Hz), 5.26 (1H, dd, J ) 10.4,
1.3 Hz), 5.19 (1H, t, J ) 2.8 Hz), 4.89 (1H, dd, J ) 9.6, 2.2
Hz), 4.82 (2H, d, J ) 5.5 Hz), 4.32 (1H, dd, J ) 4.5, 3.2 Hz),
4.20 (2H, bm), 3.95 (1H, m), 3.56 (2H, t, J ) 6.3 Hz), 3.42 (1H,
m), 3.27 (4H, m), 2.65 (4H, m), 2.48 (2H, bt, J ) 7.2 Hz), 2.10
(3H, s), 2.09 (3H, s), 2.08 (3H, s), 1.81 (1H, bs), 1.77 (2H, m),
1.31 (2H, bm), 1.12 (2H, bm). HRMS FAB (m/e) calcd for
2-P r op en yl 1-Cyclop r op yl-1,4-d ih yd r o-6-flu or o-7-[4-(3-
[(â-glu cop yr a n osyl)oxy]p r op yl)p ip er a zin yl]-4-oxoqu in o-
lin e-3-ca r boxyla te, 19a . To a solution of the bromide 15a
(253.1 mg, 0.5393 mmol) and ciprofloxacin allyl ester hydro-
chloride (11) (200 mg, 0.4903 mmol) in 5 mL of dry DMF was
added triethylamine (410 mL, 2.9418 mmol). The reaction
mixture was heated at 90-100 °C for 24 h under an argon
atmosphere. The solvent was then removed in vacuo to give
an oily residue. Flash column chromatography (silica gel, 4%
MeOH-chloroform) of this crude residue gave 184.6 mg (45%
1
yield) of the desired product 19a . H NMR (400 MHz, CDCl3)
δ: 8.51 (1H, s), 7.98 (1H, d, J ) 13.2 Hz), 7.24 (1H, d, J ) 7.1
Hz), 6.03 (1H, ddt, J ) 17.2, 10.4, 5.4 Hz), 5.46 (1H, d, J )
17.2 Hz), 5.25 (1H, d, J ) 10.4 Hz), 5.20 (1H, t, J ) 9.5 Hz),
5.08 (1H, t, J ) 9.7 Hz), 4.99 (1H, t, J ) 8.1 Hz), 4.80 (2H, d,
J ) 5.4 Hz), 4.50 (1H, d, J ) 7.9 Hz, anomeric), 4.25 (1H, dd,
J ) 12.3, 4.6 Hz), 4.13 (1H, dd, J ) 12.2, 2.2 Hz), 3.94 (1H,
m), 3.69 (1H, m), 3.58 (1H, m), 3.42 (1H, bm), 3.27 (4H, m),
2.63 (4H, bm), 2.46 (2H, bm), 2.08 (3H, s), 2.05 (3H, s), 2.01
(3H, s), 2.00 (3H, s), 1.81 (2H, m), 1.30 (2H, m), 1.12 (2H, m).
HRMS FAB (m/e) calcd for C37H47FN3O13 (M + H)+ 760.309292,
found 760.310322.
C
35H45FN3O12 (M + H)+ 718.298728, found 718.299275.
Eth yl 2,4,5-Tr iflu or o-r-oxoben zen ep r op a n oa te, 23a ,
a n d Eth yl 3-Hyd r oxy-3-(2,4,5-tr iflu or op h en yl)-2-p r op e-
n oa te, 23b. To a solution of the monoethyl malonate (1.0 g,
7.58 mmol) and triphenylmethane (∼3 mg) in 30 mL of THF
under an argon atmosphere was slowly added n-butyllithium
(2.5 M in THF) until the solution turned orange. The solution
was then cooled to -50 °C and to it was added the solution of
the acid chloride 22 (0.5 g, 2.53 mmol) in 8 mL of THF
dropwise. After the addition, the reaction mixture was warmed
to room temperature and stirred for an additional 1 h. After
it was diluted with ether, the reaction mixture was washed
with 10% HCl solution, saturated sodium bicarbonate solution,
and brine. The organic layer was dried over MgSO4 and
evaporated to yield the crude trifluorobenzoyl acetates 23a ,b
(0.63 g, 100%) as a yellow oil, which exist as a mixture of enol
and keto tautomers. Compound 23a : 1H NMR (400 MHz,
CDCl3) δ: 12.71 (1H, s), 7.74 (1H, m), 7.00 (1H, m), 5.84 (1H,
s), 4.26 (2H, q, J ) 7.2 Hz), 1.34 (3H, t, J ) 7.2 Hz). Compound
23b: 1H NMR (400 MHz, CDCl3) δ: 7.82 (1H, m), 7.02 (1H,
m), 4.21 (2H, q, J ) 7.2 Hz), 4.26 (3H, t, J ) 7.2 Hz), 3.94
(2H, d, J ) 3.8 Hz).
E t h yl 2,4,5-Tr iflu or o-â-([(4-h yd r oxyp h en yl)a m in o]-
m eth ylen e)-r-oxoben zen ep r op a n oa te, 24. A solution of the
esters 23a ,b (1 g, 4.06 mmol) in ethyl orthoformate (0.71 g,
6.13 mmol) and acetic anhydride (5.30 g, 52 mmol) was heated
at 130 °C under an argon atmosphere for 2 h with removal of
the ethyl acetate formed during the reaction. The solution was
evaporated under reduced pressure to give an oil that was
dissolved in dichloromethane (40 mL). 4-Hydroxyaniline (0.50
g, 4.5 mmol) was added to the solution. After stirring at room
temperature for 1 h, the solution was evaporated to dryness
and a light yellow solid was obtained. The solid was washed
with hexane, filtered, and dried under vacuum to give the
phenol 24 (1.357 g, 91%) as a creamy white solid as a mixture
of E and Z isomers. Z isomer: 1H NMR (400 MHz, CDCl3) δ:
13.4 (1H, bd, J ) 13.7 Hz), 8.48 (1H, d, J ) 13.7 Hz), 7.30
(1H, m), 7.13 (2H, d, J ) 8.8 Hz), 6.92-6.78 (3H, m), 5.50 (1H,
bs), 4.11 (2H, q, J ) 7.1 Hz), 1.10 (3H, t, J ) 7.1 Hz). E
isomer: 1H NMR (400 MHz, CDCl3) δ: 14.3 (1H, bd, J ) 14.3
Hz), 8.42 (1H, d, J ) 14.2 Hz), 7.30 (1H, m), 7.08 (2H, d, J )
8.8 Hz), 6.92-6.78 (3H, m), 5.50 (1H, bs), 4.09 (2H, q, J ) 7.1
Hz), 0.98 (3H, t, J ) 7.1 Hz).
2-P r op en yl 1-Cyclop r op yl-1,4-d ih yd r o-6-flu or o-7-[4-(3-
[(â-ga la ctopyr a n osyl)oxy]pr op yl)p ip er a zin yl]-4-oxoqu in -
olin e-3-ca r boxyla te, 19b. To a solution of the bromide 15b
(281 mg, 0.598 mmol) and ciprofloxacin allyl ester hydrochlo-
ride (11) (222 mg, 0.5442 mmol) in 6 mL of dry DMF was added
triethylamine (455 mL, 3.2654 mmol). The reaction mixture
was heated at 90-100 °C for 23 h under an argon atmosphere.
The solvent was then removed in vacuo to give an oily residue.
Flash column chromatography (silica gel, 4-5% MeOH-
chloroform) of this crude residue gave 155.9 mg (34% yield) of
1
the desired product 19b. H NMR (400 MHz, CDCl3) δ: 8.49
(1H, s), 7.96 (1H, d, J ) 13.3 Hz), 7.23 (1H, d, J ) 7.1 Hz),
6.04 (1H, ddt, J ) 17.1, 10.4, 5.5 Hz), 5.45 (1H, dd, J ) 17.1,
1.4 Hz), 5.37 (1H, d, J ) 3.0 Hz), 5.25 (1H, dd, J ) 10.5, 1.2
Hz), 5.18 (1H, dd, J ) 10.4, 8.0 Hz), 5.00 (1H, dd, J ) 10.5,
3.4 Hz), 4.79 (2H, d, J ) 5.5 Hz), 4.46 (1H, d, J ) 7.9 Hz,
anomeric), 4.17 (1H, dd, J ) 11.2, 6.4 Hz), 4.09 (1H, dd, J )
11.2, 7.1 Hz), 3.95 (1H, m), 3.89 (1H, t, J ) 6.8 Hz), 3.57 (1H,
m), 3.41 (1H, m), 3.26 (4H, m), 2.63 (4H, m), 2.47 (2H, t, J )
6.3 Hz), 2.14 (3H, s), 2.05 (3H, s), 2.03 (3H, s), 1.97 (3H, s),
1.80 (2H, m), 1.28 (2H, m), 1.11 (2H, m). HRMS FAB (m/e)
calcd for C37H47FN3O13 (M + H)+ 760.309292, found 760.310437.
2-P r op en yl 1-Cyclop r op yl-1,4-d ih yd r o-6-flu or o-7-[4-(3-
h yd r oxyp r op yl)p ip er a zin yl]-4-oxoqu in olin e-3-ca r boxy-
la te, 20. A solution of ciprofloxacin allyl ester hydrochloride
(11) (500 mg, 1.22 mmol), 3-bromopropanol (200 mg, 1.41
mmol), and triethylamine (1.0 mL, 7.2 mmol) in 3.0 mL of dry
DMF was heated at 100-110 °C for 15 h under an argon
atmosphere. After the reaction mixture was cooled to room
temperature, the solids were filtered off and rinsed with ∼5
mL of DMF. The DMF was removed under vacuum on a rotary
evaporator to give an oily residue. Flash column chromatog-
raphy (90:10 chloroform-methanol) of this crude residue
provided the desired N-(3-hydroxypropyl) product 20 as a white
1
solid (222 mg, 42%). H NMR (360 MHz, CDCl3) δ: 8.47 (1H,
s), 7.92 (1H, d, J ) 13.2 Hz), 7.21 (1H, d, J ) 7.0 Hz), 6.03
(1H, ddt, J ) 17.1, 10.7, 5.2 Hz), 5.44 (1H, d, J ) 17.3 Hz),
5.25 (1H, d, J ) 10.4 Hz), 4.78 (2H, d, J ) 5.3 Hz), 3.82 (2H,
bt, J ) 5.0 Hz), 3.40 (1H, bm), 3.24 (4H, bm), 2.74 (6H, bm),
2.50 (1H, bt, J ) 5.0 Hz), 1.77 (2H, bt, J ) 5.2 Hz), 1.27 (2H,
bm), 1.11 (2H, bm). 13C NMR (90 MHz, CDCl3) δ: 172.87,
165.13, 153.23 (d, J ) 247 Hz), 148.15, 144.19 (d, J ) 11 Hz),
137.80, 132.27, 122.93 (d, J ) 7 Hz), 118.05, 113.00 (d, J ) 23
Hz), 109.80, 104.86, 65.26, 64.34, 58.52, 52.90, 49.81, 34.44,
26.96, 8.01. HRMS FAB (m/e) calcd for C23H29FN3O4 (M + H)+
430.214210, found 430.214416.
Eth yl 6,7-Diflu or o-1,4-d ih yd r o-1-(4-h yd r oxyp h en yl)-4-
oxoqu in olin e-3-ca r boxyla te, 25. Sodium hydride (60% sus-
pension in oil, 0.162 g, 4.06 mmol) was added slowly to a cold
solution of the benzoylacrylate 24 (1.35 g, 3.7 mmol) in THF
(30 mL). The mixture was heated to reflux for 3 h under an
argon atmosphere and cooled to room temperature. Water was
added, and the precipitate was filtered, washed with water,
and dried under vacuum, yielding the quinolone 25 (1.23 g,
1
96%) as a light yellow solid. H NMR (400 MHz, DMSO-d6) δ:
2-P r op en yl 1-Cyclop r op yl-1,4-d ih yd r o-6-flu or o-7-[4-(3-
10.11 (1H, bs), 8.35 (1H, s), 8.04 (1H, m), 7.41 (2H, d, J ) 8.3